Indirect comparison of changes of parameters of hemostasis during short-term use of ticlopidine and clopidogrel in patients with non-ST elevation acute coronary syndrome

Effects of thienopyridines ticlopidine (TIC) and clopidogrel (CL) on hemostasis in patients (pts) with non-ST-elevation acute coronary syndromes (NSTEACS) have not been compared. AIM: To compare changes of some markers of coagulation and platelet activation during short term use of TIC and CL in pts with NSTEACS. METHODS: Aspirin treated pts with NSTEACS (<48 hours from pain onset, Braunwald class IIIb) were included into 2 consecutive studies: 37 pts receiving unfractionated heparin (UFH) were randomized to open TIC (n=19, 500 mg BID for 2 days and 250 mg BID for subsequent 5 days) or no TIC (n=18); 19 pts receiving enoxaparin were randomized to CL (n=10, 300 mg on day 1 and 75 mg/day for subsequent 6 days) or no CL (n=9). At baseline, on days 1, 3, 7 and 14 (7 days after thienopyridines discontinuation) we measured ADP-induced and spontaneous platelet aggregation (PA), levels of prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), von Willebrand factor (vWF), fibrinogen, tissue type plasminogen activator antigen (tPA), plasminogen activator inhibitor activity (PAI) and D-dimer (Dd), and counted platelet number. RESULTS: Maximal suppression of PA was obtained on 7-th and 3-rd days in TIC and CL groups, respectively. Compared with their controls TIC treated pts in 7 days after TIC discontinuation had lower levels of TAT (3.61 and 2.77 ng/ml, respectively, r<0.05) and fibrinogen (3.84 and 3.16 g/l, respectively, r<0.05). There were no significant differences between intervention and control groups in these parameters in study with CL. Level of vWF in TIC treated pts was lower than in controls on days 3 (163 and 186%, respectively, r<0.05) and 14 (144 and 173%, respectively, p<0.01). In CL treated pts vWF level was lower relative to controls on days 3 and 7 (152 and 185%, r<0.05, 141 and 166%, r<0.05, respectively). tPA levels in study with TIC did not differ between intervention and control groups. tPA in CL treated pts exceeded its level in controls on days 3, 7, and 14 (25.7 and 20.2 ng/ml, 26.5 and 12.9 ng/ml, 24.6 and 15.7 ng/ml, respectively). On the same days level of Dd in pts receiving CL was significantly higher than in control group (969 and 702 ng/ml, 970 and 575 ng/ml, 806 and 484 ng/ml on days 3, 7 and 14, respectively). Activity of PAI in TIC group was higher than in controls on day 7 (13.6 and 8.2 U/l, r<0.05), and at this moment level of Dd was lower in TIC treated patient (770 and 515 ng/ml in control and TIC groups, respectively, r<0.05). CL and control groups had similar PAI activity. Mean platelet volume rose relative to initial level and to control group only in CL treated patients (9.0 and 8.4 fl, 9.6 and 8.4 fl, 9.4 and 8.5 fl in CL and control groups on days 0, 7 and 14, respectively; r<0.05 for comparison between groups on days 7 and 14). CONCLUSION: In pts with NSTEACS both thienopyridines attenuated acute phase elevation of vWF. The use of TIC in UFH treated pts was associated with indirect signs of decreased thrombin activity and some inhibition of fibrinolysis while the use of CL in enoxaparin treated pts was associated with signs of activation of fibrinolysis.     

