The Role of Thrombosis in Ischemic Heart Disease
Although acute coronary syndromes are divided for the purpose of treatment assignment into unstable angina, non–ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI), the clinical manifestations in all three instances usually are triggered by disruption of atherosclerotic plaque and the development of superimposed thrombus. Arterial thrombi, which form under high shear conditions, consist of platelet aggregates held together by small amounts of fibrin. After plaque disruption, platelets adhere to newly-exposed subendothelial matrix components, particularly collagen and von Willebrand factor, via constitutively expressed receptors ( Fig. 22-1 ). Adherent platelets become activated and recruit additional platelets by synthesizing thromboxane A 2 and releasing adenosine diphosphate (ADP). Platelet activation induces conformational changes in glycoprotein (GP) IIb/IIIa, one of the most abundant receptors on the platelet surface. By binding fibrinogen or, under high shear conditions, von Willebrand factor, conformationally activated GP IIb/IIIa cross-links adjacent platelets, resulting in platelet aggregation.
Damage to the vascular wall also exposes tissue factor (TF)-expressing cells to blood. Lipid-laden macrophages in the core of atherosclerotic plaques are particularly rich in TF, thereby explaining the propensity for thrombus formation at sites of plaque disruption. Exposed TF binds activated factor VII, which is found in small amounts in plasma as well as factor VII. Once bound to TF, factor VII can undergo autoactivation, thereby augmenting the local concentration of factor VIIa.
The factor VIIa/TF complex, also known as extrinsic tenase, activates factors IX and X, leading to the generation of factors IXa and Xa, respectively. Factor IXa binds to factor VIIIa on the surface of activated platelets to form intrinsic tenase, a complex that also activates factor X. Factor Xa, generated through the extrinsic and intrinsic tenase complexes, assembles on the surface of activated platelets as part of the prothrombinase complex (factor Xa, factor Va, and calcium) that converts prothrombin to thrombin. Thrombin converts fibrinogen to fibrin, and activates factor XIII, which by cross-linking the fibrin network, stabilizes the platelet/fibrin thrombus. Thrombin also triggers thrombus growth via several mechanisms. It amplifies its own generation by feedback activation of factors V and VIII and it also serves as a potent platelet agonist. The resultant intraluminal thrombus superimposed on disrupted atherosclerotic plaque impairs blood flow.
Because arterial thrombosis involves activation of coagulation in addition to platelet aggregation, most current strategies for its prevention and treatment focus on both attenuating thrombin generation and inhibiting platelet aggregation. Coronary arteries occluded by thrombus can have blood flow restored by mechanical or pharmacologic means. Mechanical reperfusion is effected by balloon angioplasty with or without coronary stent insertion, whereas pharmacologic reperfusion therapy involves the administration of fibrinolytic drugs to degrade the fibrin component of the coronary thrombus.
Antithrombotic therapy is a mainstay of treatment of acute coronary syndromes. Antithrombotic drugs fall into three categories: antiplatelet agents, anticoagulants, and fibrinolytic drugs ( Fig. 22-2 ). Antiplatelet agents inhibit platelet activation and/or aggregation, whereas anticoagulants target one or more of the clotting factors, thereby attenuating fibrin formation. As indicated earlier, fibrinolytic drugs are administered to degrade fibrin.
This chapter focuses on anticoagulants. Currently available anticoagulants include parenteral agents and orally active drugs. The parenteral agents are unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and fondaparinux. Although LMWH and fondaparinux represent advances over UFH, they still must be administered parenterally. The only orally available anticoagulants licensed for long-term use are the vitamin K antagonists. Although effective, these drugs have a narrow therapeutic window and an unpredictable dose response, necessitating frequent monitoring to ensure that a therapeutic effect is achieved. Focusing on anticoagulants used in the management of acute coronary syndromes, their mechanisms of action and recent clinical trial data supporting their use will be reviewed. Particular attention will be paid to more recently developed anticoagulants and the opportunities presented by these agents.
Anticoagulants
Currently available anticoagulants include both parenteral and oral agents. Rapidly acting parenteral agents are typically used for the initial treatment of arterial thromboembolism, whereas oral agents are used for long-term therapy. Anticoagulants can inhibit initiation or propagation of coagulation. Agents that target the factor VIIa/TF complex block the initiation of coagulation, whereas propagation of coagulation can be blocked by drugs that target factors IXa or Xa, or by inactivation of factors Va or VIIIa, key cofactors in coagulation. Thrombin inhibitors prevent fibrin formation, block thrombin-mediated feedback activation of factors V and VIII, and attenuate thrombin-induced platelet aggregation ( Fig. 22-3 ).
Thrombin Inhibitors
The procoagulant effects of thrombin can be blocked either by inactivating the enzyme itself or by preventing its generation from precursor coagulation proteins. Indirect thrombin inhibitors such as UFH and LMWH activate the naturally occurring thrombin inhibitor, antithrombin. Direct thrombin inhibitors act in an antithrombin-independent manner by binding directly to thrombin and blocking its interaction with its substrates. The most extensively studied direct thrombin inhibitors are hirudin and bivalirudin.
Indirect Thrombin Inhibitors
Unfractionated Heparin
Mechanism of Action
Unfractionated heparin acts as an anticoagulant by activating antithrombin. A pentasaccharide sequence, randomly distributed along one third of the heparin chains, mediates the interaction between heparin and antithrombin ( Fig. 22-4 ). Upon binding, heparin induces a conformational change in the reactive site loop of antithrombin that changes it from a slow thrombin and factor Xa inhibitor to a very rapid inhibitor of these coagulation enzymes. To enhance thrombin inhibition by antithrombin, heparin must bind simultaneously to the enzyme and the inhibitor, thereby promoting formation of a ternary thrombin/antithrombin/heparin complex. , Only pentasaccharide-containing chains that contain at least 13 additional saccharide units and have a molecular mass of 5400 or greater are of sufficient length to perform this bridging reaction. In contrast, because bridging is unnecessary to enhance the inactivation of factor Xa by antithrombin, pentasaccharide-containing chains of any length will catalyze this reaction.
Indications
Acute Myocardial Infarction with Thrombolysis
The role of subcutaneous UFH after thrombolysis in aspirin-treated patients has been examined in three large multicenter randomized trials. Together, these studies indicate that high-dose subcutaneous UFH (12,500 units twice daily, beginning 4 to 12 hours after initiation of thrombolytic therapy) produces no statistically significant reduction in long-term mortality, although there may be a reduction in deaths during the treatment period. Moreover, UFH produces a small, but statistically significant, increase in major bleeds. The substitution of intravenous heparin for subcutaneous heparin provides no advantage in terms of reducing mortality and nonfatal stroke in patients receiving streptokinase. Based primarily on the data suggesting an early mortality benefit, the American College of Chest Physicians Consensus Guidelines provides a weak recommendation for the use of intravenous UFH in patients receiving streptokinase.
