The antiangiogenic effects of levosimendan in a CAM assay

BackgroundThere is a physiological balance between the stimulatory and inhibitory signals for blood vessel growth. In many symptomatic patients with peripheral artery disease, coronary artery disease, and ischemic chronic wounds, there is a pathological insufficiency of angiogenesis. Therefore, determining the angiogenic or antiangiogenic effects of molecules currently used in cardiovascular treatment is crucial. Although levosimendan is the most well studied calcium sensitizer in preclinical and clinical practice, to the best of our knowledge, there are no previous studies investigating its angiogenic or antiangiogenic effects. In the present study, we aimed to investigate the effects of levosimendan on angiogenesis.MethodsThe antiangiogenic efficacy of levosimendan was examined in vivo in the chick chorioallantoic membrane (CAM) model by using 20 fertilized eggs and drug solutions of 1 and 10 μmol/L concentrations. Decreases in the density of the capillaries were assessed and scored.ResultsSignificant antiangiogenic effects were observed at 1 and 10 μmol/L concentrations of levosimendan. The antiangiogenic scores of levosimendan at 1 and 10 μmol/L concentrations were 0.6 and 1.10, respectively. The antiangiogenic score of bevacizumab, used as a positive control, was 0.95 at 1.0 μmol/L concentration. No significant difference was found between the antiangiogenic scores of levosimendan and bevacizumab (p = 0.54).ConclusionsOur results indicate that levosimendan has antiangiogenic effects on the chorioallantoic membrane. However, these findings must be confirmed in future studies on humans.     

Effects of unfractionated and low molecular weight heparins on plasma levels of hemostatic factors in patients with acute coronary syndromes.

BACKGROUND AND OBJECTIVES: Unfractionated heparin (UFH) and enoxaparin (low molecular weight heparin) constitute fundamental therapies in the treatment of patients with acute coronary syndrome (ACS). Since enoxaparin appears to offer clinical advantages over UFH in managing ACS, markers of thrombin generation, endothelial function and acute phase response could manifest different responses to UFH or enoxaparin. The purpose of the present study was to investigate the effect that treatment with either UFH or enoxaparin has on plasma hemostatic markers in 24 patients with ACS. DESIGN AND METHODS: The patients were randomized to receive 5,000 IU intravenous bolus and continuous infusion of 18 IU/Kg/h UFH (n=11) or 1 mg/kg/12h subcutaneous enoxaparin (n=13). The plasma levels of fibrinogen (Fg), prothrombin fragment 1+2 (F1+2), thrombin antithrombin complex (TAT), von Willebrand factor (vWF), tissue factor (TF) and tissue factor pathway inhibitor (TFPI) were assayed at admission and 6, 12, 24 and 48 hours after heparin treatment. RESULTS: Upon admission, UFH and enoxaparin patients showed a significant increase in all the hemostatic parameters measured with respect to the levels in the control subjects. In comparison with the baseline levels of the UFH- and enoxaparin-treated patients, Fg showed a significant increase at 48 h and TFPI at 6, 12 and 24 hours. However, at 48 hours TFPI levels were not significantly higher than the basal values. There were no significant changes in F1+2, TAT, vWF or TF. INTERPRETATION AND CONCLUSIONS: Markers of thrombin generation, endothelial function and acute-phase reactants manifest a similar response to UFH and enoxaparin. An increase in thrombin generation may be a result of persistently activated inflammatory and endothelial processes, despite UFH and enoxaparin treatment.     

