Publication
Article
Supplements and Featured Publications
Effective Anticoagulation Therapy: Defining the Gap Between Clinical Studies and Clinical Practice
Author(s):
Atrial fibrillation (AF) greatly increases the risk ofstroke. Long-term oral therapy with warfarin reducesthe risk of AF-related stroke by 62%, and nationalguidelines now call for warfarin therapy in mostpatients without specific contraindications to anticoagulation.However, the drug's narrow therapeuticindex means that warfarin therapy must be guidedby coagulation monitoring. This requirement andother inherent limitations of warfarin have led towidespread underutilization and underanticoagulationin AF patients who require antithrombotic therapyfor stroke prevention. Recent studies indicatethat in many health systems less than half of warfarin-eligible patients take the drug and even fewerare adequately maintained within a protective therapeuticrange. Similarly, despite the documented efficacyof anticoagulation in patients at risk for deepvein thrombosis (DVT) and related pulmonaryembolism, prophylaxis for DVT, even in high-risksituations such as following orthopedic surgery, issuboptimal. This article explores the scope of warfarinunderutilization and underanticoagulation thatexists in current clinical practice. The clinical consequencesof warfarin underuse are also described.Discussion in the roundtable after this reviewexplores the causes for the wide treatment gapbetween anticoagulation clinical trial results andclinical practice outcomes. The economic implicationsof such a gap and strategies for closing the gapare also discussed by the panelists.
(Am J Manag Care. 2004;10:S297-S306)
Atrial fibrillation (AF) and venousthromboembolism (VTE) are diseasestates that affect an increasingly largeproportion of the population. Effective anticoagulationtherapy can prevent the seriousand costly comorbidities related to theseconditions, such as stroke, deep vein thrombosis(DVT), and pulmonary embolism (PE).But this therapy is frequently underused andunderdosed. As a prelude to the roundtablediscussion focusing on the causes and theeconomic consequences of this less-than-idealuse of anticoagulation in clinical practice,this article reviews the evidence basesupporting the safety and efficacy of anticoagulationin AF and VTE and summarizesrecent studies detailing actual utilization ofanticoagulation in diverse health systemsettings.
The Scope of AF and Stroke
AF is the most common heart rhythmdisturbance, accounting for one third of allhospital admissions for arrhythmia.1 Theprevalence of AF in the United States is estimatedto be 2.2 million.2 Overall, about 0.4%of the general population has AF, with therate increasing from about 0.1% among personsyounger than 55 to 60 years of age toabout 9% to 10% among those aged 80 yearsand older.2,3 During the next 20 years, theprevalence is projected to increase to 5.6million, with more than half of the affectedindividuals aged 80 years or older.3
AF is responsible for about 15% to 20% ofthe 700 000 new and recurrent strokes thatoccur every year in the United States.2Several large longitudinal studies have establishedthat AF increases the risk of stroke by5- to 7-fold (Table 1).4-7 This risk for strokeattributable to AF increases with age. Thus,although the overall annualized risk ofstroke is approximately 3% in patients withAF, the yearly risk of stroke in AF patients≥80 years of age is nearly 7%.4
These stroke events in patients with AFare often fatal or severely disabling. Whenconsidered separately from other cardiovasculardiseases, stroke is the third leadingcause of death after diseases of the heart andcancer, accounting for more than 1 of 15deaths.2 More than 1 million individuals areliving with functional limitations or disabilitiesresulting from stroke,8 and the addedburden on family caregivers is widelyacknowledged though not often calculated.The mean per-patient lifetime cost of anischemic stroke has been estimated at$140 038 (1999).2,9 Overall, the economiccost of stroke in the United States has beenset at $53.6 billion, including $33 billion fordirect medical costs and $20.6 billion forlost productivity.2
Warfarin: The Current Standard ofStroke Prevention in AF
The initial steps in managing AF includeidentifying any underlying reversible causes,controlling the heart rate, and using pharmacologicor electric cardioversion to controlheart rhythm.1,10 Long-term management ofthe patient at risk for recurrent AF requireseither ongoing rate or rhythm control and,unless contraindicated, anticoagulation toprevent thromboembolic events. To preventinitial or recurring strokes in these AFpatients, long-term anticoagulant therapywith the oral vitamin K antagonist sodiumwarfarin is the therapy most often employed.