The results of small patency trials and the first GUSTO trial have been invoked to support the routine early administration of intravenous UFH in patients given other lytic agents (e.g., alteplase, anistreplase, reteplase, or tenecteplase). It is recommended that such patients be treated with heparin for 48 hours. Continuation beyond this time should be considered only in patients at high risk of systemic or venous thromboembolism. More recent meta-analyses have shown no net mortality benefit associated with intravenous UFH when used in conjunction with thrombolytics and full-dose aspirin. , Additionally, the early termination of both the TIMI-9A and GUSTO IIa trials because of excessive major bleeding in patients receiving intravenous UFH (despite the fact that the heparin dose used was only 20% higher than that used in previous trials), emphasizes the potential hazards of high-dose UFH in this setting. This concern is reflected in subsequent recommendations to use a weight-based dosing nomogram with a reduced intensity of UFH treatment in patients receiving thrombolytic therapy. ,
Unless a specific contraindication exists, patients undergoing coronary thrombolysis who do not receive high-dose UFH should be given thromboprophylaxis with low-dose heparin therapy until ambulatory.
Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction
There is considerable confusion and controversy regarding recommendations for the use of UFH in patients with unstable angina or NSTEMI. Interpretation of data is difficult because of variations in regimens, patient population heterogeneity, and small trial size. A number of small trials have shown limited benefit when heparin is added to aspirin in these patients. A meta-analysis of these trials demonstrated a 33% reduction in the relative risk of MI or death with the addition of intravenous UFH to aspirin in patients with unstable angina. Although this difference was not statistically significant, it suggests there may be a benefit. Current practice guidelines, therefore, support the use of intravenous UFH in addition to aspirin for treatment of unstable angina.
Percutaneous Coronary Interventions
Intravenous UFH has been used since the advent of percutaneous coronary interventions to prevent arterial thrombus formation at the site of arterial injury and to reduce the thrombogenicity of catheter equipment and guide wires used during the procedure. , There is no evidence to support the routine use of postprocedural heparin in patients undergoing uncomplicated coronary angioplasty. ,
Limitations of Unfractionated Heparin
The discontinuation of UFH treatment in patients with unstable angina or NSTEMI is associated with a clustering of recurrent ischemic events , and abrupt vessel closure after successful coronary angioplasty occurs in up to 10% of patients, despite the use of high-dose heparin in addition to aspirin. This reactivation of the thrombotic process after heparin discontinuation has been attributed, at least in part, to the inability of the heparin/antithrombin complex to inactivate thrombin bound to fibrin, , fibrin degradation products, and activated factor X (factor Xa) bound to activated platelets trapped within the thrombus. , By activating prothrombin, bound factor Xa increases the amount of thrombin available to bind to fibrin. Because thrombin bound to fibrin remains enzymatically active and protected from inactivation, it can trigger thrombus growth by locally activating platelets and amplifying coagulation.
Nonspecific binding of UFH to endothelial cells, plasma proteins, or proteins released from activated platelets at the site of plaque rupture results in reduced bioavailability, a dose-dependent half-life, and an unpredictable anticoagulant response. This necessitates careful laboratory monitoring when UFH is given in therapeutic doses.
Advantages of Unfractionated Heparin
UFH does have advantages over other anticoagulants. First, its anticoagulant effects can be rapidly and completely neutralized by protamine sulfate, a useful characteristic if bleeding occurs or urgent cardiopulmonary bypass is required. Second, UFH is not cleared by the kidneys and, therefore, can be used in patients with renal insufficiency.
Dosages
Because the anticoagulant response to UFH varies among patients, laboratory monitoring is essential to ensure that adequate anticoagulation is achieved. UFH is usually monitored using the activated partial thromboplastin time (aPTT). The therapeutic aPTT range, which targets a minimum and a maximum anticoagulant effect, differs depending on the aPTT reagent and coagulometer used to perform the test. Several studies have demonstrated that the use of a nomogram to adjust heparin doses improves the likelihood of obtaining a therapeutic effect. ,
In general, the doses of heparin recommended for treatment of acute coronary syndromes are lower than those to treat venous thromboembolism. Although it is accepted that the therapeutic aPTT range for treatment of venous thromboembolism corresponds to a heparin level of 0.3 to 0.7 anti-Xa units/mL (0.2 to 0.4 units/mL by protamine titration), the therapeutic range for coronary indications is unknown, but is likely to correspond to heparin levels that are about 10% lower than those needed to treat patients with venous thromboembolism. In patients with unstable angina or NSTEMI, the American College of Cardiology recommends that intravenous UFH be initiated with a bolus of 60 to 70 units/kg to a maximum of 5000 units, followed by an initial maintenance dose of 12 to 15 units/kg/hour (maximum of 1000 units/hour). , Patients with acute MI treated with thrombolytics should receive even lower doses. Here the recommended bolus of UFH is 60 units/kg to a maximum dose of 4000 units at the initiation of thrombolysis, followed by an initial maintenance infusion of 12 units/kg/hour, to a maximum dose of 1000 units. , It is suggested that UFH be continued for 48 hours post thrombolysis. Prophylactic doses of heparin range from 5000 to 7500 units subcutaneously twice daily.
Percutaneous Coronary Interventions
Monitoring of heparin anticoagulation in patients undergoing percutaneous coronary interventions is performed using the activated clotting time (ACT), rather than the aPTT because of the need for point-of-care results and because the large doses of heparin used in these settings produce immeasurably high aPTT results. Patients undergoing percutaneous coronary angioplasty (PTCA) or stent placement without concomitant use of GP IIb/IIIa antagonists should receive a heparin bolus of 60 to 100 units/kg prior to procedure. Incremental boluses should be given to maintain the ACT at 250 to 350 seconds during procedure. The sheath should be removed 4 to 6 hours after an uncomplicated PTCA. Continuation of heparin therapy depends on whether a thrombus or large vessel wall dissection is detected at the end of the procedure. In patients receiving concomitant GP IIb/IIIa antagonists, the heparin bolus should be reduced to 50 to 70 units/kg and incremental boluses given to maintain the ACT between 200 and 250 seconds.
Side Effects
The major complication of UFH is hemorrhage. The absolute risk of hemorrhage depends on the total dose of heparin, the patient’s age, the tendency for bleeding, and the concomitant use of thrombolytic drugs, antiplatelet agents, and oral anticoagulants. The risk of major hemorrhage ranges from 1% to 5% when heparin is added to aspirin in low-risk patients, and is as high as 19% in heparin-treated patients receiving concomitant thrombolytic therapy.
Another complication is heparin-induced thrombocytopenia (HIT), which usually develops between 5 and 15 days after heparin is initiated, although it can occur within hours in patients previously exposed to heparin. Arterial or venous thrombosis has been estimated to occur in up to 50% of patients with this syndrome. Venous thrombosis is more common, but arterial thrombosis that includes MI, ischemic stroke, or limb ischemia can occur in patients with HIT.
HIT is initiated when heparin binds to platelets, causing platelet activation and release of platelet factor 4. Heparin binds to platelet factor 4, alters its conformation, and induces the formation of antibodies against the heparin/platelet factor 4 complex. , Simultaneous binding of these antibodies, usually of the IgG type, to the heparin/platelet factor 4 complex and to platelet Fc receptors causes platelet activation. Thrombosis is thought to be triggered by immune complex-mediated platelet activation, which causes platelet microparticle formation. By serving as a phospholipid surface on which clotting factors assemble, these microparticles can promote thrombin generation, thereby triggering thrombosis.
