Ao X

Fig. 16. Comparison of the inhibitory effects of argatroban against fluid phase (circles) and clot-bound (squares) thrombin activity. Thrombin or fibrin clots were incubated with the chromogenic synthetic substrate S2238 in the presence or absence of argatroban. p-nitro-aniline (p-NA) release was then assayed and the percent inhibition ofp-na release was calculated for each inhibitor concentration. Reproduced with permission from ref. 156.

ICC 1000 10000

ICC 1000 10000

Fig. 17. Mechanism of action of heparin vs LMWH. UFH induces a conformational chane in ATIII, allowing the latter to more readily inhibit thrombin and factor Xa. In the case of thrombin inhibition, UFH also acts as a catalytic template, forming a ternary complex with thrombin and ATIII and accelerating their interaction by greater than 1000-fold. In contrast, LMWH does not contain a sufficient number of polysaccharide residues to act as a catalytic template for ATIII and thrombin, but still can induce the conformational change in ATIII and therefore is primarily a factor Xa inhibitor.

Fig. 17. Mechanism of action of heparin vs LMWH. UFH induces a conformational chane in ATIII, allowing the latter to more readily inhibit thrombin and factor Xa. In the case of thrombin inhibition, UFH also acts as a catalytic template, forming a ternary complex with thrombin and ATIII and accelerating their interaction by greater than 1000-fold. In contrast, LMWH does not contain a sufficient number of polysaccharide residues to act as a catalytic template for ATIII and thrombin, but still can induce the conformational change in ATIII and therefore is primarily a factor Xa inhibitor.

primarily by inhibition of thrombin generation that is achieved by inactivating factor Xa (Fig. 17) (181). Like UFH, LMWH cannot inactivate clot-bound thrombin (182), nor can it inactivate factor Xa once it is part of the prothrombinase complex. LMWHs are resistant to inactivation by platelet factor 4 (183), are less bound by acute phase reactants and vascular endothelial cells, thereby resulting in a more predictable anticoagulation effect (128,179), and are far less likely to trigger HIT (184) (although in a patient with HIT and antiplatelet antibodies LMWH may cross-react). The LMWHs have different chemical characteristics, different degrees of anti-Xa:anti-IIa activity, and different effects on tissue factor pathway inhibitor, and thus, should not be considered as a single class of agents (185). The two most-studied LMWHs are enoxaparin (Lovenox) and dalteparin (Fragmin), which have anti-Xa:anti-IIa activity ratios of 3.8 and 2.7, respectively.

Clinical Data

Several studies have shown improved angiographic results in patients receiving LMWH compared with UFH. In the Biochemical Markers in Acute Coronary Syn dromes II (BIOMACS II) study, 101 patients with ST-elevation myocardial infarction were treated with streptokinase and aspirin and were randomized to subcutaneous dal-teparin or placebo. There was a trend toward higher rates of TIMI flow grade 3 in patients treated dalteparin (68 vs 51%, p = 0.10) and a lower rate of recurrent ischemic episodes (16 vs 38%, p = 0.04).

Dalteparin (30 U/kg IV bolus and 90 U/kg subcutaneously, followed by 120 U/kg sub-cutaneously 2X daily for 4-7 d) was compared to IV UFH (for 48 h) in 439 patients undergoing fibrinolysis with alteplase in the ASSENT Plus trial (186). Late angiography after 4-7 d revealed higher rates of patency (87 vs 76%, p = 0.006) and a trend towards modestly higher rates of TIMI flow grade 3 (69 vs 63%, p = 0.16).

The LMWH enoxaparin was studied in three angiographic trials. In the Acute Myocardial Infarction-Streptokinase (AMI-SK) trial, 496 patients receiving streptokinase for ST-elevation myocardial infarction were randomized to enoxaparin (30 mg IV bolus, followed by 1 mg/kg subcutaneously 2X daily) or placebo (187). Late angiography (d 5-10) revealed higher rates of patency (87.6 vs 71.7%,p < 0.001) and TIMI flow grade 3 (70.3 vs 57.8%,p < 0.01). Complete ST segment resolution was also higher at both 90 min (15.7 vs 11.1%, p = 0.012) and at 180 min (36.3 vs 25.4%, p = 0.004).

In the 400 patients undergoing fibrinolysis with alteplase in HART-II, enoxaparin (30 mg IV bolus, followed by 1 mg/kg subcutaneously every 12 h) was compared to iv UFH (188). After 90 min, treatment with enoxaparin resulted in modest trends towards higher rates of patency (80.1 vs 75.1%) and TIMI flow grade 3 (52.9 vs 47.6%) at 90 min. Patients with a patent infarct-related artery at 90 min underwent follow-up angiography at 5-7 d. In this subgroup, treatment with enoxaparin was associated with a trend towards lower rates of reocclusion (5.9 vs 9.8%).

In the ENTIRE study, several enoxaparin regimens (with and without a bolus; different subcutaneous maintenance doses) were compared to iv UFH. There were no significant differences between the enoxaparin regimens. Compared to UFH, enoxaparin resulted in similar rates of TIMI flow grade 3, but a trend towards higher rates of complete ST segment resolution by 180 min. Among patients receiving full dose TNK-tPA, ischemic events (death, nonfatal myocardial infarction) were less frequent in patients receiving enoxaparin (4.4 vs 15.9%, p = 0.005).

As detailed above, ASSENT-3 was a phase III trial comparing three pharmacologic reperfusion regimens: full-dose TNK-tPA plus UFH, full-dose TNK-tPA plus the LMWH enoxaparin, or reduced-dose TNK-tPA plus abciximab (92). The 30-d mortality rates did not statistically significantly differ between the groups (5.4% for enoxaparin, 6.6% for abciximab, and 6.0% for UFH, p = 0.25) (Fig. 18). However, the rate of the composite end point of death, in-hospital reinfarction, or in-hospital refractory ischemia was lower in the enoxaparin and abciximab arms compared with the unfrac-tionated heparin arm (11.4 and 11.1 vs 15.4%, p < 0.001). Major bleeding rates were 3.0% in the enoxaparin arm, 4.3% in the abciximab arm, and 2.2% in the unfractionated heparin arm (p = 0.0005).

Thus, compared with using UFH, adjunctive anticoagulation in fibrinolysis using LMWH appears to offer a reduction in ischemic events with only a minimal excess in bleeding. This is in contrast to combining a GP IIb/IIIa inhibitor with a reduced-dose fibrinolytic, which was also associated with a reduction in ischemic events, but with a significant excess in bleeding. However, as discussed above, the latter option does offer an easier transition to the cardiac catheterization laboratory. Despite several studies sug-

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