Randomized trials from the 1980s andearly 1990s have documented the benefits oforal anticoagulation with warfarin in preventingstroke associated with AF. A metaanalysisof 5 major primary preventiontrials11-15 and 1 secondary prevention study16involving an aggregate of more than 4600patients with AF showed that warfarinreduced the relative risk of stroke by 62%compared with placebo or control (Figure1).17 Although there are clear benefits toaspirin administration in these patients, thebenefits do not approach those attributableto warfarin.18 Compared with placebo orcontrol, aspirin reduced the relative risk ofstroke by 22% in the major trials that includedthis comparison. However, comparedwith aspirin, warfarin reduced the relativerisk of stroke by 36%. A number of observationalstudies, although limited by theirsmall size and selective patient populations,generally support the findings of randomizedtrials that warfarin is significantly moreeffective than placebo or aspirin in preventingstroke in AF patients.19-23
Based on this large body of convincingevidence, clinical guidelines for stroke prevention in AF have been developed.Consensus guidelines from the AmericanCollege of Chest Physicians (ACCP) arebased on stratification of patients into high-,moderate-, and low-risk groups for stroke(Table 2).24 In fact, most patients with AFhave more than 1 moderate-risk factor or atleast 1 high-risk factor, which means thatpatients with AF require long-term oral anticoagulationwith warfarin. The widelyaccepted goal for the international normalizedratio (INR) in these patients is 2.0 to3.0, a range intended to preserve the efficacyof stroke prevention while minimizing therisk of major hemorrhage. Updated ACCPguidelines are expected later this year.
Although the evidence supporting warfarinefficacy in stroke prevention leaves littleroom for interpretation, the practicallimitations associated with this oral anticoagulantare equally clear. The array of warfarinlimitations include delayed onset ofaction (3-5 days to achieve an antithromboticeffect), highly variable dose-responseeffect, a narrow therapeutic index,drug—drug interactions, drug—food interactions(eg, dietary vitamin K and excessivealcohol), and disease state interactions.These inherent limitations of warfarin createthe need for routine coagulation monitoring,a need that has been addressed in manyhealthcare settings by the implementation ofanticoagulation clinics. But even within thesupportive environment of the anticoagulationclinic, patients and physicians haveproblems initiating and adhering to warfarintherapy. In most clinical practice settingsoutside of the artificial clinical study setting,warfarin is underutilized. And even whenthe drug is initiated, the intensity of anticoagulationis often too low.
Underutilization of Warfarin
A growing body of evidence indicates thatwarfarin is routinely underutilized for strokeprevention in patients with AF. For example,in a quality-of-care report recently publishedby the Centers for Medicare &Medicaid Services, only 57% of inpatientswere found to receive warfarin for AF.2 Oneof the earliest summaries documenting theextent of warfarin underutilization camefrom the Clinical Quality ImprovementNetwork in Canada, a group that evaluated3575 patients diagnosed with AF as theywere leaving 1 of 12 study hospitals.25 Although24% of patients were released with aprescription for warfarin, 30% for aspirin,and 8% for both antithrombotics, 33% ofpatients left the hospital without any kind ofstroke prevention medication.
Similar levels of warfarin underutilizationhave been demonstrated in ambulatorypatients, a population that is generallyyounger and with less comorbid disease. Alarge health maintenance organization(HMO) reviewed warfarin use in the 3 monthsbefore or after AF diagnosis in 11 082patients with nonvalvular AF and no knowncontraindications to the antithromboticagent.20 Overall, 55% of these warfarin-eligiblepatients were actually using the drug,with the lowest rates seen in the oldestpatients—the group that is at highest risk ofstroke (Figure 2). Although the overall levelof utilization in this HMO was actually higherthan that reported in previous analyses ofoutpatients, the authors still conclude thatinterventions are needed to increase the useof warfarin among appropriate candidates.
More recently, warfarin use was evaluatedin 429 residents of a Connecticut long-termcare facility who had AF.26 Overall, only 42%of these individuals (mean age, 87 years)were receiving warfarin; more than 30% ofat-risk residents received neither aspirin norwarfarin. Even among the 83 patients identifiedas ideal candidates for warfarin (ie, norisk factor for hemorrhage), only 44 (53%)received warfarin. The extreme level ofphysician caution in warfarin prescribing inthe elderly is also reflected in this study'sfinding that INR values were within the therapeuticrange only 51% of the time.
