1. D. Current clinical options Warfarin: Issues and challenges
Warfarin in AF: Stroke risk reductions
Content Points:
Meta-analysis of six randomized, placebo-controlled trials of adjusted-dose warfarin in patients with AF demonstrate the benefit of anticoagulant therapy in stroke reduction.1
Statistically significant reductions were reported in four of these trials.
Overall, warfarin reduced the relative risk for stroke by 62%.
1Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A meta-analysis. Ann Intern Med. 1999;131:

2. Aspirin in AF: Stroke risk reductions Content Points:
In contrast to the experience with warfarin, the evidence pointing to a benefit with antiplatelet therapy (aspirin) is weaker.
Meta-analysis of six placebo-controlled trials shows that in all but one trial the confidence limits overlapped unity.1
Overall, aspirin reduced the relative risk for stroke by 22%.
1Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A meta-analysis. Ann Intern Med. 1999;131:

3. Oral anticoagulants vs aspirin for stroke prevention in AF
Content Points:
Previous meta-analyses of trials comparing the effects of oral anticoagulant and antiplatelet therapies on stroke used summary data from published trial reports. To more fully assess the differences between these therapies on stroke, van Walraven et al conducted a meta-analysis using pooled, individual patient data.1
The trials compared warfarin or 4-hydroxycoumadin versus aspirin. Compared with aspirin, oral anticoagulant therapy reduced the risk of all strokes by 45%, ischemic strokes by 52%, and cardiovascular events by 29% (P < for all comparisons). There was a greater incidence of major bleeding in oral anticoagulant groups (hazard ratio 1.71; P = 0.02), although overall mortality did not differ between patient groups.
The investigators concluded that oral anticoagulant therapy is more effective than oral antiplatelet therapy (aspirin) in decreasing the risk of stroke and cardiovascular events in patients with AF.
These clinical findings are consistent with current understanding of the vascular biology of AF-related stroke, which assigns a less important role to platelet activation relative to activation of the coagulation system.
1van Walraven C, Hart RG, Singer DE, Laupacis A, Connolly S, Petersen P, et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: An individual patient meta-analysis. JAMA. 2002;288:

4. Coagulation cascade Content Points:
The cascade comprises a regulated series of linked reactions involving the sequential activation of coagulation factors.1
The primary pathway (the extrinsic system) is triggered by exposure or expression of tissue factor (TF) to form a complex with factor VIIa. This complex converts factor X to factor Xa. Factor Xa (in complex with factor Va) then converts prothrombin (factor II) to thrombin (factor IIa), the most important protein in the coagulation cascade.
Thrombin converts fibrinogen to fibrin, which polymerizes to form a three-dimensional matrix.2 Thrombin also activates factor XIII, which catalyzes formation of this matrix.2 Cross linking of platelets with fibrinogen recruits circulating platelets to the growing thrombus.3
Thrombin then binds to fibrin, remaining in the growing clot, where it continues to be active.2
The intrinsic system plays an accessory role in amplification of the cascade. The VIIIa/IXa complex formed by this pathway is approximately 50 times more efficient than the VIIa/TF complex.1
1Mann KG. Thrombin formation. Chest. 2003;124(suppl):4S-10S.
2Nesheim M. Thrombin and fibrinolysis. Chest. 124(suppl):33S-39S.
3Brass LF. Thrombin and platelet activation. Chest. 124(suppl):18S-25S.

5. Anticoagulant action of warfarin: Slow onset Content Points:
Coagulation factors II (prothrombin), VII, IX, and X require post-translational carboxylation for biological activity.1 The reaction involves oxidation of vitamin KH2 (the reduced form of vitamin K) to vitamin K epoxide (vitamin KO).
Conversion of vitamin KO back to vitamin KH2 is accomplished by two reductases:
- KO-reductase, which is sensitive to inhibition by warfarin.
- K-reductase, which is relatively insensitive to warfarin.
Since factors II, VII, IX, and X have turnover times of 24 to 60 hours, an anticoagulant effect is not achieved with warfarin for 4 to 7 days.
2Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119:8S-21S.

6. Warfarin: Narrow therapeutic window Content Points:
Warfarin therapy requires a balance between prevention of ischemic stroke and avoidance of hemorrhage.
As discussed in previous slides, an INR <2.0 is associated with incomplete efficacy.1,2
Conversely, INR values >~3.0 are associated with increased risk of hemorrhage.3
1Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, Singer DE. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med. 2003;349:
2The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:
3Fuster V, Rydén LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force of Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation). J Am Coll Cardiol. 2001;38:

7. Limitations of warfarin Content Points:
Because warfarin has a slow onset of action, warfarin therapy is routinely overlapped with heparin therapy for 4 to 5 days, after which heparin therapy is discontinued.1
The pharmacokinetics of warfarin are subject to genetic variability, which leads to variable dose requirements.2
Numerous foods and medications interact with warfarin, which along with its narrow therapeutic window (discussed in the preceding slide) necessitate frequent monitoring of anticoagulant activity.
1Hirsh J. Current anticoagulant therapy-Unmet clinical needs. Thromb Res. 2003;109:S1-S8.
2Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119:8S-21S.

8. Warfarin limitations lead to under-treatment of AF Content Points:
Go et al examined warfarin use in ambulatory patients with AF using data collected as part of the ATRIA study.1
In the study population of 13,428 patients, warfarin use by age group demonstrated a bell-shaped curve, with highest usage (61%) among those 65 to 74 years of age. Overall, only 55% of patients were being treated with warfarin.
The ATRIA investigators concluded that many eligible patients are not receiving warfarin.
Warfarin's limitations are likely reasons for this under-utilization. The difficulty of maintaining warfarin therapy within the therapeutic range is well recognized. Physicians with more experience using warfarin are more likely to prescribe it than those with little experience.2
1Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. Ann Intern Med. 1999;131:
2Bungard TJ, Ghali WA, Teo KK, McAlister FA, Tsuyuki RT. Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med. 2000;160:41-46.