Direct Thrombin Inhibitors: Alternatives to Heparin
Direct Thrombin Inhibitors: Alternatives to Heparin
After more than 70 years of effective clinical use, heparin remains the most common anticoagulant in use and one of the most commonly prescribed drugs to hospitalized patients. However, the biologic variability and immunogenicity limit its utility. With increasing volumes of vascular intervention and an aging population, an increase in the need for anticoagulation can be anticipated. This article reviews current viable options and barriers to the use of heparin.
All elements of the Virchow triad are encountered during both vascular therapy and intrinsic vascular disease. Anticoagulation is routinely used during procedures to prevent thrombosis above the level of vessel occlusion (ie, angioplasty, aortic occlusion during endograft placement) and to prevent thrombus formation about a nidus such as a sheath or catheter. In addition, many patients requiring vascular disease management or therapy may have a hypercoagulable state. Up to 10% of patients undergoing peripheral vascular procedures have a hypercoagulable state, and there is evidence that the platelets of patients with peripheral vascular disease are overactive.
Heparin was introduced into clinical use in 1935 and remains the most common anticoagulant in use today. It is estimated that 30% of all patients admitted to a hospital receive some form of heparin. The most commonly prescribed form is unfractionated heparin (UFH), which is a mixture of polysaccharide chains. Heparin complexes with endogenous antithrombin and inactivates coagulation factors Xa, XIIa, Xia, and IXa. UFH is quickly available after intravenous administration (within 3 minutes), and its effect is easily assessed by way of the activated clotting time (ACT). The duration of action depends on the dose administered but is roughly 60 minutes. The activated partial thromboplastin time (aPTT) is used to monitor longer-term therapy. Heparin has an antidote in protamine, which complexes with heparin in a ratio of 1 mg protamine to 100 units of heparin and prevents the binding of heparin to AT. Heparin is ineffective against existing thrombus and has significant biologic variability owing to variable levels of plasma protein binding. There are no firm recommendations regarding dosing of heparin for vascular interventions. High-risk interventions (brachiocephalic, small vessels) may benefit from administration of 75 to 100 units of heparin per kilogram of body mass during balloon angioplasty, whereas straightforward aortoiliac interventions may only require doses of 25 to 50 U/kg. However, lower doses may be safe. One study demonstrates the safety and efficacy of roughly 50 U/kg for coronary interventions, implying that lower doses may be sufficient even for small-vessel interventions.
Low-molecular-weight heparins (LMWHs) are shorter segments of depolymerized UFH. Several are available clinically, and they are differentiated by the specific fraction used in the preparation and slight differences in anticoagulant strength. LMWHs offer more anti-Xa activity than UFH and less anti-IIa activity. This theoretically leads to greater efficacy and lower bleeding complications. In addition, LMWHs are administered as a single subcutaneous injection and do not require monitoring to determine anticoagulant ability owing to more predictable biologic activity. This, however, is also their greatest weakness as there is no rapid method to assess anticoagulant adequacy. Several studies show both the efficacy and the safety of LMWH as the sole anticoagulant administered for the purpose of percutaneous coronary intervention (PCI).
The indirect activity of heparin represents a major drawback to its use. In addition to variable biologic activity, the downfall of all heparins is their immunogenicity. Heparin-induced thrombocytopenia (HIT) syndrome occurs in roughly 1 to 3% of all patients who receive heparin. Heparin complexes with endogenous platelet factor 4 to form a unique epitope against which an antibody (most commonly immunoglobulin G) develops. In the presence of exogenous heparin, this antibody binds to platelets and leads to platelet cross-linking and generation of procoagulant microparticles and endothelial damage. The morbidity and mortality of HIT were recently assessed at 30% and 7%, respectively. Therapy for HIT requires immediate cessation of all heparin, including flushes, and a decision regarding the need for further anticoagulation. Although LMWH is historically associated with a lower rate of antibody formation, once heparin associated antiplatelet antibodies (HAAbs) are present, 20 to 60% of patients with HAAb owing to UFH will cross-react to LMWH. Also, plasma from 34% of patients with HIT will aggregate platelets in the presence of LMWH. In addition to immunogenicity, UFH is associated with hemorrhagic complications. In a study evaluating patients treated with 59.1 ± 20.0 U/kg of heparin for peripheral vascular interventions, major bleeding occurred in 4.6%, and 7.6% required emergent repeat revascularization of the same target vessel.