Non ST elevation acute coronary syndrome. Some characteristics of coagulation and von Willebrand factor during short term use of ticlopidine or clopidogrel

Levels of some markers of coagulation and platelet activation such as prothrombin fragment 1+2 (F1+2) thrombin-antithrombin complex (TAT) and von Willebrand factor (vWF), are related to outcome in non ST-segment elevation acute coronary syndrome (NSTEACS). Effects of thienopyridines ticlopidine and clopidogrel on acute changes of these parameters in patients with NSTEACS are not well investigated. AIM: To study changes of markers of coagulation and platelet activation during short term use of ticlopidine and clopidogrel in NSTEACS patients treated with aspirin and antithrombin. METHODS: Patients with NSTEACS, treated with aspirin and unfractionated heparin (n=37, <48 hours from pain onset, Braunwald class IIIb) were randomized to open ticlopidine (n=19, 500 mg BID loading dose for 2 days and 250 mg BID for subsequent 5 days) or no ticlopidine (n=18). In another substudy with the same design 19 aspirin and enoxaparin treated patients were randomized to clopidogrel (n=10, 300 mg loading dose and 75 mg/day for subsequent 6 days) or no clopidogrel (n=9). Levels of F1+2, TAT and vWF were measured at baseline, on days 1, 3, 7 and 14 (7 days after discontinuation of thienopyridines). RESULTS: At baseline values of parameters studied were similar in each pair (thienopyridine - control) of patient groups. Compared with their controls ticlopidine treated patients in 7 days after ticlopidine discontinuation had lower levels of TAT (2.77 and 3.61 ng/ml, r<0.05) and fibrinogen (3.16 and 3.84 g/l, r<0.05). The level of vWF in ticlopidine treated patients was lower relative to control group on days 3 (163 and 186%, r<0.05) and 14 (144 and 173%, p<0.01). In substudy with clopidogrel differences between groups existed only in vWF levels. In clopidogrel treated patients the level vWF was lower relative to controls on days 3 (152 and 185%, r<0.05) and 7 (141 and 166%, r<0.05). CONCLUSION: Short term use of ticlopidine in patients with NSTEACS treated with aspirin and unfractionated heparin was associated with lower levels of TAT and fibrinogen (relative to control group) on day 14. This could be interpreted as delayed effect of ticlopidine on thrombin activity. Both ticlopidine and clopidogrel used in regimes with loading doses in NSTEACS patients treated with aspirin and antithrombin prevented acute phase elevation of vWF.     

Non ST elevation acute coronary syndrome. Parameters of fibrinolysis during short term use of ticlopidine or clopidogrel

Whether thienopyridines (ticlopidine or clopidogrel) produce similar effects on fibrinolysis in patients with non ST elevation acute coronary syndrome (NSTEACS) was not well elucidated. AIM: To study changes of parameters of fibrinolysis during short term use of ticlopidine and clopidogrel in NSTEACS patients treated with aspirin and antithrombin. MATERIAL: Patients with NSTEACS treated with aspirin and unfractionated heparin (UFH, n=37) or enoxaparin (n=19). METHODS: The UFH treated patients were randomized to ticlopidine (1000 mg/day for 2 and then 500 mg/day for 5 days, n=19) or no ticlopidine (n=18). Enoxaparin treated patients were randomized to either clopidogrel (300 mg/day for 1 and then 75 mg/day for 6 days, n=10) or no clopidogrel (n=9). Levels of tissue plasminogen activator (TPA) antigen, D-dimer, and activity of plasminogen activator inhibitor (PAI) were measured before and in 24 hours, 3, 7, 14 days after randomization. RESULTS: At baseline values of parameters studied were similar in each pair (thienopiridine - control) of patients groups. Compared with their controls ticlopidine treated patients on day 7 had less pronounced lowering of PAI activity (13.6 and 8.2 U/l, p<0.05) and lower D-dimer concentration (515 and 770 ng/ml, respectively, p<0.05). Clopidogrel treated patients on days 3, 7 and 14 had higher levels of TPA both compared with controls (25.7 and 20.2, p<0.05; 26.5 and 12.9, p<0.01; 24.6 and 15.7 ng/ml, p<0.01; respectively) and baseline. D-dimer levels in these patients on same time points were also higher than in controls (969 and 702, p<0.05, 970 and 575, p<0.01, 806 and 484 ng/ml, p<0.01, respectively). CONCLUSION: Compared with controls the use of ticlopidine in patients with NSTEACS treated with aspirin and UFH was associated with less pronounced lowering of PAI activity and lower level of D-dimer. This could be interpreted as consequence of inhibition of fibrinolysis. The use of clopidogrel in similar patients treated with aspirin and enoxaparin was associated with elevated levels of TPA and D-dimer what presumably reflected augmentation of fibrinolytic activity.     

