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Beyond Heparin and Aspirin
New Treatments for Unstable Angina and Non–Q-Wave Myocardial Infarction
Jeffrey I. Weitz, MD;
Shannon M. Bates, MD
Arch Intern Med. 2000;160:749-758.
ABSTRACT
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The goals of therapy for unstable angina and non–Q-wave myocardial infarction (MI) are to maintain myocardial perfusion by inhibiting platelet aggregation and fibrin deposition at sites of plaque rupture, thereby preventing ongoing or new myocardial ischemia and cardiac death. Although aspirin and heparin sodium are cornerstones in the management of unstable angina and non–Q-wave MI, both have significant limitations that have prompted the development of new agents. The thienopyridines, ticlopidine hydrochloride and clopidogrel, appear to be at least as effective as aspirin in the management of unstable angina. Glycoprotein IIb/IIIa receptor antagonists are a new class of platelet inhibitors that are more potent than aspirin, because they target the final common pathway of platelet aggregation. Low-molecular-weight heparins provide a more stable pharmacodynamic response and are more convenient to use than unfractionated heparin. Direct thrombin inhibitors show promise for inhibiting thrombin-mediated platelet aggregation and fibrin deposition. We focus on the opportunities presented by these agents, detailing mechanisms of action, advantages over aspirin and heparin, and performance in recent clinical trials.
INTRODUCTION
Patients with unstable angina pectoris are a heterogeneous group, encompassing those with progressive or accelerating angina and high-risk patients with angina at rest and reversible ST-segment changes on their electrocardiogram.1 Disruption of atherosclerotic plaque and superimposed thrombosis are fundamental steps in the pathogenesis of unstable angina. Rupture of the plaque exposes thrombogenic components, such as collagen, lipids, macrophages, tissue factor, and surface-bound von Willebrand factor, to intraluminal blood (Figure 1). Platelets adhere to exposed collagen and von Willebrand factor, where they become activated and recruit additional platelets by synthesizing thromboxane A2 and releasing adenosine diphosphate (ADP). Platelet activation induces a conformational change in glycoprotein IIb/IIIa (GPIIb/IIIa) that, by ligating fibrinogen, cross-links adjacent platelets.2-6 Exposure of blood to tissue factor in the necrotic core of the plaque activates the coagulation cascade and leads to the generation of thrombin. In addition to converting fibrinogen to fibrin, thrombin activates factor XIII, which stabilizes the fibrin clot. Thrombin also activates factors V and VIII, which promote further thrombin generation.2-6 A potent platelet agonist, thrombin activates platelets and contributes to the formation of a platelet-rich thrombus, the so-called white thrombus. Depending on the extent of activation of coagulation and the degree of stasis in the affected artery, a fibrin- and erythrocyte-rich thrombus (red thrombus) may develop and extend upstream or downstream from the ruptured plaque.1, 3 Because white thrombus is typically labile, the thrombus may be degraded rapidly so that only partial occlusion of the lumen occurs,7 leading to unstable angina with or without rest pain. Alternatively, the thrombus may become incorporated into the plaque, causing its growth (Figure 2). Persistence of a nonocclusive thrombus or development of an occlusive thrombus, with or without associated vasoconstriction, can result in non–Q-wave or Q-wave myocardial infarction (MI).8
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Figure 1. Arterial thrombogenesis. Aspirin inhibits thromboxane A2 synthesis, whereas ticlopidine hydrochloride and clopidogrel block the platelet adenosine diphosphate (ADP) receptor. Glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists block the final common pathway of platelet aggregation, preventing aggregation in response to thromboxane A2, ADP, and thrombin. Direct thrombin inhibitors bind and inactivate thrombin.
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Figure 2. Consequences of plaque rupture.
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Disrupted plaques are found beneath 75% of the thrombi responsible for acute coronary artery syndromes.5 After plaque disruption, hemorrhage into the plaque, luminal thrombosis, and/or vasospasm may cause sudden flow obstruction and result in new symptoms.5 Among patients with unstable angina who receive treatment, 1% to 5% die, and 2% to 10% experience an MI within the first 28 days after hospital admission.9
Usual treatment for unstable angina includes aspirin, for its platelet-inhibitory effects, heparin sodium to block the generation and activity of thrombin, or a combination of both.10-14 Despite this treatment, the number of patients in whom an MI develops underscores the limitations of current therapy. Because it only inhibits thromboxane A2–dependent platelet aggregation, aspirin incompletely blocks platelet aggregation triggered by collagen exposed at sites of vascular injury or by thrombin generated as a consequence of plaque rupture. Consequently, more potent inhibitors of platelet aggregation have been developed. These include the thienopyridines, ticlopidine hydrochloride and clopidogrel, and GPIIb/IIIa antagonists.
