Effects of Fixed Low-Dose Warfarin, Aspirin-Warfarin Combination Therapy, and Dose-Adjusted Warfarin on Thrombogenesis in Chronic Atrial Fibrillation

Abstract

Background and Purpose-Recent clinical trials have established that adjusted-dose warfarin (international normalized ratio [INR] 2.0 to 3.0) is highly effective in the reduction of ischemic stroke in patients with nonvalvular atrial fibrillation (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, an index 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, meanϮSD age 64Ϯ19 years) who were not receiving any antithrombotic therapy were prospectively randomized into 1 of 3 treatment groups: warfarin (2 mg) (nϭ23; group 1), combination 1 mg warfarin plus 300 mg aspirin (nϭ21; group 2) or combination 2 mg warfarin plus 300 mg aspirin (nϭ17; group 3). Subjects from all 3 AF groups were matched for sex, age, and blood pressure. Blood samples were taken for sequential measurements for changes in plasma fibrin D-dimer, PAI-1, fibrinogen, and vWf before and at 2 and 8 weeks after randomization (phase 1). All patients were subsequently offered adjusted-dose warfarin therapy (phase 2), and an additional blood sample was taken 6 weeks later. Results-When pretreatment results were compared with those from 60 age-and sex-matched healthy control subjects in sinus rhythm, there were significant elevations in levels of fibrinogen (Pϭ0.025), vWf (PϽ0.0001), and fibrin D-dimer (PϽ0.0001) in patients with AF compared with control subjects. There were no significant changes in the levels of various indices measured after 2 and 8 weeks of therapy in all 3 groups, except for an increase in PAI-1 level (Pϭ0.024) in group 3. After 6 weeks of therapy with dose-adjusted warfarin (INR 2.0 to 3.0), there was a significant decrease in plasma fibrinogen (Pϭ0.023) and fibrin D-dimer (Pϭ0.0067) levels. There were no significant changes in the levels of PAI-1 (Pϭ0.198) or vWf (Pϭ0.33). Conclusions-The present results confirmed that high levels of vWf, fibrinogen, and fibrin D-dimer levels were present in patients with AF compared with control subjects. Moreover, the introduction of 300 mg aspirin plus low-dose warfarin (1 mg/d), low-dose warfarin alone (2 mg/d), or 300 mg aspirin plus low-dose warfarin (2 mg/d) did not significantly reduce any of the hemostatic markers studied (except PAI-1 levels), whereas conventional full-dose warfarin (INR 2.0 to 3.0) significantly reduced levels of fibrin D-dimer and fibrinogen. These results are in keeping with the disappointing ineffectiveness of low-intensity warfarin therapy, aspirin-warfarin combination, and ultralow-dose warfarin therapy in the recent prematurely terminated clinical trials and the established benefits of conventional adjusted-dose anticoagulation therapy. (Stroke. 2000;31:828-833.)

Comparison of Diagnostic Accuracies in Outpatients and Hospitalized Patients of D-Dimer Testing for the Evaluation of Suspected Pulmonary Embolism

“…Mean plasma D-dimer concentrations of untreated patients with chronic atrial fibrillation are higher than those of control individuals and decrease to concentrations similar to those of the controls on anticoagulation therapy (41,42 ). The D-dimer assay appears to retain utility in select patient groups, but the results need to be more carefully considered (43,44 ).…”

Von Willebrand Factor: Multimeric Structure and Functional Activity in Patients With Atrial Fibrillation With and Without Oral Anticoagulation

“…21 Li-Saw-Hee et al and Jeffrey Liles et al confirmed the presence of higher levels of vWF in patients with AF compared to healthy controls. 22,23 Ammash et al demonstrated that elevated vWF:Ag may help identify patients with AF at risk of left atrial appendage thrombus. 24 Meanwhile, Roldán et al demonstrated that high plasma vWF levels are an independent risk factor for adverse events in anticoagulated patients with AF, 8 and Lind et al associated vWF factor with all-cause mortality and cardiovascular events in patients with AF.…”

“…21,29 Plasma levels of vWF antigen are somewhat reduced by OAC treatment. 23,25 As it is well known, vWF possesses several functions in hemostasis; among them, some of the most important might be protecting factor VIII from proteolysis or cellular uptake besides binding to the surface of activated platelets and endothelial cells. 5 Thrombin cleaves vWF off of FVIII, releasing it to mediate platelet adhesion and aggregation.…”

Von Willebrand factor predicts major bleeding and mortality during oral anticoagulant treatment

“…Blood samples were collected only once during OAC treatment and there are conflicting views regarding the possible effects of concomitant OAC treatment on VWF levels [28][29][30]. ABO blood group status is known to affect the levels of VWF [31,32], but such data were not available.…”