Risk of intracranial haemorrhage with combined fibrinolytic and glycoprotein IIb/IIIa inhibitor therapy in acute myocardial infarction. Dichotomous response as a function of age in the GUSTO V trial.

Background: Intracranial haemorrhage is an important limitation to pharmacologic reperfusion therapy for acute myocardial infarction. The combination of a glycoprotein IIb/IIIa inhibitor, half-dose plasminogen activator and reduced-dose heparin has been evaluated as an alternative to standard fibrinolytic therapy in this setting. Methods and results: We evaluated the relation between univariate and multivariate predictors of intracranial haemorrhage and the effect of treatment with either reteplase alone (10 U bolus twice, 30 min apart) with standard-dose heparin (5000 U bolus followed by an infusion of 1000 Uh(-1)for patients > or =80 kg and 800 Uh(-1)for those <80 kg) or combination therapy with abciximab (0.25mg/kg bolus and 0.125 microg/kg/min for 12h) and half-dose reteplase (two boluses of 5U 30 min apart) with reduced-dose heparin (60 Ukg(-1)bolus, maximum 5000 U, followed by an infusion of 7 Ukg(-1)h(-1)) in the 16 588 patients randomized in the GUSTO V trial. Overall, the incidence of intracranial haemorrhage was similar in the two groups (0.6% vs 0.6%; OR 1.05, 95% CI 0.71, 1.56). The median (25th-75th) time from drug administration to intracranial haemorrhage was 5.5 (3.4-11) hours with combination therapy and 9.2 (5.9-22) hours with reteplase (P=0.048). Among the multivariable predictors of intracranial haemorrhage, only age showed a significant interaction with treatment effect (age per treatment interaction chi-square 4.60, P=0.032) with a lower risk of combination therapy for younger patients and a higher risk for the elderly. Conclusions: Although no additional risk of intracranial haemorrhage has been observed with combination therapy in the whole population, a significant age pertreatment interaction exists, with a lower risk with combination therapy in younger patients, and a higher risk in the elderly.     

Abciximab in the treatment of acute myocardial infarction eligible for primary percutaneous transluminal coronary angioplasty. Results of the Glycoprotein Receptor Antagonist Patency Evaluation (GRAPE) pilot study.

OBJECTIVES: We sought to study the effect of early infusion of abciximab on coronary patency before primary angioplasty in patients with acute myocardial infarction. BACKGROUND: Glycoprotein IIb/IIIa antagonists have proved to be effective in reducing ischemic events associated with coronary angioplasty. The present study explores whether abciximab alone, without administration of thrombolytic therapy, may induce reperfusion in patients with acute myocardial infarction. METHODS: In the Glycoprotein Receptor Antagonist Patency Evaluation pilot study 60 patients with less than 6 h signs and symptoms of acute myocardial infarction eligible for primary angioplasty received in the emergency room a bolus of abciximab 250 microg/kg followed by a 12-h infusion of 10 microg/min. All patients were also treated with an oral dose of 160 mg aspirin and 5,000 IU of heparin intravenously. As soon as possible a diagnostic angiography was performed to evaluate the patency of the infarct-related artery. RESULTS: The median time between onset of symptoms and the administration of the abciximab bolus was 150 min (range 45 to 345), and the median time between abciximab bolus and first contrast injection in the infarct-related artery was 45 min (range 10 to 150). In 24 patients (40%, 95% confidence interval 28% to 52%) Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 was observed at a median time of 45 min (range 10 to 150) after abciximab bolus; TIMI flow grade 3 was observed in 11 patients (18%, 95% confidence interval 9% to 28%). There was no difference in percentage of TIMI flow grade 2 or 3 between patients who received abciximab within 2.5 h after onset of symptoms or thereafter. CONCLUSIONS: Abciximab therapy given in the emergency room in patients awaiting primary angioplasty is associated with full reperfusion (TIMI flow grade 3) in about 20% and with TIMI flow grade 2 or 3 in about 40% of the patients at a median time of 45 min. These figures are higher than those in primary angioplasty trials without such pretreatment. Randomized controlled trials of very early infusion of abciximab, either prehospital or in-hospital, in patients eligible for angioplasty are warranted.     

Effect of glycoprotein IIb/IIIa inhibition without thrombolytic therapy on reperfusion in acute myocardial infarction: results of ReoMI pilot study.