In contrast to the indirect inhibition of thrombin offered by heparin, direct thrombin inhibitors (DTIs) require no preceding interaction prior to their effect on thrombin (factor IIa). DTIs are more specific and have activity on both soluble and thrombus-bound thrombin. This is in stark contrast to heparin, which has no activity against thrombus-bound thrombin. In addition to these issues, several other factors may make DTIs more attractive pharmacologic agents for vascular patients. Thrombin itself has long been understood to have functions other than catalysis of fibrinogen to fibrin. The "receptors" for thrombin, a family of molecules known as protease-activated receptors, are found on endothelial and vascular smooth muscle cells. Thrombin leads to proliferation of vascular smooth muscle cells and upregulates vascular endothelial growth factor expression. In addition to direct effects on vascular cells, thrombin also has a proinflammatory role. There is increasing evidence that inflammation is critically important in the development and progression of vascular disease.
Given the central position of thrombin in vascular cell and platelet signaling, as well as inflammation, it is reasonable to hypothesize that DTIs would have beneficial effects on vascular physiology. There are multiple in vitro and in vivo studies of the effect of DTIs on vascular physiology. In an in vivo study of blood from patients undergoing PCI, DTIs reduced platelet surface expression of P-selectin and decreased platelet-leukocyte aggregation compared with the blood from patients who had received heparin with a glycoprotein IIb-IIIa inhibitor. Furthermore, a reduction in leukocyte activation was also observed. This may translate into a reduction in progressive atherogenesis owing to platelet-leukocyte interactions. The relationship between thrombosis and inflammation has been explored in the pulmonary bed, and inflammation was diminished through use of a DTI. This inflammatory link is further supported by an experimental reduction in atherosclerotic lesion size after treatment with DTI. Myocardial reperfusion injury has also been found to be moderated after DTI treatment.
The first approved DTI was lepirudin (Refludan, Berlex Laboratories, Wayne, NJ). Lepirudin is a recombinant derivative of hirudin, the anticoagulant present in the saliva of the medicinal leech (Hirudo medicinalis). Lepirudin is a bivalent DTI, binding at both the catalytic site of thrombin (preventing the conversion of fibrinogen to fibrin) and the fibrinogen-binding site. Lepirudin is renally cleared, and its effect is markedly prolonged in patients with renal failure. There is no direct antidote for overdosage with lepirudin, but activated factor VII has been reported to be able to salvage coagulation after a failure to clear lepirudin. The dose for patients with normal renal function is a bolus of 0.4 mg/kg followed by continuous infusion at 0.15 mg/kg/h, and the half-life is 80 minutes.
The US Food and Drug Administration (FDA) approved lepirudin for the treatment of HIT. The anticoagulant effect is monitored by the aPTT. It may also be monitored at point-of-care via the ecarin clotting time (ECT). Caution is required when observing common laboratory measures of anticoagulation during treatment with lepirudin. The international normalized ratio is elevated out of proportion to the anticoagulant effect in patients receiving lepirudin.Alternate testing is possible during dosing with lepirudin. A thromboelastograph, a common clinical coagulation instrument, has been successfully used to monitor the effects of hirudin in vitro, and additional tests are in development. The inability to rapidly assess the effect of leipirudin limits its utility. As a point-of-care test, the ECT is not readily available at all institutions, and the aPTT does not provide the rapid response that is required during intervention.
Lepirudin is a safe and effective anticoagulant for patients with HAAb. Although some patients form antibodies against hirudin, 23 patients were prospectively studied, and 56% developed antibodies against hirudin as detected by enzyme-linked immunosorbent assay. However, no patient demonstrated resistance or other effects attributable to the antihirudin antibodies. Any clinical significance of these antibodies is yet to be shown.
