effects of fixed low-dose warfarin, aspirin-warfarin combination therapy, and dose-adjusted warfarin...

Foo Leong Li-Saw-Hee, Andrew D. Blann and Gregory Y. H. LipDose-Adjusted Warfarin on Thrombogenesis in Chronic Atrial Fibrillation

Effects of Fixed Low-Dose Warfarin, Aspirin-Warfarin Combination Therapy, and

Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 2000 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Stroke doi: 10.1161/01.STR.31.4.828

2000;31:828-833Stroke.

http://stroke.ahajournals.org/content/31/4/828World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://stroke.ahajournals.org//subscriptions/

is online at: Stroke Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer process is available in the

Request Permissions in the middle column of the Web page under Services. Further information about thisOnce the online version of the published article for which permission is being requested is located, click

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.Strokein Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:

by guest on January 11, 2014http://stroke.ahajournals.org/Downloaded from by guest on January 11, 2014http://stroke.ahajournals.org/Downloaded from

http://stroke.ahajournals.org/content/31/4/828

http://stroke.ahajournals.org/content/31/4/828

http://www.ahajournals.org/site/rights/

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://www.lww.com/reprints



http://stroke.ahajournals.org/




Effects of Fixed Low-Dose Warfarin, Aspirin-WarfarinCombination Therapy, and Dose-Adjusted Warfarin on

Thrombogenesis in Chronic Atrial FibrillationFoo Leong Li-Saw-Hee, MRCP; Andrew D. Blann, PhD, MRCPath; Gregory Y.H. Lip, MD, FRCPE

Background and Purpose—Recent clinical trials have established that adjusted-dose warfarin (international normalizedratio [INR] 2.0 to 3.0) is highly effective in the reduction of ischemic stroke in patients with nonvalvular atrialfibrillation (AF). We hypothesized that the introduction of fixed low-dose warfarin alone or in combination with aspirin(300 mg) could normalize hemostatic markers, namely plasma fibrin D-dimer (an index of thrombogenesis),plasminogen activator inhibitor-1 (PAI-1, an index of fibrinolysis), fibrinogen, and von Willebrand factor (vWf, anindex of endothelial dysfunction), in a manner comparable to adjusted-dose warfarin (target INR 2.0 to 3.0).

Methods—Sixty-one patients with AF (44 men, mean6SD age 64619 years) who were not receiving any antithrombotictherapy were prospectively randomized into 1 of 3 treatment groups: warfarin (2 mg) (n523; group 1), combination 1mg warfarin plus 300 mg aspirin (n521; group 2) or combination 2 mg warfarin plus 300 mg aspirin (n517; group 3).Subjects from all 3 AF groups were matched for sex, age, and blood pressure. Blood samples were taken for sequentialmeasurements for changes in plasma fibrin D-dimer, PAI-1, fibrinogen, and vWf before and at 2 and 8 weeks afterrandomization (phase 1). All patients were subsequently offered adjusted-dose warfarin therapy (phase 2), and anadditional blood sample was taken 6 weeks later.

Results—When pretreatment results were compared with those from 60 age- and sex-matched healthy control subjects insinus rhythm, there were significant elevations in levels of fibrinogen (P50.025), vWf (P,0.0001), and fibrin D-dimer(P,0.0001) in patients with AF compared with control subjects. There were no significant changes in the levels ofvarious indices measured after 2 and 8 weeks of therapy in all 3 groups, except for an increase in PAI-1 level (P50.024)in group 3. After 6 weeks of therapy with dose-adjusted warfarin (INR 2.0 to 3.0), there was a significant decrease inplasma fibrinogen (P50.023) and fibrin D-dimer (P50.0067) levels. There were no significant changes in the levels ofPAI-1 (P50.198) or vWf (P50.33).