The efficacy of abciximab and moderate dose heparin in attaining reperfusion in acute MI was tested in a multicenter pilot study. Patients with acute MI of less than 6-hr onset triaged to primary PTCA received intravenous abciximab bolus and infusion and heparin (70 u/kg) in the emergency room. Mean time to angiography from administration of abciximab was 34 +/- 23 min. TIMI flow rates were: grade 0-62%, grade I-20%, grade II-9%, and grade III-9%. Primary PTCA was performed with 100% success rate. Access site bleeding occurred in 10% of patients with no incidence of intracranial bleeding. TIMI II/III flow rates were 50% in a patient subset where angiography was delayed by 45 min. While not an alternative to thrombolytics in AMI, abciximab administration in the emergency room in patients triaged to PTCA may be beneficial in situation where door to needle time is delayed as TIMI II/III flows may be attained in some patients. Cathet. Cardiovasc. Intervent. 48:430-434, 1999.     

Effects of the early administration of heparin in patients with ST-elevation myocardial infarction treated by primary angioplasty.

BACKGROUND: The effect of adjunctive heparin for primary angioplasty in patients with ST-elevation myocardial infarction (STEMI) is not well established, so the authors investigated the effect of early heparin administration in the emergency room (ER) on initial patency of the infarct-related artery (IRA) and on the clinical outcome in STEMI patients. METHODS AND RESULTS: One hundred and twenty consecutive patients who presented with STEMI less than 12 h from pain onset and who were eligible for primary percutaneous coronary intervention were allocated to an early heparin group (heparin administered in ER) or a late heparin group (heparin administered after angiography). In the early heparin group, unfractionated heparin (60 U/kg bolus IV, then 14 U . kg(-1) . h(-1) IV infusion) or enoxaparin (1 mg/kg bolus SC) were administered 144+/-95 min before angioplasty. No significant differences in baseline characteristics were observed between the early heparin group (n=56) and the late heparin group (n=64). However, initial Thrombolysis In Myocardial Infarction (TIMI) flow grade in the IRA was significantly different between the 2 groups (frequency of TIMI 0/1/2/3; 48/4/7/41% vs 70/8/11/11%, early vs late respectively, p=0.002). TIMI 2 or 3 flow was significantly more frequent in the early heparin group than in the late heparin group (48% vs 22%, p=0.002). However, no significant differences were noted between the 2 groups in terms of in-hospital major adverse cardiac events (7% vs 11%, p=0.472) and TIMI major bleeding (2% vs 3%, p=0.639). CONCLUSIONS: In STEMI patients, early heparin therapy administered in the ER improves coronary patency, despite not reaching clinical benefit.     

Comparison in patients having primary coronary angioplasty of abciximab versus tirofiban on recovery of left ventricular function

In patients treated with primary coronary angioplasty, the use of abciximab improves microvascular perfusion and enhances the recovery of contractile function. This study compared the effects of the new dose regimen of tirofiban (25-microg/kg bolus followed by an 18-hour infusion at 0.15 microg/kg/min) on left ventricular function with those of abciximab in patients who underwent direct angioplasty. One hundred patients who underwent primary coronary angioplasty were randomized to receive a standard dose of abciximab or a large-dose bolus of tirofiban. The primary end point of the study was change in the infarct-zone wall motion score index between the initial and 30-day follow-up echocardiographic studies. The secondary end points were procedural evaluations before and after Thrombolysis In Myocardial Infarction (TIMI) grade flow, TIMI grade myocardial perfusion, and corrected TIMI frame count. Baseline global and regional ventricular functions were similar in the 2 treatment groups. After the procedure, a TIMI grade 3 flow was obtained in 86% of patients treated with abciximab and 88% of those receiving tirofiban (p = 1.0), whereas TIMI grade 3 myocardial perfusion was present in 70% and 76%, respectively (p = 0.65); corrected TIMI frame count was 22.5 +/- 1.9 and 22.1 +/- 2.5 (p = 0.37). After 30 days, we obtained 87 paired echocardiographic studies. The infarct-zone wall motion score index decreased from 2.20 +/- 0.3 to 1.99 +/- 0.2 in the abciximab group and from 2.18 +/- 0.3 to 1.95 +/- 0.3 in the tirofiban group (p = 0.67). Thus, in patients who had primary coronary angioplasty, abciximab, and the large-dose bolus of tirofiban showed similar effects on the initial angiographic results and 30-day recovery of left ventricular function.     

