Lessons from the European Cooperative recombinant tissue-type plasminogen activator (rt-PA) versus placebo trial

AbstractA new European Cooperative Study Group trial of 721 patients has recently found recombinant tissue-type plasminogen activator (rt-PA) to positively affect infarct size, ten ventricular function, cardiovascular morbidity and early survival. In this 26 center trial, patients were randomized to receive either placebo or 100 mg rt-PA intravenously over 3 h. Heparin (5,000 U bolus injection and then 1,000 U/h) and aspirin (250 mg initially, then 75 to 125 mg every other day) were given to all patients until angiography was performed (10 to 22 days after allocation).Enzymatic infarct size was found to be 20% smaller in the rt-PA group (2p = 0.0018) than in the control group. At angiography, 83% of rt-PA-treated patients had a patent infarct-relaled vessel compared with 77% of the placebotreated patients. Ejection fraction was 2.2% points higher (2p = 0.04) and end-diastolic and end-systolic volumes were ± 6 ml smaller (2p = 0.003) than in the control group, indicating an improved left ventricular pump function in the thrombolysis group. Cardiovascular complications such as shock, ventricular fibrillation and pericarditis were markedly fewer in patients treated with rt-PA, but bleeding complications occurred more frequently. An intracranial hemorrhage within 3 days after the infusion of rt-PA was observed in five patients (1.4%). None of these bleeding episodes was causally related to death. Although this European Cooperative trial was not designed primarily as a mortality study, important reductions in early mortality rates were observed. At 14 days, the death rate among rt-PA-treatcd patients was 2.8%, which is 51% (95% confidence interval −76% to +1%, 2p = 0.053) lower than the 5.7% mortality rate of the control group. At 3 months, the mortality rate was 5.1% in the rt-PA group, which is 36% (95% confidence interval −63% to +13%, 2p = 0.121) lower than the 7.9% in the control group. In patients treated within 3 h of symptoms, the European Cooperative Study Group reported mortality reductions of 82% (95% confidence interval −95% to −31%, 2p = 0.009) at 14 days and 59% (95% confidence interval −83% to −2%, 2p = 0.045) at 3 months. The early mortality rates observed in this trial were very similar to those reported previously by the same European Cooperative Study Group for a similarly selected and treated group of patients and are the lowest so far published in large trials with intravenously administered thrombolytic agents.The results of these European multicenter trials, together with the recent findings of large studies conducted in the United States (Johns Hopkins Hospital trial, Thrombolysis and Angioplasty in Myocardial Infarction [TAMI], Thrombolysis in Myocardial Infarction [TIMI]), further add to evidence that early thrombolytic treatment with rt-PA in addition to antithrombotic and antiplatelet medication is of major benefit for patients with an acute myocardial infarction

Reperfusion treatment in acute myocardial infarction in elderly patients

In this paper the current knowledge of reperfusion therapy in elderly patients with an ST-segment elevation acute myocardial infarction (STEMI) is summarised. Placebo-controlled trials of fibrinolytic agents, direct comparative trials of fibrinolytic agents and antithrombotic co-therapies, and randomised trials of primary percutaneous coronary intervention (PCI) versus fibrinolytic therapy as well as registries are briefly reviewed, focusing on the impact of age. The benefit and risk of a combined pharma-cological and mechanical approach is presented. Important differences between a “facilitated PCI” and a “pharmaco-invasive strategy”, particularly in older STEMI patients, are highlighted. It will become clear at the end of this review that the knowledge about the benefit and risk of reperfusion therapy in the elderly is still incomplete and that more clinical trials in the elderly are needed. Practical recommendations for elderly patients with STEMI based on the current knowledge have been provided

Commentary: Use of registries to investigate the past and develop the future.

International audienceIdeally, collection of clinical data should be an integral part of healthcare systems. Without systematic collection of individual patient data and outcome it is impossible for individual doctors, healthcare providers, or regulatory agencies to understand how, when, and to whom healthcare is provided and the actual outcome of specific procedures or devices..