Unfractionated heparin also has limitations in patients with unstable angina. It produces an unpredictable anticoagulant response, making careful laboratory monitoring necessary to ensure that a therapeutic heparin level is achieved. Heparin is neutralized by platelet factor 4, large quantities of which are released from platelets activated at sites of plaque rupture.15 In addition, heparin is unable to inactivate activated factor X (factor Xa) bound to activated platelets trapped within the thrombus.16 Bound factor Xa activates prothrombin, and the resultant thrombin then binds to fibrin, where it also is protected from inactivation by heparin. Fibrin-bound thrombin remains enzymatically active17 and causes thrombus growth by locally activating platelets18 and amplifying coagulation.19 Low-molecular-weight heparin (LMWH) preparations and direct thrombin inhibitors were developed to overcome the limitations of unfractionated heparin.
NEW ALTERNATIVES TO ASPIRIN
ADP Receptor Antagonists
Ticlopidine and clopidogrel irreversibly inhibit the ADP receptor on platelets, thereby blocking ADP-dependent platelet activation.20-21 Ticlopidine, the first of these agents to be developed, was better than placebo at reducing the risk for stroke, MI, and vascular death in patients with atherosclerotic disease.22-23 When compared with aspirin, ticlopidine reduced the risk for stroke, MI, and vascular death by 10%, a reduction that was not statistically significant.22 Side effects of ticlopidine include bone marrow suppression, diarrhea, and rash. The most serious adverse effects, severe reversible neutropenia and thrombotic thrombocytopenic purpura, necessitate complete blood cell counts every 2 weeks during the first 3 months of therapy.
Clopidogrel, an analogue of ticlopidine,21 can be given once daily.21, 24 It has an overall safety profile that is at least as good as that of aspirin and is superior to that of ticlopidine.24 Neutropenia and thrombotic thrombocytopenic purpura are rare, making blood cell count monitoring unnecessary.24 Like aspirin, however, clopidogrel and ticlopidine inhibit only 1 mechanism of platelet aggregation, leaving several others unchecked.25
Because platelet activation in response to collagen is mediated by thromboxane A2 and ADP, the combination of aspirin and a thienopyridine derivative may be better than either agent alone. This combination is used widely in patients undergoing coronary stent insertion, where it has been shown to be superior to aspirin alone or aspirin plus warfarin sodium.26
Thromboxane Synthase Inhibitors and Thromboxane A2 Receptor Antagonists
Unlike aspirin, thromboxane synthase inhibitors block the generation of thromboxane A2 without affecting prostacyclin synthesis. Since inhibition of prostacylin synthesis has the potential to promote thrombogenesis, these more selective agents should, in theory, be more effective than aspirin. Studies in laboratory animals, however, did not demonstrate the expected superiority of these drugs. Agents that combine thromboxane A2 synthase inhibition and thromboxane A2 receptor blockade were developed to prevent prostaglandin endoperoxide intermediates that accumulate when thromboxane A2 synthase is inhibited from acting as an agonist for thromboxane A2 receptors on platelets. Although one of these combined inhibitors, ridogrel, demonstrated efficacy in a phase 2 study, none has been evaluated in a phase 3 clinical trial.27
GPIIb/IIIa Receptor Antagonists
A new class of agents—the GPIIb/IIIa receptor antagonists—has shown promise for the treatment of unstable angina and non–Q-wave MI. By inhibiting fibrinogen binding to GPIIb/IIIa, these agents block the final common pathway of platelet aggregation. Although GPIIb/IIIa receptor antagonists inhibit platelet aggregation induced by all agonists, they do not block coagulation factor assembly that occurs on the surface of activated platelets and that results in thrombin generation. Consequently, GPIIb/III antagonists may need to be used in combination with agents that block thrombin generation or activity.
The GPIIb/IIIa receptors can be blocked with monoclonal antibodies against GPIIb/IIIa or with synthetic GPIIb/IIIa antagonists. Abciximab (ReoPro; Centocor, Malvern, Pa) is the only monoclonal antibody against GPIIb/IIIa that has undergone extensive clinical testing. The 2 synthetic GPIIb/IIIa antagonists that are approved for clinical use are eptifibatide (Integrelin; COR Therapeutics, South San Francisco, Calif) and tirofiban hydrochloride (Aggrastat; Merck, White House Station, NJ). All must be given intravenously. Each will be discussed briefly in turn.
