SPECIAL FEATURE Vol.6 No.5 (July 2001)

Advances in Anti-thrombotic Treatment

Dr. Chen Wai-Hong
Division of Cardiology, Department of Medicine, Ruttonjee Hospital

Introduction

Atherosclerotic plaque rupture followed by activation of platelets and coagulation cascade is the pathogenesis of the acute coronary syndromes (ACS). Platelets mediate the primary hemostasis at the site of a ruptured plaque via adhesion, activation, and aggregation. In the final step of platelet aggregation, fibrinogen (or Von Willebrand factor) binds to activated platelet glycoprotein (GP) IIb/IIIa receptors. Cross-linking of fibrinogen bound to activated platelets culminates in a growing platelet aggregate and thrombus formation. Thrombin is an important molecule in the ACS because of its extensive procoagulant and prothrombotic actions. In addition to mediating the transformation of soluble fibrinogen to fibrin monomers and activating factor XIII to produce cross-linked fibrin, thrombin promotes clot formation by activating factors V and VIII. It is also one of the most potent agents for platelet adhesion, activation, and aggregation. In vessels with a diseased endothelium, thrombin promotes the release of the vasoconstrictor endothelin-1.

GP IIb/IIIa inhibitors bind to the IIb/IIIa receptor and thereby block the final common pathway of platelet aggregation. Independent of the original stimulus for platelet activation, platelet activities are affected by IIb/IIIa inhibitors. Therefore this class of drugs is more potent than other antiplatelet agents like aspirin and ADP receptor antagonists (ticlopidine and clopidogrel). The standard antithrombin agent used in clinical practice is unfractionated heparin (UFH). UFH exerts its anticoagulant effect by activating antithrombin III (AT III). UFH is limited by a variable anticoagulant effect (requiring frequent activated partial thromboplastin time monitoring), neutralisation by platelet factor 4, less effective inhibition of clot-bound versus fluid-phase thrombin, and the potential to cause thrombocytopenia and heparin-induced thrombocytopenia syndrome (HITS).

Direct antithrombins are distinguished from heparin by not requiring AT III for antithrombin activity. They are effective against both fluid-phase and clot-bound thrombin, producing a more stable and predictable level of anticoagulation. The potential improvement in efficacy was the inspiration for subsequent large randomised
trials.

Low-molecular-weight heparins (LMWHs) have enhanced anti-Xa activity in relation to anti-IIa activity compared to UFH, which is important in inhibiting thrombin generation. Decreased binding to plasma proteins, endothelial cells, and macrophages explain the pharmacokinetic advantages of LMWHs over UFH, which include better bioavailability, longer half-life, and dose-independent clearance. Together with the ease of administration by the subcutaneous route, a decreased sensitivity to inactivation by platelet factor IV and lower rates of thrombocytopenia and HITS, LMWHs are clinically attractive alternatives to UFH.

Numerous clinical trials have been conducted on the use of GP IIb/IIIa inhibitors, direct antithrombins, and LMWHs in ACS. The coming sections highlight principal findings from some of these trials.


Platelet Glycoprotein IIb/IIIa Inhibitors in Unstable Angina/non-Q-wave Myocardial Infarction

The Platelet Receptor Inhibition for Ischemic Syndrome Management-Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) and the Platelet IIb/IIIa in Unstable Angina Receptor Suppression Using Integrilin Therapy (PURSUIT) trials studied the small-molecule GP IIb/IIIa inhibitors tirofiban and eptifibatide respectively in high-risk patients with unstable angina/non-Q-wave myocardial infarction (UA/NQWMI). Adding tirofiban to aspirin and UFH reduced the composite primary endpoint of death, MI or refractory ischaemia at 7 days, when compared with aspirin and UFH. The benefit did not reach statistical significance at 30 days but was significant at 6 months. The PURSUIT trial showed a significant reduction in the primary endpoint of death or MI at 30 days by eptifibatide when combined with aspirin and UFH. Although benefits of abciximab have been demonstrated in patients undergoing percutaneous coronary intervention (PCI), the fourth Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IV ACS) trial did not show a reduction of death or MI at 30 days by 24- or 48-hour infusions of abciximab in patients with UA or non-ST-elevation MI who were not planned to undergo PCI. Various potential explanations have been put forward to account for the surprisingly negative results. These include patient selection in the trial; notably, the influence of the mandated conservative treatment strategy; the overall risk profile of the patients; and, finally, the dosing strategy of abciximab.


Platelet Glycoprotein IIb/IIIa Inhibitors in ST-elevation Myocardial Infarction

Realising that platelets play a central role in failed reperfusion and reocclusion following fibrinolysis in ST-elevation (STE) MI, GP IIb/IIIa inhibitors have been tested as adjunct to fibrinolysis in this setting. Promising results emerged from two phase-II trials which studied abciximab combined with reduced-dose fibrinolytic agents. The best combo in Thrombolysis In Myocardial Infarction (TIMI) 14 trial is half-dose alteplase combined with standard-dose abciximab, which produced 72% TIMI 3 flow at 60 minutes. In the Strategies for Patency Enhancement in the Emergency Department (SPEED) trial, reteplase 5+5 U plus abciximab resulted in 62% TIMI 3 flow at 60 minutes. Major haemorrhage was not increased by the combination therapies in these trials. Whether the significant improvement in the early patency will translate into mortality reduction remains to be proven by the GUSTO-IV AMI trial.