In vivo effects of contrast media on coronary thrombolysis

AbstractObjectives. The aim of the present study was to evaluate the influence of radiographic contrast media (CM) on alteplase-induced coronary thrombolysis.Background. Contrast media inhibit fibrinolysis in vitro and interact with endothelial cells, platelets and the coagulation system. The in vivo effects of CM on thrombolysis are not known.Methods. Occlusive coronary artery thrombosis was induced in 4 groups of 10 dogs by the copper coil technique. After 70 min of occlusion the dogs were randomized to intracoronary injection of 2 ml kg−1of either saline, a low-osmolar ionic CM (ioxaglate), a low-osmolar nonionic CM (iohexol) or a high-osmolar ionic CM (amidotrizoate). Thrombolysis with alteplase and co-therapy with aspirin and heparin was initiated after 90 min of occlusion. The coronary artery flow was monitored with an electromagnetic flowmeter throughout the experiment.Results. Iohexol and amidotrizoate, but not ioxaglate, were associated with longer reperfusion delays (time to optimal reperfusion: 67 ± 48 min and 65 ± 49 min, respectively, vs. 21 ± 11 min after placebo; p < 0.05) and shorter periods of coronary perfusion (optimal perfusion time: 21 ± 26 min and 21 ± 28 min, respectively, vs. 58 ± 40 min after placebo; p < 0.05). No significant differences were observed between groups with regard to activated partial thromboplastin times, circulating thrombin-antithrombin III complex concentrations and fibrinogen.Conclusions. In this animal model administration of iohexol and amidotrizoate before thrombolysis significantly delayed reperfusion. This interaction should be considered in the design of clinical trials of thrombolytic therapy that evaluate coronary artery patency and in patients receiving local infusions of fibrinolytic agents

Combined thromboxane A2synthase inhibition and prostaglandin endoperoxide receptor antagonism limits myocardial infarct size after mechanical coronary occlusion and reperfusion at doses enhancing coronary thrombolysis by streptokinase

AbstractObjectives. We sought to examine to what extent a combination of strong thromboxane A2, synthase inhibition and moderate endoperoxide receptor blockade enhances streptokinase-induced coronary thrombolysis and provides anti-ischemic activity independent from its thrombolytic activity.Methods. Coronary thrombi, induced by crush injury and stenosis of the coronary artery, were lysed with streptokinase, 10,000 IU/kg body weight over 90 min, in dogs receiving solvent (n = 11), ridogrel, 0.31 mg/kg intravenously, for thromboxane A2synthase inhibition (n = 7) or ridogrel, 5 mg/kg, for additional prostaglandin endoperoxide receptor antagonism in addition to thromboxane A2synthase inhibition (n = 7) 10 min before the administration of Streptokinase.Results. Thrombolytic efficacy was greatest in animals receiving both dual-acting ridogrel, 5 mg/kg intravenously, and streptokinase as evidenced by the highest incidence of high grade coronary reperfusion (solvent 3 of 11; ridogrel, 0.31 mg/kg, 5 of 7; ridogrel, 5 mg/kg, 7 of 7; p < 0.05 vs. solvent) within the shortest delay (solvent 210 min; ridogrel, 0.31 mg/kg, 85 min; ridogrel, 5 mg/kg, 37 min; p < 0.05 vs. solvent and ridogrel, 0.31 mg/kg) and the lowest incidence of reocclusion (solvent 5 of 7; ridogrel, 0.31 mg/kg, 2 of 7; ridogrel, 5 mg/kg, 1 of 7; p < 0.05 versus solvent).Myocardial infarct size after coronary artery figation (90 min) and subsequent reperfusion (150 min) in anesthetized dogs was 49.3 ± 4.5% venus 29 ± 3.9% (p < 0.05 vs. solvent) of the area of the left ventricle at risk in dogs receiving solvent (n = 9) or ridogrel, 5 mg/kg intravenously (n = 10), respectively, despite similar hemodynamic characteristics, collateral blood flow and area risk in both groups.Conclusions. Combined thromboxane A2synthase inhibition and endoperoxide receptor antagonism 1) upgrades thrombolysis with Streptokinase in canine coronary arteries, 2) limits myocardial infaret size after nonthrombotic coronary occlusion and reperfusion, and 3) may preserve ventricular function compromised by coronary occlusion through dual manipulation of the arachidonic acid cascade in blood and myocardial tissue, respectively