Conclusions—The present results confirmed that high levels of vWf, fibrinogen, and fibrin D-dimer levels were presentin patients with AF compared with control subjects. Moreover, the introduction of 300 mg aspirin plus low-dosewarfarin (1 mg/d), low-dose warfarin alone (2 mg/d), or 300 mg aspirin plus low-dose warfarin (2 mg/d) did notsignificantly reduce any of the hemostatic markers studied (except PAI-1 levels), whereas conventional full-dosewarfarin (INR 2.0 to 3.0) significantly reduced levels of fibrin D-dimer and fibrinogen. These results are in keeping withthe disappointing ineffectiveness of low-intensity warfarin therapy, aspirin-warfarin combination, and ultralow-dosewarfarin therapy in the recent prematurely terminated clinical trials and the established benefits of conventionaladjusted-dose anticoagulation therapy.(Stroke. 2000;31:828-833.)

Key Words: aspirinn atrial fibrillation n drug therapy, combinationn hemostaticsn warfarin

Recent clinical trials have firmly established that adjusted-dose warfarin (target international normalized ratio

[INR] 2.0 to 3.0), is highly effective in reducing ischemicstroke in patients with nonvalvular atrial fibrillation (AF).1

Because of bleeding and other contraindications, the inter-ruption of anticoagulation treatment is frequent, even inclinical trials. In addition, patients require regular monitoringof anticoagulant intensity, which contributes to the expenseand inconvenience of this treatment strategy. Therefore, there

has been a necessity to develop new strategies to improvethromboprophylaxis in patients with AF.

Recent studies have focused on the use of low-intensityanticoagulation or aspirin-anticoagulation regimens. For ex-ample, ultralow-dose warfarin (1 mg/d) has been successfullyused to prevent thrombosis of central venous catheters2 and toprevent venous thrombosis in malignancy.3 In the MRCthrombosis prevention trial, 5499 men aged 45 to 69 years athigh risk of ischemic heart disease were treated with low-

Received August 16, 1999; final revision received January 13, 1999; accepted January 13, 2000.From the Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, England.Correspondence to Dr G.Y.H. Lip, Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital,

Birmingham B18 7QH, England. E-mail [email protected]© 2000 American Heart Association, Inc.

Stroke is available at http://www.strokeaha.org

828 by guest on January 11, 2014http://stroke.ahajournals.org/Downloaded from



intensity anticoagulation (mean INR 1.47), 75 mg/d aspirin,or placebo.4 The trial investigators found that aspirin reducednonfatal ischemic heart disease (by 32%) and low-intensitywarfarin mainly reduced fatal events (by 39%), whereas thecombination of warfarin-aspirin therapy was more effectivethan either agent alone.4 The possibility that low-intensityantithrombotic strategies would be suitable as thrombopro-phylaxis for AF seemed attractive and plausible.

Recent evidence has established that AF confers a hyper-coagulable state that is independent of underlying structuralheart disease or etiology.5 The usefulness of the measurementof various markers of hypercoagulability to indicate theeffectiveness of antithrombotic therapy has been demon-strated in a randomized trial in which fixed ultralow-dosewarfarin (1 mg) or aspirin (300 mg) did not significantlyreduce elevatedb-thromboglobulin (a marker of plateletactivation) and fibrin D-dimer (an index of thrombogenesis)levels in patients with nonvalvular AF, although conventionaladjusted-dose warfarin therapy (INR 2.0 to 3.0) did normalizelevels of these markers.6 This trial was consistent with thebeneficial effect of adjusted-dose warfarin in the preventionof stroke and thromboembolism in patients with AF andsuggested that fixed ultralow-dose warfarin or aspirin maynot exert similar beneficial effects in the reduction of throm-bogenesis. This was in keeping with the subsequent publica-tion of the results from the second Copenhagen AtrialFibrillation Aspirin and Anticoagulant Therapy Study(AFASAK 2) clinical trial.7

