Abstract
Background: Since coronary artery bypass graft patients remain at risk of coronary artery and bypass graft occlusion after successful surgery, adjunct treatment regimens are under investigation. In a study of the patients of the multicenter Post Coronary Artery Bypass Graft (Post CABG) Trial, 1[emsp4 ]mg warfarin was found to have no important effect on coagulation parameters.
Study design: The effects of 1, 2 and 3[emsp4 ]mg warfarin were evaluated at six-week intervals in 20 Post CABG Trial patients receiving titrated dose increases in comparison to 20 patients of similar age, gender and time from CABG treated with placebo.
Results: International normalized ratio (INR) values increased with warfarin dose increments for 1, 2, and 3[emsp4 ]mg, respectively (0.95±0.16, 1.08±0.19, and 1.34±0.39) and in comparison to placebo treated patients (dose×treatment p<0.001). Factor VII coagulant activity decreased with warfarin titration (1[emsp4 ]mg, 119.0±18.3%%; 2[emsp4 ]mg, 100.6±32.8%%; 3[emsp4 ]mg, 95.0±27.8%%) and in comparison to placebo (dose×treatment p=0.008). Levels of prothrombin fragment F1.2, tissue plasminogen activator, fibrinogen and von Willebrand factor were unchanged with warfarin dose increments and in comparison to placebo.
Conclusions: At doses up to 3[emsp4 ]mg, warfarin acts on the INR through a reduction of factor VII with no effect on the fibrinolytic system, fibrinogen or von Willebrand factor. At these doses F1.2 did not document reduced coagulation activity. The observations of this study were consistent with the decision in the Post CABG Trial to increase the warfarin dose above 1[emsp4 ]mg to achieve a distinct effect of warfarin that was less than full anticoagulation.
Similar content being viewed by others
References
The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of lowdensity lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;336:153–162.
Neitzel GF, Barboriak JJ, Pintar K, Qureshi I. Atherosclerosis in aortocoronary bypass grafts. Morphologic study and risk factor analysis 6 to 12 years after surgery. Arteriosclerosis 1986;6:594–600.
Solymoss BC, Nadeau P, Millette D, Campeau L. Late thrombosis of saphenous vein coronary bypass grafts related to risk factors. Circulation 1988;78(Suppl I):I–140–I–143.
Levine GN, Stein B, Nadir Ali M. Antithrombotic therapy in cardiovascular disease. In: Loscalzo J, Schafer AI, eds. Thrombosis and Hemorrhage. Baltimore: Williams & Wilkins, 1998:1309–1336.
Turpie AGG, Gunstensen J, Hirsh J, Nelson H, Gent M. Randomised comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet 1988;i:1242–1245.
Gohlke H, Gohlke-Barwolf C, Sturzenhofecker P, et al. Improved graft patency with anticoagulant therapy after aortocoronary bypass surgery: A prospective, randomized study. Circulation 1981;64(Suppl 2):II22–II27.
van der Meer J, Hillege HL, Dunselman PHJM, et al. Oral anticoagulation in the prevention of one-year vein graft occlusion after aortocoronary bypass surgery: Optimal therapeutic range and practical limitations. Thromb Haemost 1994;72:676–681.
Poller L, McKernan A, Thomson JM, Elstein M, Hirsch PJ, Jones JB. Fixed minidose warfarin: A new approach to prophylaxis against venous thrombosis after major surgery. Br Med J 1987;295:1309–1312.
Poller L, MacCallum PK, Thomson JM, Kerns W. Reduction of factor VII coagulant activity (VIIC) a risk factor for ischemic heart disease by fixed dose warfarin: A double blind crossover study. Br Heart J 1990;63:231–233.
O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs. Initiation of warfarin therapy without a loading dose. Circulation 1968;38:169–177.
Harrison L, Johnston M, Massicotte MP, Crowther M, Moffat K, Hirsh J. Comparison of 5–mg and 10–mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997;126:133–136.