Use of abciximab prior to primary angioplasty in STEMI results in early recanalization of the infarct-related artery and improved myocardial tissue reperfusion - results of the Austrian multi-centre randomized ReoPro-BRIDGING Study.

AIMS: The aim of the ReoPro-BRIDGING Austrian multi-centre study was to investigate the effects of abciximab (ReoPro) on early reperfusion in ST-elevation myocardial infarction prior to or during primary percutaneous coronary angioplasty (pPCI). METHODS AND RESULTS: Fifty-five patients with STEMI were randomized either to start abciximab (0.25 mg/kg bolus followed by 10 microg/min infusion) during the organization phase for pPCI (Group 1, n=28) or immediately before pPCI (Group 2, n=27). The time between first bolus of abciximab and first balloon inflation of pPCI was 83+/-18 vs 21+/-13 min in Group 1 vs 2. The pre-pPCI ST-segment resolution (55+/-21.4% vs 42.4+/-18.2%, p=0.005), TIMI flow grade 3 (29% vs 7%, p=0.042), corrected TIMI frame count (58.4+/-32.7 vs 78.9+/-28.4 frame, p=0.018) %diameter stenosis (76.3 /63.5-100/ vs 100 /73.5-100/; median /interquartile range/, p=0.023), were significantly higher in Group 1 vs Group 2. Quantitative myocardial dye intensity measurement revealed a significantly higher grade of myocardial tissue perfusion (1 /0-9.25/ vs 0 /0-3.0/ grey pixel unit, p=0.048) in Group 1 before pPCI. Rapid release of cardiac enzymes was observed in Group 1 as compared with Group 2: rate of rise of CK was 210+/-209 vs 97+/-95 U/l/h (p=0.015). QRS score indicated a smaller infarct size in Group 1 (4.8+/-3.8 vs 7.6+/-3.5, p=0.011) on day 7. CONCLUSION: The use of abciximab in the organization phase for pPCI results in signs of early recanalization of the infarct-related artery and a subsequent improved myocardial tissue reperfusion.     

Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction: results of the integrilin and tenecteplase in acute myocardial infarction (INTEGRITI) Phase II Angiographic Trial

OBJECTIVES: The goal of this study was to evaluate combinations of eptifibatide with reduced-dose tenecteplase (TNK) in ST-elevation myocardial infarction (STEMI). BACKGROUND: Glycoprotein IIb/IIIa inhibitors enhance thrombolysis. The role of combination therapy in clinical practice remains to be established. METHODS: Patients (n = 438) with STEMI <6 h were enrolled. In dose-finding, 189 patients were randomized to different combinations of double-bolus eptifibatide and reduced-dose TNK. In dose-confirmation, 249 patients were randomized 1:1 to eptifibatide 180 microg/kg bolus, 2 microg/kg/min infusion, and 180 microg/kg bolus 10 min later (180/2/180) plus half-dose TNK (0.27 mg/kg) or standard-dose (0.53 mg/kg) TNK monotherapy. All patients received aspirin and unfractionated heparin (60 U/kg bolus; infusion 7 U/kg/h [combination], 12 U/kg/h [monotherapy]). The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 epicardial flow at 60 min. RESULTS: In dose-finding, TIMI grade 3 flow rates were similar across groups (64% to 68%). Arterial patency was highest for eptifibatide 180/2/180 plus half-dose TNK (96%, p = 0.02 vs. eptifibatide 180/2/90 plus half-dose TNK). In dose-confirmation, this combination, compared with TNK monotherapy, tended to achieve more TIMI 3 flow (59% vs. 49%, p = 0.15), arterial patency (85% vs. 77%, p = 0.17), and ST-segment resolution (median 71% vs. 61%, p = 0.08) but was associated with more major hemorrhage (7.6% vs. 2.5%, p = 0.14) and transfusions (13.4% vs. 4.2%, p = 0.02). Intracranial hemorrhage occurred in 1.0%, 0.6%, and 1.7% of patients treated with any combination, eptifibatide 180/2/180 and half-dose TNK, and TNK monotherapy, respectively. CONCLUSIONS: Double-bolus eptifibatide (180/2/180) plus half-dose TNK tended to improve angiographic flow and ST-segment resolution compared with TNK monotherapy but was associated with more transfusions and non-cerebral bleeding. Further study is needed before this combination can be recommended for general use.     

Facilitation of early percutaneous coronary intervention after reteplase with or without abciximab in acute myocardial infarction: results from the SPEED (GUSTO-4 Pilot) Trial.