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.     

Non ST elevation acute coronary syndrome: early use of pravastatin or atorvastatin is associated with divergent changes of parameters of hemostasis

PURPOSE: To find out whether pravastatin and atorvastatin rapidly (in 1-2 weeks) and similarly affect hemostasis in patients with non-ST elevation acute coronary syndrome (NSTEACS). METHODS: Ninety aspirin and heparin treated patients with NSTEACS were randomized <24 hours from pain onset to open pravastatin 40 mg/day (n=31), atorvastatin 10 mg/day (n=30) or atorvastatin 40 mg/day (n=29). At baseline, on days 7, 14 plasma thrombin-antithrombin complex (TAT), prothrombin fragments 1+2 (F1+2), D-dimer, von Willebrand factor (vWF) were measured by ELISA. Results were compared with data from controls (n=18) of another randomized study on similarly treated patients. RESULTS: In all treatment groups levels of low-density lipoprotein cholesterol (LDLCH) were lowered by days 7 (p<0,01) and 14 (p<0,01 vs. baseline and for both atorvastatin groups vs. day 7). In pravastatin group levels of TAT and F1+2 decreased, while vWF level increased. In atorvastatin groups levels of TAT and F 1+2 increased while level of vWF decreased. Contrary to pravastatin group changes in atorvastatin treated patients more resembled those in controls not receiving lipid lowering drugs. Changes of both LDLCH and TCH directly correlated only with changes of vWF (r=0.23, p=0.03 and r=0.25, p=0.02, respectively). No consistent changes of D-dimer occurred. CONCLUSION: Early use of atorvastatin and pravastatin in patients with NSTEACS was associated with rapid divergent changes of some hemostatic parameters. Except lowering of von Willebrand factor changes in atorvastatin treated patients more resembled those in controls not receiving lipid lowering drugs. Von Willebrand factor was the only parameter which changes weakly but significantly correlated with changes of CH and LDL CH levels.     

The course of disseminated intravascular coagulation is predicted by changes in thrombin-antithrombin III complex levels--is there any difference between treatment with standard heparin or low-molecular-weight heparin?

Changes in thrombin-antithrombin III complex (TAT) over a one week period studied in 42 cases of disseminated intravascular coagulation (DIC); 19 treated with standard (or unfractionated) heparin (UFH) and 23 treated with low-molecular-weight heparin (LMWH). Closer examination of short term changes in TAT (determined 2, 6, 12, 24, 48, and 72 h after starting anticoagulant therapy) was performed in ten cases of DIC; six treated with UFH and four treated with LMWH. In twelve of the 19 cases of DIC treated with UFH and 19 of the 23 cases treated with LMWH, plasma levels of TAT decreased one day after starting anticoagulant therapy, and no exacerbation of DIC was observed for the following week. In the other cases, these levels further increased and most patients had persistently high levels of TAT for the next week. Plasma levels of TAT were significantly lower in patients treated with LMWH than in those treated with UFH, which may suggest that LMWH is more beneficial in DIC. A transient increase in plasma levels of TAT was observed 6 h after the start of anticoagulant therapy in two of the six cases treated with UFH and one of the four cases treated with LMWH. From these results we conclude that fluctuation of TAT was not influenced by the type of heparin (UFH or LMWH), and that the course of DIC for the following week can be predicted by the changes in plasma TAT levels one day after starting anticoagulant therapy.     

