NORTHBROOK, ILL—Recently released guidelines from the American College of Chest Physicians reflect the major developments that have occurred in antithrombotic therapy in the past few years.[1] Since publication of the previous guidelines in 1998, research has demonstrated that low doses of aspirin are at least as effective as higher doses in cerebrovascular disease.

In addition, several new antithrombotics—including the oral antiplatelet clopidogrel and three intravenous glycoprotein (GP) IIb/IIIa antagonists—gained Food and Drug Administration approval. Studies with the oral GPIIb/ IIIa antagonists, however, have been disappointing.

Further, it is now clear that subcutaneous low-molecular-weight heparin (LMWH) can replace unfractionated heparin in therapy for venous thromboembolism (VTE) and acute ischemic coronary syndromes.

Data on antithrombotic therapy now include more randomized clinical trials, added Jack Hirsh, MBBS, MD, cochair of the guideline panel and Director of the Hamilton Civic Hospitals Research Centre in Ontario.

As a result, the evidence supporting the guidelines themselves are better than ever, Dr. Hirsh said in an interview with PULMONARY REVIEWS.

EFFICACY OF LOW-DOSE ASPIRIN

Low-dose (80 to 325 mg/d) aspirin has long been known to reduce the risk of acute myocardial infarction (MI). However, research has now proved that it is as effective as, and possibly better than, high-dose (500 to 1,000 mg/d) aspirin in preventing ischemic stroke in patients having carotid endarterectomy for cerebrovascular disease.[2]

Low-dose aspirin has also been shown to prevent stroke in patients with atrial fibrillation and to prevent VTE in patients undergoing hip-fracture repair. However, in neither of these settings is it as effective as traditional anticoagulants. Additional studies are needed to define aspirin’s role for these indications.

For most patients at risk for cardiovascular or cerebrovascular events, the benefits of low-dose aspirin are now established. “I think everybody now agrees that 160 mg/d is probably the right dose for aspirin [therapy],” commented James E. Dalen, MD, MPH, also a cochair of the guideline panel and Dean of the College of Medicine at the University of Arizona in Tucson. “That should be sufficient in prevention of stroke and myocardial infarction.”

CLOPIDOGREL FOR PREVENTION

This antithrombotic has been approved for the prevention of future atherosclerotic events in patients with recent stroke or MI or who have established peripheral arterial disease.[2] The drug’s approval was based on the CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events) study, a large phase 3 trial comparing clopidogrel with aspirin in those three types of patients.[3]

Clopidogrel was modestly more effective than aspirin. The annual atherosclerotic event rates were 5.32% for clopidogrel and 5.83% for aspirin; thus, the relative risk reduction with clopidogrel was 8.7%. Most of this modest benefit was due to clopidogrel’s better efficacy in patients with peripheral arterial disease; in this group, clopidogrel lowered the relative risk of atherosclerotic events by 23.8%.

Clopidogrel, like ticlopidine, appears to work synergistically with aspirin. The drug has replaced ticlopidine at many centers due to its superior safety profile.

GPIIb/IIIa ANTAGONISTS

The new intravenous GPIIb/IIIa antagonists include abciximab, a monoclonal antibody; tirofiban, a nonpeptide tyrosine derivative; and eptifibatide, a synthetic disulfide-linked cyclic heptapeptide.[2] Abciximab is indicated for the prevention of cardiac ischemic events in patients undergoing percutaneous coronary interventions. When used in conjunction with conventional antithrombotic therapy in such patients, it has been shown to reduce the incidence of death or MI at 30 days by at least 30%.

Tirofiban and eptifibatide are approved for patients with acute coronary syndromes, including those undergoing percutaneous interventions. In placebo-controlled trials involving patients with unstable angina or non–Q-wave MI, tirofiban produced an 18% to 27% reduction in the relative risk of death or MI at 30 days. Eptifibatide decreased the relative risk of these adverse events by 10% in a similar trial. In patients undergoing percutaneous coronary interventions, tirofiban and eptifibatide decreased the risk of these events by 22% and 18%, respectively. Like abciximab, both of these agents should be used in combination with conventional antithrombotic therapy.

Although the intravenous GPIIb/IIIa antagonists have proved themselves as useful antithrombotic agents, “the ineffectiveness of the oral GPIIb/IIIa antagonists was a real surprise,” said Dr. Hirsh. “They were seen as the ultimate in antiplatelet drugs because they block everything.” In three clinical trials, mortality was higher in the patients who received the oral GPIIb/IIIa antagonists sibrafiban and orbofiban than in those given aspirin, although the difference was significant in only one trial. The oral GPIIb/IIIa antagonists also produced markedly more bleeding complications.

LOW–MOLECULAR-WEIGHT AND UNFRACTIONATED HEPARINS

The guidelines’ conclusion that subcutaneous LMWH is an acceptable replacement for unfractionated heparin for patients with VTE is based on a large number of studies showing comparable efficacy and bleeding rates with the two types of heparin.[4] However, LMWH is easier to administer and requires less frequent monitoring (because the dose-response relationship is more predictable). Thus, it has become the “anticoagulant of choice” for many general surgical and high-risk medical patients.

There have been fewer studies on the use of LMWH in patients with acute ischemic coronary syndromes. However, these studies also support the conclusion that LMWH and unfractionated heparin are equally effective and produce similar bleeding rates.

IMPORTANT RECOMMENDATIONS FOR ORAL-ANTICOAGULANT USE

The guidelines include two important recommendations concerning the use of oral anticoagulants in patients with atrial fibrillation.[5]

The first concerns the target international normalized ratio (INR); the second involves the combined use of aspirin and low-intensity warfarin.

The target INR should be between 2.0 and 3.0 (ideally, 2.5) in most patients. Randomized trials have shown that when the INR is at that level, the balance between ischemic stroke prevention and the risk of major hemorrhage is optimized.

The combination of aspirin and low-intensity warfarin has not been proven more effective than aspirin alone, and it produces more bleeding.

Instead, patients with atrial fibrillation should undergo risk stratification. Those at high risk should be given warfarin; those at low risk should receive aspirin. Those at intermediate risk can be given either warfarin or aspirin.

—Timothy Begany

References
1. Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest. 2001;119(suppl)1S-370S.

2. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest. 2001;119:39S-63S.

3. CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet. 1996;348:1329-1339.

4. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001;119:64S-94S.

5. Albers GW, Dalen JE, Laupacis A, et al. Antithrombotic therapy in atrial fibrillation. Chest. 2001;119:194S-206S.

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