When given for longer than 1 month, heparin may cause osteoporosis. , Allergic reactions, alopecia, skin necrosis, and hypoaldosteronism are rare complications of UFH therapy.
Contraindications and Drug Interactions
Therapeutic doses of UFH should not be given to patients who are actively bleeding or who are at high risk of life-threatening bleeding diatheses ( Box 22-1 ). UFH should not be given to patients with a history of HIT.
BOX 22-1 Absolute
- •
Active bleeding
- •
Severe bleeding diathesis
- •
Severe thrombocytopenia
- •
Recent neurosurgery, ocular surgery (excluding cataract surgery), or intracranial bleed
Relative
- •
Moderate thrombocytopenia
- •
Bleeding diathesis
- •
Brain metastases
- •
Recent major trauma
- •
Recent major abdominal surgery (<1 or 2 days)
- •
Gastrointestinal or genitourinary bleeding within the past 14 days
- •
Endocarditis
- •
Severe hypertension
- •
Systolic blood pressure > 200 mm Hg and/or diastolic blood pressure > 120 mm Hg at presentation
Concomitant use of oral anticoagulants, antiplatelet agents, fibrinolytic drugs, and GP IIb/IIIa receptor antagonists increases the risk of hemorrhage. ,
Low-Molecular-Weight Heparin
Mechanism of Action
Low-molecular-weight heparins (LMWHs), which have replaced UFH for most indications, are fragments of UFH produced by chemical or enzymatic depolymerization processes that yield glycosaminoglycan chains with a mean molecular mass of approximately 5000 daltons. Like UFH, LMWHs act as anticoagulants by activating antithrombin via a pentasaccharide sequence found on about 20% of these smaller heparin chains (see Fig. 22-4 ). LMWH exhibits less activity against thrombin than against factor Xa because less than half of the heparin chains are long enough to bridge antithrombin to thrombin. , Since heparin catalysis of factor Xa inhibition by antithrombin does not require bridging between factor Xa and antithrombin, the smaller pentasaccharide-containing chains in LMWH retain their ability to catalyze factor Xa inhibition.
Because binding to endothelial cells and to plasma proteins is chain-length dependent, with longer heparin chains having higher affinity than shorter chains, LMWHs bind less avidly to plasma proteins , and the endothelium than UFH. Consequently, LMWHs produce a more predictable dose-response , than UFH, and have a longer half-life. With these pharmacokinetic advantages, routine coagulation monitoring of LMWHs is unnecessary. The advantages of LMWH over UFH are summarized in Table 22-1 . Because LMWHs are cleared principally by the kidneys and their biologic half-life is prolonged in patients with renal failure, monitoring is necessary when therapeutic doses are given to patients with renal insufficiency. In these individuals, the dose of LMWH should be adjusted to achieve a peak anti-factor Xa heparin concentration of 0.5 to 1.2 units/mL, depending on whether once or twice daily dosing is used and on the type of LMWH utilized. Monitoring may also be advisable in obese patients, although weight adjusted dosing usually results in therapeutic anti-factor Xa levels.
| Advantage | Effect | Clinical Consequence |
|---|---|---|
| Better bioavailability | Higher drug levels achieved after subcutaneous injection | Subcutaneous administration for prophylaxis or treatment |
| Reduced binding to proteins | More predictable anticoagulant response | Routine monitoring is unnecessary |
| Reduced binding to and clearance by endothelial cells and macrophages | Clearance predominantly by renal mechanisms | Longer plasma half-life permits once-daily dosing |
| Reduced binding to osteoblasts | Reduced activation of osteoclasts | Lower incidence of osteopenia and less risk of heparin-associated osteoporosis and fracture with prolonged treatment |
| Reduced affinity for platelets and platelet factor 4 | Less platelet activation with reduced release of platelet factor 4; reduced formation of complexes of heparin/platelet factor 4 | Reduced incidence of heparin-induced thrombocytopenia |
Indications
Myocardial Infarction with Thrombolysis
There is limited experience with LMWH in STEMI. When compared with placebo in patients receiving thrombolysis in four small trials, LMWH reduced reinfarction but was associated with an increased risk of major bleeding, including intracranial hemorrhage. In the CREATE trial in which 15,570 patients with ST-segment elevation or new left bundle branch block presenting within 12 hours of symptom onset were randomized to weight-adjusted reviparin or placebo, in addition to usual treatment with fibrinolysis and antiplatelet therapy, treatment with LMWH was associated with a reduction in the primary composite outcome of death, myocardial reinfarction, or stroke at 7 days. Again, there was a small but significant excess of hemorrhagic strokes, as well as an increase in the frequency of life-threatening or major bleeding in patients randomized to reviparin. However, overall, the net clinical benefit (composite outcome of death, MI, stroke, and life-threatening hemorrhage at 7 days) remained in favor of reviparin.
A number of small to moderate-sized trials have compared enoxaparin with UFH as an adjunct to thrombolysis and in STEMI patients ineligible for thrombolysis. Overall, enoxaparin therapy was associated with a reduction in reinfarction but an increase in major bleeds, with no overall reduction in mortality. Major bleeding was observed more frequently in patients older than 75 years of age. It has been hypothesized that this was the result of the initial use of a non-weight adjusted intravenous bolus of enoxaparin and the failure to modify enoxaparin dosing according to renal function. Consequently, in the ExTRACT TIMI 25 trial that compared enoxaparin for a median of 7 days with UFH for a median of 2 days in patients receiving fibrinolysis for STEMI, the initial 30-mg intravenous enoxaparin bolus was eliminated and the dose of enoxaparin was adjusted from 1 mg/kg subcutaneously every 12 hours (to a maximum of 100 mg) to 0.75 mg/kg subcutaneously every 12 hours (to a maximum of 75 mg) in patients older than 75 years of age. Additional dose adjustments were made for elevations in baseline creatinine levels. The primary efficacy outcome of all-cause mortality and nonfatal reinfarction at 30 days was significantly lower in the enoxaparin arm than in those receiving UFH. The benefit of enoxaparin was also evident at 48 hours, when both treatments were active. Again there was a significant increase in major and minor bleeds at 30 days in the enoxaparin-treated patients. However, there was no significant difference in the frequency of intracranial hemorrhages between the enoxaparin and UFH-treated groups, and the net clinical benefit (30-day mortality, nonfatal MI, or major bleeding) remained in favor of enoxaparin.
Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction
A number of randomized trials have examined the role of LMWH in aspirin-treated patients with non–ST-segment elevation acute coronary syndromes. When added to aspirin in the acute setting, dalteparin is superior to placebo, but similar to UFH, for prevention of death and MI. In contrast, a brief course of therapy with enoxaparin results in a reduction in the risk of death, MI, and recurrent angina compared with UFH; this reduction is sustained for at least 1 year. Another LMWH, nadroparin, has not been shown to be more effective than UFH in patients with unstable angina or NSTEMI.