Although it is approved for the treatment of HIT alone, lepirudin has been successfully used for anticoagulation during procedures in patients with HAAb. Lepirudin has been used for anticoagulation during renal replacement therapy with hemodialysis and for anticoagulation during cardiopulmonary bypass.
Argatroban (Glaxo SmithKline Pharmaceuticals, Research Triangle Park, NC) is a small (527 Da), synthetic direct thrombin inhibitor derived from l-arginine. Unlike lepirudin, argatroban binds reversibly to the catalytic domain of thrombin at only this single location as it is a univalent inhibitor. There is activity against both free and clot-bound thrombin, with no activity against factor Xa or plasmin. In a study of anticoagulation for PCI using historical controls (HIT patients treated with heparin), argatroban resulted in improved clinical outcomes and no increase in hemorrhagic complications. Standard dosing is 2 mg/kg/min intravenously, and the drug is titrated to achieve an aPTT of 1.5 to 3 times control and may be monitored at point-of-care via the ACT. Argatroban undergoes hepatic metabolism and excretion. It is a reversible inhibitor, with a half-life of 40 to 50 minutes, allowing rapid restoration of coagulation after infusion. Given that it is not renally cleared, it has a predictable effect in patients with renal insufficiency. There is no specific antidote for argatroban, and administration should be discontinued if suspicion of overdosage or hemorrhagic complication exists. In the setting of PCI, argatroban is approved for use in patients with HIT and has been used at a dose of 25 µg/kg/min after a 350 µg/kg initial bolus and titrated to an ACT of 250 to 300 seconds. The results in these patients are comparable to those in historical heparin controls.
Another direct thrombin inhibitor, bivalirudin, has been more extensively studied in PCI than the others but not in placebo-controlled trials. It has been evaluated as a safe and effective foundation anticoagulant for use in PCI. Bivalirudin (Angiomax The Medicines Company, Parsippany, NJ; previous name hirulog) has been studied in subtherapeutic doses (Thrombin Inhibition in Myocardial Ischemia [TIMI] 7), and in heparin-controlled trials (Hirulog and Early Reperfusion or Occlusion [HERO]-2, TIMI 8). In a large (5,674 patients) meta-analysis of six studies looking at outcomes after myocardial infarction, bivalirudin was associated with a significant reduction in the composite of death or infarction and in major hemorrhage. The HERO-11 trial evaluated angiography in patients undergoing fibrinolysis, and the HERO-2 trial specifically evaluated bivalirudin in PCI. Compared with heparin, bivalirudin failed to reduce mortality but reduced the postprocedure myocardial reinfarction rate. The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Outcomes (REPLACE)-2 trial compared bivalirudin with provisional glycoprotein IIb-IIIa inhibition with heparin with glycoprotein IIb-IIIa inhibition during PCI. The dose of bivalirudin in this study was a 0.75 mg/kg bolus and a subsequent 1.75 mg/kg/h infusion. Only 7.2% of patients in the bivalirudin group received IIb-IIIa inhibitors, and there were similar 30-day outcomes in both groups.
Warfarin sodium is the most commonly prescribed oral anticoagulant. Its use is complicated by a narrow therapeutic window and significant risk of hemorrhage at therapeutic concentrations. Dosing is difficult and requires frequent invasive monitoring. Alternatives to this oral option have been slow to come. Ximelagatran, an oral prodrug of the DTI melagatran, had shown efficacy in the prevention and treatment of venous thromboembolism, as well as stroke prevention in patients with atrial fibrillation. Despite its efficacy and promise, ximelegatran has been withdrawn owing to hepatic toxicity.
In summary, despite the safety profile and long history of heparin use, there are drawbacks that mandate that we continue to look for alternatives for our patients. Direct inhibition of thrombin may offer similar anticoagulant properties but also impact the underlying disease process. As we continue to gain experience and develop new DTIs, a new balance may be struck among cost, safety, and efficacy. Additional studies are still required to further our understanding of these important pharmacologic adjuncts.