Acute promyelocytic leukemia cell adhesion to vascular endothelium is reduced by heparins

Adhesion of acute promyelocytic leukemia (APL) cells to endothelial cells (EC) is among the mechanisms of the APL-associated coagulopathy, responsible for early hemorrhagic deaths in affected patients. We compared the effects of dalteparin and enoxaparin, two low-molecular-weight heparins (LMWH), and unfractionated heparin (UFH), on APL NB4 adhesion to micro- (HMEC-1) and macro-vascular EC (HUVEC), in resting and interleukin-1β (IL-1β)-stimulated conditions. The heparin effect on EC adhesion molecule (ICAM-1, VCAM-1, E-selectin) expression was also assessed. In HMEC-1, dalteparin inhibited IL1β-induced NB4 adhesion by 80%, enoxaparin by 52%, and UFH by 44%. Similar results were obtained in HUVEC. This was associated with a significant decrease of VCAM-1 and ICAM-1 expression. In conclusion, we show that LMWH significantly counteract APL cell adhesion to the vessel wall, by modulating EC adhesion molecule expression. This property of heparins may represent one approach for hampering excess clotting activation and microthrombi deposition in APL.     

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.     

Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin

Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4) bound to heparin. Immunogenicity of heparins differs in that unfractionated heparin (UFH) induces more anti-PF4/heparin antibodies than low-molecular-weight heparin (LMWH) and UFH also causes more HIT. Fondaparinux, a synthetic anticoagulant modeled after the antithrombin-binding pentasaccharide, is believed to be nonimmunogenic. We tested 2726 patients for anti-PF4/heparin antibodies after they were randomized to receive antithrombotic prophylaxis with fondaparinux or LMWH (enoxaparin) following hip or knee surgery. We also evaluated in vitro cross-reactivity of the IgG antibodies generated against PF4 in the presence of UFH, LMWH, danaparoid, or fondaparinux. We found that anti-PF4/heparin antibodies were generated at similar frequencies in patients treated with fondaparinux or enoxaparin. Although antibodies reacted equally well in vitro against PF4/UFH and PF4/LMWH, and sometimes weakly against PF4/danaparoid, none reacted against PF4/fondaparinux, including even those sera obtained from patients who formed antibodies during fondaparinux treatment. At high concentrations, however, fondaparinux inhibited binding of HIT antibodies to PF4/polysaccharide, indicating that PF4/fondaparinux interactions occur. No patient developed HIT. We conclude that despite similar immunogenicity of fondaparinux and LMWH, PF4/fondaparinux, but not PF4/LMWH, is recognized poorly by the antibodies generated, suggesting that the risk of HIT with fondaparinux likely is very low.     

Efficacy and Safety of Low-Molecular-Weight Heparins As An Adjunct to Thrombolysis in Acute ST-Elevation Myocardial Infarction

A 48-hour course of intravenous unfractionated heparin (UFH) is the standard of treatment in conjunction with fibrin-specific thrombolysis in ST-elevation myocardial infarction (STEMI). In recent trials, the efficacy and safety of in-hospital administration of subcutaneous low-molecular-weight heparins (LMWH), previously proven effective in non-ST-elevation acute coronary syndromes, have been investigated in the setting of STEMI. The aim of this review was to evaluate the available evidence supporting the use of LMWH in STEMI.Overall, about 27,000 patients treated with various thrombolytic regimens, were included in 12 open-label randomized clinical trials, where dalteparin, reviparin or enoxaparin were administered. While acknowledging the wide variability in study dimensions, designs and end-points, a higher efficacy of LMWH was observed overall as compared to placebo, and also to UFH (mainly as regards the occurrence of reinfarction). As regards safety, bleedings were more frequent than placebo and comparable to UFH in LMWH groups, with the exception of the pre-hospital ASSENT-3 PLUS trial, where in elderly patients, enoxaparin had an incidence of intracranial hemorrhage twice higher than UFH. In a recent double-blind, randomized, mega-trial including over 20,000 patients, the superior efficacy on in-hospital and 30-day adverse cardiac events (namely reinfarction), and comparable safety on intracranial bleedings, of enoxaparin compared to UFH, was shown.In conclusion, in-hospital subcutaneous administration of dalteparin, reviparin and enoxaparin, as an adjunct to various thrombolytics in STEMI, appears feasible and at least as effective and safe as 48-hour intravenous treatment with UFH. In accordance with the available strongest evidence, an initial intravenous bolus of enoxaparin followed by twice daily subcutaneous administration for about 1 week should be the preferred regimen, and should be strongly considered instead of intravenous UFH. Along with its easiness of use, not requiring laboratory monitoring, subcutaneous administration of LMWH following STEMI treated with thrombolysis allows extended antithrombotic treatment, while permitting early mobilization (and rehabilitation) of patients.Key Words: ST-elevation acute myocardial infarction, enoxaparin, dalteparin, reviparin, unfractionated heparin.     