We had hypothesized that the introduction of fixed low-dose warfarin regimens (2 mg) alone or in combination withaspirin (300 mg) could normalize hemostatic markers,namely plasma fibrin D-dimer (an index of thrombogenesis),plasminogen activator inhibitor-1 (PAI-1, an index of fibri-nolysis), fibrinogen, and von Willebrand factor (vWf, anindex of endothelial dysfunction), in a manner comparable toadjusted-dose warfarin (target INR 2.0 to 3.0). The presentstudy was initiated before the premature termination of thethird Stroke Prevention in Atrial Fibrillation Trial (SPAF III),the Minidose Warfarin (MIWAF) trial, the Primary Preven-tion of Arterial Thrombo-embolism in Non-rheumatic AtrialFibrillation (PATAF) trial, and the Copenhagen AFASAK 2trial of the effect of fixed aspirin-warfarin combination,conventional-dose warfarin, and aspirin regimens in patientswith AF.7–10

Subjects and MethodsWe studied outpatients with chronic nonvalvular AF who were notreceiving antithrombotic therapy and had been referred to a specialistoutpatient clinic for the consideration of anticoagulation. Chronic AFwas confirmed on ECG on$2 separate occasions ($6 weeks apart).All subjects underwent a 2-dimensional, targeted M-mode, Dopplerultrasound examination with a Hewlett-Packard Sonos 100 echocar-diograph to exclude any significant valvular disease or moderate-to-severe left ventricular systolic dysfunction.

After informed consent was obtained, patients were prospectivelyrandomized into 1 of 3 groups: low-dose warfarin (2 mg) (n523;group 1), combination ultralow-dose warfarin (1 mg) plus aspirin(300 mg) (n521; group 2), or combination low-dose warfarin (2 mg)plus aspirin (300 mg) (n517; group 3). Patients were seen at baseline(visit 1) and then at 2 and 8 weeks after randomization (phase 1);subsequent to this, all patients were offered conventional adjusted-

dose warfarin therapy (achieving INR 2.0 to 3.0) (phase 2), but dueto patient withdrawals, complete samples for hemostatic markerswere taken at the 6-week follow-up visit in only 20 fully anticoag-ulated patients. Nevertheless, patients were seen at intervals duringthat period to ensure therapeutic anticoagulation was rapidlyachieved and maintained at INR 2.0 to 3.0.

Baseline results in patients with AF were compared with thosefrom age- and sex-matched normotensive healthy control subjectsdrawn from healthy hospital staff and from those who were attendeesat hospital for hernia repair, varicose veins, or minor surgery. Nonehad diabetes, and all were without any signs or symptoms ofcardiovascular or connective tissue disease. The study protocol wasapproved by the West Midlands District Ethics Committee.

Blood Samples and Assay ProceduresBlood samples were taken from the antecubital fossa vein and placedinto sodium citrate; they were centrifuged within 2 hours ofcollection at 3000gand 4°C for 20 minutes to obtain plasma, whichwas then separated and stored at270°C before assay.

The plasma markers were measured in batches: vWF with anestablished ELISA (DAKO), fibrin D-dimer with an ELISA fromAgen, fibrinogen with a modified Clauss technique on a Pacifichemostasis coagulometer and reagents from Alpha Laboratories, andPAI-1 with an ELISA from Immuno GmbH. Intra-assay and inter-assay coefficients of variation for all ELISA assays were,5% and,10%, respectively.

Data and Statistical AnalysesResults are expressed as mean6SD, except for PAI-1 and fibrinD-dimer, for which results are expressed as median and interquartilerange (IQR). Comparisons between cases and controls were per-formed with thet test or Mann-WhitneyU test. With 3 sets of data(pretreatment and 2 and 8 weeks after treatment in phase 1), resultswere analyzed with Friedman’s repeated-measures ANOVA(RMANOVA). Paired data, which were comparisons of data forbaseline with those for 6-week treatment with dose-adjusted conven-tional adjusted-dose warfarin therapy (phase 2), were measured withpaired t test or paired Wilcoxon test, as appropriate. Correlationswere performed with Spearman’s rank correlation, and categoricaldata were compared with use of thex2 test. All statistical calculationswere performed on a microcomputer with a commercially availablestatistical package (Minitab release 11; Minitab Inc). A value ofP,0.05 was considered statistically significant.