OBJECTIVES: We examined the utility of early percutaneous coronary intervention (PCI) in a trial that encouraged its use after thrombolysis and glycoprotein IIb/IIIa inhibition for acute myocardial infarction (MI). BACKGROUND: Early PCI has shown no benefit when performed early after thrombolysis alone. METHODS: We studied 323 patients (61%) who underwent PCI with planned initial angiography, at a median 63 min after reperfusion therapy began. A blinded core laboratory reviewed cineangiograms. Ischemic events, bleeding, angiographic results, and clinical outcomes were compared between early PCI and no-PCI patients (n = 162), between patients with Thrombolysis in Myocardial Infarction (TIMI) flow grade 0 or 1 before PCI versus flow grade 2 or 3, and among three treatment regimens. RESULTS: Early PCI patients showed a procedural success (<50% residual stenosis and TIMI flow grade 3) rate of 88% and a 30-day composite incidence of death, reinfarction, or urgent revascularization of 5.6%. These patients had fewer ischemic events and bleeding complications (15%) than did patients not undergoing early PCI (30%, p = 0.001). Early PCI was used more often in patients with initial TIMI flow grade 0 or 1 versus flow grade 2 or 3 (83% vs. 60%, p < 0.0001). Patients receiving abciximab with reduced-dose reteplase (5 U double bolus) showed an 86% incidence of TIMI grade 3 flow at approximately 90 min and a trend toward improved outcomes. CONCLUSIONS: In this analysis, early PCI facilitated by a combination of abciximab and reduced-dose reteplase was safe and effective. This approach has several advantages for acute MI patients, which should be confirmed in a dedicated, randomized trial.     

Effect of the thrombolytic agent, streptokinase, on the responses to endotoxemia in conscious rats

The potential role of coagulation defects as a pathologic mediator in septic shock is well documented, especially as it relates to increased thromboxane formation, thrombocytopenia, and disseminated intravascular coagulation. The present study was designed to determine the effect of the thrombolytic agent streptokinase on the sequelae of endotoxemia in the rat. Conscious male Sprague-Dawley rats were given a bolus intravenous dose of Salmonella enteritidis endotoxin (20 mg/kg; LD90 dose) 5 min after the intravenous administration of streptokinase (10,000 U/kg bolus + 1,000 U/kg/hr infusion), or heparin (100 U/kg bolus + 30 U/kg/hr infusion). The effects of streptokinase or heparin on blood clotting were determined by measuring ex vivo clot formation 1 hr after the administration of endotoxin. In naive and endotoxemic animals, both agents significantly reduced clot formation (P less than 0.05). In endotoxemic animals, streptokinase or heparin improved survival to 70%, compared to 8% survival in the endotoxin + vehicle group (P less than 0.05). The improvement in survival with streptokinase was dose-dependent. Neither streptokinase nor heparin prevented the thrombocytopenia or hemoconcentration which developed in endotoxemic animals. These results demonstrate the potential utility of streptokinase for improving survival in endotoxemia and further confirm the deleterious contribution of coagulation disorders in endotoxic mortality.     

The level I cardiovascular center: is it time?

There is no uniform approach to treating the 1.5 million US citizens who have an acute myocardial infarction (AMI) each year. This contrasts with the trauma system developed to efficiently triage and treat the critically injured accident victim. Only two thirds of patients with ST-segment elevation AMI in the United States are treated with thrombolytic therapy or primary angioplasty (percutaneous coronary intervention [PCI]) which can reduce the 30-day mortality rate from approximately 15% to 6%-10%. The Early Retavase-Thrombolysis in Myocardial Infarction (ER-TIMI) 19 trial demonstrated that AMI patients who received prehospital thrombolytic therapy and were brought to the nearest receiving hospital experienced a 32-minute reduction in the time to treatment and time to ST-elevation resolution compared with those treated at their time of hospital arrival. This expedited therapy was associated with a low in hospital mortality rate (4.7%). The potential benefit of facilitated PCI with partial-dose thrombolysis and abciximab administration was demonstrated by the Strategies for Patency Enhancement in the Emergency Department (SPEED) investigators who found that double bolus recombinant plasminogen activator (reteplase) (5 + 5 megaunits) and abciximab with the addition of early PCI, resulted in a final infarct-related artery TIMI 3 flow rate of 86% compared with 77% with combination therapy alone. The Primary Angioplasty in Acute Myocardial Infarction (PAMI) investigators have shown that patients admitted with infarct-related artery TIMI 3 flow at the time of primary PCI had less than a 1% 6-month mortality. Treating AMI patients with prehospital, partial dose thrombolysis followed by immediate transport to a Level I cardiovascular center (bypassing the closest hospital if necessary) for facilitated infarct-related artery PCI has the potential to reduce the mortality in ST-elevation AMI patients from 6%-10% to less than 4% which could translate into saving approximately 500 lives per day in the United States. It is time to validate this strategy with a randomized clinical trial, the Prehospital Administration of Thrombolytic Therapy With Urgent Culprit Artery Revascularization trial (PATCAR).     