Cellular effects of factor Xa on vascular smooth muscle cells--inhibition by heparins?

In addition to its key function as a clotting enzyme, factor Xa (FXa) also elicits cellular effects. In cultured human venous smooth muscle cells (SMCs), FXa induced a mitogenic response that was independent of thrombin and platelet-derived growth factor (PDGF). Unfractionated heparin (UFH) as well as low molecular weight heparin (LMWH) (enoxaparin) inhibited the mitogenic effects of FXa, thrombin and fetal calf serum (FCS), but did not reduce mitogenesis induced by PDGF. Similarly, both UFH and LMWH inhibited the activation of extracellular signal-regulated kinase (ERK-1/2) by FXa, thrombin and FCS, but not by PDGF. This indicates that heparins can influence cellular signaling in SMC via an antithrombin-II (AT-III)-independent mechanism. The inhibition of ERK-1/2 correlated with the inhibition of mitogenesis by the heparins. Thus, the inhibition of ERK-1/2 phosphorylation by heparins might predict an antimitogenai response in this system.     

Recurrent cardiac ischemic events early after discontinuation of short-term heparin treatment in acute coronary syndromes: results from the Thrombolysis in Myocardial Infarction (TIMI) 11B and Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) studies

OBJECTIVES: The aim of this study was to determine whether discontinuation of low-molecular-weight heparin (LMWH) treatment results in a clustering of cardiac ischemic events as previously observed after cessation of unfractionated heparin (UFH) in acute coronary syndrome (ACS) patients. BACKGROUND: Clinical trials in patients with ACS have shown early recurrent ischemic events after discontinuation of UFH treatment. We analyzed whether LMWH cessation also results in early ischemic recurrence events and if continuation of a fixed-dose LMWH prevents this complication. METHODS: The combined incidence of death, myocardial infarction, or urgent revascularization in the first seven days after discontinuation of UFH (n = 3,012), short-term enoxaparin 1 mg/kg subcutaneously twice a day (n = 2,011), and short-term enoxaparin followed by prolonged enoxaparin 60 mg subcutaneously twice a day (n = 1,075) was analyzed from the combined Thrombolysis In Myocardial Infarction (TIMI) 11B/Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) database in a per patient analysis. RESULTS: The cessation of both UFH and short-term enoxaparin resulted in a similar clustering of recurrent ischemic events on the first day, with an incidence of the primary end point of 2.8% in both groups. Of all recurrent events in the first week after cessation, 40% occurred in the first 24 h. The continuation of a fixed-dose enoxaparin treatment prevented this early excess, with a first day incidence of 0.4% (p < 0.0001). The TIMI risk score characteristics predicted the incidence of early rebound ischemic events. CONCLUSIONS: There is significant clustering of recurrent ischemic events within 24 h after cessation of both short-term UFH and enoxaparin treatment, and patients should be carefully monitored during that period. This early rebound may be prevented by continuation of a fixed dose of enoxaparin.     