ResultsWe studied 61 patients with chronic AF (44 men and 17women, mean age 64619 years). Baseline indices in thesepatients were compared with those for 60 age- and sex-matched healthy subjects in sinus rhythm (mean age 6666years). There were no significant differences in mean age, sexratio, and blood pressures between patients and controlsubjects (Table 1). Similarly, there were no significantdifferences among the 3 treatment groups (groups 1, 2, and 3)in mean age, sex ratio, and blood pressures (data not shown).

Baseline for Patients Versus Control SubjectsThere were significant elevations in levels of plasma fibrin-ogen (P50.025), vWf (P,0.0001), and fibrin D-dimer(P,0.0001) in patients with AF compared with controlsubjects. There was a nonsignificant trend toward higherplasma PAI-1 levels in the patients with AF (P50.0706)(Table 2).

There were 16 patients with lone AF, which was definedfor the purposes of the present study as AF in the absence ofany known predisposing factors. PAI-1 levels were signifi-cantly lower in those with lone AF compared with those

Li-Saw-Hee et al Low-Intensity Warfarin and Aspirin-Warfarin Therapy in AF 829

by guest on January 11, 2014http://stroke.ahajournals.org/Downloaded from



without lone AF (n545) (P50.02). There were no statisti-cally significant differences in age, blood pressures, or levelsof plasma fibrinogen (P50.24), vWf (P50.34), and fibrinD-dimer (P50.777) in the patients with one AF comparedwith those without one AF (Table 3).

There were significant correlations between fibrin D-dimerand diastolic blood pressure (r520.274), PAI-1 (r520.257),and fibrinogen (r50.322) levels (Spearman, allP,0.05).There were no significant correlations between INR andmeasured parameters at baseline or between other measuredparameters (data not shown).

Treatment GroupsIn group 1 (2 mg warfarin), there were no significant changesin the levels of various measured indices and INR after 2 and8 weeks of therapy with 2 mg/d warfarin (Table 4). There wasa nonsignificant trend toward a reduction in fibrin D-dimerlevels (P50.055).

In group 2 (1 mg warfarin and 300 mg aspirin), there wereno significant changes in the levels of any of the variousmeasured indices and INR after 8 weeks of therapy with 1 mgwarfarin and 300 mg/d aspirin (Table 4).

In group 3 (2 mg warfarin and 300 mg aspirin), there wasno significant changes in the levels of fibrinogen, vWf, orfibrin D-dimer and INR values after 8 weeks of therapy with2 mg warfarin and 300 mg/d aspirin (Table 4). However,there was a significant increase in PAI-1 levels (from 6.0IU/dL at week 0 to 7.8 IU/dL at week 8,P50.024).

In phase 2 (subsequent treatment with conventional dose-adjusted warfarin, INR 2.0 to 3.0), there were significantdecreases in the levels of plasma fibrinogen (P50.023) andfibrin D-dimer (P50.0067) and in the median INR value(P,0.00001) after 6 weeks of therapy with dose-adjustedwarfarin (mean6SD INR 2.460.7). There were no signifi-cant changes in PAI-1 and vWf levels (Table 5). There wereno significant correlations between the INR and fibrinD-dimer or PAI-1 levels in any of the treatment groups.

TABLE 1. Demographic Data for Study Population

ControlSubjects

PatientsWith AF P

n 60 61

Age, y 6666 64619 0.64

Sex, n (% male) 45 (75) 44 (72) 0.78

Smokers, n (%) 7 (11.2) 8 (15.4) 0.84

Systolic blood pressure, mm Hg 145621 142623 0.88

Diastolic blood pressure, mm Hg 80611 82612 0.73

Known hypertension, .160/90 mm Hg, n (%) 0 13 (21.3) z z z

Lone AF, n (%)* 0 16 (26.2) z z z

Coronary artery disease, n (%) 0 12 (19.7) z z z

Prior thromboembolic stroke, n (%) 0 3 (4.9) z z z

Diabetes mellitus, n (%) 0 4 (6.6) z z z

Peripheral vascular disease, n (%) 0 4 (6.6) z z z

*Lone AF was defined for the purposes of the present study as AF in the absence of any knownpredisposing factors (eg, cardiovascular disease, hypertension, thyroid disease, and so on).