Antiplatelet effects of abciximab, tirofiban and eptifibatide in patients undergoing coronary stenting

OBJECTIVES: We sought to investigate whether abciximab, tirofiban and eptifibatide achieve comparable antiplatelet effects with coronary stenting. BACKGROUND: The glycoprotein (GP) IIb/IIIa antagonists abciximab, tirofiban and eptifibatide differ in chemical structure, binding site and pharmacokinetics. METHODS: Sixty patients undergoing coronary stenting were randomly assigned to abciximab (bolus 0.25 mg/kg body weight, infusion 10 microg per min for 12 h), tirofiban (bolus 10 microg/kg, infusion 0.15 microg/kg per min for 72 h) or eptifibatide (bolus 180 microg/kg, infusion 2 microg/kg per min for 72 h). We took serial blood samples to analyze platelet function by using flow cytometry, turbidimetric aggregometry and the rapid platelet-function assay (RPFA). RESULTS: As assessed by RPFA, platelet aggregation after 2 h of infusion was reduced to 5.9 +/- 7.8% (mean +/- SD) of baseline by abciximab, to 5.0 +/- 5.4% by tirofiban and to 7.8 +/- 7.1% by eptifibatide (p = 0.42). Turbidimetric aggregometry with adenosine diphosphate stimulation yielded similar results, whereas percent inhibition of platelet aggregation after thrombin receptor stimulation was 45.8 +/- 16.8% with abciximab, 51.3 +/- 17.6% with tirofiban and 52.9 +/- 14.8% with eptifibatide (p = 0.37). Tirofiban and eptifibatide maintained their level of platelet inhibition during infusion. Flow cytometry revealed that the reduction in the monocyte-platelet interaction by abciximab, tirofiban and eptifibatide was not significantly different (20.0 +/- 21.9%, 23.8 +/- 18.2% and 21.0 +/- 19.8%, respectively; p = 0.87). CONCLUSIONS: Abciximab, tirofiban and eptifibatide, at currently recommended doses, achieved similar levels of inhibition of platelet aggregation and a similar reduction in the platelet-monocyte interaction.     

High Dose Bolus Heparin as Initial Therapy Before Primary Angioplasty for Acute Myocardial Infarction: Results of the Heparin in Early Patency (HEAP) Pilot Study

Objectives. We sought to determine the effect of high dose intravenous bolus heparin on early coronary patency before primary angioplasty.Background. Early coronary angiography after thrombolysis for acute myocardial infarction has shown better patency when intravenous heparin is used as an adjunct. The present study explores whether heparin alone can induce reperfusion.Methods. In the Heparin in Early Patency (HEAP) pilot study, 108 patients with signs and symptoms of acute myocardial infarction <6 h eligible for primary angioplasty received a single intravenous bolus of 300 U/kg of heparin together with aspirin (160 mg chewed) in the emergency room. The median dose of bolus heparin given was 27,000 U. Patency of the infarct-related artery (IRA) was assessed by coronary angiography at a median of 85 min after the heparin bolus.Results. In 55 patients (51%, 95% confidence interval 38% to 64%), Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 was observed at 90 min: TIMI flow grade 3 in 33 patients (31%); TIMI flow grade 2 in 22 (20%). Thirty-two (64%) of 50 patients with symptoms ≤2 h had TIMI flow grade 2 or 3 versus 23 (40%) of 58 patients with symptoms >2 h (p = 0.02). No significant bleeding was seen. Two patients (2%) died in the hospital. The patency results obtained in patients treated with the high dose bolus heparin were compared with those in 108 patients from a large primary angioplasty database, who were treated with standard therapy, including aspirin but not intravenous heparin, and were matched for clinical and angiographic characteristics with the HEAP pilot study patients. They showed an 18% patency rate (p < 0.001) of the IRA (TIMI flow grade 3 in 9%, TIMI flow grade 2 in 9%) before primary angioplasty.Conclusions. Early therapy with high dose heparin is associated with full coronary reperfusion in a considerable number of patients with acute myocardial infarction, especially in those treated early (<2 h). This simple, inexpensive, probably safe and easily antagonizable treatment may be an attractive first treatment of acute myocardial infarction both before and during the hospital stay in conjunction with primary angioplasty.     