Abciximab is a recombinant chimeric monoclonal antibody fragment that blocks GPIIb/IIIa receptors.28 Abciximab also blocks the closely related vitronectin receptor,  v 3.29 Although it is uncertain whether inhibition of v3 contributes to the effectiveness of abciximab in humans, in laboratory animals v3 blockade attenuates injury-induced smooth muscle migration and neointimal hyperplasia.30 Abciximab has been approved as an adjunct to percutaneous coronary interventions in high-risk patients, including those with unstable angina refractory to medical therapy. In an early study, abciximab reduced ischemic episodes in this patient population and decreased the complication rate during subsequent percutaneous transluminal coronary angioplasty (PTCA).31
A potential drawback to abciximab is its immunogenicity. The original formulation of this compound, a murine antibody, was associated with a relatively high incidence of immunogenicity and anti–murine antibody formation. The chimeric antibody fragment currently available is much less immunogenic. Nevertheless, low titers of human antichimeric antibodies specific to the murine epitope of the antibody fragment will develop in approximately 6.5% of patients receiving abciximab.32 Antibody titers peak 1 week to 1 month after abciximab administration and gradually decline during the ensuing months. The antibodies are IgG and do not appear to interfere with the binding of abciximab to the unoccupied GPIIb/IIIa receptor. The exact clinical significance of positive antibody titers is unclear; the presence of a positive antibody response has not been correlated with any adverse sequelae. Readministration of abciximab does not seem to be associated with a risk for anaphylaxis or diminished clinical benefit. It may, however, increase the risk for thrombocytopenia.32 Although its initial plasma half-life is only 30 minutes after intravenous bolus injection, this rapid clearance reflects its interaction with platelet surface GPIIb/IIIa receptors.33 Maximum receptor blockade and subsequent inhibition of platelet aggregation and prolongation of the bleeding time occur 2 hours after a bolus injection of abciximab and return to near normal levels within 12 hours.33 Small amounts of abciximab, however, can still be detected on circulating platelets 8 to 15 days later, as the antibody redistributes on newly produced platelets.34 The prolonged antihemostatic effect of abciximab has the potential to increase the risk for bleeding, especially in patients who require urgent revascularization for abrupt closure or stent thrombosis.25, 33
Eptifibatide, a cyclic lysine-glycine-aspartic acid (KGD)–containing heptapeptide, is a highly selective inhibitor of GPIIb/IIIa and does not block the vitronectin receptor.32 It has a shorter half-life than abciximab, with bleeding times returning to normal 1 hour after discontinuing eptifibatide infusions.27 Eptifibatide has been approved for treatment of patients with unstable angina or non–Q-wave MI and as adjunctive therapy during PTCA.
A nonpeptide arginine-glycine-aspartic acid (RGD) mimetic, tirofiban is a selective inhibitor of GPIIb/IIIa. Like eptifibatide, tirofiban has a short plasma half-life and provides reversible inhibition of GPIIb/IIIa. Alone or in combination with heparin, tirofiban has been studied in patients with unstable angina. Tirofiban combined with heparin also has been compared with heparin in patients undergoing PTCA or atherectomy.
NEW ALTERNATIVES TO HEPARIN
Low-Molecular-Weight Heparins
Like heparin, LMWHs act as anticoagulants by activating antithrombin.35 The LMWHs are fragments of unfractionated heparin produced by chemical or enzymatic depolymerization.36 A pentasaccharide sequence randomly distributed along the heparin chains mediates the interaction between heparin and antithrombin. Binding of the pentasaccharide to antithrombin causes a conformational change in the latter, accelerating antithrombin-mediated inactivation of thrombin and factor Xa nearly 1000-fold. Because heparin catalysis of factor Xa inhibition by antithrombin does not require bridging between factor Xa and antithrombin, the smaller chains in LMWH retain their ability to catalyze factor Xa inhibition. Unfractionated heparin, therefore, has equivalent activity against factor Xa and thrombin, whereas LMWH exerts greater activity against factor Xa.37
The LMWHs offer better bioavailability than does unfractionated heparin, because they bind less to plasma proteins and endothelium. Lack of both protein and cellular binding endows LMWHs with dose-independent clearance and a longer plasma half-life, permitting once-daily subcutaneous dosing.37 These enhancements result in a more predictable anticoagulant response.15, 37
Although careful laboratory monitoring is essential with unfractionated heparin, no monitoring is necessary with LMWHs. It is probably best to avoid LMWHs in patients with significant renal dysfunction, because these drugs are cleared via the kidneys.37-38 Heparin-induced thrombocytopenia occurs less frequently with LMWHs than with unfractionated heparin,39 and LMWHs may also cause less osteoporosis than unfractionated heparin in long-term therapy.40
Direct Thrombin Inhibitors
Unlike heparin and LMWHs, which act as anticoagulants by activating antithrombin, direct thrombin inhibitors act in an antithrombin-independent manner and bind directly to thrombin, thereby blocking its active site and/or preventing it from interacting with its substrates. The 2 direct thrombin inhibitors that have been studied most extensively are hirudin and bivalirudin. Both agents are bivalent inhibitors of thrombin that bind to the active and the substrate recognition sites (exosite 1) on thrombin. Hirudin forms a slowly reversible complex with thrombin and has a plasma half-life of 40 minutes after intravenous administration, and approximately 120 minutes after subcutaneous injection.27 Bivalirudin has a plasma half-life of 24 minutes after intravenous infusion.41 Unlike hirudin, bivalirudin produces only transient inhibition of the active site of thrombin and may, therefore, be safer.27 In contrast to heparin, direct thrombin inhibitors can inactivate fibrin-bound thrombin as well as free thrombin.17, 42 Furthermore, they produce a more predictable anticoagulant response than unfractionated heparin.43-44 Of both agents, hirudin has been tested in patients with unstable angina and non–Q-wave MI, whereas bivalirudin has been studied as an alternative to heparin in patients undergoing PTCA, including patients undergoing PTCA for ongoing pain after a recent MI.
