Effects of fixed low-dose warfarin, aspirin-warfarin combination therapy, and dose-adjusted warfarin on thrombogenesis in chronic atrial fibrillation

Background and Purpose-Recent clinical trials have established that adjuste d-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 l ow-dose warfarin alone or in combination with aspirin (300 mg) could normal ize hemostatic markers, namely plasma fibrin D-dimer tan index of thromboge nesis), plasminogen activator inhibitor-1 (PAI-1, an index of fibrinolysis) , fibrinogen, and von Willebrand factor (vWf, an index of endothelial dysfu nction), in a manner comparable to adjusted-dose warfarin (target INR 2.0 t o 3.0). Methods-Sixty-one patients with AF (44 men, mean+/-SD age 64 +/- 19 years) who were not receiving any antithrombotic therapy were prospectively random ized into 1 of 3 treatment groups: warfarin (2 mg) (n=23; group I), combina tion 1 mg warfarin plus 300 mg aspirin (n=21; group 2) or combination 2 mg warfarin plus 300 mg aspirin (n = 17; group 3). Subjects from all 3 AF grou ps were matched for sex, age, and blood pressure. Blood samples were taken for sequential measurements for changes in plasma fibrin D-dimer, PAI-1, fi brinogen, and vWf before and at 2 and 8 weeks after randomization (phase 1) . All patients were subsequently offered adjusted-dose warfarin therapy (ph ase 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 significa nt elevations in levels of fibrinogen (P=0.025), vWf(P<0.0001), and fibrin D-dimer (P<0.0001) in patients with AF compared with control subjects. Ther e were no significant changes in the levels of various indices measured aft er 2 and 8 weeks of therapy in all 3 groups, except for an increase in PAI- 1 level (P=0.024) in group 3. After 6 weeks of therapy with dose-adjusted w arfarin (INR 2.0 to 3.0), there was a significant decrease in plasma fibrin ogen (P=0.023) and fibrin D-dimer (P=0.0067) levels. There were no signific ant changes in the levels of PAI-1 (P=0.198) or vWf (P=0.33). Conclusions-The present results confirmed that high levels of vWf, fibrinog en, and fibrin D-dimer levels were present in patients with AF compared wit h control subjects. Moreover, the introduction of 300 mg aspirin plus low-d ose 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 hem ostatic markers studied (except PAI-1 levels), whereas conventional full-do se warfarin (INR 2.0 to 3.0) significantly reduced levels of fibrin D-dimer and fibrinogen. These results are in keeping with the disappointing ineffe ctiveness of low-intensity warfarin therapy, aspirin-warfarin combination, and ultralow-dose warfarin therapy in the recent prematurely terminated cli nical trials and the established benefits of conventional adjusted-dose ant icoagulation therapy.