Determinants of improvement in epicardial flow and myocardial perfusion for ST elevation myocardial infarction; insights from TIMI 14 and InTIME-II.

BACKGROUND: When evaluating new reperfusion regimens for ST elevation MI, it is important to adjust for factors that influence the likelihood of achieving normal epicardial flow and complete ST resolution. METHODS AND RESULTS: A total of 610 patients from TIMI 14 contributed to the angiographic analyses. The electrocardiographic analyses were based on 544 patients from TIMI 14 and 763 patients from InTIME-II. For each hour from onset of symptoms to initiation of pharmacological reperfusion, the odds of achieving TIMI 3 flow at 90 min or complete ST resolution at 60-90 min decreased significantly (P=0.03). Anterior location of infarction was associated with a reduction in the odds of achieving TIMI 3 flow or complete ST resolution. The use of abciximab as part of the reperfusion regimen significantly increased the odds of TIMI 3 flow (P=0.01) and ST resolution (P<0.001). The fibrinolytic administered (alteplase, reteplase, lanoteplase) did not influence the odds of TIMI 3 flow or ST resolution after adjusting for time to treatment, infarct location, and use of abciximab. CONCLUSIONS: The influence of time from symptoms on epicardial flow and STRES reinforces the need for increased efforts to reduce treatment delays in patients with ST elevation MI. The significant benefits of abciximab with respect to facilitation of epicardial and myocardial reperfusion are evident even after adjusting for time to treatment and infarct location. To adjust for determinants of success of reperfusion regimens, phase II trials evaluating new drug combinations should consider using a randomization scheme that stratifies patients based on infarct location and time from symptoms.     

Lower-dose heparin with fibrinolysis is associated with lower rates of intracranial hemorrhage

BACKGROUND: The optimal heparin dose as an adjunct to fibrinolysis and its role in causing intracranial hemorrhage (ICH) is unclear. METHODS: We reviewed the heparin regimens and rates of ICH in 3 sets of recent fibrinolytic trials: (1) studies with accelerated recombinant tissue plasminogen activator (TPA, alteplase) plus intravenous heparin, in which the heparin regimen was changed during the course of the trial; (2) phase III trials with accelerated TPA plus intravenous heparin; and (3) trials of new single-bolus fibrinolytic agents. RESULTS: Lower rates of ICH were observed among studies of accelerated TPA that reduced the heparin dose mid-trial (TIMI 9A --> 9B: 1.87% --> 1.07%, GUSTO-IIa --> IIb: 0.92% --> 0.71%, TIMI 10B: 2.80% --> 1.16%). Rates of ICH with accelerated TPA gradually increased from GUSTO-I (0.72%) in 1990 to 1993 to ASSENT-2 (0.94%) in 1997 to 1998. However, this trend was reversed in InTIME-II, which used the lowest heparin dose and most aggressive activated partial thromboplastin time monitoring and observed an ICH rate of 0.64% with accelerated TPA. Lower ICH rates were also observed when the heparin dose was reduced with single-bolus tenecteplase (TNK-TPA) and lanoteplase. CONCLUSIONS: Nonrandomized comparisons with accelerated TPA suggest that lower doses of intravenous heparin are associated with lower rates of ICH. This observation also appears to apply to single-bolus TNK-TPA and novel plasminogen activator. A lower-dose, weight-adjusted heparin regimen (60 U/kg bolus; maximum, 4000 U; 12 U/kg per hour infusion; maximum, 1000 U/h) with earlier monitoring of activated partial thromboplastin time is currently recommended in the revised American College of Cardiology/American Heart Association myocardial infarction guidelines and should be used in clinical practice.     

Efficacy and safety of two unfractionated heparin dosing strategies with tenecteplase in acute myocardial infarction (results from Assessment of the Safety and Efficacy of a New Thrombolytic Regimens 2 and 3)

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.     

Treatment of porcine sepsis with high-dose antithrombin III reduces tissue edema and effusion but does not increase risk for bleeding.