Antiangiogenesis is produced by nontoxic doses of vinblastine

The effects of vinblastine (VBL) on endothelial cell functions involved in angiogenesis, namely proliferation, chemotaxis, spreading on fibronectin (FN), secretion of matrix-metalloproteinase-2 (MMP-2) and MMP-9, and morphogenesis on Matrigel were tested in vitro, whereas its effects on angiogenesis were studied in vivo by using the chick embryo chorioallantoic membrane (CAM) model. In vitro, at noncytotoxic doses (0.1, 0.25, 0. 5, 0.75, and 1 pmol/L), VBL impacted all these functions, except secretion of MMPs, in a dose-dependent fashion. By contrast, proliferation of other primary cells such as fibroblasts and lymphoid tumor cells was not impacted. In vivo, VBL at 0.5, 0.75, and 1 pmol/L again displayed a dose-dependent antiangiogenic activity. Lack of cytotoxicity in vitro and in vivo was shown both morphologically, and also because the antiangiogenic effects were rapidly abolished when VBL was removed. Apoptosis was not induced. At the ultrastructural level, impairment of cell functions in vitro was associated with thin disturbance of the cytoskeleton, in the form of slight depolymerization and accumulation of microfilaments, which was equally reversible. Results suggest that VBL has an antiangiogenic component at very low, noncytotoxic doses, and that antiangiogenesis by VBL could be used to treat a wide spectrum of angiogenesis-dependent diseases, including certain chronic inflammatory diseases, Kaposi's sarcoma, and cancer.     

Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: the EVET trial

Background

Low-molecular weight heparins have different pharmacokinetic and pharmacodynamic characteristics and may vary in efficacy. We compared the efficacy of enoxaparin with that of tinzaparin in the management of non-ST-segment elevation acute coronary syndromes (NSTACS).

Methods

A total of 438 patients with NSTACS were randomized to receive subcutaneous treatment with enoxaparin, 100 IU/kg twice daily (equivalent to 1 mg/kg twice daily; n = 220), or tinzaparin, 175 IU/kg once daily, (n = 218) for as long as 7 days. The primary composite end point was recurrent angina, myocardial infarction (or reinfarction), or death at day 7. Secondary end points were the primary end point at day 30 and the occurrence of individual events at days 7 and 30.

Results

The incidence of the primary end point was 12.3% in the enoxaparin group and 21.1% in the tinzaparin group (P = .015). At day 7, the rate of recurrent angina was lower with enoxaparin than with tinzaparin (11.8% vs 19.3%). At day 30, the incidences of the composite end point, recurrent angina, and myocardial infarction were also lower with enoxaparin, 17.7% vs 28.0% (P = .012), 17.3% vs 26.1% and 0.5% vs 2.8%, respectively. The rate of revascularization was lower in the enoxaparin group, 8.6% vs 17.9% (P = .010) at day 7 and 16.4% vs 26.1% (P = .019) at day 30. Rates of bleeding complications were similar in the 2 treatment groups.

Conclusions

This study indicates a benefit of enoxaparin (100 IU/kg twice daily) as compared with tinzaparin (175 IU/kg once daily) in the treatment of patients with NSTACS, which is sustained for at least 30 days.     

Pharmacodynamic considerations in the selection of dosage of tinzaparin for various indications: experimental studies in primates

Like unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs) are polypharmacologic agents that can modulate the hemostatic system at multiple points. Thus, to select an optimal dose of LMWH for a given indication, it is necessary to consider multiple actions of the drug. In this study, nonhuman primates were treated with intravenous or subcutaneous boluses of the LMWH tinzaparin or UFH. Doses were selected on the basis of the expected prophylactic (75 U/kg) and therapeutic (175 U/kg) dosing of tinzaparin. Blood samples were drawn periodically up to 24 hours after administration. Circulating anti-Xa and anti-thrombin (anti-IIa) activities determined using amidolytic assays were used to estimate plasma tinzaparin (heparin) concentrations. In addition, total tissue factor pathway inhibitor (TFPI) levels were measured in these primates. Subcutaneous administration of 75 U/kg tinzaparin resulted in plasma levels of approximately 0.2 to 0.3 U/mL, concentrations sufficient for DVT prophylaxis. Such drug levels were not associated with a significant release of TFPI. Intravenous administration of the same dose resulted in a peak drug level of approximately 1.5 anti-Xa U/mL. The elimination half-life was approximately 1 hour. Thus, intravenously administered tinzaparin may be useful for providing anticoagulation during coronary interventions. Subcutaneous administration of 175 U/kg resulted in tinzaparin levels of approximately 0.7 anti-Xa U/mL and a significant increase in TFPI levels. Interestingly, the increase in TFPI levels occurred over a different time frame than anticoagulant activity. Intravenous administration of 175 U/kg resulted in peak drug concentrations of almost 5 anti-Xa U/mL. The pharmacokinetic behavior of intravenously administered tinzaparin was comparable to that of UFH. The data show that the pharmacokinetic and pharmacodynamic effects measured using different assays widely differ. For a proper pharmacodynamic analysis, multiple assays should be considered, given that both UFH and LMWHs are polycomponent in nature.     

Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: results of the enoxaparin versus tinzaparin (EVET) trial at 6 months

Background

We have previously reported significant benefits of using enoxaparin, compared to tinzaparin, in the 7- and 30-day incidence of the composite triple end point of death, myocardial infarction (MI), or recurrent angina in patients with non-ST-segment elevation acute coronary syndromes (NSTACS). In the present study, we aimed to determine whether the observed benefits of enoxaparin were maintained beyond the early phase and report the results of the 6-m follow-up of patients in the EVET study.

Methods

We recruited 438 patients with NSTACS. All patients received oral aspirin and were randomized to also receive enoxaparin, 100 IU/kg subcutaneously twice daily (equivalent to 1 mg/kg twice daily; n = 220), or tinzaparin, 175 IU/kg subcutaneously once daily (n = 218), for up to 7 days.

Results

At 6 m, the incidence of the composite triple end point of death, MI, or recurrent angina was lower among patients receiving enoxaparin compared to those receiving tinzaparin (25.5% vs 44.0%, P < .001). A lower incidence of the secondary composite end point of death or MI was also found in the enoxaparin group compared to tinzaparin group (2.7% vs 6.9%, P = .046). The need for revascularization procedures was also lower in the enoxaparin group compared to tinzaparin group (23.2% vs 37.2%, P = .002).

Conclusions

In patients with NSTACS, enoxaparin significantly reduced the rates of recurrent ischemic events and therapeutic procedures in the short term, with sustained benefit at 6 m compared to tinzaparin.     

依诺肝素0.75 mg/kg动脉推注在冠状动脉造影和介入术中的应用

目的在中国人群中评价冠状动脉（冠脉）造影和经皮经腔冠脉介入术（PCI）中应用依诺肝素0．75mg／kg经动脉鞘管注射抗凝的安全性及有效性。方法160例择期PCI术患者随机分为两组,依诺肝素组给予依诺肝素0．75mg／kg,手术时间超过90min者再给0．3mg／kg;普通肝素组给予普通肝素100U／kg。结果注射依诺肝素后2h内,患者血浆抗Xa因子水平在0．5IU／ml以上。补充依诺肝素后可使所有患者血浆抗Xa因子水平4h内维持于0．5IU／ml以上。依诺肝素组鞘管内血栓发生率明显高于普通肝素组（26．6％比10．0％,P〈0．001）。两组30d内不良临床事件和出血事件发生率相似。结论择期PGI术中应用依诺肝素0．75mg／kg经动脉鞘管弹丸式注射进行抗凝是安全和有效的,有效抗凝强度至少可维持2h,手术时间超过2h的患者应补充依诺肝素。     

In vitro comparison of the novel,dual-acting FIIa/FXa-inhibitor EP217609C101, unfractionated heparin,enoxaparin, and fondaparinux in preventing cardiac catheter thrombosis

Efficient and safe anticoagulation is crucial in patients requiring percutaneous coronary intervention (PCI) or extracorporeal circulation during cardiac surgery. Although new anticoagulant strategies have emerged for PCI as alternatives to the established treatment with heparins, the development of new anticoagulants with an improved efficacy/safety ratio is still necessary. Our study compared the efficacy of the novel, dual-acting, neutralizable FIIa/FXa-inhibitor EP217609C101 (EP) at 2, 1.2, 0.9, and 0.6 μg/ml to unfractionated heparin (UFH), enoxaparin, and fondaparinux in preventing cardiac catheter thrombosis under in vitro conditions. Blood drawn by venepunction from healthy male volunteers (n = 10) pretreated with 500 mg aspirin orally was treated with the anticoagulant to test and continuously circulated through a cardiac catheter for 60 min or until the catheter became blocked by thrombotic debris. Anticoagulant efficacy was assessed by thrombus weight, electron microscopic features of the developing thrombi, and laboratory parameters. Whereas UFH, enoxaparin, EP 2, and EP 1.2 μg/ml secured maximum circulation times, statistically significant premature catheter occlusions were observed for EP 0.9, EP 0.6 μg/ml, and fondaparinux. The UFH group and both high-dose concentrations of EP showed significantly lower thrombus weights than the low-dose concentrations of EP and fondaparinux, (p ≤ 0.05). On electron microscopic analysis of the thrombotic debris no differences were observed in erythrocyte deposition between UFH, enoxaparin, and all EP concentrations tested. A significant reduction in fibrin deposition was achieved by UFH and EP 2 μg/ml but no significant differences in platelet deposition were found, except for a significant reduction for EP 0.6 μg/ml. Our in vitro study showed that EP217609C101 is a promising new drug that is dose-dependently superior to classical (UFH, enoxaparin) and newer (fondaparinux) drugs in preventing heart catheter thrombosis.     