CLINICAL TRIALS
Thienopyridines
A randomized study, Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE), compared aspirin (325 mg/d) with clopidogrel (75 mg/d) in patients with recent ischemic stroke, recent MI, or symptomatic peripheral artery disease.24 A total of 19 185 patients were enrolled in the study and were observed for 1 to 3 years (mean, 1.9 years). A total of 4059 of the participants withdrew from the study early, 21.3% in the clopidogrel and 21.1% in the aspirin groups, primarily because of adverse events. In those who remained in the study, the end point, a composite of ischemic stroke, MI, or vascular death, occurred in 5.3% of those given clopidogrel and in 5.8% of patients treated with aspirin. This translates into a relative risk reduction (RRR) of 8.7% (P = .04) with clopidogrel. Although this study indicates that long-term clopidogrel therapy is slightly more effective than aspirin therapy in patients with atherosclerotic disease, further studies are needed to define the role of clopidogrel in patients with unstable angina.
GPIIb/IIIa Antagonists
Four trials have evaluated GPIIb/IIIa antagonists in patients with unstable angina and/or non–Q-wave MI. One trial examined the utility of abciximab,45 another studied eptifibatide,46 and 2 trials studied tirofiban.47-48 Each is briefly described below.
The c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) study randomized 1265 patients with refractory unstable angina to abciximab or placebo starting 18 to 24 hours before PTCA and continuing until 1 hour after the procedure.45 All patients received aspirin and heparin. At 30 days, the primary end point, a composite of death, MI, or need for urgent intervention, occurred in 71 (11.3%) of 630 patients given abciximab, compared with 101 (15.9%) of 635 randomized to placebo (P = .01; RRR, 28.9%). Thrombocytopenia (platelet count, <100 x 109/L) occurred in 5.6% of those given abciximab and 1.3% of those receiving placebo. Although the rate of major bleeding episodes was low, major bleeding was more frequent in patients receiving abciximab than in those given placebo (3.8% and 1.9%, respectively; P = .04). Logistic regression analysis revealed that abciximab therapy and heparin dose per kilogram of body weight were significantly related to the risk for major bleeding.
During the 6-month follow-up, slightly more deaths occurred in patients who had received abciximab than in those randomized to placebo (2.8% and 2.2%, respectively), but MI occurred less frequently in those given abciximab compared with placebo (6.6% and 9.3%, respectively). The composite end point of death, MI, and need for revascularization occurred in 193 patients in both groups. Therefore, although abciximab significantly reduced the rate of MI before, during, and within the first few days after PTCA, it provided no significant benefit with respect to any of the outcomes after this period.
The efficacy of eptifibatide in addition to aspirin and heparin in patients with acute coronary syndromes but no electrocardiographic ST-segment elevation was assessed in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrelin Therapy (PURSUIT) study.46 A total of 10 948 patients with unstable angina or non–Q-wave MI were enrolled in the study and randomized to receive placebo or 1 of 2 doses of eptifibatide (180 µg/kg, followed by an infusion of 1.3 µg/kg per minute, or the same loading dose followed by an infusion of 2.0 µg/kg per minute). The low-dose arm of the study was discontinued in July 1996 after 3218 patients had been randomized, when an interim review of safety data demonstrated that the higher dose had an acceptable safety profile.
At 30 days, patients receiving eptifibatide experienced a 1.5% reduction in the primary end point, a composite of death, MI, and need for revascularization compared with those given placebo (14.2% and 15.7%, respectively; RRR, 9.6%; P = .04). Mortality rates were similar in patients given eptifibatide and placebo (3.5% and 3.7%, respectively) as was the incidence of MI (12.6% and 13.5%, respectively). Patients given eptifibatide experienced a significantly higher rate of major bleeding events compared with those given placebo (10.6% and 9.1%, respectively; P = .02).
Tirofiban has been shown to be effective in reducing acute cardiac ischemic events in patients with unstable angina. The Platelet Receptor Inhibition for Ischemic Syndrome Management (PRISM) study compared GPIIb/IIIa antagonist therapy with heparin treatment in patients with unstable angina or non–Q-wave MI.47 The primary end point of the study was the composite of death, MI, or refractory ischemia at 48 hours. Patients were randomly assigned to receive a 48-hour intravenous infusion of tirofiban (loading dose of 0.6 µg/kg per minute for 30 minutes, adjusted downward to 0.15 µg/kg per minute for the next 47.5 hours) or a 5000-U bolus of unfractionated heparin followed by a continuous infusion adjusted to maintain the activated partial thromboplastin time (aPTT) at twice the control value for 48 hours. All patients received aspirin before and for 48 hours after randomization. Thereafter, it was given at the discretion of the physician, unless contraindicated.