In patients with AF and a recent historyof stroke, warfarin utilization is also disturbinglylow. In a study tracking 278Medicare patients with AF discharged followingischemic stroke, the rate of warfarinuse was 78% in patients 65 to 74 years of age,58% in those 75 to 84 years of age, and only31% in patients 85 years of age or older.27
Finally, clinicians should be aware thatwarfarin use might be even less prevalentamong patients of lower socioeconomic status.A recent evaluation of 11 699 OhioMedicaid patients with new-onset nonvalvularAF showed that only 12% of theseindividuals who had no apparent contraindications(and only 10% of all patients) filled aprescription for warfarin in the week beforeor the month after development of AF.28Factors that predicted decreased use of warfarinincluded age younger than 55 years or85 years and older, past intracranial or gastrointestinalhemorrhage, and alcohol ordrug abuse. Homelessness, psychiatric disease,and a lack of a caregiver were alsonoted by the authors as possible causes oflow warfarin prescribing.
P
P
This discouraging snapshot of currentwarfarin use patterns should be viewed inhistorical perspective. During the pastdecade, there have been encouraging trendsin the proper utilization of warfarin in strokeprevention. In particular, following the publicationof the major randomized trials withwarfarin and the treatment guidelines basedon these trials, the overall outpatient use oforal anticoagulation steadily increased frombelow 10% in the early 1980s to as high as50% in the mid-1990s.29,30 As shown inFigure 3, a community-based study of anticoagulationuse in nearly 6000 patients withAF identified on electrocardiograms showedthat overall use of warfarin increased 4-fold from 13% in 1990 to about 50% in 1996( <.001).29 Such steady improvement inappropriate anticoagulation over the yearshas been attributed in some settings to theemergence of anticoagulation clinics to helpmanage the complex monitoring of warfarintherapy. These clinics typically provide astructured environment for patient educationand counseling, order and review ofINR test results, make dosing adjustments,and provide consultations related to issuessuch as whether to provide bridge therapyduring temporary discontinuation of warfarinbefore invasive procedures. However,even while viewing the generally positivetemporal trend of anticoagulant use in AFdepicted in Figure 3, it should be notedthat patients older than 80 years of age arestill significantly less likely to receive warfarin( <.001).29
P
P
The consequences of underuse of appropriateantithrombotic therapy were recentlymade clear in a study of nearly 600 Medicarepatients with long-term AF.21 Similar to theutilization studies, only 328 (55%) of the 597patients received some form of antithrombotictherapy at discharge—34% warfarinand 21% aspirin. The rates of thromboticevents were measured in these elderly frailpatients (a group typically excluded fromrandomized clinical trials) during a 2-yearperiod. As shown in Figure 4, the proportionof patients having no ischemic events ordeaths from any cause was lower in patientsreceiving warfarin versus those not receivingtherapy or aspirin. Warfarin was associatedwith a relative risk reduction of 24% ( =.003). The risk reduction associated withaspirin was only 5% ( = .56).
Underanticoagulation with Warfarin
In improving the quality of anticoagulationtherapy for stroke prevention, cliniciansand health systems must not onlystrive to place more of their appropriatelyscreened AF patients on warfarin regimens,but also to ensure that these patients aremaintained within the proper therapeuticrange. An INR range of 2.0 to 3.0 is thewidely accepted goal for most patients withnonvalvular AF.1,24 Insufficient dosing ofwarfarin (with INR below 2.0) can lead toischemic stroke and death, whereas excessivedosing (INR above 4.0) increases therisk of intracranial bleeding.31-33 Althoughthis numerical INR range is widely understoodby clinicians, what is less appreciatedis that the slope of increased bleeding riskassociated with INR over 3.0 is not as steepas the slope of increased stroke risk for INRsbelow 2.0 (Figure 5).31,32 In other words,underanticoagulation may be riskier thanovercoagulation. And so, notwithstandingthe natural clinician tendency to "first do noharm," it is absolutely critical to maintainthe INR above the lower limit of the therapeuticrange. An INR of 1.5 or 1.7 is dramaticallyless effective in preventing stroke inmost patients with AF, but is unfortunatelyall too common in everyday clinical practice.