Holbrook AM, Wells PS, Crowther NR. Pharmacokinetics and drug interactions with warfarin, New York: Arnold Oxford University Press, 1996;30–48.
Walenga JM, Hoppensteadt D, Pifarré R, et al. The hemostatic effects of 1 mg daily warfarin on Post CABG patients. J Thromb Thrombolysis 1999;7:313–318.
Liang KY, Zeger SL, Qaqish B. Multivariate regression analysis for categorical data (with discussion). J Royal Stat Soc, Series B, 1991;54:3–40.
Knatterud GL, Rosenberg Y, Campeau L, et al. Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial. Circulation 2000;102:157–165.
Dale C, Gallus AS, Wycherley A, Langlois S, Howie D. Prevention of venous thrombosis with minidose warfarin after joint replacement. Br Med J 1991;303:224.
Fordyce MJF, Baker AS, Staddon GE. Efficacy of fixed minidose warfarin prophylaxis in total hip replacement. Br Med J 1991;303:219–220.
Poller L, Thomson JM, MacCallum PK, Nicholson DA, Weighill FJ, Lemon JG. Minidose warfarin and failure to prevent deep vein thrombosis after joint replacement surgery despite inhibiting the post operative rise in plasminogen activator inhibitor activity. Clin Appl Throm Hemost 1995;1:267–273.
Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: Insight gained from studies using markers of hemostatic system activation. Blood 1987;70:343–350.
Millenson MM, Bauer KA, Kistler JP, Barzegar S, Tulin L, Rosenberg RD. Monitoring “mini-intensity” anticoagulation with warfarin: Comparison of the prothrombin time using a sensitive thromboplastin with prothrombin fragment F1 + 2 levels. Blood 1992;79:2034–2038.
Tripodi A, Cattaneo M, Molteni A, Cesana BM, Mannucci PM. Changes of prothrombin fragment 1 + 2 (F 1 + 2) as a function of increasing intensity of oral anticoagulation. Considerations on the suitability of F 1 + 2 to monitor oral anticoagulant treatment. Thromb Haemost 1998;79:571–573.
Coumadin Aspirin Reinfarction Study (CARS) Investigators. Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Lancet 1997;350:389–396.
Stroke Prevention in Atrial Fibrillation (SPAF) 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;348:633–638.
Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants. Mechanisms of action, clinical effectiveness, and optimal therapeutic range. Chest 1998;114:445S–469S.
The Medical Research Council's General Practice Research Framework. Thrombosis prevention trial: Randomized trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischemic heart disease in men at increased risk. Lancet 1998;351:233–241.
Rumley A, Lowe GDO, Sweetnam PM, Yarnell JWG, Thomas HF, Ford RP. Factor VIII, von Willebrand factor and the risk of major ischemic heart disease in the Caerphilly Study. Br J Haematol 1999;105:110–116.
Lowe GDO, Yarnell JWG, Sweetnam PM, Rumley A, Thomas HF, Elwood PC. Fibrin D-dimer, tissue plasminogen activator, plasminogen activator inhibitor, and the risk of major ischemic heart disease in the Caerphilly Study. Thromb Haemost 1998;79:129–133.
Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: A meta-analysis and review of the literature. Ann Intern Med 1993;118:963–965.
Junker R, Heinrich J, Schulte H, van de Loo J, Assmann G. Coagulation factor VII and the risk of coronary heart disease in healthy men. Arterioscler Thromb Vasc Biol 1997;17:1539–1544.
Sakata T, Kario K, Matsuo T, et al. Suppression of plasma-activated factor VII levels by warfarin therapy. Arterioscler Thromb Vasc Biol 1995;15:241–246.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Walenga, J.M., Hoppensteadt, D., Pifarre´, R. et al. The Hemostatic Effects of Warfarin Titration in Post CABG Patients in Comparison to Placebo Treatment. J Thromb Thrombolysis 11, 143–149 (2001). https://doi.org/10.1023/A:1011276700426
Issue Date:
DOI: https://doi.org/10.1023/A:1011276700426