- Email: [email protected]
Recent advances in anticoagulant therapy for acute coronary syndromes
Recent advances in anticoagulant therapy for acute coronary syndromes Eric Topol, MD Cleveland, Ohio
Background Despite major advances in the treatment of acute coronary syndromes (ACS), ischemic heart disease is still the leading cause of death in the industrialized world. Although unfractionated heparin (UFH) has been the anticoagulant of choice in ACS treatments, both low-molecular-weight heparins and direct thrombin inhibitors are at least as effective as UFH in comparative clinical trials. UFH has been linked to a discontinuation rebound in thrombin generation, which is associated with greater ischemic end points than those with the direct thrombin inhibitor hirudin. Furthermore, UFH can increase platelet activation in ACS. Methods This review summarizes the investigation of new molecular approaches to further improve clinical outcomes in ACS.
Results The more recently developed synthetic pentasaccharide Org31540/SR90107A provides potent antithrombotic activity through selective inhibition of Factor Xa by high-affinity binding to antithrombin III. Unlike UFH, the pentasaccharide does not bind platelet factor 4 and is not associated with platelet activation. New approaches to coronary thrombosis prevention/treatment that involve inhibition higher up the extrinsic coagulation pathway have been suggested. In view of its undesirable features, UFH may become obsolete with the advent of newer antithrombotic agents.
Conclusions Applications for the pentasaccharide and other new anticoagulants await results from definitive, largescale trials. (Am Heart J 2001;142:S22-9.)
Coronary arterial thrombosis is the principal therapeutic target in acute myocardial infarction (AMI)1-3 and other acute coronary syndromes (ACS).4,5 Even before the thrombolytic era, antithrombotic drugs, specifically heparin, warfarin, and aspirin, played a role in the treatment of acute ischemic heart disease. In the modern era of AMI treatment, the usefulness of all three agents, both with and without coronary recanalization, has been validated by large-scale clinical trials, as reviewed by Van de Werf (see Van de Werf, p. S16). Unfractionated heparin (UFH), the backbone of anticoagulant therapy in ACS for many years, is prepared from porcine intestine in a multistep process. In contrast, many of the new antithrombotic agents are prepared by highly refined chemical and biochemical synthetic processes. There are, however, other factors that make UFH a less-than-optimal therapeutic agent. The antithrombotic activity of heparin is attributed to a specific pentasaccharide (PS) that is present on approximately one third of the heparin molecules. By depolymerizing the parent heparin molecule, smaller From the Department of Cardiology, the Cleveland Clinic, Cleveland, Ohio. Reprint requests: Eric J. Topol, MD, Department of Cardiology, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: topole@ ccf.org Copyright © 2001 by Mosby, Inc. 0002-8703/2001/$35.00 + 0 4/0/117034 doi:10.1067/mhj.2001.117034
low-molecular-weight compounds are obtained, of which approximately 20% contain the specific PS. These low-molecular-weight heparins (LMWHs) have been shown to have heightened clinical efficacy for the prevention and treatment of venous thrombosis and pulmonary embolism.
Thrombin hypothesis The thrombin hypothesis was tested in the Global Use of Strategies to Open Occluded Arteries (GUSTO) II trial by directly comparing a direct thrombin inhibitor (DTI), which acts on both clot-bound and circulating thrombin, with heparin, which acts only on circulating thrombin. However, this study only tested the direct effects of the thrombin activation component of the thrombin hypothesis, because DTIs do not inhibit thrombin generation. Thrombolysis in Myocardial Infarction (TIMI) 9B and GUSTO IIb—two large trials that evaluated more than 15,000 patients with AMI or unstable angina comparing potent thrombin inhibitors with standard UFH—did not find a statistically significant difference in death or myocardial infarction (MI) at 30 days.6,7 These results have been interpreted as not supporting the thrombin hypothesis.8,9 However, in GUSTO IIb, certain important therapeutic differences were seen between the thrombin inhibitor desirudin and heparin. Figure 1 demon-
American Heart Journal Volume 142, Number 2
Topol S23
Figure 1
Kaplan-Meier estimate of probability of death or myocardial infarction (MI) or reinfarction during first 72 hours after random assignment in GUSTO IIb. (Adapted with permission from Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO] IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996;335:775-82. Copyright © 1996 Massachusetts Medical Society. All rights reserved.)