Coronary thrombolysis with recombinant tissue-type plasminogen activator: Patency rate and regional wall motion after 3 months

In a double-blind, placebo-controlled, randomized trial the long-term (± 3 months) effects of intravenous administration of recombinant tissue-type plasminogen activator (rt-PA) versus placebo were compared in relation to left ventricular function, coronary patency rate and antigenicity in 28 patients with a first myocardial infarction. Patency rate of the infarct-related coronary artery at the end of the rt-PA/placebo infusion and after 3 months of medical treatment (including oral anticoagulant agents) was 86 and 71%, respectively, in the rt-PA group, and 21 and 58%, respectively, in the placebo group.Regional wall motion of the infarct-related area was quantitated with digital subtraction angiography. Intra-patient comparisons revealed significant improvement in regional wall motion after 3 months in both the rt-PA and placebo groups. The improvement in the rt-PA group was not significantly greater than that in the placebo group. Thirteen patients (10 with rt-PA and 3 with placebo) with persistent patency (both early and late) of the infarct-related coronary artery showed a significant improvement of both global and regional left ventricular function, while 8 patients (2 with rt-PA and 6 with placebo) with persistent occlusion showed no changes. Antibodies against rt-PA were not detected in serum 2 weeks after the infusion, which is indicative of the lack of antigenicity of rt-PA and allows for its repeated administration

Prehospital and in-hospital use of healthcare resources in patients surviving acute coronary syndromes: an analysis of the EPICOR registry.

OBJECTIVE: The aim of this report is to provide insight into real-world healthcare resource use (HCRU) during the critical management of patients surviving acute coronary syndromes (ACS), using data from EPICOR (long-tErm follow-up of antithrombotic management Patterns In acute CORonary syndrome patients) (NCT01171404). METHODS: EPICOR was a prospective, multinational, observational study that enrolled 10 568 ACS survivors from 555 hospitals in 20 countries in Europe and Latin America, between September 2010 and March 2011. HCRU was evaluated in patients with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation ACS (NSTE-ACS), with or without a history of cardiovascular disease (CVD). Multivariable analysis was performed to determine factors that affected resource use. RESULTS: Before hospitalisation, more patients with STEMI than with NSTE-ACS had their first ECG (44.1% vs 36.4%, p<0.0001) and received antithrombotic medication (26.6% vs 15.2%, p<0.0001). Patients with NSTE-ACS with prior CVD were less likely than those without to be catheterised (73.1% vs 82.8%, p<0.0001). More patients with STEMI than with NSTE-ACS had percutaneous coronary intervention (77.1% vs 54.9%, p<0.0001), but fewer underwent coronary artery bypass grafting (1.2% vs 3.7%, p<0.0001). Multivariable analysis showed that resource use, including length of hospital stay and coronary revascularisation, was significantly influenced by multiple factors, including ACS type, site characteristics and region (all p≤0.05). CONCLUSIONS: In this large-scale, real-life study, findings were generally in line with clinical logic, although site characteristics and region still significantly affected resource use. Moreover, and unexpectedly, resource use tended to be slightly higher in patients without a history of CVD. TRIAL REGISTRATION NUMBER: NCT01171404 (ClinicalTrials.gov)

International patterns of dual antiplatelet therapy duration after acute coronary syndromes