One retrospective study evaluated theproportion of time that 660 patients with AFmanaged by internists or family practitionerswere maintained within their INR goal.In the one third of the group (34.7%) thatwas actually receiving warfarin therapy, theINR values were out of range more than halfof the time; 38.2% were below 2.0 and 18.2%were above 3.0.34 Practices with access toanticoagulation clinics had slightly higherrates of within-goal INRs, but even such relativelyintensive management will likelyachieve anticoagulation goals only 65% or70% of the time. Overall, this evaluationpoints out the current magnitude of ineffectivenesswith oral anticoagulation. If thisstudy reflects the facts in most clinical practicestoday, which it likely does, then about65% of AF patients seen in primary care arenot receiving any warfarin, 6% are above INRrange, 13% are below range, and only 15% ofthese eligible patients are being treated andare within INR range.34
The clinical impact of subtherapeuticanticoagulation with warfarin has beenexplored in a recent study by Hylek and colleagues.33 In almost 600 patients with AFpresenting to a hospital with ischemicstroke, 32% were receiving warfarin therapy.Warfarin-treated patients with an INR of lessthan 2.0 at the time of admission were muchmore likely to have a fatal or severe strokeevent. In patients with INRs below or above2.0, the rates of fatal stroke were 9% and 1%,respectively, and the rates of major stroke(ie, patients not independent in their day-todayfunctioning) were 44% and 38%, respectively.Overall, 59% of warfarin-treatedpatients with INRs below 2.0 had a severestroke as defined across 3 categories comparedwith 43% of patients with INRs above2.0 (odds ratio, 1.9; 95% confidence interval[CI]; INR, 1.1-3.4). In addition, thosepatients maintained above the 2.0 INR had alower 30-day mortality rate compared withthose below their INR target (hazard ratio,3.4; 95% CI; INR, 1.1-10.1). In fact, the 30-day mortality rate among warfarin-treatedpatients below INR 2.0 was similar to thatseen in AF patients taking only aspirin(Figure 6).33 Thus, INRs above 2.0 not onlyreduce the frequency of stroke in patientswith AF but also stroke severity and stroke-relatedmortality.
Prophylaxis of VTE
The rate of VTE is estimated to occur in48 of 100 000 persons, and the rate of thosewith DVT and PE is estimated to occur in 69of 100 000 persons.35 The average death ratefrom PE is about 8%, which usually occursduring the first 30 days of onset.36
The ACCP has determined that the risk ofVTE without prophylaxis is substantial(Table 3); in the group of patients at highestrisk for VTE, such as those undergoingorthopedic surgery, the risk of fatal PEapproaches 5%.37
However, the risk of VTE can be greatlyreduced with timely anticoagulation (Table4).37,38 Despite the ongoing controversiesabout the selection of individual drugs forVTE prophylaxis (eg, unfractionated heparinvs low-molecular-weight heparin in the medicallyill patient) and timing of the initiationof prophylaxis (eg, pre- or postoperativeadministration), there is clearly a large numberof surgical and medical patients whostand to benefit from VTE prophylaxis.
For long-term prevention of recurrentVTE, warfarin is increasingly being administeredbeyond the acute phase, and in somecases the outpatient oral anticoagulation iscontinued indefinitely.39-43 Current guidelinescall for individualization of therapybased on the patient's underlying risk forrecurrence as well as the risk of bleeding; forexample, patients with a first DVT andreversible risk factors such as surgery,immobilization, or trauma should receive 3to 6 months of warfarin.37,43,44,45
Unfortunately, as with AF, a large bodyof literature now documents the underutilizationin high-risk patients, such as thoseundergoing surgery or who are medicallyill. One of the largest and most recent studiesgauging the level of adequate anticoagulationfor VTE was the DVT FREE Registry,a coordinated effort that prospectively evaluated5451 patients with DVT from 183 differentclinical sites around the UnitedStates.46 Of the 2726 patients who had DVTdiagnosed while in the hospital, only 1147(42%) had received prophylaxis in the past30 days.