Figure 2
Desirubin in GUSTO IIb Acute Coronary Syndromes Trial: Death or myocardial infarction (MI) at 30 days. (Adapted with permission from Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO] IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996;335:775-82. Copyright © 1996 Massachusetts Medical Society. All rights reserved.)
strates the risk of death or MI for the first 72 hours after beginning treatment.6 There was, in fact, a substantial decrease in these end points; patients who received desirudin were 27% less likely to be adversely affected after 3 days than patients who received heparin. After
the first 24 hours, the difference in death or MI was 1.3% versus 2.1% (P = .001) for desirudin and heparin, respectively.6 However, by 30 days, these differences were no longer evident (Figure 2) for all patients with ACS, with or without ST-segment elevation.6 Another
American Heart Journal August 2001
S24 Topol
Figure 3
Effect of hirudin and heparin on cardiovascular death or myocardial infarction up to 35 days in OASIS-2. (Adapted with permission from Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Effects of recombinant hirudin [lepirudin] compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Lancet 1999;353:429-38. Copyright © 1999 by The Lancet Ltd.)
Figure 4
Blocking thrombin. APC, Activated protein C; FPA, fibrinopeptide A; TFPI, tissue factor pathway inhibitor.
recent clinical trial, Organization to Assess Strategies for Ischemic Syndromes (OASIS)-2, found similar results, with an early benefit in favor of hirudin, but no statistically significant difference in cardiovascular death or new MI at either 7 days or 35 days in a subgroup of patients with ACS who were randomly assigned to treat-
ment with either hirudin or heparin (Figure 3).10 These findings suggest that an agent that only blocks thrombin activation for a brief period will not produce a substantial, lasting benefit. How can the thrombin hypothesis be fully tested in light of these clinical trial results? Figure 4 is a representation of the two pivotal aspects of thrombin: its generation by prothrombin and its activity. The right side of the figure demonstrates the antithrombin effect of interfering with thrombin activity with DTIs derived from hirudin. During this process, fibrinopeptide A is released and can serve as a marker for antithrombin activity. The left side of the figure shows thrombin generation from prothrombin, an enzymatic process catalyzed by coagulation Factor Xa. This reaction is marked by the production of the cleavage peptide prothrombin F1.2. Antithrombotic drugs such as UFH, LMWHs, and newer synthetic agents block thrombin generation. Importantly, agents blocking the coagulation cascade upstream of thrombin—such as inhibitors of Factor Xa or Factor VII or enhancers of endogenous inhibition such as activated protein C or tissue factor pathway inhibitor—will function as antithrombotic agents by reducing circulating thrombin levels, reflected by lower F1.2, not thrombin activity. When the prothrombin F1.2 levels of several hundred patients from the GUSTO IIb trial were analyzed, the levels were found to be lowered by heparin only while the drug was used; when the heparin was discontinued, F1.2 levels rose, surpassing the levels in the
American Heart Journal Volume 142, Number 2
Topol S25
Figure 5
GUSTO IIb: Effect of rebound on outcome. MI, Myocardial infarction.
Image available in print only
patients receiving desirudin. The comparable thrombotic benefits of the two drugs are lost as thrombin generation is no longer blocked. In the clinical sequelae (Figure 5), the F1.2 levels are correlated with the out-
comes of death and MI at 30 days. Death or MI at 30 days is significantly associated with F1.2 levels (P = .03), which suggests that elevated thrombin generation may, in fact, be related to adverse clinical outcomes in ACS.
American Heart Journal August 2001
S26 Topol
Figure 7
Risk ratios for death or myocardial infarction (MI) in clinical trials comparing LMWH with UFH.
Platelet activation Patients with ACS have increased platelet activation that decreases with time after the acute event.11 In this setting, the use of heparin, which has a platelet activation effect, could lead to a paradoxic prothrombotic state. Furthermore, by only inhibiting circulating thrombin and leaving clot-bound thrombin unbound, UFH sets up conditions for rebound after discontinuation.12 At high doses especially, UFH clearly increases platelet activation and aggregation, whereas LMWH has only a minimal effect and the DTIs have none. The comparative effects of UFH, LMWH, and the DTI argatroban on the percentage of maximum platelet activation by the platelet agonist adenosine diphosphate and thrombin receptor agonist peptide are shown in Figure 6.12 Only UFH shows a significant increase over saline.