After 48 hours of therapy, patients in the tirofiban group had a 32% (P = .01) reduction in the composite outcome of death, MI, or refractory ischemia, compared with patients who received heparin. However, at 30 days, the frequency of the composite end point was similar in both groups (15.9% in those receiving tirofiban and 17.1% in those receiving heparin; RRR, 7.0%; P = .34). At the same time point, 2.3% of patients given tirofiban and 3.6% of those who had received heparin had died (P = .02). Major hemorrhagic complications occurred in 0.4% of patients in both groups. Reversible thrombocytopenia occurred more often with tirofiban (platelet counts, <90 x 109/L in 0.4% of heparin- and 1.1% of tirofiban-treated patients [P = .04]; <50 x 109/L in 0.1% of heparin- and 0.4% of tirofiban-treated patients [P = .04]). This study demonstrates that tirofiban reduced ischemic events in this patient population during the 48-hour infusion period. Although the incidence of refractory ischemia and MI was not reduced at 30 days, mortality was lower among patients given tirofiban (2.3% compared with 3.6% in the heparin group; P = .02).
The nearly 1600 patients enrolled in the Patients Limited to Very Unstable Signs and Symptoms (PRISM-PLUS) study represented a higher risk than those in the PRISM trial.48 All patients in the PRISM-PLUS trial had unstable angina or non–Q-wave MI, as well as ST-segment changes on their electrocardiograms or elevated cardiac enzymes (creatine kinase and creatine kinase myocardial band) and prolonged angina during the 12 hours before enrollment. More than 90% had ST-segment changes on their presenting electrocardiogram compared with 33% in the PRISM study. In addition, 45% had evidence of non–Q-wave MI, whereas only 25% of those in the PRISM study had similar findings.
Patients were randomized to receive tirofiban, heparin, or tirofiban plus heparin. Patients also received aspirin unless its use was contraindicated. Study medications were infused for a mean (±SD) of 71.3 ± 20.0 hours. The study was stopped prematurely for the group receiving tirofiban alone because of excess mortality at 7 days compared with patients treated with heparin (4.6% and 1.1%, respectively).
The frequency of the composite primary end point (death, MI, or refractory ischemia) at 7 days was 32% lower among patients receiving tirofiban plus heparin than among those who received heparin alone (12.9% and 17.9%, respectively; RRR, 27.9%; P = .004). The frequency of death or MI was 4.9% in the tirofiban-plus-heparin group, compared with 8.3% in the heparin-only group (P = .006).
At 30 days, the composite end point of death, acute MI, or refractory ischemia occurred less frequently among patients randomized to combination therapy compared with those in the heparin monotherapy group (18.5% vs 22.3%; P = .03), and the incidence of death and acute MI was decreased by 31% (P = .03). The incidence of death, acute MI, or refractory ischemia remained lower at 6 months among patients who received tirofiban plus heparin than among those who received heparin alone (27.7% vs 32.1%; P = .02). Major bleeding events occurred in 3.0% of heparin-treated patients and 4.0% of those given heparin plus tirofiban (P = .34). Transfusions were somewhat more frequent with the combination therapy than with heparin alone (4.0% and 2.8%, respectively; P = .21).
The PRISM-PLUS trial, therefore, showed that the addition of tirofiban to heparin and aspirin therapy decreased morbidity and mortality in high-risk patients with unstable angina, without compromising safety.
Low-Molecular-Weight Heparins
The promising results of a small trial comparing subcutaneous LMWHs with unfractionated heparin given by continuous intravenous infusion in patients with unstable angina49 prompted a number of large randomized trials of LMWHs in aspirin-treated patients.
The Fragmin During Instability in Coronary Artery Disease (FRISC) trial, a multicenter, double-blind, randomized, placebo-controlled study, assessed the efficacy of adding dalteparin sodium (Fragmin) to aspirin therapy for patients with unstable angina.50-51
A total of 1506 patients (963 men and 543 women) with chest pain, the last episode of which had occurred within the previous 72 hours, and transient or persistent ST-segment depression and/or T-wave inversion of at least 0.1 mV in at least 2 adjacent leads were enrolled in the study. Patients were randomized to placebo or subcutaneous dalteparin sodium (120 anti–factor Xa U/kg body weight twice daily for the first 6 days, and 7500 anti–factor Xa U once daily for 35 to 45 days thereafter).
At 6 days, there was an absolute decrease of 3.0% and a relative reduction of 63% in the primary end point of death or new MI in patients receiving dalteparin therapy (P<.001). Subgroup analyses suggested that the effects of dalteparin were most prominent in nonsmokers, patients with a lower body mass index, and those with non–Q-wave MI at presentation. There was an increased event rate during the initial 3 to 5 days after dose reduction in the active treatment group, which was greatest in smokers. However, after this period, the event rate continued to be lower in the dalteparin group. Although the benefit of LMWH was maintained for 40 days, by 150 days there were no significant differences in the occurrence of death, new MI, or need for revascularization between the groups.
During the acute phase, there were few major bleeding events in either group and no differences between groups. Compliance with outpatient injection treatment was good. After 40 to 50 days of scheduled treatment, 11% of patients in the active treatment group and 8% in the placebo group had terminated the injections at their request. This study, therefore, demonstrated that, when added to aspirin therapy, dalteparin protects against cardiac events in the acute phase of unstable coronary artery disease. Furthermore, because the drug can be administered subcutaneously on an outpatient basis, more prolonged treatment is feasible.