The reason for the difference between the results of studies using dalteparin and nadroparin and those using enoxaparin , is uncertain. Dalteparin and nadroparin are depolymerized by different chemical methods from enoxaparin, and all three LMWHs have different molecular weight distributions. However, these differences are unlikely to explain the more favorable results seen with enoxaparin because a more aggressive LMWH regimen (both in terms of anti-Xa and anti-IIa units) was utilized in the study comparing dalteparin with UFH than in the enoxaparin-containing studies. , Although the UFH dosage regimens were similar in all of the studies, the average duration of UFH therapy was shorter than that of LMWH therapy in one of the studies evaluating enoxaparin. Additionally, the event rates in patients assigned UFH were higher in the studies evaluating enoxaparin , than in the trial assessing dalteparin. Although the favorable results with enoxaparin might have been the result of chance, this explanation is less likely given that there are two positive studies with this drug. , In a single-center open-label randomized comparison of two LMWH preparations in which 438 patients with NSTEMI were randomized to receive 100 units/kg of enoxaparin twice daily or 175 units/kg of tinzaparin once daily for up to 7 days in addition to usual care, enoxaparin was superior to tinzaparin in preventing the primary endpoint (death, MI, refractory angina, or recurrence of unstable angina at day 7). , The superiority of enoxaparin was maintained through day 30. The superiority of enoxaparin was primarily driven by differences in the rates of recurrent angina at day 7 and day 30, although there was also a difference in the frequency of MI at day 30. The number of hemorrhagic events was similar in the two groups.
Overall, LMWH is associated with at least as favorable outcomes as UFH in this setting. Given these results, the practical convenience of use, and the reduced risk of HIT, LMWHs appear to be a better choice in this setting than UFH.
The prolonged use of LMWH in patients with unstable angina has been examined in four trials. In the first two, prolonged use of a reduced once-daily dose of dalteparin after day 6 did not provide any additional benefit over aspirin. , Although 3 months of treatment with a higher dose of twice-daily dalteparin significantly reduced the risk of death and MI compared with placebo at 30 days in the FRISC II study, these benefits were not sustained during longer-term follow-up. Similarly, no additional benefit, beyond that seen with in-hospital administration, has been derived from continuing once-daily subcutaneous enoxaparin on an outpatient basis. Given these results, and the increased risk of bleeding complications with extended anticoagulation, the role of outpatient LMWH remains controversial.
The combination of LMWH and GP IIb/IIIa inhibitors has been examined in a number of studies. The results of initial investigations suggested that the combination of LMWH with GP IIb/IIIa inhibitors was likely to be at least as safe and efficacious as UFH plus GP IIb/IIIa antagonists in this patient population. These findings were confirmed in a subsequent multicenter open-label noninferiority study of patients with NSTEMI receiving tirofiban in which 2026 participants were randomized to enoxaparin (1 mg/kg subcutaneously every 12 hours) and 1961 received UFH. Enoxaparin was noninferior (but not superior) to UFH with respect to the primary composite endpoint of death, recurrent MI, or refractory ischemia at 7 days. Rates of bleeding were low and similar in both treatment arms.
Percutaneous Coronary Angioplasty
LMWH is replacing heparin for treatment of patients with non–ST-segment elevation acute coronary syndromes, many of whom will require percutaneous coronary interventions, and there is increasing experience with short-term LMWH in place of UFH in this setting. The safety and efficacy of these procedures do not appear diminished by this substitution.
Monitoring of LMWH levels during percutaneous coronary interventions is difficult and, consequently, empiric dosing strategies have been developed. In the SYNERGY trial, more than 10,000 high risk non–ST-segment elevation acute coronary artery syndrome patients with planned early invasive intervention were randomized to receive UFH or enoxaparin, in addition to routine medications (including aspirin, clopidogrel, and GP IIb/IIIa antagonists). Enoxaparin was given subcutaneously at a dose of 1 mg/kg every 12 hours. For patients randomly assigned to enoxaparin, cardiac catheterization was performed any time after dosing and the sheath was removed at least 6 to 8 hours after the last LMWH dose. If the last dose of enoxaparin was given less than 8 hours before balloon inflation, no additional LMWH was given during percutaneous coronary intervention. However, if the last dose of enoxaparin was given 8 hours or more before balloon inflation, 0.3 mg/kg of enoxaparin was given intravenously before proceeding with intervention. If intravenous enoxaparin was used, the sheath could be removed at least 4 to 6 hours after the additional dose. Dosing of UFH was according to established guidelines. Enoxaparin was non-inferior (but not superior) to UFH with respect to the primary efficacy outcome of all-cause death or nonfatal MI during the first 30 days after randomization. However, there was a modest excess of major (but not severe) bleeding with the enoxaparin strategy.
Short-term administration of LMWH after percutaneous intervention does not appear to reduce the occurrence of early ischemic events or restenosis and, therefore, the extended use of LMWH cannot be recommended for this purpose.
Dosages
In general, when given in treatment doses, LMWH can be given once- or twice-daily subcutaneously in weight-adjusted doses without laboratory monitoring. However, for most available LMWHs, only twice-daily dosing regimens have been evaluated in patients with acute coronary syndromes. For dalteparin, the recommended dose is 120 anti-Xa units/kg twice daily, , whereas for enoxaparin it is 100 anti-Xa units/kg (1 mg/kg) twice daily. , In patients receiving enoxaparin prior to percutaneous intervention, an intravenous bolus of 0.3 mg/kg is suggested if the last enoxaparin dose is administered between 8 and 12 hours before the procedure. For patients with acute STEMI receiving lytic therapy and enoxaparin who are younger than 75 years of age and have normal renal function, an additional initial 30-mg intravenous bolus of enoxaparin is recommended ; however, the bolus is eliminated and the enoxaparin dose reduced to 75 unit/kg every 12 hours for those at least 75 years of age. Based on results of the CREATE trial, if reviparin is used in patients with STEMI receiving thrombolysis, recommended every 12 hourly doses are 3436 units for patients less than 50 kg, 5153 units for those 50 to 75 kg, and 6871 units for those greater than 75 kg. Treatment should be continued for 7 days.
Side Effects and Drug Interactions
Based on results of trials comparing LMWH with UFH in patients with non–ST-segment elevation acute coronary syndromes, LMWH does not increase the risk of major bleeding. In the TIMI-11A trial, patients receiving more than 1 mg/kg (100 U/kg) of enoxaparin subcutaneously twice daily were more likely to develop major hemorrhage. These findings suggest that 1 mg of enoxaparin subcutaneously twice daily represents the maximum dose that can be safety given in this setting. The use of LMWH in patients receiving lytic therapy has been associated with a small absolute excess of serious bleeding compared with that seen in patients receiving UFH, especially in those older than 75 years of age or with renal dysfunction.
Protamine sulfate, widely used as an antidote to neutralize the high doses of UFH administered to patients undergoing cardiopulmonary bypass surgery and to antagonize its hemorrhagic side effects, completely blocks the inhibitory effects of LMWH on thrombin. Because only longer LMWH chains bind protamine sulfate, the anti-Xa activity of LMWH is incompletely reversed. Although studies in laboratory animal models suggest that bleeding produced by very high concentrations of LMWH is reduced with protamine sulfate, similar studies in humans are lacking.
There is evidence from a randomized trial that the incidence of heparin-induced IgG formation and of HIT are lower in patients treated with prophylactic doses of LMWH than in those treated with low-dose UFH, possibly because LMWHs cause less platelet activation and release of platelet factor 4, and because the lower affinity of LMWH for platelet factor 4 results in reduced formation of heparin/platelet factor 4 complexes.