Clinical comparison of LMWHs and DTIs with UFH Although UFH may exhibit several features that may make it clinically undesirable for ACS treatment, its derivatives, the LMWHs, do not appear to share many of these properties. Figure 7 lists 4 clinical trials (approximately 11,000 patients) and compares the outcome measures of death and MI for LMWH versus UFH in ACS. If enoxaparin alone was compared with UFH (Efficacy and Safety of Subcutaneous Enoxaparin for the Non–Q-Wave Coronary Events [ESSENCE] and TIMI IIB), there would be an 18% relative reduction in death and MI. However, if the results of dalteparin (Fragmin in Unstable Coronary Artery Disease, FRIC) and nadroparin (Fraxiparine in
Ischemic Syndrome, FRAXIS) treatment were combined with those of enoxaparin, no statistical benefit would be shown. It is important to point out that the interpretation of data involving standard UFH is complicated by its multiple sites of anticoagulant action. Heparin binds to and enhances the inhibitory effect of the endogenous Factor Xa inhibitor antithrombin III (AT-III). The heparin molecule also contains a contiguous binding site for thrombin itself as well as having some inhibitory effect on the activated coagulation Factors XI, IX, and VII. LMWH, likewise, acts as an inhibitor of thrombin generation (anti–Factor Xa) as well as thrombin activity. DTIs bind clot-bound thrombin. Thus, both LMWHs and DTIs have potential advantages over UFH, which acts only on circulating thrombin. In fact, comparisons in clinical trials of UFH with enoxaparin (ESSENCE and TIMI IIB) and hirudin (GUSTO IIb, OASIS-1, OASIS-2) showed that both enoxaparin and hirudin provided outcome advantages over UFH for death and MI. Despite these advances, and even with the most recent antithrombotic regimens, overall morbidity and mortality rates in ACS remain in the range of 10% or greater. Even the addition of more powerful antiplatelet drugs such as glycoprotein (GP) IIb/IIIa inhibitors has not substantially reduced the risk of adverse clinical outcomes beyond these levels. The recent GUSTO IV study did not show a statistically significant difference at 30 days in death or MI in 7800 patients with ACS who were randomly assigned to receive GPIIb/IIIa inhibitors or placebo (8.7% and 8.0% for GPIIb/IIIa inhibitor and placebo, respectively).
American Heart Journal Volume 142, Number 2
Topol S27
Figure 8
Biochemical properties of Org31540/SR90107A: Platelet activation in plasma from heparin-induced thrombocytopenic patients; venous and arterial thrombosis in rat; and bleeding time in rat. (Reprinted with permission from Petitou M, Hérault J-P, Bernat A, et al. Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature 1999;398:417-22. Copyright © 1999 Macmillan Magazines Ltd.)
Future directions To further improve clinical outcomes in ACS, several new molecular approaches have been investigated. One approach has been an attempt to enhance the assets of the heparin molecule and to reduce its liabilities. A similar approach, discussed earlier, fractionates the parent compound into low-molecular-weight derivatives that retain full antithrombotic activity while lessening the undesirable effects such as platelet activation. Efforts to find the minimal AT-III binding site, the active antithrombotic site for heparin, resulted in the identification of a unique PS that had anti–Factor Xa activity but no antithrombin activity.13 Further enhancements in the chemical synthesis of this molecule yielded a PS with potent anti-Xa activity, Org31540/SR90107A.14 Laboratory evaluation of this compound showed a 5- to 10-fold increase in potency over UFH in arterial and venous thrombosis, with no effect on bleeding time (Figure 8).13 The enhanced clinical efficacy of Org31540/SR90107A over the LMWH enoxaparin is presented by Dr Turpie (see Turpie, p. S9). The emphasis on this new compound derives from the critical role of Factor Xa at the crossroads of the extrinsic and intrinsic clotting systems, leading to the generation of thrombin and fibrin. A second area of interest has been the modulation of coagulation at a higher level in the coagulation cascade than Factor X. Thus it is now possible to inhibit 2 components of the extrinsic system, namely, tissue factor and Factor VII. Factor VII is activated by tissue factor released during vascular damage. Tissue factor can be blocked by a specific antibody, whereas Fac-
Figure 9
Coagulation cascade. TFPI, Tissue factor pathway inhibitor.