After more than 70 years of effective clinical use, heparin remains the most common anticoagulant in use and one of the most commonly prescribed drugs to hospitalized patients. However, the biologic variability and immunogenicity limit its utility. With increasing volumes of vascular intervention and an aging population, an increase in the need for anticoagulation can be anticipated. This article reviews current viable options and barriers to the use of heparin.
All elements of the Virchow triad are encountered during both vascular therapy and intrinsic vascular disease. Anticoagulation is routinely used during procedures to prevent thrombosis above the level of vessel occlusion (ie, angioplasty, aortic occlusion during endograft placement) and to prevent thrombus formation about a nidus such as a sheath or catheter. In addition, many patients requiring vascular disease management or therapy may have a hypercoagulable state. Up to 10% of patients undergoing peripheral vascular procedures have a hypercoagulable state, and there is evidence that the platelets of patients with peripheral vascular disease are overactive.
Heparin was introduced into clinical use in 1935 and remains the most common anticoagulant in use today. It is estimated that 30% of all patients admitted to a hospital receive some form of heparin. The most commonly prescribed form is unfractionated heparin (UFH), which is a mixture of polysaccharide chains. Heparin complexes with endogenous antithrombin and inactivates coagulation factors Xa, XIIa, Xia, and IXa. UFH is quickly available after intravenous administration (within 3 minutes), and its effect is easily assessed by way of the activated clotting time (ACT). The duration of action depends on the dose administered but is roughly 60 minutes. The activated partial thromboplastin time (aPTT) is used to monitor longer-term therapy. Heparin has an antidote in protamine, which complexes with heparin in a ratio of 1 mg protamine to 100 units of heparin and prevents the binding of heparin to AT. Heparin is ineffective against existing thrombus and has significant biologic variability owing to variable levels of plasma protein binding. There are no firm recommendations regarding dosing of heparin for vascular interventions. High-risk interventions (brachiocephalic, small vessels) may benefit from administration of 75 to 100 units of heparin per kilogram of body mass during balloon angioplasty, whereas straightforward aortoiliac interventions may only require doses of 25 to 50 U/kg. However, lower doses may be safe. One study demonstrates the safety and efficacy of roughly 50 U/kg for coronary interventions, implying that lower doses may be sufficient even for small-vessel interventions.
Low-molecular-weight heparins (LMWHs) are shorter segments of depolymerized UFH. Several are available clinically, and they are differentiated by the specific fraction used in the preparation and slight differences in anticoagulant strength. LMWHs offer more anti-Xa activity than UFH and less anti-IIa activity. This theoretically leads to greater efficacy and lower bleeding complications. In addition, LMWHs are administered as a single subcutaneous injection and do not require monitoring to determine anticoagulant ability owing to more predictable biologic activity. This, however, is also their greatest weakness as there is no rapid method to assess anticoagulant adequacy. Several studies show both the efficacy and the safety of LMWH as the sole anticoagulant administered for the purpose of percutaneous coronary intervention (PCI).
The indirect activity of heparin represents a major drawback to its use. In addition to variable biologic activity, the downfall of all heparins is their immunogenicity. Heparin-induced thrombocytopenia (HIT) syndrome occurs in roughly 1 to 3% of all patients who receive heparin. Heparin complexes with endogenous platelet factor 4 to form a unique epitope against which an antibody (most commonly immunoglobulin G) develops. In the presence of exogenous heparin, this antibody binds to platelets and leads to platelet cross-linking and generation of procoagulant microparticles and endothelial damage. The morbidity and mortality of HIT were recently assessed at 30% and 7%, respectively. Therapy for HIT requires immediate cessation of all heparin, including flushes, and a decision regarding the need for further anticoagulation. Although LMWH is historically associated with a lower rate of antibody formation, once heparin associated antiplatelet antibodies (HAAbs) are present, 20 to 60% of patients with HAAb owing to UFH will cross-react to LMWH. Also, plasma from 34% of patients with HIT will aggregate platelets in the presence of LMWH. In addition to immunogenicity, UFH is associated with hemorrhagic complications. In a study evaluating patients treated with 59.1 ± 20.0 U/kg of heparin for peripheral vascular interventions, major bleeding occurred in 4.6%, and 7.6% required emergent repeat revascularization of the same target vessel.
