Effects of fixed low-dose warfarin, aspirin-warfarin combination therapy, and dose-adjusted warfarin on thrombogenesis in chronic atrial fibrillation.
OBJECTIVE
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). METJODS: Sixty-one patients with AF (44 men, mean+/-SD age 64+/-19 years) who were not receiving any antithrombotic therapy were prospectively randomized into 1 of 3 treatment groups: warfarin (2 mg) (n=23; group 1), combination 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 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 (P=0.025), 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 of various indices measured after 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 warfarin (INR 2.0 to 3.0), there was a significant decrease in plasma fibrinogen (P=0.023) and fibrin D-dimer (P=0.0067) levels. There were no significant 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, 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.
Li-Saw-Hee
F L
FL
Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, England.
Blann
A D
AD
Lip
G Y
GY
D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000627:therapeutic use; D001241:Aspirin / Q000008:administration & dosage* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000097:blood / Q000150:complications* / Q000188:drug therapy*; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis*; D005340:Fibrinogen / Q000032:analysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D011446:Prospective Studies; D012016:Reference Values; D013927:Thrombosis / Q000209:etiology*; D014859:Warfarin / Q000008:administration & dosage* / Q000627:therapeutic use; D014841:von Willebrand Factor / Q000032:analysis
D000925:Anticoagulants; D004338:Drug Combinations; D005338:Fibrin Fibrinogen Degradation Products; D017395:Plasminogen Activator Inhibitor 1; D010975:Platelet Aggregation Inhibitors; C036309:fibrin fragment D; D014841:von Willebrand Factor; D014859:Warfarin; D005340:Fibrinogen; D001241:Aspirin