Efficacy and Safety of a New Streptokinase Regimen with Enoxaparin in Acute Myocardial Infarction

OBJECTIVE: To compare a new streptokinase regimen combined with either enoxaparin or unfractionated heparin (UFH) and the traditional streptokinase regimen combined with UFH in patients with acute myocardial infarction (AMI). METHODS: 412 patients (<75 years), hospitalized within 6 hours of the onset of chest pain, were allocated thrombolytic therapy by the treating physician: streptokinase 0.75 MU/10 minutes, repeated if no coronary reperfusion after one dose, plus enoxaparin 40 mg intravenously followed by 1 mg/kg bodyweight subcutaneously at 12-hour intervals for 5-7 days (n = 102); the same streptokinase regimen plus UFH 1000 IU/60 minutes intravenously for 48-72 hours ( n = 106); or streptokinase 1.5 MU/60 minutes plus the same UFH regimen (n = 204). All patients received 250-325 mg aspirin/day. Coronary reperfusion rates, 30-day mortality and hemorrhagic complications were recorded. RESULTS: Coronary reperfusion rates with 0.75 streptokinase + enoxaparin (78.4%) and 0.75 streptokinase + UFH (74.5%) were significantly higher than those with 1.5 streptokinase + UFH (62.2%), but there was no significant difference between the groups receiving the new regimen. Overall 30-day mortality (6.3%) was significantly lower than with 1.5 streptokinase + UFH (12.7%) ( p = 0.037). The incidence of major and minor hemorrhagic events was similar in all groups. CONCLUSIONS: The accelerated streptokinase regimen was well tolerated and resulted in a significantly higher coronary reperfusion rate and significantly lower mortality compared with the traditional regimen. The 0.75 streptokinase + enoxaparin combination was at least as efficacious as the 0.75 streptokinase + UFH combination and is preferred because of its ease of administration and predictable anticoagulant effect.     

Comparison of effects on markers of blood cell activation of enoxaparin,dalteparin, and unfractionated heparin in patients with unstable angina pectoris or non-ST-segment elevation acute myocardial infarction (the ARMADA study)

The low-molecular-weight heparins (LMWHs) enoxaparin and dalteparin have shown superior and equivalent efficacy, respectively, over unfractionated heparin (UFH) in patients with unstable angina pectoris (UAP) or non-ST-segment elevation myocardial infarction (NSTEMI). This study aimed to identify markers of blood cell activation that are independent predictors of outcomes at 1 month and to compare the effects of enoxaparin, dalteparin, and UFH on any such markers. In this multicenter, prospective, open-label study, 141 patients with UAP or NSTEMI were randomized to treatment for 48 to 120 hours with enoxaparin (n = 46), dalteparin (n = 48), or UFH (n = 47). Blood samples were taken at the time of randomization and after > or =48 hours of treatment but before catheterization. Multivariate analysis identified increased plasma levels of von Willebrand factor (vWF) and decreased platelet levels of glycoprotein Ib/IX complexes as independent predictors of 1-month adverse outcome (a composite of death, myocardial infarction, and recurrent ischemia). vWF release was strongly related to and may have been released by inflammation as measured by C-reactive protein. Both LMWHs reduced the release of vWF in plasma (as well as C-reactive protein) compared with UFH. Enoxaparin had a more favorable effect on glycoprotein Ib/IX complexes than either dalteparin or UFH. The incidence of the composite clinical efficacy end point was: 13% (enoxaparin), 19% (dalteparin), and 28% (UFH). vWF and its receptor glycoprotein Ib/IX play a key role in acute coronary syndromes. vWF is linked to inflammation and, like glycoprotein Ib/IX, is affected more favorably by the LWMHs than by UFH.     

