Atrial fibrillation (AF) is associated with hemostatic abnormalities and increased risk of thrombotic cardiovascular events even during oral anticoagulant therapy (OAT). The aim of our study was to evaluate the predictive value of hemostatic markers for the risk of major cardiovascular events during OAT. The study group comprised 113 patients with chronic AF (70.2 ± 5.4 years old, 60% men), referred for OAT. Established clinical risk factors and levels of prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes (TAT), D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) antigen and activity, before and during OAT (after 3.9 ± 0.7 months; INR 2.57 ± 0.57) were determined. In all patients OAT significantly suppressed levels of F1+2 by 67%, TAT by 30% and D-dimer by 48% (all p <0.001). During an average follow-up of 44 months 22/111 (20%) patients suffered a combined cardiovascular event (stroke, myocardial infarction, peripheral vascular occlusion or vascular death). Patients with cardiovascular events were significantly older, had more frequent heart failure/systolic dysfunction and had significantly increased levels of D-dimer at entry (63 vs 39 ng/mL, p = 0.005) and during OAT (33 vs 18 ng/mL, p = 0.002), and of t-PA antigen at entry (14.3 vs 10.9 ng/mL, p = 0.02) and during OAT (15.0 vs 11.2 ng/mL, p = 0.05) (all values are medians). In multivariate Cox proportional hazard models, heart failure/systolic dysfunction (hazard ratio 2.91; 95% CI 1.17-7.26; p = 0.02), high levels of D-dimer on OAT (top vs. lower two quartiles) (hazard ratio 4.78, 95% CI 1.39-16.41; p = 0.01) and t-PA antigen levels (continuous variable) (hazard ratio 1.09; 95% CI 1.01-1.17; p = 0.02) were significantly associated with combined cardiovascular events.
In conclusion, high levels of D-dimer and t-PA antigen during OAT are significant predictors of combined cardiovascular events in AF patients and, on this basis, could be useful additional markers of cardiovascular risk in such patients.
2
Fuster V,
Badimon L,
Badimon JJ.
et al. The pathogenesis of coronary artery disease and acute coronary syndromes. (First of two parts). N Engl J Med 1992; 326: 242-50.
3
Asakura H,
Hifumi S,
Jokaji H.
et al. Prothrombin fragment F1+2 and thrombinantithrombin III complex are useful markers of hypercoagulable state in atrial fibrillation. Blood Coagul Fibrinol 1992; 3: 469-73.
4
Kumagai K,
Fukunami M,
Ohmori M.
et al. Increased intracardiovascular clotting in patients with chronic atrial fibrillation. J Am Coll Cardiol 1990; 16: 377-80.
6
Kahn SR,
Solymoss S,
Flegel KM.
Increased tissue plasminogen activator levels in patients with nonvalvular atrial fibrillation. Can Med Assoc J 1997; 157: 685-9.
10
Ridker PM,
Hennekens CH,
Cerskus A.
et al. Plasma concentration of cross-linked fibrin degradation product (D-dimer) and the risk of future myocardial infarction among apparently healthy men. Circulation 1994; 90: 2236-40.
12
Thompson SG,
Kienast J,
Pyke SDM.
et al. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332: 635-41.
13
Ridker PM,
Hennekens CH,
Stampfer MJ.
et al. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994; 343: 940-3.
15
Palareti G,
Legnanai C,
Cosmi B.
et al. Risk of venous thromboembolism reccurence: high negative predictive value of D-dimer performed after oral anticoagulantion is stopped. Thromb Haemost 2002; 87: 7-12.
16
Feinberg WM,
Pearce LA,
Hart RG.
et al. for the Stroke Prevention in Atrial Fibrillation investigators. Markers of thrombin and platelet activity in patients with atrial fibrillation: correlation with stroke among 1531 participants in the Stroke Prevention in Atrial Fibrillation III Study. Stroke 1999; 30: 2547-53.
17
Bruhn HD,
Conard J,
Mannucci M,
Monteagudo J,
Pelzer H,
Reverter JC.
et al. Multicentric evaluation of a new assay for prothrombin fragment F1+2 determination. Thromb Haemost 1992; 68: 413-7.
18
Bauer KA,
Rosenberg RD.
The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. Blood 1987; 70: 343-50.
19
Giansante C,
Fiotti N,
Calabrese S.
et al. D-dimer and anticoagulation in patients with mechanical prostetic heart valves. A 2 year follow up. Arterioscler Thromb Vasc Biol 1997; 17: 1320-4.
20
Fattorini A,
Crippa L,
Vigano’D’Angelo S.
et al. Risk of deep vein thrombosis recurrence: high negative predictive value of D-dimer performed during oral anticoagultion. Thromb Haemost 2002; 88: 162-3.
22
Tunstall-Pedoe H,
Kuulasmaa K,
Amouyel P.
et al. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Circulation 1994; 90: 583-612.
23 The atrial fibrillation follow-up investigation of rhythm management (AFFIRM) investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347: 1825-33.
24
Van Walraven C,
Hart RG,
Singer DE.
et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation. An individual patient meta-analysis. JAMA 2002; 288: 2441-8.
25
Hylek EM,
Skates SJ,
Sheehan MA.
et al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335: 540-6.
26
Kistler JP,
Singer De,
Millenson MM.
et al. Effect of low intensity warfarin anticoagulation on level of activity of hemostatic system in patients with atrial fibrillation. Stroke 1993; 42: 1360-5.
27
Lip GYH,
Lip PL,
Zarifis J.
et al. Fibrin D-dimer and β tromboglobulin as markers of thrombogenesis and platelet activation in atrial fibrillation. Circulation 1996; 94: 425-31.
28
Koefoed BG,
Fedderson C,
Gulløv AL.
et al. Effect of fixed minidose warfarin, conventional dose warfarin and aspirin on INR and pro-thrombin fragment 1+2 in patients with atrial fibrillation. Thromb Haemost 1997; 77: 845-8.
30 Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: 633-8.
32
Mahé I,
Drouet L,
Chassany O.
et al. D-dimer: a characteristic of the coagulation state of each patient with chronic atrial fibrillation. Throm Res 2002; 107: 1-6.
34
Gibbs CR,
Blann AD,
Watson RDS.
et al. Abnormalities of hemorheological, endothelial, and platelet function in patients with chronic heart failure in sinus rhythm. Circulation 2001; 103: 1746-51.
35
Dries DL,
Exner DV,
Gersh BJ.
Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. J Am Coll Cardiol 1998; 32: 695-703.
36
Cioffi G,
Pozzoli M,
Forni G.
et al. Systemic thromboembolism in chronic heart failure. A prospective study in 406 patients. Eur Heart J 1996; 17: 1381-9.
37
Chandler WL,
Alessi MD,
Aillaud MF.
et al. Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex. Relationship to elevated TPA antigen in patients with high PAI-1 activity levels. Circulation 1997; 96: 761-8.
38
Conway DSG,
Pearce LA,
Chin BSP.
et al. Prognostic value of plasma von Willebrand factor and soluble P-selectin as indices of endothelial damage and platelet activation in 994 patients with nonvalvular atrial fibrillation. Circulation 2003; 107: 3141-5.
