ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background The Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A trial compared the efficacy and safety of intravenous hirudin with heparin as adjunctive therapy to thrombolysis and aspirin in patients with acute myocardial infarction. The primary safety end point was the occurrence of major hemorrhage or anaphylaxis.=80 kg) with titration to a target activated partial thromboplastin time (aPTT) of 60 to 90 seconds. Because rates of hemorrhage in both treatment arms were higher than expected, randomization was suspended in TIMI 9A after 757 patients had been enrolled. Intracranial hemorrhage occurred in 1.7% of patients treated with hirudin and 1.9% of those treated with heparin (P=NS). Major spontaneous hemorrhage at a nonintracranial site occurred more frequently in hirudin- than in heparin-treated patients (7.0% versus 3.0%; P=.02), whereas major hemorrhage at instrumented sites was similar (5.2% in both hirudin and heparin groups). Patients who developed a major hemorrhage were older (P<.001) and had higher aPTT values, especially in the first 12 hours after thrombolysis (P=.001).Conclusions The rate of major spontaneous hemorrhage for both heparin and hirudin in TIMI 9A was higher than that seen in TIMI 5, TIMI 6, and GUSTO 1. This was possibly a result of high levels of anticoagulation at the doses of heparin and hirudin used, low previous estimates of the hemorrhage risk at the doses of hirudin used in TIMI 9A due to the relatively small number of patients receiving that dose in earlier studies, and enrollment of patients at higher risk of hemorrhage. Because a prolonged aPTT was associated with an increased risk of major hemorrhage in both heparin- and hirudin-treated patients, it now appears important to monitor aPTT on a regular basis when using either antithrombin to identify those patients who require downward adjustment of the infusion. TIMI 9B has therefore been configured with a lower hirudin bolus (0.1 mg/kg) and infusion (0.1 mg/kg per hour) and lower heparin infusion (1000 U/h without weight adjustment). Infusions of both antithrombins will be titrated to a target aPTT of 55 to 85 seconds. (Circulation. 1994;90: 1624-1630.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Although intravenous heparin is routinely used in the treatment of patients with acute coronary syndromes, this anticoagulant requires antithrombin III as a cofactor, has no affinity to clot-bound thrombin, and is bound or inactivated by several plasma proteins and platelet factor 4. Recombinant hirudin, the prototypic direct thrombin inhibitor, has been demonstrated in pilot studies to yield improved angiographic and clinical outcomes compared with heparin. We compared these two antithrombins in a large-scale randomized trial.Methods and Results At 275 participating hospitals in 12 countries, patients within 12 hours from the onset of ischemic chest discomfort with an abnormal ECG were randomly assigned to receive a 72-to 120-hour infusion of heparin (5000-U bolus and 1000- to 1300-U/h infusion, adjusted to activated partial thromboplastin time (APTT) of 60 to 90 seconds or hirudin (0.6-mg/kg bolus and 0.2-mg/kg per hour infusion without aPTT adjustment) on a double-blind basis. Although recruitment of 12 000 patients was planned, the trial was stopped earlier because of an excess of intracerebral hemorrhagic events after 2564 patients were enrolled. The overall incidence of hemorrhagic stroke tended to be higher for patients receiving hirudin (1.3%) compared with heparin (0.7%), P=.11, but the incidence was significantly higher in patients receiving thrombolytic therapy (1264 patients, 1.8%) compared with those who did not (1168 patients, 0.3%), P<.001. The hemorrhagic stroke rate varied by the thrombolytic and antithrombin combination: tissue-type plasminogen activator and heparin, 0.9%; with hirudin, 1.7%; streptokinase with heparin, 2.7%; with hirudin, 3.2%. All these rates are higher than the overall incidence of hemorrhagic stroke in the patients receiving thrombolytic therapy and intravenous heparin in the GUSTO I trial (30 892 patients with rate of 0.7%, 95% CI of 0.6 to 0.8%). Among the 26 patients who had intracerebral hemorrhages, the aPTT was significantly elevated compared with the event-free patients (110+-46 versus 87+-36 seconds at 12 hours of therapy, respectively), P=.03.Conclusions At the dose of hirudin tested, there was a trend of an excess of hemorrhagic stroke compared with heparin. Heparin, at a slightly higher dose than previously used in a large-scale trial (approximately 20% increase) was accompanied by a twofold risk of hemorrhagic stroke in patients receiving thrombolytic therapy. With both thrombin inhibitors, the aPTT appears to be a useful index for predicting risk of hemorrhagic stroke in patients receiving thrombolytic therapy. (Circulation. 1994;90:1631-1637.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