The Low Molecular Weight Heparin,Tinzaparin, in Thrombosis and Beyond

Standard unfractionated heparin (UFH) has been in clinical use for over 50 years. The commercial use of low molecular weight heparins (LMWHs) began in the mid 1980s for hemodialysis and the prophylaxis of deep vein thrombosis (DVT). Initially, the clinical development of LMWHs was concentrated on the European continent. Subsequently, LMWHs were introduced in North America as well. In the initial stages of development of these drugs only nadroparin, dalteparin and enoxaparin were used. Subsequently, several other LMWHs such as ardeparin, tinzaparin, reviparin and parnaparin were introduced. LMWHs constitute a group of important medications with total sales reaching nearly 2.5 billion dollars with expanded indications reaching far beyond the initial indications for the prophylaxis of post‐surgical DVT. This review highlights the pharmacology of tinzaparin. Unlike other LMWHs, tinzaparin is prepared by enzymatic hydrolysis with heparinase, while various chemical depolymerization methods are used for the synthesis of other LMWHs. As compared with the standard heparin, LMWHs have different pharmacodynamic, and pharmacokinetic properties; they also differ in clinical benefits.     

Occurrence of thrombosis and haemorrhage, relationship with anti-Xa, anti-IIa activities, and D-dimer plasma levels in patients receiving a low molecular weight heparin, enoxaparin or tinzaparin, to prevent deep vein thrombosis after hip surgery

Studies in experimental animal models and in patients receiving low molecular weight heparin (LMWH) to prevent thromboembolic events after surgery have not demonstrated a clear relationship between anti-Xa and anti-IIa activities in plasma and either bleeding or prevention of thrombosis. The relationship between these clinical outcomes and ex vivo anti-Xa and anti-IIa activities, activated partial thromboplastin time (APTT) and D-dimers were evaluated in 440 patients undergoing total hip replacement and given prophylaxis once daily with a LMWH (tinzaparin or enoxaparin) in a multicentre double-blind randomized study. 221 patients received 4500 anti-Xa IU of tinzaparin; 219 patients received 40 mg (4000 anti-Xa IU) of enoxaparin. Both regimens were administered subcutaneously once daily. Blood samples for anti-IIa, anti-Xa, D-dimers levels and APTT were taken at baseline, on day 1, day 5 and on the day of discharge (days 8-14) and clinical assessments were performed dafly until day 14. All patients had bilateral venography between days 8 and 14. All coagulation tests were performed in central laboratories. A significant correlation was observed between anti-IIa activity and anti-Xa activity and the dose of each LMWH injected. The anti-Xa activity was significantly higher with enoxaparin and the anti-IIa activity was significantly higher with tinzaparin. No clear relationship between these two activities and the clinical outcomes was observed. This was also true with regards to APTT. Before and after surgery, D-dimers were significantly higher in patients with deep vein thrombosis (DVT) than in those without DVT but had no predictive value. Interestingly, a significant post-operative increase of D-dimers persisted in both groups of patients during the whole observation period, possibly suggesting that a longer duration of prophylactic treatment may be appropriate.     