Another registry-based study evaluatingprophylaxis of DVT/PE is the NationalAnticoagulation Benchmark and OutcomesReport (NABOR) Project.47 This large ongoingstudy has already found that 14.4% oforthopedic surgery patients—who are atextremely high risk for VTE—had receivedeither inadequate prophylaxis (ie, aspirin)or none at all. Also, although current evidencesupports continuing anticoagulationfor a minimum of 7 to 10 days, and possiblyas long as 30 days, in this surgical setting,the NABOR data indicate that mostpatients having major orthopedic surgeryare receiving only 3 to 5 days of anticoagulation(Figure 7). This inadequate averageduration of prophylaxis can undoubtedlybe attributed in some measure to thetrend toward shorter hospital stays aftersurgery. But even as the postsurgical inpatientrecovery time is truncated, onlyabout 70% of patients having total kneeor hip replacement are discharged withanticoagulation.
Summary
Anticoagulation offers a clear benefit inpatients with AF, and clinical guidelineshave been developed to support anticoagulationwith warfarin for stroke prevention.However, the inherent properties of warfarinrelated to bleeding risk and the requirementfor therapeutic monitoring have contributedto a vast underutilization of this oral therapyto prevent stroke in patients with AF.Furthermore, in those patients who aremaintained on warfarin, physician andpatient reluctance to pursue the goal INRbetween 2.0 and 3.0 contributes to widespreadunderanticoagulation. Thus, althoughit remains the most widely used oral anticoagulantin North America,47 this vitamin Kantagonist has never achieved in everydayclinical practice the levels of stroke reductionproved in formal clinical trials. In thearea of VTE prophylaxis, anticoagulants aresimilarly underutilized.48 Again, althoughthe benefits of extended anticoagulation insettings such as orthopedic surgery areclear, the actual initiation and intensity ofanticoagulation falls well short of the standardset by national guidelines. In theroundtable discussion, which appears in thissupplement, the potential causes of suboptimalanticoagulation are explored along withthe economic implications of such a gapbetween clinical studies and clinical reality.In the concluding article, the potential ofnovel antithrombotic therapies to close thistreatment gap is briefly reviewed.
J Am Coll Cardiol.
1. Fuster V, Ryden LE, Asinger RW, et al.ACC/AHA/ESC guidelines for the management ofpatients with atrial fibrillation: executive summary. AReport of the American College of Cardiology/AmericanHeart Association Task Force on Practice Guidelines andthe European Society of Cardiology Committee forPractice Guidelines and Policy Conferences (Committeeto Develop Guidelines for the Management of Patientswith Atrial Fibrillation): developed in collaboration withthe North American Society of Pacing and Electrophysiology. 2001;38:1231-1266.
Heart Disease andStroke Statistics—2004 Update.
2. American Heart Association. Dallas, Tex: AmericanHeart Association; 2003.
JAMA.
3. Go AS, Hylek EM, Phillips KA, et al. Prevalence ofdiagnosed atrial fibrillation in adults: national implicationsfor rhythm management and stroke prevention: theAnticoagulation and Risk Factors in Atrial Fibrillation(ATRIA) study. 2001;285:2370-2375.
Stroke.
4. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation asan independent risk factor for stroke: the Framinghamstudy. 1991;22:983-988.
Stroke.
5. Nakayama T, Date C, Yokoyama T, Yoshiike N,Yamaguchi M, Tanaka H. A 15.5-year follow-up studyof stroke in a Japanese provincial city. The Shibata study. 1997;28:45-52.
Eur Heart J.
6. Onundarson PT, Thorgeirsson G, Jonmundsson E,Sigfusson N, Hardarson T. Chronic atrial fibrillation—epidemiologic features and 14 year follow-up: a casecontrol study. 1987;8:521-527.
J Am Coll Cardiol.
7. Chugh SS, Blackshear JL, Shen WK, Hammill SC,Gersh BJ. Epidemiology and natural history of atrial fibrillation:clinical implications. 2001;37:371-378.
MMWR MorbMortal Wkly Rep.
8. Prevalence of disabilities and associated health conditionsamong adults—United States, 1999. 2001;50:120-125.
Stroke.
9. Taylor TN, Davis PH, Torner JC, Holmes J, MeyerJW, Jacobson MF. Lifetime cost of stroke in the UnitedStates. 1996;27:1459-1466.