A second study, Fragmin in Unstable Coronary Artery Disease (FRIC), compared the efficacy and safety of subcutaneous dalteparin with intravenous unfractionated heparin in 1482 patients with unstable angina or non–Q-wave MI.52 During the acute phase of the study (days 1-6), 751 patients received dalteparin sodium (120 anti–factor Xa U/kg subcutaneously twice daily), and 731 were given unfractionated heparin (5000-U bolus followed by a continuous infusion at an initial rate of 1000 U/h, then adjusted to maintain the aPTT at 1.5 times the control value). After initial treatment, 1126 patients received prolonged therapy with dalteparin sodium (7500 anti–factor Xa U once daily) or placebo.
During the first 6 days, the rate of death, MI, or recurrence of angina was similar in both groups (7.6% in those treated with unfractionated heparin and 9.3% in those receiving dalteparin; P = .33). The corresponding rates in both treatment groups for the composite end point of death or MI were 3.6% and 3.9%, respectively (P = .80). Adverse events including major bleeding, minor bleeding, thrombocytopenia, and allergic reaction were rare and equally distributed between both groups.
The frequency of the primary outcome (death, MI, or recurrent angina) between days 6 and 45 was 12.3% in both treatment groups. The frequencies of the individual outcomes also were similar. The similarity of event rates was consistent across all predefined patient subgroups, including those with non–Q-wave MI, smokers, and nonsmokers. The rate of adverse events also was equivalent during the chronic phase, with the exception of minor bleeding, which occurred more frequently in the dalteparin group (5.1% vs 2.8% in the placebo group).
Although not powered to demonstrate true equivalence, this study suggests that twice daily subcutaneous dalteparin is an alternative to unfractionated heparin in the acute treatment of unstable angina or non–Q-wave MI. Prolonged treatment with lower-dose, once-daily dalteparin did not provide additional benefit over aspirin in this study.
The Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events (ESSENCE) trial53 was a multicenter trial in which a total of 3171 patients with angina at rest or non–Q-wave MI were randomized to subcutaneous enoxaparin sodium or intravenous unfractionated heparin. Patients in the enoxaparin sodium group received 1 mg/kg (100 anti–factor Xa U/kg) twice daily and a bolus and infusion of placebo. Those in the unfractionated heparin group received subcutaneous placebo injections and unfractionated heparin as a 5000-U bolus followed by a continuous infusion adjusted according to the aPTT. Therapy was continued for a minimum of 48 hours and a maximum of 8 days. All patients received aspirin.
At 14 days, the risk for death, MI, or recurrent angina, the primary end point, was significantly lower in patients assigned to enoxaparin than in those randomized to unfractionated heparin (16.6% vs 19.8%, respectively; RRR, 16.2%; P = .02). At 30 days, the risk for this composite end point remained significantly lower in the enoxaparin group (19.8% vs 23.3% in those receiving unfractionated heparin; P = .02). Although no statistically significant difference was observed between both groups with respect to serious bleeding complications, minor bleeding events were more common in patients treated with enoxaparin than in those given placebo (18.4% vs 14.2%; P = .001), primarily related to ecchymoses at injection sites.
This study, therefore, demonstrated that enoxaparin is more effective than unfractionated heparin in patients with unstable angina or non–Q-wave MI. This benefit was sustained for at least 1 year.54
In the acute phase (until day 8) of the Thrombolysis in Myocardial Infarction (TIMI) 11B study,55 3910 patients with unstable angina or non–Q-wave MI were randomized to receive intravenous unfractionated heparin in weight-adjusted doses for at least 72 hours or enoxaparin sodium (given as an intravenous 30-mg [3000 anti–factor Xa U] bolus followed by a 1-mg/kg [100 anti–factor Xa U/kg] subcutaneous injection twice daily). The median treatment duration for those receiving enoxaparin was 4.6 days compared with 3.0 days for those receiving unfractionated heparin. From day 8 to day 43, patients randomized to unfractionated heparin received subcutaneous placebo injections, whereas those in the enoxaparin group continued to receive a reduced dose of subcutaneous enoxaparin.
In the acute phase of the study, enoxaparin proved superior to unfractionated heparin, reducing the absolute frequency of death, MI, or need for urgent revascularization by 2.6% (RRR, 15%; P = .03). This superiority was attained without a significant increase in the risk for major hemorrhage.
Although the initial benefit observed with enoxaparin was sustained through day 43, no further decrease in events relative to the placebo-treated group was observed. Major hemorrhage occurred in 2.9% of those treated with enoxaparin compared with 1.5% of those receiving placebo (P = .02). Taken together, the results of these studies suggest that LMWH is at least as effective as unfractionated heparin in patients with unstable angina. However, LMWH is more convenient because it can be given subcutaneously without laboratory monitoring. Only enoxaparin has consistently demonstrated a clear benefit over unfractionated heparin in this patient population.
DIRECT THROMBIN INHIBITORS
Hirudin
Although promising results were obtained in phase 2 studies comparing hirudin with unfractionated heparin in patients with unstable angina using angiographic end points,56 there was no significant difference in the rate of death or MI between heparin- and hirudin-treated patients in the subset of patients entered in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO)–IIb trial57 who did not have ST-segment elevation and, therefore, did not receive thrombolytic therapy (9.1% vs 8.3%; P = .22).