TABLE 2. Plasma Levels of Fibrinogen, von Willebrand Factor,Plasminogen Activator Inhibitor-1, and Fibrin D-Dimer inPatients With Chronic AF and Control Subjects

Patientswith AF

ControlSubjects P

n 61 60

Fibrinogen, g/L 2.960.9 2.660.8 0.025

von Willebrand factor,IU/dL

143637 105630 ,0.0001

Plasminogen activatorinhibitor-1, IU/dL

6.3(3.9–10.4)

4.9(3.2–7.6)

0.0706

Fibrin D-dimer, ng/mL 212(98–515)

60(7.5–167)

,0.0001

Data are mean6SD (analyzed with t test) for fibrinogen and von Willebrandfactor; median (interquartile range) (analyzed with Mann-Whitney test) is givenfor plasminogen activator inhibitor-1 and fibrin D-dimer.

TABLE 3. Plasma Levels of Fibrinogen, von Willebrand Factor,Plasminogen Activator Inhibitor-1, and Fibrin D-Dimer inPatients With and Without Lone AF

PatientsWith Lone AF

PatientsWithout Lone AF P

n 16 45

Age, y 69615 66613 0.50

Male, n (%) 11 (69%) 33 (73%) 0.19

Systolic bloodpressure, mm Hg

133623 143624 0.12

Diastolic bloodpressure, mm Hg

8169 83612 0.35

Fibrinogen, g/L 2.760.7 3.060.9 0.24

von Willebrand factor, IU/dL 149626 141639 0.34


4.3(2.6–6.34)

7.5(4.5–10.8)

0.0201

Fibrin D-dimer, ng/mL 200(90–468)

214(90–700)

0.777

Lone AF indicates AF in the absence of any known predisposing factors;patients without lone AF, AF with one or more known predisposing factors.

Data are mean6SD for fibrinogen and von Willebrand factor (analyzed witht test); median (interquartile range) (analyzed with Mann-Whitney test) is givenfor plasminogen activator inhibitor-1 and fibrin D-dimer.

830 Stroke April 2000




DiscussionThe present results have confirmed the presence of highlevels of vWf, fibrin D-dimer, and fibrinogen and a trendtoward an increased PAI- 1 level in patients with AFcompared with healthy control subjects in sinus rhythm,consistent with a hypercoagulable state associated with thisarrhythmia.5,6,11 The presence of high fibrin D-dimer levelssuggests ongoing fibrin turnover and thrombogenesis inpatients with chronic AF at baseline compared with controlsubjects in sinus rhythm.6,11,12High vWf levels are suggestiveof endothelial dysfunction, whereas increased plasma fibrin-ogen levels indicate abnormal hemorheology and clotting,which are significantly correlated to thrombogenesis (asindicated by fibrin D-dimer levels).11 The high PAI-1 levelssuggest a tendency toward a hypofibrinolytic state in chronicAF, which also appears to be correlated with fibrin D-dimerlevels.13 The presence of all of these abnormalities in hemo-static markers fulfills 2 components of the Virchow’s triad forthrombogenesis: abnormal blood constituents and vessel wall.The presence of abnormal hemodynamic flow in chronic AF,with atrial stasis, fulfills the third component of Virchow’striad and may contribute to the increased risk of stroke andthromboembolism in patients with AF.5

Anticoagulation with warfarin is effective thromboprophy-laxis in patients with AF.1 However, there are problems withconventional full-dose warfarin: inconvenience and safety.This may account for the reluctance in clinical practice toprescribe anticoagulants for all patients with AF. The possi-

bility that low-intensity antithrombotic strategies would besuitable as thromboprophylaxis for AF seemed attractive andplausible.