Comparative pharmacokinetics of LMWHs

A variety of pharmaceutical preparations of low-molecular-weight heparins (LMWHs) are available. They belong to the same family of compounds-ie, heparin derivatives with a narrow distribution of mean molecular weights (MWs). LMWHs have different methods of preparation, which result in variations in mean MW, distribution of MW, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles. The mean MW of these compounds ranges from 3,600 to 6,500 daltons. The ratio of anti-Xa (aXa) and anti-IIa (aIIa) activities of the different LMWHs ranges from 1.5 to >10. After subcutaneous (SC) injection of a prophylactic or therapeutic dose, the peak values for plasma aXa or aIIa activity may vary twofold to threefold because of differences in bioavailability, plasma clearance (Clplasma), and half-life (t1/2). The injection of equivalent amounts of product, based on aXa and aIIa international units (IU), may result in different areas under the curve for the respective activities. Although tinzaparin has a high aIIa specific activity per milligram (and consequently, a low aXa/aIIa ratio), SC injection of 40 mg of enoxaparin (4,000 aXa IU) results in a higher aXa peak value in patients with total hip replacement than 4,500 aXa IU of tinzaparin. Differences in aIIa and aXa peak activities are more striking when high doses of LMWHs are used. The activated partial thromboplastin time (aPTT) can be significantly prolonged, an effect that is related to aIIa and aXa activity. The volume of distribution of LMWHs is of the same order of magnitude as that of the plasma volume. The mean retention time of aXa activity varies from 5.2 (dalteparin) to approximately 7 h (enoxaparin, nadroparin). Bioavailability of prophylactic doses of LMWHs ranges from 86% (dalteparin) to 98% (enoxaparin, nadroparin). PK parameters appear to be minimally affected by a patient's age. The Clplasma is different for each LMWH: 16 mL/min enoxaparin, 21 mL/min nadroparin, 33 mL/min dalteparin, 19 mL/min reviparin, and 22 mL/min tinzaparin. Accumulation of product has been observed for almost all LMWHs in patients with renal insufficiency. LMWHs are effective and safe for treatment or prophylaxis of venous thromboembolism during pregnancy, because they do not cross the placenta. No data are available regarding the passage of LMWHs into the milk in lactating women. Although LMWHs are also effective in prevention and treatment of thromboembolic disease in children, optimal use of these agents in pediatric patients has not been determined. In summary, the PD and PK of LMWHs have been well documented and have demonstrated that LMWHs have a more predictable response, a greater bioavailability, and a longer aXa t1/2 than unfractionated heparin. However, their distribution of MW affects their physicochemical and biological properties, as well as PK characteristics. The concept of aXa/aIIa ratio (determined in vitro) does not account for the differing PK of aXa and aIIIa activity in circulating blood.     

TNP-470 and recombinant human interferon-alpha2a inhibit angiogenesis synergistically

The hypothesis that the combination of two known antiangiogenic agents TNP-470 and interferon (IFN)-alpha exerts synergistic effects has been investigated in vitro and in vivo. In vitro, TNP-470 and recombinant human IFN-alpha2a (rhIFN-alpha2a) resulted in a dose-dependent inhibition of proliferation of human umbilical vein endothelial cells (HUVECs) and EA.hy926 endothelial cells. Compared with the two agents used singly at their lowest or ineffective doses, combined treatment with the same doses inhibited more intensely in the absence of cytotoxicity and displayed similar behaviour on cell chemotaxis and capillary morphogenesis on Matrigel. However, the secretion of matrix metalloproteinase 2 (MMP-2) and MMP-9 was not influenced by the two agents, either alone or in combination, even when they were applied at their lowest efficacious doses or at higher cytotoxic doses. Experiments in vivo with the chick embryo chorioallantoic membrane (CAM)-sponge assay revealed the same dose-dependent inhibition and synergy. As the basic fibroblast growth factor (bFGF)-induced angiogenesis in the CAM-sponge model was strongly inhibited by the combined treatment, TNP-470 and rhIFN-alpha2a would appear to exert antiangiogenesis synergistically, perhaps by interfering with the bFGF-mediated pathway.     