We evaluated the effectiveness of antithrombin III (AT III) infusions designed to achieve supraphysiologic plasma levels of this serine protease inhibitor in preventing vascular permeability and disseminated intravascular coagulation in a pig model of sepsis. In addition, we determined whether high AT III doses were associated with increased bleeding risk. Sepsis was induced in 18 pigs by injection of lipopolysaccharide (LPS) (0.25 microg/kg per h for 3 h). At 90 min after the start of LPS infusion, pigs were randomized (n = 6 per group) to receive either human serum albumin as a placebo, AT III 120/5 (120 U/kg, 30-min bolus + 5 U/kg per h for 240 min), or AT III 250/10 (250 U/kg + 10 U/kg per h). Three additional animals served as negative controls (no LPS, no AT III). Treatment with AT III significantly reduced the amount of effluents in body cavities and fibrin monomers. AT III did not significantly increase bleeding risk as determined by organ hemorrhage. An additional assessment of AT III's bleeding risk [skin bleeding time (SBT)] was carried out in 35 nonseptic pigs treated with either AT III alone (120/5 or 250/10) or in the combination with heparin. Heparin administration alone produced a dose-dependent increase in SBT, but AT III alone did not. Addition of AT III 120/5 to heparin did not induce a further increase in bleeding time over heparin alone. These results indicate that administration of AT III in doses designed to achieve very high plasma concentrations significantly ameliorates symptoms of sepsis-induced vascular leakage and disseminated intravascular coagulation without increasing bleeding risk.     

A randomized two‐by‐two comparison of high‐dose bolus tirofiban versus abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary revascularization and stent placement: The tirofiban evaluation of novel dosing versus abciximab with clopidogrel and inhibition of thrombin (TENACITY) study trial

Background : In the absence of high‐dose thienopyridines, placebo‐controlled trials have demonstrated a reduction in ischemic events with intravenous glycoprotein IIb/IIIa antagonists during percutaneous coronary intervention (PCI). One head‐to‐head trial comparing abciximab and tirofiban among PCI patients found tirofiban to be inferior, and laboratory evidence confirmed that the bolus dose of tirofiban tested in that trial to be less effective than abciximab. Whether a higher bolus dose of tirofiban would be as efficacious as abciximab during PCI is uncertain. Methods and Results : Patients undergoing PCI were randomized equally to abciximab or to tirofiban, given as high‐dose bolus (25 μg/kg) plus 12‐hr infusion (0.15 μg/kg/min). All patients received aspirin and clopidogrel and were additionally randomized to unfractionated heparin or bivalirudin. Approximately 8,000 patients were to be studied, but after 383 were enrolled, the study sponsor discontinued the trial for financial reasons. The primary endpoint of 30‐day death, myocardial infarction, or urgent target vessel revascularization occurred in 8.8% of patients randomized to abciximab and 6.9% of those randomized to tirofiban. The respective rates of major bleeding were 1.5 and 1.6%. Additionally, the primary endpoint occurred in 8.1% of patients randomized to unfractionated heparin and 7.6% of those randomized to bivalirudin. The respective rates of major bleeding were 2.5% and 0.5%. Conclusion : With limited assessment, this direct comparison of high‐dose bolus tirofiban versus abciximab produced encouraging results and suggests that further study of this tirofiban dose regimen is warranted. The limited assessments comparing heparin and bivalirudin are consistent with prior observations. © 2010 Wiley‐Liss, Inc.     

阿昔单抗降低急性心肌梗死直接PTCA术缺血危险性的观察

目的　探讨血小板Ⅱb/Ⅲa受体拮抗剂阿昔单抗在急性心肌梗死直接经皮冠状动脉腔内成形术 (PTCA)术中应用的安全性 ,合理性和对PTCA术后缺血并发症及预后的影响。方法　对 6 0例胸痛小于 2h施行直接PTCA治疗的急性心肌梗死患者 ,随机分成对照组 30例和阿昔单抗组 30例 ,对照组静脉注射常规剂量肝素 10 0U/kg ,阿昔单抗组静脉注射小剂量肝素 70U/kg和阿昔单抗 0 .2 5mg/kg,随后以阿昔单抗 10 μg/min持续静脉滴注 12h ,观察 30d时两组死亡率、心肌梗死、再次急诊冠脉血运重建术和出血发生率。结果　随访 30d ,两组均未见出血并发症 ,对照组复合终点事件发生率为 10 %;阿昔单抗组无 1例死亡 ,也未发生心肌梗死和施行再次冠脉血运重建术。结论　在急性冠脉缺血综合征中 ,应用血小板Ⅱb/Ⅲa受体拮抗剂是安全合理的 ,血小板Ⅱb/Ⅲa受体拮抗剂阿昔单抗能降低急性心肌梗死患者直接PTCA术后缺血并发症 ,改善患者预后。     