tor VIIa can be blocked by upregulation of tissue factor pathway inhibitor (Figure 9). The potential importance of these factors is shown by an “experiment of nature.” Several naturally occurring single nucleotide polymorphisms have been described either in the promotor region (A1A2) or in exon 8 of the Factor VII gene. Figure 1015 gives the frequencies of these two single nucleotide polymorphisms along with the resultant Factor VIIa plasma levels for the wild type, heterozygotes, and homozygotes of each. Results showed that patients with the A2A2 and QQ genotypes had the lowest levels. The effect of the reduced levels of Factor VIIa (as a result of the polymorphisms on the Factor VII gene) and the corresponding risk of MI in patients with coronary artery disease are shown
American Heart Journal August 2001
S28 Topol
Figure 10
Plasma levels of Factor VIIa according to genotype for polymorphism in Factor VII gene. P value is for comparison among patients with given polymorphism. Data from Girelli et al.15
Figure 11
Genotype frequencies for polymorphisms in Factor VII gene in patients with or without history of myocardial infarction. SNP, Single nucleotide polymorphism. Data from Girelli et al.15
in Figure 11.15 There is a statistically significant association with MI for both varieties of heterozygotes (P = .008 for A1A2; P = .01 for RQ); for example, genotypes A1A2 and RQ are protective against MI.15 It is interesting to note that alteration higher up the coagulation cascade ladder appears to be associated with an approximately 50% reduction in the risk of having an MI.
Conclusions UFH has evolved as the standard anticoagulant therapy in ACS. However, this agent has many undesirable features that may eventually make it obsolete. Newer antithrombotic drugs, for inhibition of thrombin generation (LMWHs) and thrombin activity (DTIs), have been introduced and represent significant advances in the treatment of ACS. Furthermore, selective inhibition
American Heart Journal Volume 142, Number 2
upstream in the coagulation cascade at the level of Factor VII or Factor X may lead to still greater clinical success in the future.
References 1. Duguid JB. Thrombosis as a factor in the pathogenesis of coronary atherosclerosis. J Pathol Bacteriol 1946;58:207-12. 2. Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (second of two parts). N Engl J Med 1992;326:310-8. 3. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-402. 4. Mizuno K, Satomura K, Miyamoto A, et al. Angioscopic evaluation of coronary-artery thrombi in acute coronary syndromes. N Engl J Med 1992;326:287-91. 5. TIMI IIIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non–Q-wave myocardial infarction: results of the TIMI IIIB Trial. Circulation 1994;89:1545-56. 6. Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996;335:775-82. 7. Antman EM, for the TIMI 9B Investigators. Hirudin in acute myocardial infarction: Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B Trial. Circulation 1996;94:911-21.
Topol S29
8. White HD. Thrombin hypothesis: the TIMI 9B and GUSTO IIB trials have successfully disproven/proven the thrombin hypothesis. J Thromb Thrombolysis 1997;4:317-9. 9. Andreotti F. The TIMI 9b and GUSTO IIb Trials and the “Thrombin Hypothesis.” J Thromb Thrombolysis 1997;4:311-3. 10. Organisation to Assess Strategies for Ischemic Syndromes (OASIS2) Investigators. Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Lancet 1999;353:429-38. 11. Ault KA, Cannon CP, Mitchell J, et al. Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial. J Am Coll Cardiol 1999;33:634-9. 12. Xiao Z, Théroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecularweight heparin and with a direct thrombin inhibitor. Circulation 1998;97:251-6. 13. Petitou M, Hérault J-P, Bernat A, et al. Synthesis of thrombininhibiting heparin mimetics without side effects. Nature 1999;398: 417-22. 14. Herbert JM, Petitou M, Lormeau JC, et al. SR 90107A/Org 31540, a novel anti-factor Xa antithrombotic agent. Cardiovasc Drug Rev 1997;15:1-26. 15. Girelli D, Russo C, Ferraresi P, et al. Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease. N Engl J Med 2000;343:774-80.