Heparin binding to osteoblasts and osteoclast activation are chain length-dependent and in animal models, bone loss is less marked with LMWH than with UFH. , These laboratory findings are consistent with the results of small randomized studies that showed a lower incidence of bone fracture and decreased bone mineral density in patients assigned to LMWH than in those randomized to UFH. It should be noted, however, that the risk of osteoporosis with long-term LMWH has yet to be established in large studies.
Contraindications
LMWH should not be used in patients who have absolute contraindications to anticoagulant therapy (see Box 22-1 ). The risk of hemorrhage is increased with concomitant use of oral anticoagulants, antiplatelet agents, or thrombolytic drugs.
Although the incidence of HIT is lower in patients treated with LMWH than in those given UFH, there is a high degree of in vitro cross-reactivity between LMWHs and the antibody that causes HIT. Additionally, the administration of LMWH can be associated with the development of thrombocytopenia, both in previously unexposed individuals and in those with a history of HIT. Therefore, LMWH should not be given to patients with established HIT.
It is probably best to avoid LMWHs in patients with significant renal dysfunction (creatinine clearance below 30 mL/minute) because these drugs are cleared via the kidneys. , Of the various LMWHs, tinzaparin is the least likely to accumulate in patients with renal impairment because it has the highest mean molecular weight and exhibits less renal excretion than the others.
Fondaparinux
This first-generation synthetic pentasaccharide analogue has high affinity for antithrombin. , Because it is too short to bridge antithrombin to thrombin, fondaparinux enhances the rate of factor Xa inactivation by antithrombin, but has no effect on the rate of thrombin inhibition (see Fig. 22-4 ). There is minimal nonspecific binding of fondaparinux to plasma proteins other than antithrombin. Fondaparinux exhibits almost complete bioavailability after subcutaneous injection and has a dose-independent elimination half-life of approximately 17 hours. Fondaparinux is not metabolized and clearance is almost exclusively by the kidneys.
Indications
The antithrombotic efficacy of fondaparinux was demonstrated in four phase III trials comparing this agent to LMWH for thromboprophylaxis after surgery for hip fracture or for elective hip or knee arthroplasty. The results of the MATISSE DVT and MATISSE PE trials suggest that once-daily weight-based fondaparinux is as effective and safe as LMWH for the initial treatment of deep vein thrombosis and UFH for the acute treatment of pulmonary embolism.
ST-Segment Elevation Acute Myocardial Infarction
In a randomized, open-label, dose-finding trial, coadministration of fondaparinux and alteplase in STEMI produced similar angiographic patency rates at 90 minutes as did treatment with UFH and alteplase. In a subsequent randomized double-blind trial of 12,092 patients with acute STEMI, the addition of fondaparinux to conventional therapy (either placebo or heparin) for up to 8 days significantly reduced the primary endpoint of death or reinfarction at 30 days. However, in patients undergoing primary percutaneous intervention, there was a higher rate of guiding catheter thrombosis and coronary complications with fondaparinux compared with enoxaparin, although the rates of death or MI were the same in the two groups in this patient population. Among the patients who received UFH prior to primary percutaneous coronary intervention, these differences in catheter thrombosis were not as striking. However, the appropriate dosing of UFH in order to not only avoid catheter-related complications, but also bleeding, remains uncertain. Thus, although fondaparinux is recommended for patients with STEMI receiving fibrinolytic therapy, its use is not recommended in patients with STEMI undergoing primary percutaneous intervention.
Non–ST-Segment Elevation Acute Coronary Syndromes
With pilot studies in patients with unstable angina or NSTE ACSs suggesting that fondaparinux may be as effective as enoxaparin or UFH, a large phase III trial was performed in this population, as well. In the OASIS 5 trial, 20,078 patients with unstable angina or NSTE ACS were randomized to either fondaparinux or enoxaparin for 6 days. The number of patients with primary outcome events at 9 days (death, MI, or refractory ischemia) was similar in the two groups. However, there again was an excess of catheter-related thrombosis in fondaparinux-treated patients compared with enoxaparin-treated patients. Catheter thrombosis was largely avoided by the use of UFH during percutaneous catheter intervention. The frequency of major bleeding was substantially lower in those randomized to fondaparinux and the composite of the primary outcome and major bleeding at 9 days also favored fondaparinux over enoxaparin. Fondaparinux also was associated with a statistically significant reduction in the number of deaths at 30 and 180 days. More than 90% of the excess deaths that occurred in patients treated with enoxaparin occurred in those who experienced bleeding. The lower (prophylactic) dose of fondaparinux used in the OASIS 5 and 6 trials, compared with the standard “therapeutic” doses of LMWH, is likely responsible for the reduced bleeding seen in fondaparinux-treated patients in these studies. ,
Percutaneous Coronary Intervention
In the ASPIRE pilot study, patients undergoing elective or urgent percutaneous coronary intervention were randomized to receive UFH or 2.5 or 5 mg of fondaparinux intravenously. There was a trend toward a lower risk of bleeding in patients randomized to fondaparinux. Although there was no difference between the groups with respect to the composite of death, MI, urgent revascularization, or GP IIb/IIIa antagonist bail-out, there was an excess of abrupt closure or angiographic thrombus among patients receiving fondaparinux. These results combined with those seen in the OASIS 5 and 6 trials suggest that fondaparinux should not be considered first-line therapy in ACS patients with planned early invasive management.
Dosages
Based on its excellent bioavailability after subcutaneous injection, lack of variability in anticoagulant response and long half-life, fondaparinux can be administered subcutaneously in once-daily fixed doses without routine laboratory monitoring. Fondaparinux is given at a fixed dose of 2.5 mg subcutaneously per day for thromboprophylaxis. For treatment of deep vein thrombosis or pulmonary embolism, the drug is given at a dose of 7.5 mg subcutaneously daily for patients with a body weight of 50 to 100 kg, 5 mg subcutaneously per day for patients weighing less than 50 kg, and 100 mg per day in those weighing more than 100 kg. For patients with acute coronary syndromes, a once-daily fondaparinux dose of 2.5 mg is used.
Fondaparinux has not been monitored in clinical studies and, therefore, routine coagulation monitoring is not recommended. There may be circumstances when it is useful to determine the anticoagulant activity of fondaparinux and this can be measured using anti-Xa assays; however, the therapeutic anti-Xa range for fondaparinux has not been established.
Side Effects and Drug Interactions
Fondaparinux has low affinity for platelet factor 4. Although fondaparinux may induce the formation of IgG antibodies directed against the platelet factor 4/heparin complex, these antibodies rarely trigger HIT. However, a syndrome resembling HIT has been described in a patient who received fondaparinux after bilateral knee replacement.
To date, studies on the effects of fondaparinux on bone metabolism have been limited to in vitro experiments using cultured osteoblasts. In these investigations, fondaparinux has not been shown to affect osteoblastic or osteoclastic activity.
Fondaparinux does not bind to protamine sulfate, the drug widely used as an antidote to UFH. If uncontrollable bleeding occurs, recombinant factor VIIa may be effective.