冠状动脉内应用国产替罗非班对急性ST段抬高心肌梗死急诊介入治疗后心肌灌注和临床预后的影响

目的 探讨急性ST段抬高心肌梗死急诊PCI时国产替罗非班的不同应用途径（静脉内／冠状动脉内）对心肌组织水平灌注与临床预后影响的差异。方法 连续选择60例急性ST段抬高心肌梗死拟行急诊PCI的患者,随机分为替罗非班静脉内应用组（静脉组,n=30）与替罗非班冠状动脉内应用组（冠状动脉组,n=30）,比较两组术后即刻造影结果、住院期间以及随访期间主要不良心脏事件（MACE）发生的差异。结果共有54例完成试验,其中男性43例,女性11例,年龄29～75（58．80±12．57）岁,冠状动脉组在术后心外膜TIMI分级、TIMI心肌灌注分级（TIMI Myocardial Perfusion,TMP）、心电图ST段回落、梗死相关血管远端末梢栓塞、以及治疗后5～7天的心脏彩超射血分数值、左室舒张末期容积（LVEDV）、左室收缩末期容积（LVESV）等方面均显著优于静脉组,虽然心脏肌钙蛋白I（cTnI）与肌酸激酶同工酶（CK-MB）峰值浓度两组无差异,但是冠状动脉组CK-MB达峰值的时间显著缩短,两组院内MACE事件发生未达到统计学差异,平均住院日亦相同,但是30～90（平均57±21）天随访期间冠状动脉组总的MACE事件发生显著少于静脉组（7．1％与30．8％,P=0．02）。应用Cox回归比例风险模型在校正年龄、性别、高血压、糖尿病、家族史、吸烟等危险因素以及心肌梗死部位、胸痛至球囊扩张时间后,计算冠状动脉组在平均57天随访期间发生总的MACE事件的相对危险度为0．14（P=0．03）。冠状动脉组发生轻度出血与严重出血并发症有增多的趋势,但未达到统计学差异。结论 对于急性ST段抬高心肌梗死行急诊PCI治疗的患者,冠状动脉内应用替罗非班安全、有效,与静脉内应用相比可以进一步改善心肌水平再灌注状态并能提高临床预后,这对于在急诊室因为各种原因未能提前应用替罗非班的患者来说具有特殊的临床意义。     

Early administration of abciximab bolus in the emergency department improves angiographic outcome after primary PCI as assessed by TIMI frame count: results of the early ReoPro administration in myocardial infarction (ERAMI) trial.

OBJECTIVES: We assessed the safety and efficacy of early administration of abciximab prior to percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) patients. BACKGROUND: Research suggests that platelet glycoprotein IIb/IIIa receptor inhibitors, e.g. abciximab, may improve myocardial perfusion. In particular, early administration in the emergency department, prior to PCI, may result in more effective reperfusion. METHODS: Eighty AMI patients with planned PCI were randomized in a double-blind fashion to receive a 0.25 mg/kg abciximab bolus either "early" in the emergency department or "late" in the catheterization laboratory after angiographic assessment. In total, 74 patients underwent PCI after diagnostic angiography, all of which then received an abciximab infusion of 0.125 microg/kg/min for 12 hr. RESULTS: Prior to PCI, no significant differences were observed between the two groups regarding the angiographic endpoints or ST-segment resolution. After PCI, thrombolysis in MI (TIMI) frame count (TFC) was significantly improved in patients treated early rather than in those treated late (23 +/- 10 vs. 41 +/- 35; P = 0.02). Consistent trends, also favoring early treatment, were observed for TIMI flow grade 3 (TFG 3), corrected TFC (CTFC), and TIMI myocardial perfusion grade 3 (TMPG 3). Nine deaths (4 early, 5 late) and six significant bleeds (4 early, 2 late) were observed at 30 days after randomization. CONCLUSIONS: Early administration of abciximab is both feasible and safe in patients planned for primary PCI, increasing coronary flow and myocardial reperfusion after PCI, as demonstrated by significantly decreased TFC scores and trends toward improvements in TFG, CTFC, and TMPG.