Background Despite major advances in the treatment of acute coronary syndromes (ACS), ischemic heart disease is still the leading cause of death in the industrialized world. Although unfractionated heparin (UFH) has been the anticoagulant of choice in ACS treatments, both low-molecular-weight heparins and direct thrombin inhibitors are at least as effective as UFH in comparative clinical trials. UFH has been linked to a discontinuation rebound in thrombin generation, which is associated with greater ischemic end points than those with the direct thrombin inhibitor hirudin. Furthermore, UFH can increase platelet activation in ACS. Methods This review summarizes the investigation of new molecular approaches to further improve clinical outcomes in ACS.
Results The more recently developed synthetic pentasaccharide Org31540/SR90107A provides potent antithrombotic activity through selective inhibition of Factor Xa by high-affinity binding to antithrombin III. Unlike UFH, the pentasaccharide does not bind platelet factor 4 and is not associated with platelet activation. New approaches to coronary thrombosis prevention/treatment that involve inhibition higher up the extrinsic coagulation pathway have been suggested. In view of its undesirable features, UFH may become obsolete with the advent of newer antithrombotic agents.
Conclusions Applications for the pentasaccharide and other new anticoagulants await results from definitive, largescale trials. (Am Heart J 2001;142:S22-9.)
Coronary arterial thrombosis is the principal therapeutic target in acute myocardial infarction (AMI)1-3 and other acute coronary syndromes (ACS).4,5 Even before the thrombolytic era, antithrombotic drugs, specifically heparin, warfarin, and aspirin, played a role in the treatment of acute ischemic heart disease. In the modern era of AMI treatment, the usefulness of all three agents, both with and without coronary recanalization, has been validated by large-scale clinical trials, as reviewed by Van de Werf (see Van de Werf, p. S16). Unfractionated heparin (UFH), the backbone of anticoagulant therapy in ACS for many years, is prepared from porcine intestine in a multistep process. In contrast, many of the new antithrombotic agents are prepared by highly refined chemical and biochemical synthetic processes. There are, however, other factors that make UFH a less-than-optimal therapeutic agent. The antithrombotic activity of heparin is attributed to a specific pentasaccharide (PS) that is present on approximately one third of the heparin molecules. By depolymerizing the parent heparin molecule, smaller From the Department of Cardiology, the Cleveland Clinic, Cleveland, Ohio. Reprint requests: Eric J. Topol, MD, Department of Cardiology, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: topole@ ccf.org Copyright © 2001 by Mosby, Inc. 0002-8703/2001/$35.00 + 0 4/0/117034 doi:10.1067/mhj.2001.117034
low-molecular-weight compounds are obtained, of which approximately 20% contain the specific PS. These low-molecular-weight heparins (LMWHs) have been shown to have heightened clinical efficacy for the prevention and treatment of venous thrombosis and pulmonary embolism.
Thrombin hypothesis The thrombin hypothesis was tested in the Global Use of Strategies to Open Occluded Arteries (GUSTO) II trial by directly comparing a direct thrombin inhibitor (DTI), which acts on both clot-bound and circulating thrombin, with heparin, which acts only on circulating thrombin. However, this study only tested the direct effects of the thrombin activation component of the thrombin hypothesis, because DTIs do not inhibit thrombin generation. Thrombolysis in Myocardial Infarction (TIMI) 9B and GUSTO IIb—two large trials that evaluated more than 15,000 patients with AMI or unstable angina comparing potent thrombin inhibitors with standard UFH—did not find a statistically significant difference in death or myocardial infarction (MI) at 30 days.6,7 These results have been interpreted as not supporting the thrombin hypothesis.8,9 However, in GUSTO IIb, certain important therapeutic differences were seen between the thrombin inhibitor desirudin and heparin. Figure 1 demon-
American Heart Journal Volume 142, Number 2
Topol S23
Figure 1
Kaplan-Meier estimate of probability of death or myocardial infarction (MI) or reinfarction during first 72 hours after random assignment in GUSTO IIb. (Adapted with permission from Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO] IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996;335:775-82. Copyright © 1996 Massachusetts Medical Society. All rights reserved.)
