This chapter about hemorrhagic complications of anticoagulant treatment is part of the seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Bleeding is the major complication of anticoagulant therapy. The criteria for defining the severity of bleeding varies considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that vitamin K antagonist therapy, targeted international normalized ratio (INR) of 2.5 (range, 2.0 to 3.0), is associated with a lower risk of bleeding than therapy targeted at an INR > 3.0. The risk of bleeding associated with IV unfractionated heparin (UFH) in patients with acute venous thromboembolism (VTE) is < 3% in recent trials. This bleeding risk may increase with increasing heparin dosages and age (> 70 years). Low molecular weight heparin (LMWH) is associated with less major bleeding compared with UFH in acute VTE. UFH and LMWH are not associated with an increase in major bleeding in ischemic coronary syndromes, but are associated with an increase in major bleeding in ischemic stroke. Information on bleeding associated with the newer generation of antithrombotic agents has begun to emerge. In terms of treatment decision making for anticoagulant therapy, bleeding risk cannot be considered alone, ie, the potential decrease in thromboembolism must be balanced against the potential increased bleeding risk.

(CHEST 2004; 126:287S-310S)

Key words: anticoagulant; bleeding; complications; heparin

Abbreviations: AMS = anticoagulation management services; APTT = activated partial thromboplastin time; ASPECT = Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis; CARS = Coumadin-Aspirin Reinfarction Study; CHAMP = Combination Hemotherapy and Mortality Prevention; CI = confidence interval; DVT = deep vein thrombosis;

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians.

Correspondence to: Mark N. Levine, MD, MSc, Room 104, First Floor, Henderson Research Centre, 711 Concession St, Hamilton, Ontario L8V 1C3 INR = international normalized ratio; IST = International Stroke Trial; LMWH = low molecular weight heparin; NSAID = nonsteroidal anti-inflammatory drug; OR = odds ratio; RCT = randomized controlled trial; SPAF = Stroke Prevention in Atrial Fibrillation; SPIRIT = Stroke Prevention in Reversible Ischemia Trial; SPORTIF = Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation; TIMI = Thrombolysis in Myocardial Infarction; UFH = unfractionated heparin; VTE = venous thromboembolism; WARIS = Warfarin-Aspirin Reinfarction Study.

Thus, ximelagatran therapy is a promising alternative to warfarin therapy for stroke prevention in this population. With no need for coagulation monitoring, ximelagatran is more convenient than warfarin, a feature that may increase anticoagulant use in high-risk patients with atrial fibrillation.

Parenteral anticoagulants continue to have a role in the treatment of acute coronary syndromes. The results of the REPLACE-2 trial suggest that bivalirudin obviates the need for GPIIb/IIIa antagonists in the majority of patients with low-to-moderate risk who are undergoing percutaneous coronary interventions, thereby reducing the risk of bleeding.

Fondaparinux and DX9065a have yet to find a place in the treatment of acute coronary syndromes, but further studies are planned. Likewise, NAPc2 is undergoing evaluation for these indications. Although most of the attention has focused on the use of parenteral anticoagulants for short-term treatment, rapidly acting, orally active agents also may have a role in long-term therapy. There is mounting evidence that, despite initial treatment, patients with acute coronary syndromes remain at risk for recurrent ischemic attacks for months after the index event. Some studies have indicated that long-term treatment with the combination of aspirin and clopidogrel is more effective at reducing the risk of recurrent ischemia than aspirin alone. Likewise, long-term warfarin therapy also appears to be effective. We do not yet know whether therapy with aspirin plus clopidogrel is as effective as warfarin therapy, or whether treatment with all three agents can be safely administered on a long-term basis. However, recent results with warfarin raise the possibility that ximelagatran therapy may be useful for this indication, either alone or in combination with antiplatelet agents.

Another unanswered question is the utility of ximelaga-tran in patients with mechanical heart valves. With no need for anticoagulation monitoring, ximelagatran has the potential to streamline the care of these patients, particularly those living in remote areas who cannot access a coagulation laboratory. The anticoagulation management of women with mechanical heart valves during pregnancy also remains a major challenge. If the use of ximelagatran is safe in this setting, treatment would be simplified.

Summary

With a large number of new anticoagulant agents in advanced stages of development, our armamentarium of treatment options is likely to soon be expanded. Particularly promising are new oral anticoagulant agents because they have the potential to streamline the long-term prevention and treatment of patients with venous and arterial thrombosis.