冠心病介入治疗中应用低分子肝素与普通肝素的随机对照研究

目的探讨冠心病患者经皮冠状动脉介入治疗（PCI）中应用低分子肝素（LMWH）替代普通肝素（UFH）的安全性和有效性。方法自2003年10月至2005年2月共入选966例申请一次性行PCI的患者,所有患者均签署了知情同意书。966例患者中最终完成PCI治疗者455例[包括283例为非ST段抬高急性冠脉综合征（ACS）者]。未接受PCI治疗者511例。研究采用随机对照方法,将入选患者分为LMWH组和静脉UFH组,LMWH组484例,静脉UFH组482例。LMWH组采用依诺肝素（enoxaparin）,按1mg／kg的剂量于PCI手术前至少给予2次皮下注射（每12h一次）,PCI手术在最后1次皮下注射30min后开始。完成冠状动脉造影或PCI后,立即拔出鞘管。静脉UFH组的患者于手术前即刻先给予普通肝素25rIlg静脉推注,如果造影显示适合PCI时,再追加65mg。完成PCI后4h左右拔出鞘管。LMWH组和静脉UFH组中最终行PCI者各为227例和228例。结果（1）LMWH组中1例于PCI术中发生急性血栓形成致急性心肌梗死（AMI）,PCI术后及住院期间未见急性和亚急性血栓形成。静脉UFH组术中和住院期间无急性和亚急性血栓形成。住院期间心脏事件发生率（死亡、AMI和再次血管重建）在LMWH组为0．44％,静脉UFH组为0;（2）LMWH组均于术后即刻拔出鞘管,穿刺局部发生血肿8例,静脉UFH组于术后4h左右拔出鞘管,穿刺局部发生血肿20例,前者血肿发生率明显低于后者,差异有统计学意义（P〈0．05）;（3）随访1个月LMWH组心脏事件发生率为0,静脉UFH组1例于院外发生亚急性血栓致AMI,再次行PCI成功,随访期间心脏事件发生率为0．43％。结论本研究结果提示对于拟行PCI的冠心病患者或非sT段抬高ACS患者术前给予至少2次依诺肝素皮下注射（1mg／kg,每12h一次）,并于最后1次皮下注射的8h内行PCI是安全和有效的,术前和术中不需要给予静脉UFH,术后可即刻拔出鞘管。     

Haemorrhagic Effect of Enoxaparin,a Low Molecular Weight Heparin: Comparison with Unfractionated Heparin in Humans

The haemorrhagic effects of unfractionated heparin (UFH) and the low molecular weight heparin (LMWH) enoxaparin were investigated and compared in the gastric mucosa (haemorrhage induced by biopsy) and skin (haemorrhage induced by Simplate) of 12 healthy volunteers. Administration of UFH and LMWH (given in a dose of 75 anti-Xa U/kg intravenously) increased median gastric bleeding time (3.5 min) and geometric mean blood loss (11.5 l) to 19 min (p = 0.00003) and 54.1 l (p = 0.0021) after UFH and to 13 min (p = 0.008) and 29.0 l (p = 0.275) after LMWH. Median skin bleeding time (4.25 min) increased to 6.0 min after UFH (p = 0.003) and to 6.75 min after LMWH (p = 0.0008). Mean heparin activity in plasma was 20% higher after LMWH than after UFH. The calculated gastric bleeding time to heparin activity ratio was significantly lower for LMWH than for UFH (0.05).     

Neridronate inhibits angiogenesis in vitro and in vivo

The effects of the amino-bisphosphonate neridronate on endothelial cell functions involved in angiogenesis, namely, proliferation and morphogenesis on Matrigel were tested in vitro, whereas its effects on angiogenesis were studied in vivo, by using the chick embryo chorioallantoic membrane (CAM) assay. In vitro, neridronate inhibited endothelial cell proliferation in a dose-dependent fashion, peaking at 30 μM. At the same concentration, neridronate inhibited fibroblast growth factor-2 (FGF-2)-induced capillary-like tube formation in the morphogenesis assay on Matrigel. In vivo, when tested in the CAM assay, neridronate again displayed the capability to inhibit FGF-2-induced angiogenesis. Overall, these results suggest that anti-angiogenesis by neridronate could be used to treat a wide spectrum of angiogenesis-dependent diseases, including certain chronic inflammatory diseases and cancer.     

Laboratory analysis of blood samples from patients treated with tinzaparin

Tinzaparin at two dosages, 175 anti-Xa U/kg subcutaneously administered for 7 days, followed by warfarin, and 175 anti-Xa U/kg subcutaneously given for 90 days was compared with continuous intravenous unfractionated heparin (UFH) for 5 days, followed by warfarin for 3 months, were tested in the treatment of patients with proximal deep vein thrombosis. Several laboratory assays were used to monitor the effects of tinzaparin and UFH. The tinzaparin only study arm produced a 4- to 6-second prolongation of the activated partial thromboplastin time (aPTT). However, in the anti-Xa chromogenic assay and the Heptest assays, there was a prolongation after the administration of all three agents. In the two groups treated for 7 days, the anti-Xa and Heptest values returned to baseline after cessation of therapy. In the patients treated with tinzaparin for 90 days, the anti-Xa and Heptest remained elevated throughout the treatment period. The anti-IIa (anti-thrombin) results were considerably lower values in the tinzaparin-treated groups. Tissue factor pathway inhibitor (TFPI) antigen levels were elevated 2- to 2.5-fold in all three groups. In addition, the thrombin/antithrombin (TAT) complexes were also measured. After treatment, the TAT levels decreased over time. Tinzaparin was more effective in decreasing these levels. These results suggest that both Heptest and anti-Xa assays can be used to monitor patients receiving tinzaparin. TAT may be a useful test in monitoring the resolution of the clots. However, additional clinical validation is required to demonstrate the relevance of these parameters with the clinical outcome.     