Figure 2
Desirubin in GUSTO IIb Acute Coronary Syndromes Trial: Death or myocardial infarction (MI) at 30 days. (Adapted with permission from Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO] IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996;335:775-82. Copyright © 1996 Massachusetts Medical Society. All rights reserved.)
strates the risk of death or MI for the first 72 hours after beginning treatment.6 There was, in fact, a substantial decrease in these end points; patients who received desirudin were 27% less likely to be adversely affected after 3 days than patients who received heparin. After
the first 24 hours, the difference in death or MI was 1.3% versus 2.1% (P = .001) for desirudin and heparin, respectively.6 However, by 30 days, these differences were no longer evident (Figure 2) for all patients with ACS, with or without ST-segment elevation.6 Another
American Heart Journal August 2001
S24 Topol
Figure 3
Effect of hirudin and heparin on cardiovascular death or myocardial infarction up to 35 days in OASIS-2. (Adapted with permission from Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Effects of recombinant hirudin [lepirudin] compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Lancet 1999;353:429-38. Copyright © 1999 by The Lancet Ltd.)
Figure 4
Blocking thrombin. APC, Activated protein C; FPA, fibrinopeptide A; TFPI, tissue factor pathway inhibitor.
recent clinical trial, Organization to Assess Strategies for Ischemic Syndromes (OASIS)-2, found similar results, with an early benefit in favor of hirudin, but no statistically significant difference in cardiovascular death or new MI at either 7 days or 35 days in a subgroup of patients with ACS who were randomly assigned to treat-
ment with either hirudin or heparin (Figure 3).10 These findings suggest that an agent that only blocks thrombin activation for a brief period will not produce a substantial, lasting benefit. How can the thrombin hypothesis be fully tested in light of these clinical trial results? Figure 4 is a representation of the two pivotal aspects of thrombin: its generation by prothrombin and its activity. The right side of the figure demonstrates the antithrombin effect of interfering with thrombin activity with DTIs derived from hirudin. During this process, fibrinopeptide A is released and can serve as a marker for antithrombin activity. The left side of the figure shows thrombin generation from prothrombin, an enzymatic process catalyzed by coagulation Factor Xa. This reaction is marked by the production of the cleavage peptide prothrombin F1.2. Antithrombotic drugs such as UFH, LMWHs, and newer synthetic agents block thrombin generation. Importantly, agents blocking the coagulation cascade upstream of thrombin—such as inhibitors of Factor Xa or Factor VII or enhancers of endogenous inhibition such as activated protein C or tissue factor pathway inhibitor—will function as antithrombotic agents by reducing circulating thrombin levels, reflected by lower F1.2, not thrombin activity. When the prothrombin F1.2 levels of several hundred patients from the GUSTO IIb trial were analyzed, the levels were found to be lowered by heparin only while the drug was used; when the heparin was discontinued, F1.2 levels rose, surpassing the levels in the
American Heart Journal Volume 142, Number 2
Topol S25
Figure 5
GUSTO IIb: Effect of rebound on outcome. MI, Myocardial infarction.
Image available in print only
patients receiving desirudin. The comparable thrombotic benefits of the two drugs are lost as thrombin generation is no longer blocked. In the clinical sequelae (Figure 5), the F1.2 levels are correlated with the out-
comes of death and MI at 30 days. Death or MI at 30 days is significantly associated with F1.2 levels (P = .03), which suggests that elevated thrombin generation may, in fact, be related to adverse clinical outcomes in ACS.
American Heart Journal August 2001
S26 Topol
Figure 7
Risk ratios for death or myocardial infarction (MI) in clinical trials comparing LMWH with UFH.
Platelet activation Patients with ACS have increased platelet activation that decreases with time after the acute event.11 In this setting, the use of heparin, which has a platelet activation effect, could lead to a paradoxic prothrombotic state. Furthermore, by only inhibiting circulating thrombin and leaving clot-bound thrombin unbound, UFH sets up conditions for rebound after discontinuation.12 At high doses especially, UFH clearly increases platelet activation and aggregation, whereas LMWH has only a minimal effect and the DTIs have none. The comparative effects of UFH, LMWH, and the DTI argatroban on the percentage of maximum platelet activation by the platelet agonist adenosine diphosphate and thrombin receptor agonist peptide are shown in Figure 6.12 Only UFH shows a significant increase over saline.