Rebound thrombin generation after heparin therapy in unstable angina. A randomized comparison between unfractionated and low-molecular-weight heparin

OBJECTIVES: This study compared rebound coagulation in patients with acute coronary syndrome patients after discontinuation of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). BACKGROUND: Up to a quarter of patients hospitalized for unstable angina experience recurrent ischemia after discontinuation of UFH or LMWH therapy, which may be the result of rebound coagulation activation and subsequent thrombosis. It is unknown whether UFH and LMWH differ in this respect. METHODS: We randomized 71 patients admitted with unstable angina to intravenous UFH or subcutaneous LMWH (dalteparin) and measured plasma markers of coagulation before, during, and after treatment. RESULTS: A complete series of measurements was obtained in 59 patients. Plasma prothrombin fragment 1+2 (F(1+2)) levels decreased in both groups during treatment. After loss of therapeutic plasma drug levels, F(1+2) increased (within 3 h) to a maximum level at 12 to 24 h that was higher than before or during treatment in both groups (p < 0.0001). In both groups, F(1+2) levels remained higher than pretreatment up to 24 h after discontinuation. Similarly, thrombin-antithrombin (TAT) levels exceeded treatment and pretreatment levels, at a slower rate after dalteparin than after UFH. However, after dalteparin a higher peak value of TAT was observed. CONCLUSIONS: Rebound coagulation activation occurs within hours after discontinuation of both UFH and dalteparin. With both drugs, thrombin generation is significantly greater after treatment than before or during treatment. A longer duration or weaning of treatment, or continuation with another anticoagulant treatment, may reduce rebound coagulation activation and ischemic events.     

Low-molecular-weight heparin versus unfractionated heparin in the treatment of patients with acute pulmonary thromboembolism

BACKGROUND: Low-molecular-weight heparin (LMWH) appears to be as effective as unfractionated heparin (UFH) for both treatment and prophylaxis of deep vein thrombosis (DVT), but limited data are available for its use in acute pulmonary thromboembolism (PTE). OBJECTIVE: To determine whether enoxaparin, a LMWH, was clinically as efficient and safe as UFH in patients with a diagnosis of acute PTE. MATERIAL AND METHODS: After exclusion of those with massive forms, 59 patients with acute PTE were randomly assigned to either subcutaneous enoxaparin given twice daily (1 mg/kg/dose) or adjusted dose intravenous UFH. Oral anticoagulant treatment was begun on the second day and was given for at least 6 months. We compared the treatment regimens at day 8 and day 90 with respect to a combined end point of major bleeding, recurrent venous thromboembolism (VTE), and death. RESULTS: In the first 8 days of treatment, 1 of 30 patients assigned to receive UFH (3.3%) reached one of the end points (recurrence), as compared with none of 29 patients assigned to enoxaparin. Statistically this difference was not significant (p = 0.508). By day 90, 3 patients assigned to UFH (10%) had symptomatic recurrent VTE, as compared with 1 patient assigned to enoxaparin (3.4%). There was neither major bleeding nor death in the study groups. There was an absolute difference of 6.4 percentage points between the two treatment groups, but the difference was statistically not significant (p = 0.318). CONCLUSION: Initial subcutaneous treatment with enoxaparin appeared to be as effective and safe as UFH in acute PTE.     

The use of antithrombotics for acute coronary syndromes in the emergency department: considerations and impact

Evidence-based guidelines for the management of acute coronary syndromes (ACS) identify a central role for unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). A recent study has suggested that interchanging between UFH and LMWH during the course of treatment may be associated with a worse outcome than continued therapy with either form of heparin. Because this has important implications for physicians in the emergency room, this review examines the current evidence for the efficacy and safety of heparins in ACS. In patients with acute myocardial infarction, several studies have shown that LMWHs represent an effective alternative to UFH as an adjunct to thrombolytic therapy and are not associated with an increased risk of major bleeding. In patients with unstable angina or non-ST-segment elevation myocardial infarction, the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events) and TIMI 11B (Thrombolysis in Myocardial Infarction 11B) trials have shown that the LMWH enoxaparin significantly reduces the risk of cardiovascular events, compared with UFH, whereas other trials have shown that the combination of enoxaparin and a glycoprotein IIb/IIIa antagonist is not associated with an excess risk of bleeding. Recently, newer agents such as fondaparinux and bivalirudin have shown equivalent efficacy to the heparins with less bleeding and appear clinically attractive. Care paths for the use of antithrombotic therapy in patients with ACS are presented based on current US management guidelines and available clinical evidence.     