In contrast to the indirect inhibition of thrombin offered by heparin, direct thrombin inhibitors (DTIs) require no preceding interaction prior to their effect on thrombin (factor IIa). DTIs are more specific and have activity on both soluble and thrombus-bound thrombin. This is in stark contrast to heparin, which has no activity against thrombus-bound thrombin. In addition to these issues, several other factors may make DTIs more attractive pharmacologic agents for vascular patients. Thrombin itself has long been understood to have functions other than catalysis of fibrinogen to fibrin. The "receptors" for thrombin, a family of molecules known as protease-activated receptors, are found on endothelial and vascular smooth muscle cells. Thrombin leads to proliferation of vascular smooth muscle cells and upregulates vascular endothelial growth factor expression. In addition to direct effects on vascular cells, thrombin also has a proinflammatory role. There is increasing evidence that inflammation is critically important in the development and progression of vascular disease.
Given the central position of thrombin in vascular cell and platelet signaling, as well as inflammation, it is reasonable to hypothesize that DTIs would have beneficial effects on vascular physiology. There are multiple in vitro and in vivo studies of the effect of DTIs on vascular physiology. In an in vivo study of blood from patients undergoing PCI, DTIs reduced platelet surface expression of P-selectin and decreased platelet-leukocyte aggregation compared with the blood from patients who had received heparin with a glycoprotein IIb-IIIa inhibitor. Furthermore, a reduction in leukocyte activation was also observed. This may translate into a reduction in progressive atherogenesis owing to platelet-leukocyte interactions. The relationship between thrombosis and inflammation has been explored in the pulmonary bed, and inflammation was diminished through use of a DTI. This inflammatory link is further supported by an experimental reduction in atherosclerotic lesion size after treatment with DTI. Myocardial reperfusion injury has also been found to be moderated after DTI treatment.
The first approved DTI was lepirudin (Refludan, Berlex Laboratories, Wayne, NJ). Lepirudin is a recombinant derivative of hirudin, the anticoagulant present in the saliva of the medicinal leech (Hirudo medicinalis). Lepirudin is a bivalent DTI, binding at both the catalytic site of thrombin (preventing the conversion of fibrinogen to fibrin) and the fibrinogen-binding site. Lepirudin is renally cleared, and its effect is markedly prolonged in patients with renal failure. There is no direct antidote for overdosage with lepirudin, but activated factor VII has been reported to be able to salvage coagulation after a failure to clear lepirudin. The dose for patients with normal renal function is a bolus of 0.4 mg/kg followed by continuous infusion at 0.15 mg/kg/h, and the half-life is 80 minutes.
The US Food and Drug Administration (FDA) approved lepirudin for the treatment of HIT. The anticoagulant effect is monitored by the aPTT. It may also be monitored at point-of-care via the ecarin clotting time (ECT). Caution is required when observing common laboratory measures of anticoagulation during treatment with lepirudin. The international normalized ratio is elevated out of proportion to the anticoagulant effect in patients receiving lepirudin.Alternate testing is possible during dosing with lepirudin. A thromboelastograph, a common clinical coagulation instrument, has been successfully used to monitor the effects of hirudin in vitro, and additional tests are in development. The inability to rapidly assess the effect of leipirudin limits its utility. As a point-of-care test, the ECT is not readily available at all institutions, and the aPTT does not provide the rapid response that is required during intervention.
Lepirudin is a safe and effective anticoagulant for patients with HAAb. Although some patients form antibodies against hirudin, 23 patients were prospectively studied, and 56% developed antibodies against hirudin as detected by enzyme-linked immunosorbent assay. However, no patient demonstrated resistance or other effects attributable to the antihirudin antibodies. Any clinical significance of these antibodies is yet to be shown.
