Download PDF
Semin Vasc Med 2005; 5(3): 285-292
DOI: 10.1055/s-2005-916168
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Prevention of Stroke in Patients with Atrial Fibrillation

S. Bertil Olsson1 , Jonathan L. Halperin2
  • 1Department of Cardiology, University Hospital, Lund, Sweden
  • 2Mount Sinai School of Medicine, Cardiovascular Institute, Mount Sinai Medical Center, New York
Further Information

Publication History

Publication Date:
25 August 2005 (online)

    Permissions and Reprints

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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 5 Hart R G. Atrial fibrillation and stroke prevention.  N Engl J Med. 2003;  349 1015-1016
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 9 Lundstrom T, Ryden L. Chronic atrial fibrillation. Long-term results of direct current conversion.  Acta Med Scand. 1988;  223 53-59
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 14 Hylek E M, Singer D E. Risk factors for intracranial hemorrhage in outpatients taking warfarin.  Ann Intern Med. 1994;  120 897-902
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 22 Halperin J L, Rothlauf E B. Stroke prevention in atrial fibrillation.  Mt Sinai J Med. 1993;  60 289-294
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 32 The Clinical Quality Improvement Network (CQIN) Investigators . Thromboembolic prophylaxis in 3575 hospitalized patients with atrial fibrillation.  Can J Cardiol. 1998;  14 695-702
    PubMedGoogle Scholar
  • 33 Stafford R S, Singer D E. Recent national patterns of warfarin use in atrial fibrillation.  Circulation. 1998;  97 1231-1233
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 37 Halperin J L. Antithrombotic therapy in atrial fibrillation: ximelagatran, an oral direct thrombin inhibitor.  Expert Rev Cardiovasc Ther. 2004;  2 163-174
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 43 Hylek E M. Complications of oral anticoagulant therapy: bleeding and nonbleeding, rates and risk factors.  Semin Vasc Med. 2003;  3 271-278
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    Google Scholar

S. Bertil OlssonM.D. 

Department of Cardiology, University Hospital

S-221 85, Lund, Sweden