Pharmacokinetic and pharmacodynamic characterization of a medium-molecular-weight heparin in comparison with UFH and LMWH

Despite the well-established medical use of heparins, the question arises whether the efficacy-safety ratio of the available heparins can still be improved. Therefore, a medium-molecular-weight heparin (MMWH), a new heparin with an average molecular weight of 10.5 kDa and a narrow molecular weight range (9.5 to 11.5 kDa) was developed. Its in vitro activities amount to 174.9 anti-factor Xa (aXa) U/mg and 170.0 antithrombin (aIIa) U/mg. In the presented randomized, double-blind, cross-over study in healthy volunteers, the pharmacokinetics and pharmacodynamics of MMWH are compared with those of an unfractionated heparin (UFH) and a low-molecular-weight heparin (LWMH; enoxaparin). After subcutaneous administration of 9000 aXa-U of either heparin in 16 volunteers, the prolongation of the activated partial thromboplastin time (aPTT), the aXa activity, and the aIIa activities were determined at 11 time points spread over 24 hours after injection. The ex vivo analysis revealed striking pharmacodynamic and pharmacokinetic differences between the three heparins. UFH had the lowest bioavailability regarding the aPTT, aXa, and aIIa activities. Enoxaparin exhibited only low aIIa activity but the highest aXa activity. Unlike UFH and enoxaparin, MMWH showed a high recovery of aIIa activity, which suggests that it combines the high potency to inhibit thrombin that characterizes UFH with the high bioavailability of the LMWHs. Consequently, substantially lower doses are needed to bring about effects comparable to those of UFH and LMWH.     

Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis.

AIMS: To determine whether the low-molecular weight heparin enoxaparin remains favourable when compared with unfractionated heparin (UFH) among patients with acute coronary syndromes (ACS) when incorporating efficacy and safety of these adjunctive therapies using a net clinical endpoint. METHODS AND RESULTS: We performed a meta-analysis of randomized trials of enoxaparin vs. UFH in ST-elevation-MI (STEMI) or non-ST-elevation-ACS (NSTEACS) (n = 49,088 patients in 12 trials). The net clinical endpoint was defined as death, MI, or major bleeding by 30 days. Death or myocardial infarction (MI) was significantly reduced with enoxaparin when compared with UFH (9.8 vs. 11.4%, OR 0.84, P < 0.001). The net clinical endpoint occurred less frequently with enoxaparin than UFH (12.5 vs. 13.5%, OR 0.90, P = 0.051). Major bleeding was higher with enoxaparin (4.3 vs. 3.4%, OR 1.25, P = 0.019). Among STEMI trials, the net clinical endpoint was significantly lower with enoxaparin (OR 0.84, P = 0.015), but there was no difference in NSTEACS trials (OR 0.97). CONCLUSIONS: When compared with UFH, enoxaparin was associated with superior efficacy as adjunctive antithrombin therapy among >49 000 patients across the ACS spectrum. Although bleeding was increased with enoxaparin, this increase was offset by a reduction in death or MI. The net clinical benefit in favour of enoxaparin was evident among the STEMI population and was neutral among the NSTEACS population.     

