ABSTRACT
Nonvalvular atrial fibrillation (AF) is an independent risk factor for stroke that becomes increasingly prevalent as populations age. More than half a dozen clinical trials have demonstrated that anticoagulation with the vitamin K antagonist warfarin is the most effective therapy for stroke prophylaxis in AF. The narrow therapeutic index of warfarin requires that the intensity of anticoagulation be maintained within the international normalized ratio (INR) range of 2.0 to 3.0 to optimize efficacy while minimizing bleeding risk. The pharmacokinetics of warfarin are subject to variability due to interactions with multiple drugs and foods, making maintenance of the INR within this range difficult to achieve in clinical practice without close coagulation monitoring and frequent dose adjustments. Current guidelines recommend oral anticoagulation for high-risk individuals with AF but these inherent limitations lead to substantial underprescribing, particularly in elderly patients at greatest risk. This has stimulated the development of new agents with improved benefit-risk profiles, such as ximelagatran, the first of the oral direct thrombin inhibitors, which has a wider therapeutic margin and low potential for drug interactions, allowing fixed dosing without anticoagulation monitoring. Ximelagatran has been evaluated for stroke prevention in AF in the Stroke Prevention using an Oral Direct Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) program, the largest clinical trials of antithrombotic therapy for stroke prevention in AF to date. The phase III trials of ximelagatran in AF, SPORTIF III and V, found a fixed oral dose of ximelagatran (36 mg twice daily) comparable to dose-adjusted warfarin (INR 2.0 to 3.0) in preventing stroke and systemic thromboembolic complications among high-risk patients with AF. Results from the population of over 7000 patients in SPORTIF III and V demonstrate noninferiority of ximelagatran compared with warfarin. Data from SPORTIF III show an absolute reduction in stroke and systemic embolic events with ximelagatran compared with warfarin of 1.6% per year versus 2.3% per year, respectively (P = 0.10). SPORTIF V further supports noninferiority between the two agents with an absolute risk reduction of 0.45%, well within the predefined noninferiority margin (95% confidence interval -0.13, 1.03; P = 0.13). Although event rates for major bleeding did not differ significantly with ximelagatran versus warfarin in either study, combined rates for major and minor bleeding were significantly reduced with ximelagatran. The overall net clinical benefit, taking into account effects on stroke or systemic embolic events, major bleeding, and death, was also greater with ximelagatran compared with warfarin in both studies. Elevated serum transaminase enzymes were observed in ∼6% of patients given ximelagatran in these trials. These typically occurred 1 to 6 months after initiating treatment and usually abated without clinical sequelae whether or not treatment was continued. Given the consistency of response, the favorable overall benefit-risk ratio and the convenience of fixed oral dosing, ximelagatran may increase the number of patients with AF eligible for anticoagulation and amplify the potential for prophylaxis against stroke.
KEYWORDS
Atrial fibrillation - warfarin - aspirin - oral direct thrombin inhibitors - ximelagatran - SPORTIF
REFERENCES
-
1
Lloyd-Jones D M, Wang T J, Leip E P et al..
Lifetime risk for development of atrial fibrillation: the Framingham Heart Study.
Circulation.
2004;
110
1042-1046
-
2
Go A S, Hylek E M, Phillips K A et al..
Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.
JAMA.
2001;
285
2370-2375
-
3
Feinberg W M, Blackshear J L, Laupacis A, Kronmal R, Hart R G.
Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications.
Arch Intern Med.
1995;
155
469-473
-
4
Wattigney W A, Mensah G A, Croft J B.
Increased atrial fibrillation mortality: United States, 1980-1998.
Am J Epidemiol.
2002;
155
819-826
-
5
Hart R G.
Atrial fibrillation and stroke prevention.
N Engl J Med.
2003;
349
1015-1016
-
6
Wolf P A, Abbott R D, Kannel W B.
Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study.
Arch Intern Med.
1987;
147
1561-1564
-
7
Wolf P A, Abbott R D, Kannel W B.
Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.
Stroke.
1991;
22
983-988
-
8
Public health and aging: hospitalizations for stroke among adults aged > / = 65 years-United States, 2000.
MMWR Morb Mortal Wkly Rep.
2003;
52
586-589
-
9
Lundstrom T, Ryden L.
Chronic atrial fibrillation. Long-term results of direct current conversion.
Acta Med Scand.
1988;
223
53-59
-
10
Van Gelder I C, Hagens V E, Bosker H A et al..
A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation.
N Engl J Med.
2002;
347
1834-1840
-
11
Wyse D G, Waldo A L, DiMarco J P et al..
A comparison of rate control and rhythm control in patients with atrial fibrillation.
N Engl J Med.
2002;
347
1825-1833
-
12
Hart R G, Benavente O, McBride R, Pearce L A.
Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.
Ann Intern Med.
1999;
131
492-501
-
13
Fuster V, Ryden L E, Asinger R W et al..
ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on 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) developed in collaboration with the North American Society of Pacing and Electrophysiology.
Eur Heart J.
2001;
22
1852-1923
-
14
Hylek E M, Singer D E.
Risk factors for intracranial hemorrhage in outpatients taking warfarin.
Ann Intern Med.
1994;
120
897-902
-
15
Hylek E M, Skates S J, Sheehan M A, Singer D E.
An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation.
N Engl J Med.
1996;
335
540-546
-
16
Hirsh J, Fuster V, Ansell J, Halperin J L.
American Heart Association/American College of Cardiology Foundation guide to warfarin therapy.
J Am Coll Cardiol.
2003;
41
1633-1652
-
17
Petersen P, Boysen G, Godtfredsen J, Andersen E D, Andersen B.
Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.
Lancet.
1989;
1
175-179
-
18
Connolly S J, Laupacis A, Gent M, Roberts R S, Cairns J A, Joyner C.
Canadian Atrial Fibrillation Anticoagulation (CAFA) Study.
J Am Coll Cardiol.
1991;
18
349-355
-
19
The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators .
The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation.
N Engl J Med.
1990;
323
1505-1511
-
20
Ezekowitz M D, Bridgers S L, James K E et al..
Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators.
N Engl J Med.
1992;
327
1406-1412
-
21
Landefeld C S, Goldman L.
Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy.
Am J Med.
1989;
87
144-152
-
22
Halperin J L, Rothlauf E B.
Stroke prevention in atrial fibrillation.
Mt Sinai J Med.
1993;
60
289-294
-
23
Stroke Prevention in Atrial Fibrillation Study Investigators .
Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study.
Lancet.
1994;
343
687-691
-
24
Stroke Prevention in Atrial Fibrillation Investigators .
Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.
Lancet.
1996;
348
633-638
-
25
Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials.
Arch Intern Med.
1994;
154
1449-1457
-
26
Patients with nonvalvular atrial fibrillation at low risk of stroke during treatment with aspirin: Stroke Prevention in Atrial Fibrillation III Study. The SPAF III Writing Committee for the Stroke Prevention in Atrial Fibrillation Investigators.
JAMA.
1998;
279
1273-1277
-
27
The Stroke Prevention in Atrial Fibrillation Investigators .
Predictors of thromboembolism in atrial fibrillation: II. Echocardiographic features of patients at risk.
Ann Intern Med.
1992;
116
6-12
-
28
Wang T J, Massaro J M, Levy D et al..
A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study.
JAMA.
2003;
290
1049-1056
-
29
Singer D E, Albers G W, Dalen J E, Go A S, Halperin J L, Manning W J.
Antithrombotic Therapy in Atrial Fibrillation: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
Chest.
2004;
126
429S-456S
-
30
Go A S, Hylek E M, Borowsky L H, Phillips K A, Selby J V, Singer D E.
Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study.
Ann Intern Med.
1999;
131
927-934
-
31
Ageno W, Ambrosini F, Nardo B et al..
Atrial fibrillation and antithrombotic treatment in Italian hospitalized patients: a prospective, observational study.
J Thromb Thrombolysis.
2001;
12
225-230
-
32
The Clinical Quality Improvement Network (CQIN) Investigators .
Thromboembolic prophylaxis in 3575 hospitalized patients with atrial fibrillation.
Can J Cardiol.
1998;
14
695-702
-
33
Stafford R S, Singer D E.
Recent national patterns of warfarin use in atrial fibrillation.
Circulation.
1998;
97
1231-1233
-
34
Gross C P, Vogel E W, Dhond A J et al..
Factors influencing physicians' reported use of anticoagulation therapy in nonvalvular atrial fibrillation: a cross-sectional survey.
Clin Ther.
2003;
25
1750-1764
-
35
Pradhan A A, Levine M A.
Warfarin use in atrial fibrillation: a random sample survey of family physician beliefs and preferences.
Can J Clin Pharmacol.
2002;
9
199-202
-
36
Gustafsson D, Bylund R, Antonsson T et al..
A new oral anticoagulant: the 50-year challenge.
Nat Rev Drug Discov.
2004;
3
649-659
-
37
Halperin J L.
Antithrombotic therapy in atrial fibrillation: ximelagatran, an oral direct thrombin inhibitor.
Expert Rev Cardiovasc Ther.
2004;
2
163-174
-
38
Halperin J L.
Ximelagatran compared with warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation: Rationale, objectives, and design of a pair of clinical studies and baseline patient characteristics (SPORTIF III and V).
Am Heart J.
2003;
146
431-438
-
39
Olsson S B. Executive Steering Committee on behalf of the SPORTIF III Investigators .
Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial.
Lancet.
2003;
362
1691-1698
-
40
SPORTIF Executive Steering Committee for the SPORTIF V Investigators .
Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation.
JAMA.
2005;
293
690-698
-
41
Casey M, Hanley K.
A measurement of the efficacy of anticoagulation monitoring in a general practice based setting.
Ir Med J.
2001;
94
245-246
-
42
EAFT (European Atrial Fibrillation Trial) Study Group .
Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
Lancet.
1993;
342
1255-1262
-
43
Hylek E M.
Complications of oral anticoagulant therapy: bleeding and nonbleeding, rates and risk factors.
Semin Vasc Med.
2003;
3
271-278
-
44
Lee W M, Larrey D, Olsson R et al..
Hepatic findings in long-term clinical trials of ximelagatran.
Drug Saf.
2005;
28
351-370
-
45
Schulman S, Wåhlander K, Lundström T, Clason S B, Eriksson H. THRIVE III Investigators .
Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran.
N Engl J Med.
2003;
349
1713-1721
-
46
Wallentin L, Wilcox R G, Weaver W D et al..
Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial.
Lancet.
2003;
362
789-797
-
47 Albers G W. on behalf of the SPORTIF Investigators .Ximelagatran, an oral direct thrombin inhibitor, compared with dose-adjusted warfarin for primary and secondary stroke prevention in patients with AF. Presented to the American Academy of Neurology 56th Annual Meeting April 24-May 1, 2004 San Francisco, CA; Available at: http://strokecenter.stanford.edu/docs/AAN04_SP_V_final.ppt Accessed October 2004
S. Bertil OlssonM.D.
Department of Cardiology, University Hospital
S-221 85, Lund, Sweden