Enoxaparin versus unfractionated heparin in patients treated with tirofiban, aspirin and an early conservative initial management strategy: results from the A phase of the A-to-Z trial.

AIMS: In high risk patients with non-ST elevation acute coronary syndromes (ACS), enoxaparin is generally preferred to unfractionated heparin (UFH). However, less is known about the relative merits of these two forms of heparin in patients receiving concomitant glycoprotein IIb/IIIa inhibitors. METHODS AND RESULTS: The A phase of the A-to-Z trial was an open label non-inferiority trial in which 3987 patients with non-ST elevation ACS were randomised to receive either enoxaparin or UFH in combination with aspirin and tirofiban. Inclusion required either ST depression or cardiac biomarker elevation. While the selection of an early management strategy (invasive or conservative) was at the discretion of the local investigator, investigators were asked to designate their plans for an invasive or conservative strategy on the case record form. An early conservative strategy was specified for 1778 patients (45%); this subgroup forms the population for the present analyses. Among patients with a planned conservative strategy, baseline characteristics were similar between those randomised to UFH (n = 872) and those randomised to enoxaparin (n = 906). The primary endpoint of death, new MI, or documented refractory ischaemia within 7 days of randomisation occurred in 10.6% of patients randomised to UFH and 7.7% of patients randomised to enoxaparin (HR 0.72; 95% CI 0.53-0.99; p = 0.04). The combined rate of TIMI major, minor, or loss no-site bleeding was 1.3% in patients treated with UFH and 1.8% in those treated with enoxaparin (p = ns). CONCLUSIONS: When a conservative approach to catheterisation and PCI was planned for ACS patients receiving tirofiban and aspirin, enoxaparin was associated with superior efficacy and similar bleeding vs UFH.     

Comparison of anticoagulant and anti-inflammatory responses using enoxaparin versus unfractionated heparin for transesophageal echocardiography-guided cardioversion of atrial fibrillation

The Assessment of Cardioversion Using Transesophageal Echocardiography (ACUTE) II study compared enoxaparin with unfractionated heparin (UFH) as bridging therapy in patients with atrial fibrillation >2 days in duration who underwent transesophageal echocardiography-guided cardioversion. In the present study, the anticoagulant and anti-inflammatory effects of enoxaparin and UFH were compared at prespecified time points. In a randomized substudy of 155 patients from 17 clinical sites, the anticoagulant activity of enoxaparin (n = 76) was compared with that of UFH (n = 79). Blood samples were drawn at enrollment, on day 2, and on day 4 in the 2 groups. Blood samples were evaluated for anticoagulant activity by measuring the activated partial thromboplastin time, anti-Xa, anti-IIa, and tissue factor pathway inhibitor levels. In addition, levels of coagulation activation (by thrombin antithrombin complex) and inflammation (by highly sensitive C-reactive protein) were measured. The results of this substudy showed that the anti-Xa levels in the 2 groups increased on day 2. Similar increases in anti-Xa were observed on day 4. The anti-Xa levels and tissue factor pathway inhibitor levels were higher in the enoxaparin group compared with the UFH group on days 2 and 4. However, as expected, the anti-IIa levels in the UFH group were higher. In addition, markers of coagulation activation and inflammation were increased in patients with atrial fibrillation. Treatment with enoxaparin significantly decreased thrombin antithrombin complex levels compared with treatment with UFH. Highly sensitive C-reactive protein levels were also decreased after treatment in the 2 groups. In conclusion, the ACUTE II study showed that the use of enoxaparin for bridging therapy in patients with atrial fibrillation who underwent transesophageal echocardiography-guided cardioversion resulted in a more predictable and stronger anticoagulant response than that observed with UFH. Markers of inflammation were also decreased in the 2 groups.