In the pilot Organization to Assess Strategies for Ischemic Syndromes (OASIS) study,58 909 patients with unstable angina and suspected acute MI without ST-segment elevation were randomized to a 72-hour infusion of unfractionated heparin or 1 of 2 doses of hirudin. Low-dose hirudin consisted of an initial bolus of 0.2 mg/kg followed by an infusion of 0.10 mg/kg per hour, whereas the medium dose consisted of an initial bolus of 0.4 mg/kg followed by an infusion of 0.15 mg/kg per hour. Heparin and hirudin were adjusted to maintain an aPTT of 60 to 100 seconds.
The primary outcome of cardiovascular death, new MI, or refractory angina at 7 days occurred in 3.0% of patients randomized to medium-dose hirudin (RRR, 53.8%), 4.4% of those allocated to low-dose hirudin (RRR, 32.3%), and 6.5% of those treated with unfractionated heparin (heparin compared with medium-dose and low-dose hirudin; P = .045 and P = .27, respectively). There was no significant increase in major bleeding.
After discontinuation of study treatments, there was an increase in ischemic events in both hirudin groups. The RRRs for ischemic events became less marked at 35 and 180 days. At the latter time point, the differences between heparin and hirudin were of borderline statistical significance for the composite of cardiovascular death, MI, or refractory angina (P = .06).
This pilot study suggested that medium-dose hirudin is superior to unfractionated heparin in acutely preventing ischemic outcomes in patients with unstable angina or acute MI without ST-segment elevation. However, the increase in ischemic events after discontinuation of hirudin therapy emphasizes the need for a more effective long-term management study.
The OASIS-2 study was a large, phase 3 trial designed to compare the efficacy of hirudin vs heparin in patients presenting with unstable angina or suspected non–Q-wave MI59 A total of 10 141 patients were randomized to receive a 72-hour infusion of hirudin (0.4-mg/kg bolus, followed by a 0.15-mg/kg per hour infusion) or heparin (5000-U bolus followed by 15-U/kg per hour infusion). The dose of both drugs was adjusted to maintain a therapeutic aPTT. At 72 hours, cardiovascular death or new MI occurred in 2.0% of those randomized to hirudin and 2.6% of those given heparin (RRR, 23.1%; P = .35). The primary outcome, cardiovascular death or new MI at 7 days, occurred in 3.6% and 4.2% of patients, respectively (RRR, 14.3%; P = .07). These early differences persisted to at least day 35. Although hirudin caused no excess in life-threatening bleeding, major bleeding occurred more frequently in hirudin than in heparin-treated patients (1.2% and 0.7%, respectively; P = .01).
Although the primary efficacy end point in the OASIS-2 study did not achieve statistical significance (P<.05), this trial, unlike the others above, used the "hard" end points of cardiovascular death or new MI and did not include the relatively "soft" end points of need for revascularization or recurrent angina. The RRR observed with hirudin over heparin is similar in magnitude to that attained with LMWHs and GPIIb/IIIa antagonists. Furthermore, when the results of both OASIS trials are combined, hirudin produces a 19% RRR (P = .04) in cardiovascular death or MI; a 20% RRR (P = .005) in cardiovascular death, MI, or refractory angina; and a 14% RRR (P = .04) in death or MI at 35 days relative to heparin.59
Bivalirudin
Early dose-ranging studies of bivalirudin in patients with unstable angina indicate that the drug is effective and well tolerated.60-62 Bivalirudin has been studied in patients with unstable angina undergoing coronary angioplasty. In a multicenter, randomized, double-blind trial, the Hirulog Angioplasty Investigators compared unfractionated heparin (175-U/kg bolus, followed by an 18- to 24-hour infusion at 15 U/kg per hour) and bivalirudin (1.0-mg/kg intravenous bolus, followed by a 4-hour infusion of 2.5 mg/kg per hour and then a 14- to 20-hour infusion at 0.2 mg/kg per hour) in 4098 patients undergoing angioplasty for stable or postinfarction angina.63 All patients received 300 to 325 mg/d aspirin. In the total study group, bivalirudin did not reduce the incidence of the primary end point of in-hospital death, MI, abrupt closure, or rapid clinical deterioration of cardiac origin (11.4% vs 12.2% for heparin; RRR, 6.6%; P = .44). Major bleeding, however, was significantly less frequent in those receiving bivalirudin compared with those receiving unfractionated heparin (3.5% and 9.8%, respectively; P<.001). However, in a prospectively stratified group of high-risk patients with postinfarction angina, the primary end point occurred in significantly fewer patients receiving bivalirudin (9.1% vs 14.2% of those receiving heparin; RRR, 35.9%; P = .04), although these benefits were not maintained at 6 months. In this group of patients, bleeding rates also were significantly lower in those given bivalirudin (3.0% vs 11.1%; P<.001).
