ABSTRACT
The burden of atrial fibrillation (AF) worldwide is projected to increase substantially
over the next few decades in part due to an aging population. AF increases the risk
of stroke approximately fivefold. The population-attributable risk for stroke by age
is considerable: 1.5% for those individuals 50 to 59 years of age compared with 23.5%
for those ≥80 years of age. Vitamin K antagonists (VKAs) like warfarin have been shown
to greatly reduce the risk of stroke. However, despite their proven efficacy, VKAs
remain underused, particularly among elderly patients with AF. The preponderance of
evidence from randomized trials and observational studies attests to higher bleeding
rates among elderly individuals with AF. Antiplatelet therapy is not effective for
stroke prevention in AF and is also associated with significant bleeding risk. Strategies
to optimize the effectiveness of VKAs and improve their safety profiles among elderly
patients in clinical practice are direly needed. An understanding of the pathological
changes that predispose to hemorrhage, hazards of polypharmacy, and factors that contribute
to variability in dose response will facilitate a more informed use of these medications
in clinical care.
KEYWORDS
Atrial fibrillation - stroke - anticoagulant therapy - vitamin K antagonist - warfarin
REFERENCES
- 1
Miyasaka Y, Barnes M E, Gersh B J et al..
Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980
to 2000, and implications on the projections for future prevalence.
Circulation.
2006;
114(2)
119-125
- 2
Wolf P A, Abbott R D, Kannel W B.
Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.
Stroke.
1991;
22(8)
983-988
- 3
Benjamin E J, Wolf P A, D'Agostino R B, Silbershatz H, Kannel W B, Levy D.
Impact of atrial fibrillation on the risk of death: the Framingham Heart Study.
Circulation.
1998;
98(10)
946-952
- 4
Lin H J, Wolf P A, Kelly-Hayes M et al..
Stroke severity in atrial fibrillation. The Framingham Study.
Stroke.
1996;
27(10)
1760-1764
- 5
Atrial Fibrillation Investigators .
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(13)
1449-1457
- 6
Friberg L, Hammar N, Ringh M, Pettersson H, Rosenqvist M.
Stroke prophylaxis in atrial fibrillation: who gets it and who does not? Report from
the Stockholm Cohort-study on Atrial Fibrillation (SCAF-study).
Eur Heart J.
2006;
27(16)
1954-1964
- 7
Waldo A L, Becker R C, Tapson V F, Colgan K J. NABOR Steering Committee .
Hospitalized patients with atrial fibrillation and a high risk of stroke are not being
provided with adequate anticoagulation.
J Am Coll Cardiol.
2005;
46(9)
1729-1736
- 8
Nieuwlaat R, Capucci A, Lip G Y Euro Heart Survey Investigators et al.
Antithrombotic treatment in real-life atrial fibrillation patients: a report from
the Euro Heart Survey on Atrial Fibrillation.
Eur Heart J.
2006;
27(24)
3018-3026
- 9
Van Spall H G, Toren A, Kiss A, Fowler R A.
Eligibility criteria of randomized controlled trials published in high-impact general
medical journals: a systematic sampling review.
JAMA.
2007;
297(11)
1233-1240
- 10
van der Meer F J, Rosendaal F R, Vandenbroucke J P, Briët E.
Bleeding complications in oral anticoagulant therapy. An analysis of risk factors.
Arch Intern Med.
1993;
153(13)
1557-1562
- 11
The Stroke Prevention in Atrial Fibrillation Investigators .
Bleeding during antithrombotic therapy in patients with atrial fibrillation.
Arch Intern Med.
1996;
156(4)
409-416
- 12
Seto A C, Kenyon K, Wittkowsky A K.
Discrepancies in identification of major bleeding events in patients taking warfarin.
Pharmacotherapy.
2008;
28(9)
1098-1103
- 13
Chesebro J H, Knatterud G, Roberts R et al..
Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between
intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings
through hospital discharge.
Circulation.
1987;
76(1)
142-154
- 14
Bergman H, Ferrucci L, Guralnik J et al..
Frailty: an emerging research and clinical paradigm—issues and controversies.
J Gerontol A Biol Sci Med Sci.
2007;
62(7)
731-737
- 15
DiMarco J P, Flaker G, Waldo A L AFFIRM Investigators et al.
Factors affecting bleeding risk during anticoagulant therapy in patients with atrial
fibrillation: observations from the Atrial Fibrillation Follow-up Investigation of
Rhythm Management (AFFIRM) study.
Am Heart J.
2005;
149(4)
650-656
- 16
Bousser M G, Bouthier J, Büller H R Amadeus Investigators et al.
Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism
in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial.
Lancet.
2008;
371(9609)
315-321
- 17
Hylek E M, Evans-Molina C, Shea C, Henault L E, Regan S.
Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly
patients with atrial fibrillation.
Circulation.
2007;
115
2689-2696
- 18
Longstreth G F.
Epidemiology and outcome of patients hospitalized with acute lower gastrointestinal
hemorrhage: a population-based study.
Am J Gastroenterol.
1997;
92(3)
419-424
- 19
Hernandez-Diaz S, Garcia Rodriguez L A.
Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications.
BMC Med.
2006;
20
22
- 20
Hylek E M, Singer D E.
Risk factors for intracranial hemorrhage in outpatients taking warfarin.
Ann Intern Med.
1994;
120(11)
897-902
- 21
Gorter J W.
Major bleeding during anticoagulation after cerebral ischemia: patterns and risk factors.
Stroke Prevention In Reversible Ischemia Trial (SPIRIT). European Atrial Fibrillation
Trial (EAFT) study groups.
Neurology.
1999;
53(6)
1319-1327
- 22
Rosand J, Hylek E M, O'Donnell H C, Greenberg S M.