Low molecular weight heparin and non valvular atrial fibrillation

Low molecular weight heparin (LMWH) are obtained through chemical or enzyme depolymerisation of unfractioned heparins (UFH). LMWHs present several advantages over UFH: they exhibit a smaller interindividual variability of the anticoagulant effect, they have a greater bioavailability, a longer plasma half-life and do not require monitoring of the anticoagulant effect. LMWH have restrictive indications in AF patients, cardioversion (II level C and TEE for ACC/AHA/ESC and 2C for ACCP guidelines) or use as a bridge therapy (IIB, level C for ACC/AHA/ESC). The ACE study (Anticoagulation for cardioversion using enoxaparin), showed a reduction, though not statistically significant, of 42% of the composite end point (embolic event, major bleeding and death) 2.8% under enoxaparin vs. 4.8 % under conventional treatment, relative risk 0.58, CI 95% 0.23-1.46). Other studies, using dalteparin, confirmed that an anticoagulant treatment using LMWH followed by warfarin was at least as good as conventional management. ACUTE II (Assessment of cardioversion using transesophageal echochardiography), a randomized multicenter trial, compared the efficacy and tolerance of enoxaparin (1 mg/kg every 12 hours) and UFH in 155 patients eligible for a TEE-guided cardioversion. These patients were administered LMWH or UFH for 24 hours before TEE or cardioversion. There were no significative differences regarding the incidence of the study end points, in particular stroke and bleeding, and no death occurred. HAEST (Heparin in acute embolic stroke trial), a randomized, placebo-controlled, double blind trial failed to show the LMWH superiority over aspirin in patients with acute ischemic stroke and atrial fibrillation. Finally, LMWH have been proposed as a bridge therapy in patients under chronic VKA prior to surgery or invasive procedures. This strategy resulted in a low rate of thromboembolic events and major bleedings.     

Blocking inhibition of prothrombinase by tissue factor pathway inhibitor alpha: a procoagulant property of heparins

Unfractionated heparin (UFH) has procoagulant activity in antithrombin/heparin cofactor II (HCII)‐depleted plasma. UFH prevents tissue factor pathway inhibitor alpha (TFPIα) from inhibiting the procoagulant enzyme complex, prothrombinase, providing a possible mechanism for its procoagulant activity. The procoagulant potential of UFH and various low molecular weight heparins (LMWHs) were characterized for TFPIα dependence, using thrombin generation assays performed with antithrombin/HCII‐depleted plasma. UFH, the LMWHs enoxaparin and dalteparin, and the low anticoagulant LMWH 2‐O, 3‐O desulphated heparin (ODSH) all promoted thrombin generation, but fondaparinux did not, and this activity was blocked by a TFPIα antibody. UFH, enoxaparin, and dalteparin were anticoagulant in reactions containing 1–2% normal plasma. In prothrombinase activity assays, UFH, enoxaparin, dalteparin and ODSH blocked prothrombinase inhibition by TFPIα, while again fondaparinux did not. In both the plasma and purified assays, LMWHs displayed greater procoagulant potential than UFH, even when normalized to saccharide concentration. These biochemical data reveal that UFH and LMWHs, but not fondaparinux, block prothrombinase inhibition by TFPIα, thereby producing their paradoxical procoagulant activity observed in the absence of antithrombin/HCII. The findings may help to understand the complex pathophysiology and treatment of patients that are simultaneously bleeding and clotting, such as those with disseminated intravascular coagulation.     

Inhibition of coagulation and platelet adhesion to extracellular matrix by unfractionated heparin and a low molecular weight heparin

Summary In 7 healthy volunteers, the effect of a single i.v. injection of 52 mg (7,500 IU) of an unfractionated heparin (UFH) and of 52.5 mg (5,000 anti XaU) of a low molecular weight heparin (LMWH) on coagulation parameters and platelet function has been studied. Thrombininduced platelet aggregation was inhibited after the injection of both heparins. There was no significant change of ADP or collagen-induced aggregation after LMWH or UFH. Platelet adhesion to bovine extracellular matrix was not inhibited by UFH but was significantly reduced after addition in vitro and ex vivo after administration of LMWH. Further investigation should establish the time course of LMWH effects on platelet adhesion. A long duration of this effect could be partially correlated with the antithrombotic effects of LMWH.