The introduction of conventional adjusted-dose warfarin(achieving INR 2.0 to 3.0) appears to normalize abnormal levelsof thrombogenic markers,6,11 suggesting that conventional full-dose warfarin treatment was effective in preventing excessivefibrin turnover and consistent with the beneficial antithromboticeffects of conventional adjusted-dose warfarin in clinical trials.For example, Lip et al11 found that conventional adjusted-dosewarfarin significantly reduces circulating fibrin D-dimer levelsby two thirds (P,0.001), consistent with the 68% reduction inthe risk of stroke and thromboembolism in clinical trials withadjusted-dose warfarin, as reported by the Atrial FibrillationInvestigators.1 Similar observations of the marked reduction inhemostasis with conventional anticoagulation have been re-ported in other studies.6,14 By contrast, aspirin therapy results ina nonsignificant 25% reduction in markers of thrombogen-esis,6,11broadly consistent with the 21% risk reduction in strokefrom the pooled analysis of the Atrial Fibrillation Investigators.15

Similarly, Yamamoto et al16 reported that 330 mg/d aspirinsuppressed platelet function in patients with AF but did notsignificantly affect the increased coagulation activity in thesepatients.

Unfortunately, the results of clinical trials that test thestrategy of the use of low-intensity anticoagulation andaspirin-anticoagulation combinations as adequate throm-boprophylaxis in AF have been disappointing.7–10 This is

TABLE 4. Effects of Treatment on Hemostatic Markers in Patients With Chronic AF

Before Treatment

After Treatment

P2 wk 8 wk

2 mg warfarin

Fibrinogen, g/L 3.060.9 2.861.0 2.460.9 0.240

von Willebrand factor, IU/dL 144636 141640 148640 0.836

Plasminogen activator inhibitor-1,IU/dL

6.3 (3.9–10.5) 7.0 (4.2–9.5) 7.0 (5.7–12.6) 0.477

Fibrin D-dimer, ng/mL 280 (160–700) 290 (150–630) 191 (76–534) 0.055

INR 1.1 (1.0–1.2) 1.1 (1.025–1.4) 1.2 (1.1–1.4) 0.257

1 mg warfarin plus 300 mg aspirin

Fibrinogen, g/L 3.060.9 3.060.7 2.560.8 0.134



7.5 (4.2–11.1) 9.6 (4.3–20) 10 (5.6–23) 0.358


INR 1.0 (1.0–1.1) 1.1 (1.0–1.1) 1.1 (1.0–1.2) 0.126

2 mg warfarin plus 300 mg aspirin

Fibrinogen, g/L 2.860.7 2.960.9 2.960.8 0.917



6.0 (3.2–10) 7.5 (4.6–13.1) 7.8 (4.9–15.9) 0.024


INR 1.0 (1.0–1.125) 1.1 (1.0–1.2) 1.1 (1.0–1.1) 0.697

Data are mean6SD for fibrinogen and von Willebrand factor and median (interquartile range) for plasminogenactivator inhibitor-1, fibrin D-dimer, and INR. Data analyzed by RMANOVA.





not surprising because various studies (including the pres-ent study) of similar regimens of low-dose warfarin,aspirin, or combination aspirin/low-dose warfarin have notshown any significant effect on the elevated indices ofthrombogenesis in patients with AF. For example, fixedultralow-dose warfarin (1 mg) did not significantly reducethrombogenesis or platelet activation in AF,6 which is inkeeping with subsequent results from the AFASAK 2study.7 The latter group also reported that after 3 months oftherapy with fixed-dose warfarin (1.25 mg), the level ofINR increased significantly from baseline in patientsreceiving warfarin in any dose but only dose-adjustedwarfarin (INR 2.0 to 3.0) had a marked effect on F112levels, another index of thrombogenesis.17 However, ther-apy with fixed minidose warfarin, combined minidosewarfarin-aspirin, and aspirin alone did not significantlyalter F112 levels. In the SPAF III study,8 the use oflow-intensity warfarin plus 300 mg aspirin did not dem-onstrate any reduction in stroke risk compared with con-ventional anticoagulation. These findings lent weight tothe premise that conventional adjusted-dose anticoagulanttherapy is more appropriate than aspirin for the preventionof stroke and systemic embolism in patients with AF.Thus, the ineffectiveness of regimens with either aspirin,fixed-dose or low-intensity warfarin, or combination low-dose warfarin/aspirin regimens in the reduction in throm-boembolic events in clinical trials of AF7–10 parallels thefindings of various studies of hemostatic markers withsimilar regimens. Indeed, this suggests that the measure-ment of hemostatic markers might be used as surrogate endpoints to test the clinical effectiveness of an antithromboticregimen.