Warfarin-associated hemorrhage and cerebral amyloid angiopathy: a genetic and pathologic
study.
Neurology.
2000;
55(7)
947-951
- 23
Smith E E, Rosand J, Knudsen K A, Hylek E M, Greenberg S M.
Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke.
Neurology.
2002;
59(2)
193-197
- 24
Tinetti M E.
Clinical practice. Preventing falls in elderly persons.
N Engl J Med.
2003;
348(1)
42-49
- 25
Gage B F, Birman-Deych E, Kerzner R, Radford M J, Nilasena D S, Rich M W.
Incidence of intracranial hemorrhage in patients with atrial fibrillation who are
prone to fall.
Am J Med.
2005;
118(6)
612-617
- 26
Fuster V, Ryden L E, Cannom D S et al..
ACC/AHA/ESC 2006 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 (writing committee to revise the 2001 guidelines for the management of
patients with atrial fibrillation): developed in collaboration with the European Heart
Rhythm Association and the Heart Rhythm Society.
Circulation.
2006;
114
e257-354
- 27
Gage B F, Waterman A D, Shannon W, Boechler M, Rich M W, Radford M J.
Validation of clinical classification schemes for predicting stroke: results from
the National Registry of Atrial Fibrillation.
JAMA.
2001;
285(22)
2864-2870
- 28
Stroke Prevention in Atrial Fibrillation Investigators .
Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation:
Stroke Prevention in Atrial Fibrillation II Study.
Lancet.
1994;
343(8899)
687-691
- 29
Connolly S, Pogue J, Hart R ACTIVE Writing Group of the ACTIVE Investigators et al.
Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the
Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events
(ACTIVE W): a randomised controlled trial.
Lancet.
2006;
367(9526)
1903-1912
- 30
Mant J, Hobbs F D, Fletcher K BAFTA investigators et al.
Warfarin versus aspirin for stroke prevention in an elderly community population with
atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study,
BAFTA): a randomised controlled trial.
Lancet.
2007;
370(9586)
493-503
- 31
Hylek E M, Go A S, Chang Y et al..
Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial
fibrillation.
N Engl J Med.
2003;
349(11)
1019-1026
- 32
Delaney J A, Opatrny L, Brophy J M, Suissa S.
Drug-drug interactions between antithrombotic medications and the risk of gastrointestinal
bleeding.
CMAJ.
2007;
177(4)
347-351
- 33
Arima H, Hart R G, Colman S PROGRESS Collaborative Group et al.
Perindopril-based blood pressure-lowering reduces major vascular events in patients
with atrial fibrillation and prior stroke or transient ischemic attack.
Stroke.
2005;
36(10)
2164-2169
- 34
Hart R G, Tonarelli S B, Pearce L A.
Avoiding central nervous system bleeding during antithrombotic therapy: recent data
and ideas.
Stroke.
2005;
36(7)
1588-1593
- 35
King III S B, Smith Jr S C, Hirshfeld Jr J W 2005 WRITING COMMITTEE MEMBERS et al.
2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary
Intervention: a report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update
the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing
on Behalf of the 2005 Writing Committee.
Circulation.
2008;
117(2)
261-295
- 36
Gilard M, Arnaud B, Cornily J C et al..
Influence of omeprazole on the antiplatelet action of clopidogrel associated with
aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study.
J Am Coll Cardiol.
2008;
51(3)
256-260
- 37
Simon T, Verstuyft C, Mary-Krause M French Registry of Acute ST-Elevation and Non-ST-Elevation
Myocardial Infarction (FAST-MI) Investigators et al.
Genetic determinants of response to clopidogrel and cardiovascular events.
N Engl J Med.
2009;
360(4)
363-375
- 38
Garcia D, Regan S, Crowther M, Hughes R A, Hylek E M.
Warfarin maintenance dosing patterns in clinical practice: implications for safer
anticoagulation in the elderly population.
Chest.
2005;
127(6)
2049-2056
- 39
Hylek E M, Regan S, Go A S, Hughes R A, Singer D E, Skates S J.
Clinical predictors of prolonged delay in return of the international normalized ratio
to within the therapeutic range after excessive anticoagulation with warfarin.
Ann Intern Med.
2001;
135(6)
393-400
- 40
Eckman M H, Rosand J, Greenberg S M, Gage B F.
Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients
with nonvalvular atrial fibrillation.
Ann Intern Med.
2009;
150(2)
73-83
- 41
Thijssen H H, Soute B A, Vervoort L M, Claessens J G.
Paracetamol (acetaminophen) warfarin interaction: NAPQI, the toxic metabolite of paracetamol,
is an inhibitor of enzymes in the vitamin K cycle.
Thromb Haemost.
2004;
92(4)
797-802
- 42
Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. American College of
Chest Physicians .
Pharmacology and management of the vitamin K antagonists: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
Chest.
2008;
133(6, suppl)
160S-198S
- 43
Stroke Risk in Atrial Fibrillation Working Group .
Comparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular
atrial fibrillation.
Stroke.
2008;
39(6)
1901-1910
- 44
Koennecke H C.
Cerebral microbleeds on MRI: prevalence, associations, and potential clinical implications.
Neurology.
2006;
66(2)
165-171
- 45
Copenhaver B R, Hsia A W, Merino J G et al..
Racial differences in microbleed prevalence in primary intracerebral hemorrhage.
Neurology.
2008;
71(15)
1176-1182
Elaine M HylekM.D.
Department of Medicine, Research Unit-Section of General Internal Medicine, Boston
University Medical Center
801 Massachusetts Avenue, 2nd Floor, Boston, MA 02118
Email: ehylek@bu.edu