Clinical comparison of LMWHs and DTIs with UFH Although UFH may exhibit several features that may make it clinically undesirable for ACS treatment, its derivatives, the LMWHs, do not appear to share many of these properties. Figure 7 lists 4 clinical trials (approximately 11,000 patients) and compares the outcome measures of death and MI for LMWH versus UFH in ACS. If enoxaparin alone was compared with UFH (Efficacy and Safety of Subcutaneous Enoxaparin for the Non–Q-Wave Coronary Events [ESSENCE] and TIMI IIB), there would be an 18% relative reduction in death and MI. However, if the results of dalteparin (Fragmin in Unstable Coronary Artery Disease, FRIC) and nadroparin (Fraxiparine in
Ischemic Syndrome, FRAXIS) treatment were combined with those of enoxaparin, no statistical benefit would be shown. It is important to point out that the interpretation of data involving standard UFH is complicated by its multiple sites of anticoagulant action. Heparin binds to and enhances the inhibitory effect of the endogenous Factor Xa inhibitor antithrombin III (AT-III). The heparin molecule also contains a contiguous binding site for thrombin itself as well as having some inhibitory effect on the activated coagulation Factors XI, IX, and VII. LMWH, likewise, acts as an inhibitor of thrombin generation (anti–Factor Xa) as well as thrombin activity. DTIs bind clot-bound thrombin. Thus, both LMWHs and DTIs have potential advantages over UFH, which acts only on circulating thrombin. In fact, comparisons in clinical trials of UFH with enoxaparin (ESSENCE and TIMI IIB) and hirudin (GUSTO IIb, OASIS-1, OASIS-2) showed that both enoxaparin and hirudin provided outcome advantages over UFH for death and MI. Despite these advances, and even with the most recent antithrombotic regimens, overall morbidity and mortality rates in ACS remain in the range of 10% or greater. Even the addition of more powerful antiplatelet drugs such as glycoprotein (GP) IIb/IIIa inhibitors has not substantially reduced the risk of adverse clinical outcomes beyond these levels. The recent GUSTO IV study did not show a statistically significant difference at 30 days in death or MI in 7800 patients with ACS who were randomly assigned to receive GPIIb/IIIa inhibitors or placebo (8.7% and 8.0% for GPIIb/IIIa inhibitor and placebo, respectively).
American Heart Journal Volume 142, Number 2
Topol S27
Figure 8
Biochemical properties of Org31540/SR90107A: Platelet activation in plasma from heparin-induced thrombocytopenic patients; venous and arterial thrombosis in rat; and bleeding time in rat. (Reprinted with permission from Petitou M, Hérault J-P, Bernat A, et al. Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature 1999;398:417-22. Copyright © 1999 Macmillan Magazines Ltd.)
Future directions To further improve clinical outcomes in ACS, several new molecular approaches have been investigated. One approach has been an attempt to enhance the assets of the heparin molecule and to reduce its liabilities. A similar approach, discussed earlier, fractionates the parent compound into low-molecular-weight derivatives that retain full antithrombotic activity while lessening the undesirable effects such as platelet activation. Efforts to find the minimal AT-III binding site, the active antithrombotic site for heparin, resulted in the identification of a unique PS that had anti–Factor Xa activity but no antithrombin activity.13 Further enhancements in the chemical synthesis of this molecule yielded a PS with potent anti-Xa activity, Org31540/SR90107A.14 Laboratory evaluation of this compound showed a 5- to 10-fold increase in potency over UFH in arterial and venous thrombosis, with no effect on bleeding time (Figure 8).13 The enhanced clinical efficacy of Org31540/SR90107A over the LMWH enoxaparin is presented by Dr Turpie (see Turpie, p. S9). The emphasis on this new compound derives from the critical role of Factor Xa at the crossroads of the extrinsic and intrinsic clotting systems, leading to the generation of thrombin and fibrin. A second area of interest has been the modulation of coagulation at a higher level in the coagulation cascade than Factor X. Thus it is now possible to inhibit 2 components of the extrinsic system, namely, tissue factor and Factor VII. Factor VII is activated by tissue factor released during vascular damage. Tissue factor can be blocked by a specific antibody, whereas Fac-
Figure 9
Coagulation cascade. TFPI, Tissue factor pathway inhibitor.