Objective To describe international patterns of dual antiplatelet therapy (DAPT) duration after acute coronary syndrome (ACS), and explore its determinants and correlation with clinical events. Methods EPICOR (long-tErm follow-uP of antithrombotic management patterns In acute CORonary syndrome patients) is a prospective, international, observational study of 10 568 ACS hospital survivors enrolled in 555 centres from 20 countries across Europe and Latin America between 2010 and 2011, with telephone follow-up at quarterly intervals up to 24 months to assess treatment continuation and clinical events. Results Of 8593 patients discharged on DAPT, 4859 (57\%) remained on uninterrupted DAPT at end of follow-up. There were minor differences in rates of DAPT discontinuation according to age, gender, risk factors, therapeutic strategy or region, but major differences between countries. By study end, 555 of evaluable patients (5.7\%) died, 727 (10.0\%) experienced new cardiovascular (CV) events, 496 new coronary events (6.82\%) and 154 (2.11\%) clinically relevant bleeding (14 (6.7\%) fatal). Most CV events and deaths (85\%) occurred while on DAPT. DAPT interruption was associated with increased risk of CV events in the following week (HR 2.29; 95\% CI 1.08 to 4.84) but not specifically with time to first coronary event or mortality. Conclusions Despite guideline recommendations, most patients with ACS in Europe and Latin America remained on DAPT beyond 12 months, country being the most important determinant of DAPT duration. Increase in short-term CV risk was seen after switching from DAPT to less medication, as compared with continued DAPT, with no long-term effect on coronary or mortality risk.The EPICOR study was funded by AstraZeneca.S

Thrombin-receptor antagonist vorapaxar in acute coronary syndromes

BACKGROUND Vorapaxar is a new oral protease-activated–receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. METHODS In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan–Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P = 0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P = 0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. CONCLUSIONS In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage

811-1 Evolution of Left Ventricular Function, Myocardial Perfusion and Metabolism in Infarct Patients After Coronary Thrombolysis

Follow-up of regional myocardial blood flow, metabolism and function was studied in a population of thrombolysed patients. Fifty one patients with an acute myocardial infarction were prospectively enrolled. All patients received thrombolytic therapy within 6 hours after the onset of symptoms. Coronary angiography, 2D-echocardiography and 13NH3/18FDG PET were performed 5 days after the acute event. Three months after the infarction, 2D-echocardiography and 13NH3/18FDG PET studies were repeated.Thirty six patients (62% with TIMI III, 7% with TIMI II) revealed a concordant decrease of flow and metabolism in the infarct area (PET match). Fifteen patients (33% with TIMI III, 13% with TIMI II) revealed a decrease of flow with preservation of metabolism (PET mismatch). Twelve patients received further treatment (PTCA or CAGB) after the first PET scan. Myocardial blood flow improved significantly in both match (71±17ml/min/l00g at 3 months versus 60±17ml/min/100 g at 5 days, p&lt;0.01) and mismatch groups (71±26ml/min/l00 g at 3 months versus 63 ±18ml/min/100 g at 5 days, p&lt;0.05). Blood flow in remote areas did not change significantly (84±18mllmin/l 00 g at 3 months versus 82±19ml/min/l 00 gat 5 days, p=NS). In 4 patients with a match pattern at 5 days, a mismatch pattern had developed 3 months after the acute event.Functional follow-up was performed in 30 patients, 23 with a match pattern and 7 with a mismatch pattern. A variable outcome was observed: In 3 out of 7 mismatch areas contractility did not improve. On the contrary, 9 out of 23 match areas revealed functional improvement.It can be concluded that in this population of early thrombolysed patients, few mismatches were observed (29%). Flow values improved significantly in both match and mismatch groups 3 months after the acute event. In some patients, a mismatch pattern was found after 3 months, suggesting the need for further treatment. Functional outcome was variable, probably due to a variety of pathophysiologic processes such as stunning shortly after reperfusion with functional improvement after 3 months, reocclusion or progression of coronary artery disease resulting in reinfarction or hibernation