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 x kg sup -1 x h sup -1) or hirudin (0.4 mg/kg body wt bolus and 0.15 mg x kg sup -1 x h sup -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. (Circulation. 1994;90:1638-1642.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Prostacyclin elicits a potent vasodilation and inhibition of platelet aggregation through binding to its membrane receptor. The impairment of prostacyclin receptor activity is implicated in various human cardiovascular diseases. In the present study, we succeeded in the isolation and characterization of human prostacyclin receptor cDNA and elucidated its gene expression in human tissues.prostaglandin E1(PGE1PGE2, PGF2alpha, PGD sub 2, STA2. In addition, iloprost dose-dependently stimulated cAMP generation in these COS-7 cells. These results are consistent with the characteristics of the human prostacyclin receptor. Northern blotting analysis on human tissues revealed that prostacyclin receptor mRNA is abundantly expressed in the aorta, lung, atrium, ventricle, and kidney.Conclusions We cloned human prostacyclin receptor cDNA and elucidated its abundant gene expression in the human cardiovascular system. The present study will lead to better understanding of the significance of prostacyclin in humans and further facilitate the clinical application of prostacyclin. (Circulation. 1994;90:1643-1647.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Previous investigations in live animals convincingly established that arterial gene transfer, while feasible, was compromised by a low transfection efficiency. More recent studies have shown that transfection efficiency may be substantially augmented by the use of recombinant adenoviral vectors. Most in vivo transfections reported to date, however, have used direct (operative) administration of the adenoviral vector. Clinical applications of arterial gene transfer (such as prevention of restenosis), however, would require local percutaneous delivery of the transgene. The present study was designed to extend in vivo intraoperative findings to percutaneous delivery systems and to assess whether gene transfer remains site specific.Methods and Results A recombinant, replication-defective adenovirus modified to include an expression cassette for nucleus-targeted beta -galactosidase was introduced into rabbit iliac arteries in vivo using either a double-balloon catheter (DBC, n=27) or a hydrogel-coated balloon catheter (HBC, n=27). Contralateral arteries--normal, endothelium- denuded, or sham-transfected with a control adenoviral vector--served as controls. beta -Galactosidase expression was assessed by X-Gal staining. Cell-transduction efficiency was measured by morphometric analysis. Polymerase chain reaction (PCR) and histochemistry were used to detect the presence and/or expression of viral DNA in remote organs. Transgene expression was detected in all cases (46 of 46) between 3 and 14 days after transfection but was in no case detectable 28 days after transfection. In the DBC group, transgene expression was limited to endothelial cells when the endothelium was left intact and to rare medial cells (<2.2%) when it had been removed. In contrast, HBC delivery resulted in transduction of up to 9.6% of medial smooth muscle cells (P=.0001). Optimized PCR and histochemistry failed to detect evidence of extra-arterial transfection except in a small number of cells (between 1 in 3 x 102and 1 in 3 x 10 sup 5 cells) in the livers of 2 animals in the DBC group.Conclusions (1) Efficient, adenovirus-mediated, arterial gene transfer to endothelial and/or smooth muscle cells is feasible by percutaneous, clinically applicable techniques. (2) Consistent transfection of medial smooth muscle cells may be achieved when the endothelial layer is abraded. (3) Medial transfection is more efficient when an HBC, rather than a DBC, is used. (4) Percutaneous delivery of the adenoviral vector via HBC results in site-specific arterial gene transfer. Very-low-level extra-arterial transfection may occur, however, when the DBC is used. (Circulation. 1994;90:1648-1656.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background In selecting patients with acute myocardial infarction for thrombolytic therapy, it is important to identify patients who are at high risk for intracranial hemorrhage, for whom thrombolytic therapy is ill advised. We hypothesized that presenting pulse blood pressure, representing the "hammer" effect on cerebral vessels and the effects of age on arterial compliance, might predict thrombolysis-related intracranial hemorrhage better than systolic, diastolic, or mean arterial blood pressures.Methods and Results Of 3483 Thrombolytic Predictive Instrument (TPI) Project subjects receiving thrombolytic therapy for acute infarction, we identified and obtained detailed clinical data on the 19 with treatment-related intracranial hemorrhages confirmed by computed tomography and on 175 matched controls. Systolic, diastolic, mean arterial, and pulse blood pressures were each significantly related to the occurrence of intracranial hemorrhage, with pulse pressure most highly related. The mean pulse pressure in patients who developed intracranial hemorrhage was 63 mm Hg, 34% higher than the 47 mm Hg mean value for those not developing hemorrhage (P=.0001). Excess pulse pressure, defined as the extent to which a patient's pulse pressure exceeded 40 mm Hg for systolic blood pressures of at least 120 mm Hg, was even more strongly related: its mean value of 23 mm Hg for patients was 130% higher than its mean value of 10 mm Hg for controls (P<.0001). With logistic regression models to estimate the relative risks (odds ratios) for intracranial hemorrhage conferred by each form of blood pressure, the relative risk for hemorrhage was greatest for excess pulse pressure: for each 10-point pulse pressure excess, the relative risk for intracranial hemorrhage