Recent reanalysis of the results of this trial performed on an intent-to-treat basis and with centrally adjudicated end points, but using a revised, more sensitive definition of MI, identified 4312 patients, 2161 of whom were given bivalirudin (John Bittl, MD, and Bernard Chaitman, MD, oral communication, April 1999). The composite end point of death, MI, or need for revascularization at 7 days occurred in 6.2% of those treated with bivalirudin compared with 7.9% of those given heparin (RRR of 22%; P = .04). Rates of major hemorrhage remained significantly lower in patients given bivalirudin than in those treated with heparin (3.5% and 9.3%, respectively; P<.001).
In the 741 patients in the postinfarction angina subgroup, 369 of whom were given bivalirudin, in-hospital death, MI, or need for revascularization occurred in 4.9% of those given bivalirudin compared with 9.9% of those treated with heparin (RRR, 50.5%; P<.01). Likewise, death and MI occurred in 2.9% and 6.1% of patients given bivalirudin and heparin, respectively (P<.01). These differences persisted at 6 months. In this subgroup, bleeding rates remained significantly lower in those who were randomized to bivalirudin (2.4% compared with 11.8% of those receiving heparin; P<.001). Based on this reanalysis and a recent meta-analysis,64 bivalirudin appears to be a safe and effective alternative to heparin in patients with acute coronary syndromes.
COMMENT
A number of new antithrombotic agents have been evaluated in patients with unstable angina. Of these, 1 LMWH (enoxaparin), 1 direct thrombin inhibitor (hirudin), and 2 GPIIb/IIIa antagonists (tirofiban and eptifibatide) have shown benefit in this patient population. As illustrated in Table 1, when compared with unfractionated heparin, all of these agents produce similar risk reductions in patients with unstable angina. In the absence of clinical trials directly comparing these agents, no single agent can be clearly recommended over the others. Therefore, factors such as cost, convenience, and hemorrhagic potential must be considered when making therapeutic decisions. At present, both GPIIb/IIIa antagonists and hirudin are more costly than enoxaparin. Enoxaparin is the most convenient of these agents to use, because it can be given subcutaneously once or twice daily without laboratory monitoring. The longer half-life of LMWH may, however, prove disadvantageous in patients undergoing urgent cardiovascular interventions who require rapid reversal of its anticoagulant effect. Protamine sulfate, widely used as an antidote to neutralize the actions of unfractionated heparin after cardiovascular surgery and to antagonize its hemorrhagic side effects, neutralizes the antithrombin activity of LMWH, but only partially reverses its anti–factor Xa activity.65 Although studies in laboratory animal models suggest that bleeding produced by very high concentrations of LMWH is reduced with protamine,66 similar studies in humans are lacking. The hemorrhagic potential of hirudin has proved dose limiting in the setting of thrombolytic therapy.
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New Antithrombotic Agents for the Treatment of Unstable Angina*
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New combinations of antithrombotic agents, including aspirin plus clopidogrel and GPIIb/IIIa antagonists plus LMWH, may result in improved efficacy. Other strategies, such as the prolonged administration of LMWH or orally available GPIIb/IIIa antagonists or direct thrombin inhibitors may maintain early therapeutic gains that are lost with disease reactivation after discontinuation of parenteral medication therapy.
The past few years has seen the introduction of a number of new antithrombotic agents, many of which have been studied in patients with unstable angina. Four of these—enoxaparin, hirudin, tirofiban, and eptifibatide—have been shown to decrease the risk for adverse outcomes in this patient population. The challenge for the future will be to determine which will provide the greatest efficacy with the greatest degree of safety. From an economic point of view, LMWH could be substituted for unfractionated heparin in most patients presenting with unstable angina, without increasing costs.67 Higher-risk patients (those with electrocardiographic changes or elevations in cardiac enzymes) could then be targeted for more expensive treatments such as GPIIb/IIIa antagonists or hirudin.
AUTHOR INFORMATION
Accepted for publication June 29, 1999.
This work was supported in part by an unrestricted educational grant from Phase V Communications, Inc, New York, NY, as well as grants-in-aid from the Medical Research Council of Canada, Ottawa, Ontario, and Heart and Stroke Foundation of Ontario, Toronto. Dr Weitz is the recipient of a Career Investigator Award of the Heart and Stroke Foundation of Canada, Ottawa, Ontario, and Dr Bates is the recipient of a Fellowship Award from the Heart and Stroke Foundation of Ontario.
Reprints: Jeffrey I. Weitz, MD, Hamilton Civic Hospitals Research Centre, 711 Concession St, Hamilton, Ontario, Canada L8V 1C3 (e-mail: jweitz{at}thrombosis.hhscr.org).
From the Department of Medicine, McMaster University (Drs Weitz and Bates), and Hamilton Civic Hospitals Research Centre (Dr Weitz), Hamilton, Ontario. Dr Weitz is a paid consultant for The Medicines Company, Boston, Mass, and has been a paid speaker for Sanofi, Paris, France; Rhone Poulence Rorer, Collegeville, Pa; Pharmacia & Upjohn, Peapack, NJ; and Merck Frosst, Montreal, Quebec.
REFERENCES
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