Contraindications
Fondaparinux should not be used in patients who have absolute contraindications to anticoagulant therapy (see Box 22-1 ). The risk of hemorrhage is increased with concomitant use of oral anticoagulants, antiplatelet agents, or thrombolytic drugs. It is best to avoid fondaparinux in patients with significant renal dysfunction (creatinine clearance below 30 mL/minute) because fondaparinux is cleared via the kidneys. Although no placental passage of fondaparinux was demonstrated in an in vitro human cotyledon model, anti-factor Xa activity (at approximately one-tenth the concentration of maternal plasma) was found in the umbilical cord plasma in newborns of five mothers treated with fondaparinux. Although there have been reports of the successful use of this agent in pregnant women, , the quality of evidence supporting or recommending against the use of fondaparinux during pregnancy is weak and potential deleterious effects on the fetus cannot be excluded.
Direct Thrombin Inhibitors
Direct thrombin inhibitors bind thrombin and block its interaction with substrates, thus preventing fibrin formation, thrombin-mediated activation of clotting factors V, VIII, or XIII, and thrombin-induced platelet aggregation. As a class, these agents have potential biologic and pharmacokinetic advantages over heparin. Unlike UFH and LMWH, direct thrombin inhibitors inactivate fibrin-bound thrombin, in addition to fluid-phase thrombin. Consequently, direct thrombin inhibitors may attenuate thrombus accretion more effectively. In addition, direct thrombin inhibitors also produce a more predictable anticoagulant effect than UFH because they do not bind to plasma proteins and are not neutralized by platelet factor 4. ,
In vitro and in vivo studies have suggested that direct thrombin inhibitors are more potent antithrombotic agents than UFH. However, despite extensive evaluation in clinical trials, there has been uncertainty about their role in the management of patients with acute coronary syndromes. A meta-analysis based on individual data from 35,970 patients in 11 randomized trials comparing direct thrombin inhibitors (either hirudin, bivalirudin, argatroban, inogatran, or efegatran) with heparin for management of acute coronary syndromes, demonstrated a lower risk of death or MI at the end of treatment and at 30 days with direct thrombin inhibitors than with heparin. This reduction primarily reflected a lower risk of MI. Subgroup analyses indicated a benefit of direct thrombin inhibitors in both acute coronary syndrome trials and percutaneous coronary intervention trials. A reduction in death or MI was seen with hirudin and bivalirudin, but not with univalent direct thrombin inhibitors such as argatroban, inogatran, and efegatran. However, when major bleeding outcomes were analyzed by agent, hirudin was associated with an excess of major bleeding compared with heparin, while both bivalirudin and the univalent direct thrombin inhibitors had lower rates of bleeding. The characteristics of the approved direct thrombin inhibitors are highlighted in Table 22-2 .
| Property | Hirudin | Bivalirudin | Argatroban |
|---|---|---|---|
| Molecular mass | 7000 | 1980 | 527 |
| Site(s) of interaction with thrombin | Active site and exosite 1 | Active site and exosite 1 | Active site |
| Predominant mechanism of clearance | Renal | Proteolysis at sites other than kidneys and liver | Hepatic |
| Plasma half-life after intravenous administration (minutes) | 40 | 25 | 45 |
Hirudin
Mechanism of Action
Hirudin is a 65-amino acid polypeptide originally isolated from the salivary gland of the medicinal leech. A potent and specific inhibitor of thrombin, it binds to thrombin’s active site by its globular amino-terminal domain and to thrombin’s substrate recognition site (exosite 1) via its carboxy-terminal domain. , Two forms of recombinant hirudin, lepirudin and desirudin, are currently available in North America and Europe. Unlike natural hirudin, recombinant hirudins lack a sulfate group on the tyrosine residue at position 63. Although this change results in a 10-fold reduction in their affinity for thrombin, recombinant hirudins still bind tightly to the enzyme, forming an almost irreversible complex. The almost irreversible nature of this complex may be considered a relative weakness, because there is no available antidote should bleeding occur. Hirudin is not absorbed via the gastrointestinal tract and must be administered intravenously or by subcutaneous injection. Hirudin is predominantly cleared by the kidneys and undergoes little hepatic metabolism. , It has a plasma half-life of 40 minutes after intravenous administration and approximately 120 minutes after subcutaneous injection.
Indications
Lepirudin is licensed for the treatment of patients with heparin-induced thrombocytopenia, while desirudin is approved in Europe and the United States for postoperative thromboprophylaxis in patients undergoing elective hip arthroplasty. Hirudin also has been tested as an adjunct to thrombolytic therapy in patients with acute MI and as a replacement for heparin in patients with unstable angina or NSTEMI and those undergoing percutaneous coronary interventions.
Acute Myocardial Infarction with Thrombolysis
Three trials of hirudin as an adjunct to coronary thrombolysis were stopped prematurely because hirudin produced an unacceptable risk of intracranial hemorrhage. Lower doses of hirudin were then assessed in three studies. Overall, hirudin was no more effective than heparin at 30 days, , although short-term benefits at 24 hours and 48 hours were observed in one study and a 35% reduction in the rate of death and reinfarction at 30 days was seen in a retrospective analysis of the subgroup of patients who received streptokinase. No such favorable interaction was seen in patients receiving hirudin as an adjunct to tissue plasminogen activator (tPA).
Although critics of these studies have suggested that the hirudin dose was too low, treatment initiation too delayed, and treatment duration too short to obtain evidence of clinical efficacy, in the population of patients above, therapy with hirudin was no better than UFH in preventing adverse clinical outcomes.
Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction
Hirudin has been compared with heparin in two large trials involving patients with unstable angina or NSTEMI. Among those patients enrolled in the GUSTO-IIb trial who presented without ST-segment elevation and, therefore, did not receive thrombolytic therapy, there was no significant difference in the rate of death or MI between those who received intravenous UFH and those treated with hirudin, although there was a trend for an early, but transient, benefit with hirudin. The risk of moderate bleeding was increased with hirudin. In the OASIS-2 study, hirudin was more effective than UFH during the 3 days of treatment. There was no additional gain or loss of benefit after treatment stopped and a nonstatistically significant advantage in favor of hirudin with respect to cardiovascular death or new MI was still present at days 7 and 35. Combined data from the trials utilizing this agent in patients with unstable angina or NSTMI, however, demonstrate that hirudin provides a statistically significant reduction in cardiovascular death and MI rates at both 72 hours and 7 days. Although the effect persists beyond 7 days, its impact is attenuated statistically over time.
Percutaneous Coronary Interventions
Hirudin produced only transient advantages over heparin with respect to death, nonfatal MI, or need for coronary bypass surgery, stenting, or second angioplasty when used after coronary angioplasty. , Consequently, the sole use of hirudin in this setting cannot be recommended until further studies are performed.
Dosages
Hirudin’s narrow therapeutic window makes monitoring of anticoagulant effect necessary, particularly when the drug is given in conjunction with thrombolytic agents. Generally, treatment is monitored with the aPTT and the dose adjusted to achieve a target aPTT ratio of 1.5 to 2. The aPTT should be determined before treatment, 4 hours after the start of intravenous hirudin therapy, 4 hours after every dosage change, and then at least once daily. If the aPTT is subtherapeutic, the infusion rate should be increased by 20%. If the aPTT is supratherapeutic, the aPTT should be stopped for 2 hours and if the aPTT is within the therapeutic range with re-testing, the infusion should be restarted at 50% of the previous dose. Unfortunately, there are problems when the aPTT is used to monitor hirudin therapy, including variability in responsiveness between patients and the lack of a linear correlation with plasma hirudin levels. Although the ecarin clotting time provides a linear correlation with hirudin levels, this test has not been standardized and is not available on a routine basis.