Ann Intern Med.
10. McNamara RL, Tamariz LJ, Segal JB, Bass EB.Management of atrial fibrillation: review of the evidencefor the role of pharmacologic therapy, electrical cardioversion,and echocardiography. 2003;139:1018-1033.
Lancet.
11. Petersen P, Boysen G, Godtfredsen J, Andersen ED,Andersen B. Placebo-controlled, randomised trial ofwarfarin and aspirin for prevention of thromboemboliccomplications in chronic atrial fibrillation. TheCopenhagen AFASAK study. 1989;1:175-179.
Circulation.
12. Cairns JA. Stroke Prevention in Atrial FibrillationStudy. Final results. 1991;84:527-539.
N Engl J Med.
13. The effect of low-dose warfarin on the risk of stroke inpatients with nonrheumatic atrial fibrillation. The BostonArea Anticoagulation Trial for Atrial FibrillationInvestigators. 1990;323:1505-1511.
J Am Coll Cardiol.
14. Connolly SJ, Laupacis A, Gent M, Roberts RS,Cairns JA, Joyner C. Canadian Atrial FibrillationAnticoagulation (CAFA) study. 1991;18:349-355.
N Engl J Med.
15. Ezekowitz MD, Bridgers SL, James KE, et al.Warfarin in the prevention of stroke associated with nonrheumaticatrial fibrillation. Veterans Affairs StrokePrevention in Nonrheumatic Atrial FibrillationInvestigators. 1992;327:1406-1412.
16. Secondary prevention in non-rheumatic atrial fibrillationafter transient ischaemic attack or minor stroke.EAFT (European Atrial Fibrillation Trial) Study Group.Lancet. 1993;342:1255-1262.
Arch Intern Med.
17. Risk factors for stroke and efficacy of antithrombotictherapy in atrial fibrillation. Analysis of pooled data fromfive randomized controlled trials. 1994;154:1449-1457.
Ann Intern Med.
18. Hart RG, Benavente O, McBride R, Pearce LA.Antithrombotic therapy to prevent stroke in patients withatrial fibrillation: a meta-analysis. 1999;131:492-501.
Am J Manag Care.
19. Go AS. Efficacy of anticoagulation for stroke preventionand risk stratification in atrial fibrillation: translatingtrials into clinical practice. 2004;10:S58-S65.
AnnIntern Med.
20. Go AS, Hylek EM, Borowsky LH, Phillips KA, SelbyJV, Singer DE. Warfarin use among ambulatory patientswith nonvalvular atrial fibrillation: the Anticoagulationand Risk Factors in Atrial Fibrillation (ATRIA) study. 1999;131:927-934.
Stroke.
21. Gage BF, Boechler M, Doggette AL, et al. Adverseoutcomes and predictors of underuse of antithrombotictherapy in Medicare beneficiaries with chronic atrial fibrillation. 2000;31:822-827.
Stroke.
22. Evans A, Perez I, Yu G, Kalra L. Should stroke subtypeinfluence anticoagulation decisions to preventrecurrence in stroke patients with atrial fibrillation? 2001;32:2828-2832.
J Intern Med.
23. Frost L, Johnsen SP, Pedersen L, Toft E, Husted S,Sorensen HT. Atrial fibrillation or flutter and stroke: aDanish population-based study of the effectiveness oforal anticoagulation in clinical practice. 2002;252:64-69.
Chest.
24. Albers GW, Dalen JE, Laupacis A, Manning WJ,Petersen P, Singer DE. Antithrombotic therapy in atrialfibrillation. 2001;119:194S-206S.
Can JCardiol.
25. Thromboembolic prophylaxis in 3575 hospitalizedpatients with atrial fibrillation. The Clinical QualityImprovement Network (CQIN) Investigators. 1998;14:695-702.
ArchIntern Med.
26. McCormick D, Gurwitz JH, Goldberg RJ, et al.Prevalence and quality of warfarin use for patients withatrial fibrillation in the long-term care setting. 2001;161:2458-2463.
ArchIntern Med.
27. Brass LM, Krumholz HM, Scinto JD, Mathur D,Radford M. Warfarin use following ischemic strokeamong Medicare patients with atrial fibrillation. 1998;158:2093-2100.
Arch Intern Med.