The present study was started before the published resultsof ASAFAK 2, SPAF III, and other similar trials, and our aimwas to study the effect of higher low-dose warfarin (ie, theuse of 2 mg warfarin with or without 300 mg aspirin and 1 mgwarfarin with 300 mg aspirin) in patients with chronic AF.This would follow on from our previous work6 in which weinvestigated the effect of ultralow-dose warfarin (1 mg) onhemostatic markers in AF; ideally, the present study would

have been completed before the scheduled termination ofAFASAK 2, SPAF III, and other similar trials.

The present study is limited by the relatively shortfollow-up period of phase 1. With the trend (nonsignificant)toward a decrease in fibrin D-dimer levels in patients admin-istered low-dose warfarin (2 mg), it is conceivable that givena longer period of time, statistically significant decreases inthis marker may be demonstrated. We did not relate thesehemostatic abnormalities to underlying clinical risk factors ordetailed assessments of left atrial or ventricular size orfunction, because previous studies have indicated that therewas no significant relationship between these markers ofthrombogenesis and underlying medical history or othercardiac abnormalities in patients with AF.5,11,12Furthermore,the main aim of this study was to demonstrate the effects ofthe introduction of treatment with 300 mg aspirin or low-dose(2 mg) warfarin on these markers in patients with AF ratherthan to correlate the abnormalities with the underlying med-ical history or with detailed measurements of cardiac size orventricular function.

ConclusionThe results of the present study show that patients with AFhave not only an increased fibrin turnover but also areduced fibrinolytic state and abnormal endothelial func-tion. The introduction of fixed low-dose warfarin (2 mg) oraspirin-warfarin combination therapy did not significantlyreduce markers of thrombogenesis, whereas conventionaladjusted-dose warfarin (INR 2.0 to 3.0) significantlyreduced the increased levels of fibrin D-dimer in patientswith AF. These results are in keeping with the disappoint-ing ineffectiveness of low-intensity warfarin therapy,aspirin-warfarin combination, and ultralow-dose warfarintherapy in the recent prematurely terminated clinical trialsand the established benefits of conventional adjusted-dosewarfarin therapy (INR 2.0 to 3.0).

AcknowledgmentWe acknowledge the support of the City Hospital NHS TrustResearch & Development Program for the Haemostasis Thrombosisand Vascular Biology Unit.

References1. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of

anti-thrombotic therapy in atrial fibrillation: analysis of pooled data fromfive randomised controlled trials.Arch Intern Med. 1994;154:1449–1457.

2. Bern MM, Lokich JJ, Wallach SR, Bothe A, Benotti PN, Arkin CF, GrecoFA, Huberman M, Moore C. Very low doses of warfarin can preventthrombosis in central venous catheters.Ann Intern Med. 1990;112:423–428.

3. Levine M, Hirsh J, Gent M, Arnold A, Warr D, Falanga A, Samosh M,Bramwell V, Pritchard KI, Stewart D, Goodwin P. Double-blind ran-domised trial of a very-low-dose warfarin for prevention of thromboem-bolism in stage IV breast cancer.Lancet. 1994;343:886–889.

4. The Medical Research Council’s General Practice Research Framework.Thrombosis prevention trial: randomised trial of low-intensity oral anti-coagulation with warfarin and low-dose aspirin in the primary preventionof ischaemic heart disease in men at increased risk.Lancet. 1998;351:233–241.