In patients with unstable angina or NSTEMI, hirudin has been given as a 0.4 mg/kg bolus, followed by a 0.15 mg/kg/hour infusion for 72 hours, adjusted to maintain the aPTT between 60 and 100 seconds.
Side Effects
Although major bleeding has been observed to occur more frequently in patients treated with hirudin than in those receiving adjusted-dose UFH, no excess of strokes or life-threatening bleeds has been demonstrated. , No specific antidote is available to neutralize hirudin. Hirudin-induced bleeding has been reversed by prothrombin complex concentrates, hemodialysis, and hemofiltration. Using inhibition of thrombin generation in shed blood as an index of activity, recombinant factor VIIa can reverse the anticoagulant effect of direct thrombin inhibitors in healthy volunteers. The ability of this agent to reduce bleeding induced by direct thrombin inhibitors in patients has not been established.
Antibodies against hirudin develop in up to 40% of patients treated with lepirudin. Although most of these antibodies have no clinical impact, some can prolong the plasma half-life of lepirudin, resulting in drug accumulation. In addition, anaphylaxis can occur if patients with antibodies are re-exposed to hirudin.
Contraindications and Drug Interactions
Hirudin should not be given to patients with contraindications to anticoagulants (see Box 22-1 ). The drug is cleared by the kidneys and dose adjustments and careful monitoring are required if this agent is used in patients with renal dysfunction. , Investigations have documented placental transfer of hirudin in rabbits and rats. Although small numbers of case reports of successful outcomes with hirudin use in pregnancy have been published, there are insufficient data to evaluate its safety in this setting. The risk of hemorrhage is increased when hirudin is combined with antiplatelet agents and thrombolytic drugs; the interaction when hirudin is used in combination with GP IIb/IIIa receptor antagonists, UFH, or LMWH has not been well-studied.
Bivalirudin
Mechanism of Action
Like hirudin, bivalirudin also is a bivalent inhibitor of thrombin. This synthetic 20-amino acid polypeptide is comprised of an active site-directed moiety, D-Phe-Pro-Arg-Pro, linked via a tetraglycine spacer to a dodecapeptide analogue of the carboxy-terminal of hirudin that interacts with exosite 1 on thrombin. Unlike hirudin, bivalirudin produces only transient inhibition of the active site of thrombin because, once bound, thrombin cleaves the Arg-Pro bond within the amino-terminal of bivalirudin. , Without its amino-terminal segment, the carboxy-terminal portion of bivalirudin bound to exosite 1 is a much weaker thrombin inhibitor.
Bivalirudin’s plasma half-life after intravenous infusion is 25 minutes. This shorter half-life may endow bivalirudin with a better safety profile than hirudin. Only a fraction of bivalirudin is renally excreted, suggesting that hepatic metabolism and proteolysis at other sites contribute to its clearance. This agent must be administered parenterally.
Indications
Acute Myocardial Infarction with Thrombolysis
As a result of bivalirudin’s early promise in patency trials utilizing streptokinase, the HERO-2 trial, an open-label randomized study of 17,073 patients, was performed comparing this agent with UFH in patients receiving streptokinase for acute MI. Although there was no difference between the two regimens with respect to the primary endpoint of 30-day mortality in this study, bivalirudin was associated with a reduction in the rate of reinfarction at 96 hours, a pre-specified secondary endpoint. The composite net clinical benefit outcome of death, MI, and nonfatal disabling stroke favored bivalirudin. A reduction in MI in the absence of an effect on mortality is consistent with the results with other direct thrombin inhibitors. Bivalirudin therapy was associated with a small but statistically significant increase in the rate of moderate bleeding. A similar trend was also seen for excess severe bleeding and intracranial hemorrhage. This was an unexpected finding given the reduced risks of bleeding seen in earlier studies performed with bivalirudin. Post-hoc subgroup analysis suggested that the excess bleeding with bivalirudin could be accounted for by the fact that, in contrast to heparin, the dose of bivalirudin was not titrated to the aPTT. Bivalirudin has not been well evaluated in patients receiving tPA or third-generation bolus thrombolytic therapy.
Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction
Early dose-ranging studies of bivalirudin in patients with unstable angina suggest that this drug is effective and well tolerated in this clinical situation. These results, however, require confirmation in large clinical studies. Unfortunately, the TIMI 8 trial, a randomized comparison of UFH with bivalirudin in patients with unstable angina or NSTEMI, was terminated by the sponsor after only 133 of a planned 5320 patients were enrolled.
Percutaneous Coronary Interventions
Bivalirudin has been studied as an alternative to heparin in patients with unstable angina undergoing percutaneous coronary angioplasty and is licensed for this indication. Initial results of the Bivalirudin (Hirulog) Angioplasty Study found bivalirudin to be no more effective than heparin for patients undergoing percutaneous coronary angioplasty, although bivalirudin produced less bleeding than high-dose heparin and was superior to heparin in the prespecified high-risk group of patients undergoing intervention for postinfarction angina. However, in a reanalysis of the study results using a more contemporary definition of MI, bivalirudin was more effective than heparin at reducing the risk of death, MI, and revascularization at 6 months. Moreover, there was a marked relative risk reduction in bleeding complications in bivalirudin-treated patients compared with those receiving UFH. Based on this reanalysis and recent meta-analyses, , bivalirudin appears to be an effective alternative to heparin in patients undergoing coronary angioplasty.
Bivalirudin was compared with the combination of UFH and GP IIb/IIIa inhibitor in the REPLACE-2 study, a phase III trial of 6010 patients undergoing percutaneous intervention. Participants were randomized to bivalirudin plus a provisional GP IIb/IIIa inhibitor (abciximab or eptifibatide) or UFH plus GP IIb/IIIa inhibitor. Bivalirudin was given as a 0.75 mg/kg bolus followed by an infusion of 1.75 mg/kg/hour during the procedure. Use of a GP IIb/IIIa antagonist was required in only 7% of patients randomized to bivalirudin. The use of bivalirudin resulted in a nonstatistically significant reduction in the primary outcome, a composite of death, MI, urgent revascularization, or major bleeding at 30 days. However, rates of major bleeding were significantly lower in patients given bivalirudin than in those treated with UFH.
The ACUITY study compared three antithrombotic strategies in patients presenting with NSTEMI scheduled to be treated with an early invasive strategy. The investigators randomized 13,819 patients to receive one of either bivalirudin plus provisional GP IIb/IIIa inhibitor, bivalirudin plus GP IIb/IIIa inhibitor, or intravenous UFH/enoxaparin plus GP IIb/IIIa inhibitor. Clopidogrel was added to aspirin at the discretion of the local investigator and 57% of patients underwent percutaneous coronary intervention during study drug administration. In this trial, bivalirudin was started before angiography and was given as a bolus of 0.1 mg/kg followed by an infusion of 0.25 mg/kg/hour. A second bolus of 0.5 mg/kg was given immediately prior to percutaneous coronary intervention followed by an infusion of 1.75 mg/kg/hour during the procedure. Bivalirudin plus provisional GP IIb/IIIa inhibitor, as well as bivalirudin plus GP IIb/IIIa inhibitor, were noninferior to intravenous UFH/enoxaparin for the composite of death, MI, or unplanned revascularization at 30 days provided that clopidogrel was given before or at least 30 minutes after the procedure. While bivalirudin plus GP IIb/IIIa inhibitor therapy was noninferior to UFH plus GPIIb/IIa inhibitor for clinically important bleeding, bivalirudin plus provisional GP IIb/IIIa inhibitor was superior to the UFH arm for this endpoint.