tor VIIa can be blocked by upregulation of tissue factor pathway inhibitor (Figure 9). The potential importance of these factors is shown by an “experiment of nature.” Several naturally occurring single nucleotide polymorphisms have been described either in the promotor region (A1A2) or in exon 8 of the Factor VII gene. Figure 1015 gives the frequencies of these two single nucleotide polymorphisms along with the resultant Factor VIIa plasma levels for the wild type, heterozygotes, and homozygotes of each. Results showed that patients with the A2A2 and QQ genotypes had the lowest levels. The effect of the reduced levels of Factor VIIa (as a result of the polymorphisms on the Factor VII gene) and the corresponding risk of MI in patients with coronary artery disease are shown
American Heart Journal August 2001
S28 Topol
Figure 10
Plasma levels of Factor VIIa according to genotype for polymorphism in Factor VII gene. P value is for comparison among patients with given polymorphism. Data from Girelli et al.15
Figure 11
Genotype frequencies for polymorphisms in Factor VII gene in patients with or without history of myocardial infarction. SNP, Single nucleotide polymorphism. Data from Girelli et al.15
in Figure 11.15 There is a statistically significant association with MI for both varieties of heterozygotes (P = .008 for A1A2; P = .01 for RQ); for example, genotypes A1A2 and RQ are protective against MI.15 It is interesting to note that alteration higher up the coagulation cascade ladder appears to be associated with an approximately 50% reduction in the risk of having an MI.
Conclusions UFH has evolved as the standard anticoagulant therapy in ACS. However, this agent has many undesirable features that may eventually make it obsolete. Newer antithrombotic drugs, for inhibition of thrombin generation (LMWHs) and thrombin activity (DTIs), have been introduced and represent significant advances in the treatment of ACS. Furthermore, selective inhibition
American Heart Journal Volume 142, Number 2
upstream in the coagulation cascade at the level of Factor VII or Factor X may lead to still greater clinical success in the future.
References 1. Duguid JB. Thrombosis as a factor in the pathogenesis of coronary atherosclerosis. J Pathol Bacteriol 1946;58:207-12. 2. Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (second of two parts). N Engl J Med 1992;326:310-8. 3. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-402. 4. Mizuno K, Satomura K, Miyamoto A, et al. Angioscopic evaluation of coronary-artery thrombi in acute coronary syndromes. N Engl J Med 1992;326:287-91. 5. TIMI IIIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non–Q-wave myocardial infarction: results of the TIMI IIIB Trial. Circulation 1994;89:1545-56. 6. Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996;335:775-82. 7. Antman EM, for the TIMI 9B Investigators. Hirudin in acute myocardial infarction: Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B Trial. Circulation 1996;94:911-21.
Topol S29
8. White HD. Thrombin hypothesis: the TIMI 9B and GUSTO IIB trials have successfully disproven/proven the thrombin hypothesis. J Thromb Thrombolysis 1997;4:317-9. 9. Andreotti F. The TIMI 9b and GUSTO IIb Trials and the “Thrombin Hypothesis.” J Thromb Thrombolysis 1997;4:311-3. 10. Organisation to Assess Strategies for Ischemic Syndromes (OASIS2) Investigators. Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Lancet 1999;353:429-38. 11. Ault KA, Cannon CP, Mitchell J, et al. Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial. J Am Coll Cardiol 1999;33:634-9. 12. Xiao Z, Théroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecularweight heparin and with a direct thrombin inhibitor. Circulation 1998;97:251-6. 13. Petitou M, Hérault J-P, Bernat A, et al. Synthesis of thrombininhibiting heparin mimetics without side effects. Nature 1999;398: 417-22. 14. Herbert JM, Petitou M, Lormeau JC, et al. SR 90107A/Org 31540, a novel anti-factor Xa antithrombotic agent. Cardiovasc Drug Rev 1997;15:1-26. 15. Girelli D, Russo C, Ferraresi P, et al. Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease. N Engl J Med 2000;343:774-80.