Oral Anticoagulants: Mechanism of Action, Clinical Effectiveness, and Optimal Therapeutic Range Jack Hirsh, MD, FCCP, Chair; James E. Dalen, MD, Master FCCP; David R. Anderson, MD; Leon Poller, MD; Henry Bussey, PharmD; Jack Ansell, MD; and Daniel Deykin, MD Abbreviations: AFASAK = Atrial Fibrillation, Aspirin, Antico- agulation; AMI = acute myocardial infarction; AF = atrial fibrillation; CARS = Coumadin Aspirin Reinfarction Study; CI = confidence interval; DVT = deep vein thrombosis; INR = international normalized ratio; IRP = international reference prep- aration; ISI = international sensitivity index; MI = myocardial infarction; PE = pulmonary embolism; PT = prothrombin time; SPAF = Stroke Prevention in Atrial Fibrillation; WHO = World Health Organization (CHEST 2001; 119:8S–21S) T he optimal therapeutic range for oral anticoagulant therapy was reviewed by the Committee on Anti- thrombotic Therapy of the American College of Chest Physicians and the National Heart, Lung, and Blood Institute in 1986, 1989, 1992, 1995, and again in 1998. The validity of the recommendation made at the earlier con- ferences, that the intensity of warfarin treatment should be reduced for many indications, continues to be upheld. Thus, whenever a more intense international normalized ratio (INR) is compared directly in a randomized trial, with an INR of 2.0 to 3.0, the less intense INR is as effective and safer. The recommendations for the optimal therapeutic range for the various indications remains unchanged (Table 1). A recommendation of an INR of 2.0 to 3.0 is made for most indications. The exceptions are some types of me- chanical prosthetic heart valves (see chapter on Anti- thrombotic Therapy in Patients With Mechanical and Biological Prosthetic Heart Valves). In addition, certain patients with thrombosis and the antiphospholipid syn- drome may require a higher targeted INR than 2.0 to 3.0. Results of studies in atrial fibrillation (AF) support the earlier findings that the effectiveness of warfarin is re- duced when the INR falls to  2.0 and is essentially lost when the INR falls to  1.5. 145,145a The Coumadin Aspirin Reinfarction Study (CARS) 144 and recently reported CHAMP (combined hemotherapy and mortalitly preven- tion) study 144a also showed that the addition of low-dose warfarin (mean INR 1.3 and 1.9, respectively) did not improve the efficacy of aspirin in the secondary prevention of acute myocardial infarction (AMI). In contrast, the Thrombosis Prevention Trial, 119 a primary prevention study in men free of ischemic heart disease at entry, reported that warfarin is effective in reducing myocardial ischemic events (including fatal events) when used at a targeted INR of 1.3 to 1.8 (mean warfarin dose of 4.1 mg). The addition of low-dose aspirin to warfarin therapy resulted in a further small benefit but at a risk of increased bleeding. In summary, the results of studies (1) do not support the use of fixed low-dose warfarin therapy for the treatment of patients with AMI or AF 144,145 ; (2) indicate that the effectiveness of warfarin is reduced when the INR is  2.0 144,145,145a ; (3) indicate that adjusted-dose warfarin therapy produces some benefit at an INR of 1.3 to 2.0 when used for primary prevention, and that an INR of  1.5 confers some benefit in patients with AF, although the benefit is clearly less than that which occurs with an INR of  2.0 145a ; and (4) two studies evaluating the long-term treatment of deep vein thrombosis (DVT) reported that recurrences are prevented completely at an INR of 2.0 to 3.0 137,138 ; the small number of events in the warfarin group occurred when the patients discontinued treatment. These findings suggest that it might be possible to lower the INR range to  2.0, a hypothesis that is being tested in a number of randomized trials. Mechanism of Action of Coumarin Anticoagulant Drugs Coumarins are vitamin K antagonists that produce their anticoagulant effect by interfering with the cyclic inter- conversion of vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is a cofactor for the posttranslational carboxylation of glutamate residues to -carboxygluta- mates on the N-terminal regions of vitamin K-dependent proteins (Fig 1). 1–6 These coagulation factors (factors II, VII, IX, and X) require -carboxylation for their biological activity. Coumarins produce their anticoagulant effect by inhibiting the vitamin K conversion cycle, thereby causing hepatic production of partially carboxylated and decar- boxylated proteins with reduced procoagulant activity. 7,8 In addition to their anticoagulant effect, the vitamin K antagonists inhibit carboxylation of the regulatory antico- agulant proteins C and S and therefore have the potential to exert a procoagulant effect. In the presence of calcium ions, carboxylation causes a conformational change in coagulation proteins 9 –11 that promotes binding to cofactors on phospholipid surfaces. The carboxylation reaction requires the reduced form of vitamin K (vitamin KH 2 ), molecular oxygen, and carbon dioxide, and is linked to the oxidation of vitamin KH 2 to vitamin K epoxide. Vitamin K epoxide is then recycled to vitamin KH 2 through two reductase steps. The first, which is sensitive to vitamin K antagonists, 1–3 reduces vitamin K epoxide to vitamin K 1 (the natural food form of vitamin K 1 ), while the second, which is relatively insensitive to vitamin K antagonists, reduces vitamin K 1 to vitamin KH 2 . Treatment with vitamin K antagonists leads to the deple- tion of vitamin KH 2 , thereby limiting the -carboxylation of the vitamin K-dependent coagulant proteins. The effect of coumarins can be counteracted by vitamin K 1 (either ingested in food or administered therapeutically) because the second reductase step is relatively insensitive to vitamin K antagonists (Fig 1). Patients treated with a large dose of vitamin K 1 can also become warfarin resistant for Correspondence to: Jack Hirsh, MD, FCCP, Director, Hamilton Civic Hospitals Research Centre, 711 Concession St, Hamilton, Ontario L8V 1C3, Canada 8S Sixth ACCP Consensus Conference on Antithrombotic Therapy Downloaded From: http://journal.publications.chestnet.org/ by a McMaster University User on 05/17/2013