5. Lip GYH. Does atrial fibrillation confer a hypercoagulable state?Lancet.1995; 346: 1313–1314.

TABLE 5. Effect of Dose-Adjusted Warfarin (Achieving TargetINR of 2.0–3.0) on Hemostatic Markers in Patients WithChronic AF

BeforeTreatment INR 2.0–3.0 P

Fibrinogen, g/L 2.960.9 2.460.7 0.023

von Willebrand factor,IU/dL

143637 134634 0.33


6.3 (3.9–10.4) 7.4 (5.9–14.5) 0.198

Fibrin D-dimer, ng/mL 212 (98–515) 130 (61–175) 0.0067

INR 1.05 (1.125) 2.48 (2.1–2.7) ,0.00001

Data are mean6SD (analyzed with paired t test) for fibrinogen and vonWillebrand factor; median (interquartile range) (analyzed with paired Wilcoxontest) is given for plasminogen activator inhibitor-1, fibrin D-dimer, and INR.

832 Stroke April 2000




6. Lip GYH, Lip PL, Zarifis J, Watson RD, Bareford D, Lowe GD,Beevers DG. Fibrin D-dimer andb-thromboglobulin as markers ofthrombogenesis and platelet activation in atrial fibrillation: effects ofintroducing mg/d-low dose warfarin and aspirin.Circulation. 1996;94:425– 431.

7. Gulløv AL, Koefoed BG, Petersen P, Pedersen TS, Andersen ED,Godtfredsen J, Boysen G. Mini-dose warfarin and aspirin in atrial fibril-lation: Second Copenhagen Atrial Fibrillation Aspirin and Anticoagu-lation Study (AFASAK 2).Arch Intern Med. 1998;158:1513–1521.

8. Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dosewarfarin versus low-intensity fixed dose warfarin plus aspirin for highrisk patients with atrial fibrillation with atrial fibrillation: StrokePrevention in Atrial Fibrillation III randomised clinical trial.Lancet.1996;348:633– 638.

9. Vermeer F, Langenberg M, Hellemons BS, Lodder J, Schouten H, vanRee JW, Knottnerus JA. Primary prevention of arterial thrombo-embolism in non-rheumatic atrial fibrillation: results of the PATAF study.Eur Heart J. 1998;19(suppl):154. Abstract.

10. Pengo V, Zasso A, Barberi F, Banzato A, Nante G, Parissenti L, John N,Noventa F, Dalla Volta S. Effectiveness of fixed minidose warfarin in theprevention of thromboembolism and vascular death in nonrheumaticatrial fibrillation. Am J Cardiol. 1998;82:433–437.

11. Lip GYH, Lowe GD, Rumley A, Dunn FG. Increased markers of throm-bogenesis in chronic atrial fibrillation: effects of warfarin treatment.BrHeart J. 1995;73:527–533.

12. Kumagai K, Fukunami M, Kitabatake A, Kamada T, Hoki N. Increasedcardiovascular clotting in patients with chronic atrial fibrillation.J AmColl Cardiol. 1990;16:377–380.

13. Roldan V, Marin F, Marco P, Martinez JG, Calatayud R, Sogorb F.Hypofibrinolysis in atrial fibrillation.Am Heart J. 1998;136:956–960.

14. Mitusch R, Siemens HJ, Garbe M, Wagner T, Sheikhzadeh A, DiederichKW. Detection of a hypercoagulable state in nonvalvular atrial fibrillationand the effect of anticoagulant therapy.Thromb Haemost. 1996;75:219–223.

15. Atrial Fibrillation Investigators. The efficacy of aspirin in patients withatrial fibrillation. Arch Intern Med. 1997;157:1237–1240.

16. Yamamoto K, Ikeda U, Fukazawa H, Shimada K. Effects of aspirin onstatus of thrombin generation in atrial fibrillation.Am J Cardiol. 1996;77:528–530.

17. Koefoed BG, Feddersen C, Gullov AL, Petersen P. Effect of fixedminidose warfarin, conventional dose warfarin and aspirin on INR andprothrombin fragment 112 in patients with atrial fibrillation.ThrombHaemostat. 1997;77:845–848.





effects of fixed low-dose warfarin, aspirin-warfarin combination therapy, and dose-adjusted warfarin...

Documents