Although it is approved for the treatment of HIT alone, lepirudin has been successfully used for anticoagulation during procedures in patients with HAAb. Lepirudin has been used for anticoagulation during renal replacement therapy with hemodialysis and for anticoagulation during cardiopulmonary bypass.
Argatroban (Glaxo SmithKline Pharmaceuticals, Research Triangle Park, NC) is a small (527 Da), synthetic direct thrombin inhibitor derived from l-arginine. Unlike lepirudin, argatroban binds reversibly to the catalytic domain of thrombin at only this single location as it is a univalent inhibitor. There is activity against both free and clot-bound thrombin, with no activity against factor Xa or plasmin. In a study of anticoagulation for PCI using historical controls (HIT patients treated with heparin), argatroban resulted in improved clinical outcomes and no increase in hemorrhagic complications. Standard dosing is 2 mg/kg/min intravenously, and the drug is titrated to achieve an aPTT of 1.5 to 3 times control and may be monitored at point-of-care via the ACT. Argatroban undergoes hepatic metabolism and excretion. It is a reversible inhibitor, with a half-life of 40 to 50 minutes, allowing rapid restoration of coagulation after infusion. Given that it is not renally cleared, it has a predictable effect in patients with renal insufficiency. There is no specific antidote for argatroban, and administration should be discontinued if suspicion of overdosage or hemorrhagic complication exists. In the setting of PCI, argatroban is approved for use in patients with HIT and has been used at a dose of 25 µg/kg/min after a 350 µg/kg initial bolus and titrated to an ACT of 250 to 300 seconds. The results in these patients are comparable to those in historical heparin controls.
Another direct thrombin inhibitor, bivalirudin, has been more extensively studied in PCI than the others but not in placebo-controlled trials. It has been evaluated as a safe and effective foundation anticoagulant for use in PCI. Bivalirudin (Angiomax The Medicines Company, Parsippany, NJ; previous name hirulog) has been studied in subtherapeutic doses (Thrombin Inhibition in Myocardial Ischemia [TIMI] 7), and in heparin-controlled trials (Hirulog and Early Reperfusion or Occlusion [HERO]-2, TIMI 8). In a large (5,674 patients) meta-analysis of six studies looking at outcomes after myocardial infarction, bivalirudin was associated with a significant reduction in the composite of death or infarction and in major hemorrhage. The HERO-11 trial evaluated angiography in patients undergoing fibrinolysis, and the HERO-2 trial specifically evaluated bivalirudin in PCI. Compared with heparin, bivalirudin failed to reduce mortality but reduced the postprocedure myocardial reinfarction rate. The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Outcomes (REPLACE)-2 trial compared bivalirudin with provisional glycoprotein IIb-IIIa inhibition with heparin with glycoprotein IIb-IIIa inhibition during PCI. The dose of bivalirudin in this study was a 0.75 mg/kg bolus and a subsequent 1.75 mg/kg/h infusion. Only 7.2% of patients in the bivalirudin group received IIb-IIIa inhibitors, and there were similar 30-day outcomes in both groups.
Warfarin sodium is the most commonly prescribed oral anticoagulant. Its use is complicated by a narrow therapeutic window and significant risk of hemorrhage at therapeutic concentrations. Dosing is difficult and requires frequent invasive monitoring. Alternatives to this oral option have been slow to come. Ximelagatran, an oral prodrug of the DTI melagatran, had shown efficacy in the prevention and treatment of venous thromboembolism, as well as stroke prevention in patients with atrial fibrillation. Despite its efficacy and promise, ximelegatran has been withdrawn owing to hepatic toxicity.
In summary, despite the safety profile and long history of heparin use, there are drawbacks that mandate that we continue to look for alternatives for our patients. Direct inhibition of thrombin may offer similar anticoagulant properties but also impact the underlying disease process. As we continue to gain experience and develop new DTIs, a new balance may be struck among cost, safety, and efficacy. Additional studies are still required to further our understanding of these important pharmacologic adjuncts.
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