Bivalirudin also has been evaluated in patients with STEMI. In the HORIZONS AMI trial, 3600 patients were randomized within 12 hours of symptom onset to either bivalirudin (0.75 mg/kg bolus followed by an infusion of 1.75 mg/kg/hour) plus provisional GP IIb/IIIa antagonist or to UFH (60 units/kg with subsequent doses titrated to achieve a target ACT of 200 to 250 seconds) along with a GP IIb/IIIa antagonist. All patients underwent percutaneous coronary intervention. Of those randomized to bivalirudin, 7.2% received a GP IIb/IIIa antagonist. Compared with heparin plus a GP IIb/IIIa antagonist, bivalirudin did not reduce the primary endpoint of all-cause mortality, reinfarction, target vessel revascularization (TVR) or stroke, but did reduce major bleeding by 40% (from 8.3% to 4.9%; P < .0001). Bivalirudin also reduced the risk of cardiovascular mortality compared with heparin plus a GP IIb/IIIa antagonist (1.8% and 2.9%, respectively; P = .035).
Thus, it appears that bivalirudin is an effective anticoagulant in patients with acute coronary syndromes, particularly for those undergoing percutaneous coronary intervention. Bivalirudin may obviate the need for a GP IIb/IIIa inhibitor and, therefore, reduce bleeding risks. GP IIb/IIIa inhibitors may still be required in very high risk patients.
Dosages
In contrast to hirudin, there is no evidence that bivalirudin requires coagulation monitoring in patients undergoing coronary angioplasty, because the drug is safe when given in weight-adjusted doses (0.75 mg/kg bolus followed by an infusion of 1.75 mg/kg/hour during the procedure). In contrast, the results of the HERO-2 trial suggest that the dose of bivalirudin should be titrated to achieve an aPTT 1.5 to 2.5 times control if bivalirudin is used as an adjunct to streptokinase and aspirin for treatment of acute MI.
Side Effects
It has been suggested that the principal benefit of bivalirudin appears to be a reduction in the risk of major hemorrhage. In contrast to hirudin, bivalirudin is not immunogenic. However, antibodies against hirudin can cross-react with bivalirudin in vitro. The clinical significance of this cross-reactivity is unknown.
Contraindications and Drug Interactions
Bivalirudin is contraindicated in patients with the conditions listed in Box 22-1 . The concomitant use of antiplatelet agents, other anticoagulants, or thrombolytic agents with bivalirudin increases the risk of hemorrhage.
Active Site–Directed Direct Thrombin Inhibitors
Argatroban
A carboxylic acid derivative that is metabolized in the liver, argatroban binds noncovalently to the active site of thrombin. This agent has a half-life of 20 to 60 minutes and prolongs the aPTT in a dose-dependent manner. Argatroban is extensively metabolized in the liver and its plasma levels are not influenced by renal function. This drug is an effective alternative to heparin in patients with HIT and is approved for this indication. In preliminary evaluation in patients with acute STEMI receiving thrombolysis, argatroban has been associated with similar bleeding risks as UFH. , Definitive clinical trials in patients with acute coronary syndromes have not been performed.
Ximelagatran
Ximelagatran, an uncharged lipophilic drug with little intrinsic activity against thrombin, is a prodrug of melagatran, an active site–directed thrombin inhibitor. Ximelagatran is well absorbed from the gastrointestinal tract and undergoes rapid biotransformation to melagatran. , The drug produces a predictable anticoagulant response after oral administration and little or no coagulation monitoring appears to be necessary. Ximelagatran was evaluated for prevention and treatment of venous thromboembolism, prevention of cardioembolic events in patients with nonvalvular atrial fibrillation, and prevention of recurrent ischemia in patients with recent MI. Although initial studies led to the temporary approval of ximelagatran in Europe for thromboprophylaxis in patients undergoing major orthopedic surgery, the drug was eventually withdrawn from the world market because of an increased risk of hepatic toxicity. , Despite this disappointing outcome, the studies involving ximelagatran showed that effective oral anticoagulation does not necessarily require monitoring.
Dabigatran Etexilate
Dabigatran etexilate is a double prodrug that is absorbed from the gastrointestinal tract with a bioavailability of approximately 6%. Once absorbed, dabigatran etexilate is converted by esterases into its active metabolite, dabigatran (BIBR 953). Dabigatran is a reversible inhibitor that targets the active site of thrombin. Cytochrome P-450 (CYP450) plays no relevant role in this drug’s metabolism; therefore, the potential for clinically relevant interactions between dabigatran and drugs metabolized by CYP450 is low. Plasma levels of dabigatran peak at 1.5 hours and dabigatran has a half-life of 8 hours after a single dose and up to 17 hours after multiple doses. Thus, it may be possible to administer dabigatran etexilate once daily for some indications. Dabigatran is excreted unchanged via the kidneys; therefore, this drug is contraindicated in patients with renal failure.
Dabigatran has shown promise in phase II and III studies of thromboprophylaxis in patients undergoing hip or knee arthroplasty and dabigatran etexilate has been approved for this indication in Europe and Canada. The ability of dabigatran etexilate to prevent atrial fibrillation-related stroke was evaluated in the phase II PETRO study and PETRO-EX, its open-label extension. , In the PETRO study, 502 patients with atrial fibrillation were randomized to one of three doses of dabigatran etexilate alone or combined with aspirin (81 to 325 mg per day) or to warfarin for 12 weeks. Dabigatran etexilate dosed at 150 mg twice daily compared favorably to warfarin, whereas the lowest dose of 50 mg twice daily was ineffective and the highest dose of 300 mg twice daily was associated with an increased risk of major bleeding. In the phase III RELY study, 18,113 patients with atrial fibrillation were randomized to one of two blinded doses of dabigatran etexilate (150 mg twice daily or 110 mg twice daily) or to open-label dose-adjusted warfarin (INR target 2.0 to 3.0). Annual rates of the primary efficacy outcome, stroke or systemic embolism, were 1.69% in the warfarin group, 1.53% in those receiving 110 mg of dabigatran ( P < 0.001 for noninferiority) and 1.11% in the group given 150 mg of dabigatran ( P < 0.001 for both noninferiority and superiority). Annual rates of major bleeding were 3.36% in the warfarin group, 2.71% in the group receiving 110 mg of dabigatran ( P = 0.003) and 3.11% in those given 150 mg of dabigatran ( P = 0.31). Rates of hemorrhagic stroke were lower with both doses of dabigatran than with warfarin. There was no signal for elevated levels of liver transaminases in patients receiving dabigatran etexilate. Dabigatran also underwent phase II evaluation for prevention of recurrent ischemic events in patients with acute coronary syndromes.
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