Oral Platelet Glycoprotein IIb/IIIa Inhibitors

Oral GP IIb/IIIa inhibitors offer the potential for long term treatment, which can be applied during the early phase of ACS, secondary prevention after stabilisation from an ACS, or for both acute therapy and secondary prevention. The Orbofiban in Patients with Unstable Coronary Syndromes (OPUS-TIMI) 16 and Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events post-acute coronary syndromes (SYMPHONY-I) trials tested the use of oral GP IIb/IIIa inhibitors in the first two scenarios. OPUS-TIMI 16 was terminated early because of increased 30-day mortality in one of the orbofiban groups. There was no difference in the primary composite endpoint at 10 months. Major bleeding was more common with orbofiban. In SYMPHONY-I there was no difference in the primary endpoint (a composite of death, MI, and severe recurrent ischaemia at 3 months) between aspirin, low-dose sibrafiban, and high-dose sibrafiban. There was a higher rate of major bleeding in the high- and low-dose sibrafiban groups.

Some potential reasons for these failures of the "first-generation" oral GP IIb/IIIa inhibitors include a higher amount of variability in the drug level and a lower degree of platelet inhibition achieved with oral as compared with IV drugs. It also appears that some of the agents may have intrinsic proaggregatory effects.


Direct Antithrombins in Unstable Angina/non-Q-wave Myocardial Infarction

The direct antithrombin inogatran was evaluated in the Thrombin Inhibition in Myocardial Ischaemia (TRIM) study in which patients with UA were randomised to different doses of inogatran or UFH. The primary endpoint of death, MI, and recurrent or refractory ischaemia was not reduced by inogatran. In Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) hirudin was shown to be superior to UFH in reducing death, MI or refractory angina among patients with UA or suspected acute MI without ST-elevation but major bleeding was more frequent. Given the modest benefit and the increased bleeding risk, the direct antithrombins do not currently play a role in the routine treatment of patents with UA/NQWMI.


Direct Antithrombins in ST-elevation Myocardial Infarction

Following encouraging results in phase-II trials, TIMI-9A, GUSTO-IIa, and HIT-III were undertaken to evaluate hirudin as adjunctive therapy to thrombolysis. All were terminated prematurely because of unacceptable haemorrhagic complications. The dose of hirudin was reduced in subsequent TIMI-9B and GUSTO-IIb trials. Bleeding events were lowered but there was no difference in the incidence of death or MI. Except for providing a more consistent anticoagulant effect, hirudin has no advantage over UFH in STE MI.


Low-molecular-weight Heparins in Unstable Angina/non-Q-wave Myocardial Infarction

Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) and TIMI-11B demonstrated superiority of enoxaparin over UFH in reducing the composite of death, MI, and urgent revascularization. A meta-analysis of these two trials showed a significant reduction of death or MI during acute-phase treatment. Fragmin in Unstable Coronary Artery Disease Study (FRIC) and FRAXiparine in Ischaemic Syndrome (FRAXIS) revealed no difference between UFH and the two LMWHs, dalteparin and fraxiparine, respectively. It can be concluded that LMWHs are at least as effective as, or superior to UFH for acute treatment of UA/NQWMI.


Low-molecular-weight Heparins in ST-elevation Myocardial Infarction

Adjunctive UFH is the standard of care after thrombolytic therapy using fibrin-specific agents for STE MI. Although not recommended by current guidelines, streptokinase (SK) is often given in conjunction with UFH. In the Dutch SK-Enoxaparin Study comparing enoxaparin with placebo as adjunctive therapy to SK thrombolysis, infarct-related artery (IRA) patency by angiography at 8 days was significantly higher in the enoxaparin group. Death, reinfarction, and/or recurrent angina were also reduced. The second Heparin-Aspirin Reperfusion Trial (HART-II) showed no significant difference between UFH and enoxaparin in 90-minute IRA patency (75.1% vs 80.1%) when used as an adjunct to alteplase. There was a trend for fewer reocclusions. Bleeding complications were similar. Similarly, comparing dalteparin with UFH, the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-PLUS) trial revealed no difference in the TIMI 3 flow between 4-7 days in patients with STE MI treated by alteplase. Bleeding events were not increased. Thus, UFH can be safely replaced by LMWHs with equivalent efficacy as adjunct to thrombolysis.


Conclusions

It is an exciting time for clinicians when so many new antiplatelet and antithrombin agents have been developed and introduced into practice. New standards of care are set when the results of clinical trials are applied to patient management. In this rapidly evolving field, ongoing studies will help define optimal antithrombotic therapy to meet different patient needs.