28. Johnston JA, Cluxton RJ Jr, Heaton PC, Guo JJ,Moomaw CJ, Eckman MH. Predictors of warfarin useamong Ohio Medicaid patients with new-onset nonvalvularatrial fibrillation. 2003;163:1705-1710.
Arch Intern Med.
29. Smith NL, Psaty BM, Furberg CD, et al. Temporaltrends in the use of anticoagulants among older adultswith atrial fibrillation. 1999;159:1574-1578.
Circulation.
30. Stafford RS, Singer DE. Recent national patterns ofwarfarin use in atrial fibrillation. 1998;97:1231-1233.
Ann InternMed.
31. Hylek EM, Singer DE. Risk factors for intracranialhemorrhage in outpatients taking warfarin. 1994;120:897-902.
N Engl J Med.
32. Hylek EM, Skates SJ, Sheehan MA, Singer DE. Ananalysis of the lowest effective intensity of prophylacticanticoagulation for patients with nonrheumatic atrial fibrillation. 1996;335:540-546.
N Engl J Med.
33. Hylek EM, Go AS, Chang Y, et al. Effect of intensityof oral anticoagulation on stroke severity and mortalityin atrial fibrillation. 2003;349:1019-1026.
Arch Intern Med.
34. Samsa GP, Matchar DB, Goldstein LB, et al.Quality of anticoagulation management among patientswith atrial fibrillation: results of a review of medicalrecords from 2 communities. 2000;160:967-973.
Arch Intern Med.
35. Silverstein MD, Heit JA, Mohr DN, Petterson TM,O'Fallon WM, Melto LJ 3rd. Trends in the incidence ofdeep vein thrombosis and pulmonary embolism: a 25-year population-based study. 1998;158:585-593.
Am JCardiol.
36. Stein PD, Kayali F, Olson RE. Estimated case fatalityrate of pulmonary embolism, 1979 to 1998. 2004;93:1197-1199.
Chest.
37. Geerts WH, Heit JA, Clagett GP, et al. Preventionof venous thromboembolism. 2001;119(1suppl):132S-175S.
Thromb Haemost.
38. Mismetti P, Laporte-Simitsidis S, Tardy B, et al.Prevention of venous thromboembolism in internal medicinewith unfractionated or low-molecular-weightheparins: a meta-analysis of randomised clinical trials. 2000;83:14-19.
N Engl J Med.
39. Kearon C, Gent M, Hirsh J, et al. A comparison ofthree months of anticoagulation with extended anticoagulationfor a first episode of idiopathic venous thromboembolism. 1999;340:901-907.
N Engl J Med.
40. Schulman S, Granqvist S, Holmstrom M, et al. Theduration of oral anticoagulant therapy after a secondepisode of venous thromboembolism. The Duration ofAnticoagulation Trial Study Group. 1997;336:393-398.
N Engl J Med.
41. Agnelli G, Prandoni P, Santamaria MG, et al. Threemonths versus one year of oral anticoagulant therapy foridiopathic deep venous thrombosis. Warfarin OptimalDuration Italian Trial Investigators. 2001;345:165-169.
N Engl J Med.
42. Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term,low-intensity warfarin therapy for the prevention ofrecurrent venous thromboembolism. 2003;348:1425-1434.
N Engl JMed.
43. Kearon C, Ginsberg JS, Kovacs MJ, et al.Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term preventionof recurrent venous thromboembolism. 2003;349:631-639.
J Am Coll Cardiol.
44. Hirsh J, Fuster V, Ansell J, et al. American HeartAssociation/American College of Cardiology Foundationguide to warfarin therapy. 2003;41:1633-1652.
Chest.
45. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotictherapy for venous thromboembolic disease. 2001;119:176S-193S.
Am JCardiol.
46. Goldhaber SZ, Tapson VF; DVT FREE SteeringCommittee. A prospective registry of 5,451 patients withultrasound-confirmed deep vein thrombosis. 2004;93:259-262.
Circulation.
47. Caprini JA, Ballard DJ, Becker RC, et al. Disparitiesin antithrombotic management. 2004;109(20):e231-84 (abstract P148).
Am J Manag Care.
48. Nutescu EA. Antithrombotic therapy for the treatmentof venous thromboembolism. 2003;9:S103-S114.