was increased by 1.85 (P=.0002; 95% confidence interval (CI), 1.34 to 2.55) by itself and 1.76 (P=.001; 95% CI, 1.26 to 2.46) when adjusted for age. In this sample, excess pulse pressure by itself predicted hemorrhage as well as systolic pressure and age together. When excess pulse pressure was combined with age to make a logistic regression model predicting intracranial hemorrhage, age contributed less to the prediction than when combined with the other blood pressure forms, even though this model predicted better than any other combination of age and pressure (receiver-operating characteristic curve area, 0.82 versus 0.77 with systolic pressure and age, 0.75 with mean arterial pressure, 0.71 with diastolic pressure, and 0.81 with both systolic and diastolic pressures).Conclusions We found that excess pulse blood pressure predicted thrombolysis-related intracranial hemorrhage better than other forms of pretreatment blood pressure, perhaps better describing the pathophysiology of intracranial hemorrhage, including the effect of age. These findings will need confirmation in larger studies with comparable clinical detail. (Circulation. 1994;90:1657-1661.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Platelet activation plays a pivotal role in the pathogenesis of acute coronary disease. Monocytes are involved in the progression of atherosclerosis and are potent activators of blood coagulation through their ability to synthesize tissue factor (TF). The aim of this study was to compare markers of monocyte and coagulation activation in the systemic blood of patients with unstable angina, acute myocardial infarction, or stable angina.Methods and Results We studied 26 patients with unstable angina (10+-5 hours after the onset of the last episode of pain), 18 patients with acute myocardial infarction (5+-4 hours after the onset of pain), and 34 patients with stable angina. We measured levels of TF expression in peripheral blood mononuclear cells (isolated by gradient centrifugation and incubated for 16 hours, with or without endotoxin stimulation), levels of plasma prothrombin fragment 1+2 (F1+2), and levels of fibrinogen in peripheral blood. In patients with unstable angina, both stimulated and unstimulated cells exhibited higher levels of TF expression than in patients with stable angina (P=.0001). In patients with acute myocardial infarction, monocyte TF activity did not differ from that in patients with stable angina. Mean levels of F1+2 and of fibrinogen did not differ significantly between groups. Only in the unstable angina group, a modest correlation was found between fibrinogen (r=.72, P=.005) and F1+2 levels (r=.54, P=.001) levels and the degree of monocyte TF expression. In patients with unstable angina, monocyte TF expression (both stimulated and unstimulated, assessed by biological activity and by antigen techniques) and fibrinogen levels were correlated with the time elapsed from the beginning of the most recent episode of pain (.61<r<.72,.02<P<.0001). By contrast, there was no correlation between these variables and the time from onset of pain in patients with acute myocardial infarction.Conclusions A time-dependent activation of systemic monocytes and a time-dependent increase in fibrinogen levels occurs in unstable angina but not in myocardial infarction. These findings provide further evidence that a specific inflammatory process occurs in unstable angina. Further studies are required to determine whether monocyte activation is a cause or a consequence of plaque instability in patients with unstable angina and to clarify the interrelations between platelet and monocyte activation in these circumstances. (Circulation. 1994; 90:1662-1668.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Rupture in the shoulder region of a coronary atheroma is considered to be a sequel to local extracellular matrix degradation in this highly vulnerable site. Such degradation could be triggered by mast cells, which are filled with neutral proteases and are present in coronary atheromas. However, the distribution and phenotype of mast cells within coronary atheromas have not been studied.Methods and Results Specimens of normal and atherosclerotic human coronary intima from 32 autopsy cases with ages ranging from 13 to 67 years were stained with monoclonal antibodies against the two major proteases of mast cells, tryptase and chymase. Of the tryptase-containing mast cells, a variable proportion (average, 40%; range, 0% to 100%) also contained chymase. In the normal coronary intimas, mast cells amounted to 0.1% of all nucleated cells. In the fatty streaks, this proportion was higher by 9-fold, and in the cap, core, and shoulder regions of atheromas by 5-, 5-, and 10-fold, respectively. Electron and light microscopic studies of mast cells in the shoulder region of atheromas revealed degranulation of mast cells, a sign of their activation, and moreover, that the proportion of activated mast cells was much higher (85%) in this region than in the normal intima (18%).Conclusions The far higher proportion (50-fold) of activated mast cells in the shoulder region of atheromas supports the hypothesis that mast cells, a cell type capable of triggering matrix degradation, actively participate in the destabilization and ensuing rupture of coronary atheromas and thus may trigger an acute coronary event. (Circulation. 1994;90:1669-1678.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID