A Comparison of a Moderate with Moderate-high Intensity Oral Anticoagulant Treatment in Patients with Mechanical Heart Valve Prostheses

Summary

Background. The long-term administration of oral anticoagulants to patients with mechanical heart valve prostheses is generally accepted. However, the appropriate intensity of oral anticoagulant treatment in these patients is still controversial.

Methods and Results. From March 1991 to March 1994, patients referred to the Padova Thrombosis Center who had undergone mechanical heart valve substitution at least 6 months earlier were randomly assigned to receive oral anticoagulants at moderate intensity (target INR = 3) or moderate-high intensity (target INR = 4). Principal end points were major bleeding, thromboembolism and vascular death. Minor bleeding was a secondary end-point.

A total of 104 patients were assigned to the target 3 group and 101 to the target 4 group; they were followed for from 1.5 years to up 4.5 years (mean, 3 years). Principal end-points occurred in 13 patients in the target 3 group (4 per 100 patient-years) and in 20 patients in the target 4 group (6.9 per 100 patient-years). Major hemorrhagic events occurred in 15 patients, 4 in the target 3 group (1.2 per 100 patient-years) and 11 in the target 4 group (3.8 per 100 patient-years) (p = 0.019). The 12 recorded episodes of thromboembolism, 4 of which consisted of a visual deficit, were all transient ischemic attacks, 6 in the target 3 group (1.8 per 100 patient-years) and 6 in the target 4 group (2.1 per 100 patient- years). There were 3 vascular deaths in each group (0.9 and 1 per 100 patient-years for target 3 and target 4 groups, respectively). Minor bleeding episodes occurred 85 times (26 per 100 patient-years) in the target 3 group and 123 times (43 per 100 patient-years) in the target 4 group (p = 0.001).

Conclusions. Mechanical heart valve patients on anticoagulant treatment who had been operated on at least 6 months earlier experienced fewer bleeding complications when maintained on a moderate intensity regimen (target INR = 3) than those on a moderate-high intensity regimen (target INR = 4). The number of thromboembolic events and vascular deaths did not differ between the two groups.

• References

• 1 Duvoisin GE, Brandenburg RO, McGoon DC. Factors affecting thromboembolism associated with prosthetic heart valves. Circulation 1967; 35 (Suppl. 01) 70-76
• 2 Yeh TJ, Anabtawi IN, Cornett VE, Ellison RG. Influence of rhythm and anticoagulation upon the incidence of embolization associated with Starr-Edwards prostheses. Circulation 1967; 35 (Suppl. 01) 77-81
• 3 Akbarian M, Austen WG, Yurchak PM, Scannel JG. Thromboembolic complications of prosthetic cardiac valves. Circulation 1968; 37: 826-831
• 4 Baudet EM, Oca CC, Roques XF, Laborde MN, Hafez AS, Collot MA, Ghidoni IM. A 5½ year experience with the St. Jude Medical cardiac valve prosthesis Early and late results of 737 valve replacements in 671 patients. J Thorac Cardiovasc Surg 1985; 90: 137-144
• 5 Björk VO, Henze A. Management of thromboembolism after aortic valve replacement with the Björk-Shiley tilting disc valve. Scand J Thorac Cardiovasc Surg 1975; 9: 183-191
• 6 Dale J, Myhre E. Can acetylsalicylic acid alone prevent arterial thromboembolism: a pilot study in patients with aortic ball valve prostheses. Acta Med Scand 1981; 645: 73-77
• 7 Moggio RA, Hammond GL, Stansel Jr HC, Ghenn W. Incidence of emboli with cloth-covered Starr-Edwards valve without anticoagulation and with varying forms of anticoagulation: analysis of 183 patients followed for 3½ years. J Thorac Cardiovasc Surg 1978; 75: 296-299
• 8 El MakhloufA, Friedli B, Oberhansli I, Rouge JC, Faidutti B. Prosthetic heart valve replacement in children.Results and follow-up of 273 patients. J Thorac Cardiovasc Surg 1987; 93: 80-85
• 9 Brott WH, Zajtchuk R, Bowen TE, Davia J, Green DC. Dipyridamole-aspirin as thromboembolic prophylaxis in patients with aortic valve prosthesis Prospective study with the Model 2320 Starr-Edwards prosthesis. J Thorac Cardiovasc Surg 1981; 81: 632-635
• 10 Hartz RS, LoCicero JIII, Kucich V, Deboer A, O’Mara S, Meyers SN, Michaelis LL. Comparative study of warfarin versus antiplatelet therapy in patients with a St. Jude Medical valve in the aortic position. J Thorac Cardiovasc Surg 1986; 92: 684-690
• 11 Ribeiro PA, Al ZaibagMA, Idris M, Al KasabS, Davies G, Mashat E, Wareham E, Al FagihM. Antiplatelet drugs and the incidence of thromboembolic complications of the St. Jude Medical aortic prosthesis in patients with rheumatic heart disease. J Thorac Cardiovasc Surg 1986; 91: 92-98
• 12 Edmunds LH. Thrombotic and bleeding complications of prosthetic heart valves. Ann Thorac Surg 1987; 44: 430-445
• 13 Fuster V, Badimon L, Badimon JJ, Chesebro J. Prevention of thromboembolism induced by prosthetic valves. Semin Thromb Hemost 1988; 14: 50-58
• 14 Stein PD, Kantrowitz A. Antithrombotic therapy in mechanical and biological prosthetic heart valves and saphenous vein bypass grafts. Chest 1989; 95 (Suppl. 02) 107-117
• 15 Loeliger EA, Poller L, Samama M, Thomson JM, Van denBesselaar AMHP, Vermylen J, Verstraete M. Questions and answers on prothrombin time standardisation in oral anticoagulant control. Thromb Haemost 1985; 54: 515-517
• 16 British Society for Haemotology. British Committee for Standards in Haematology, Haemostasis and Thrombosis Task Force. Guidelines on oral anticoagulation. second edition J Clin Pathol. 1990; 43: 177-83
• 17 Loeliger EA, Lewis SM. Progress in laboratory control of oral anticoagulants. Lancet 1982; 2: 318-320
• 18 Boekhout MussertMJ, Briët E, Van BrummelenP, Lemkes HHPJ, Loeliger EA. Arterial thromboembolic complication with aortic ball valve prosthesis. Am Heart J 1978; 95: 270-277
• 19 Saour JN, Sieck JO, Mamo LAR, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med 1990; 322: 428-432
• 20 Kuntze CEE, Ebels T, Eijgelaar A, van derHeide JNH. Rates of thromboembolism with three different mechanical heart valve prostheses: randomised study. Lancet 1989; 19: 514-517
• 21 Pengo V, Banzato A, Garelli E, Zasso A, Biasiolo A. Reversal of excessive effect of regular anticoagulation: low oral dose of phytonadione (Vitamin Kl) compared to warfarin discontinuation. Blood Coag Fibrinolysis 1993; 4: 739-741
• 22 Kerin NZ, Blevins RD, Goldman L, Faitel K, Rubenfire M. The incidence, magnitude, and time course of the amiodarone-warfarin interaction. Arch Intern Med 1988; 148: 1779-1781
• 23 Berengo M, Pengo V, Peruzzi P, Banzato A, Schivazappa L. Organizational model for dental treatment of patients on antithrombotic prophylaxis with oral anticoagulants. G Stomatol Ortognatodonzia 1989; 8: 38-39
• 24 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-481
• 25 Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163-170
• 26 Rosendaal FR, Cannegieter SC, van derMeer FJM, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-239
• 27 Loeliger EA. Therapeutic target values in oral anticoagulation – Justification of Dutch policy and a warning against the so-called moderate intensity regimens. Ann Hematol 1992; 64: 60-65
• 28 Broekmans AW, Loeliger EA. High complication and failure rates of anticoagulant therapy are avoidable. Z Kardiol 1986; 75 (Suppl. 02) 298-301
• 29 Loeliger EA. Laboratory control, optimal therapeutic ranges and therapeutic quality control in oral anticoagulation. Acta Haematol 1985; 74: 125-131
• 30 Stein PD, Alpert JS, Copeland J, Dalen JE, Goldman S, Turpie AGG. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1992; 102 (Suppl. 04) 445-55
• 31 Sethia B, Turner MA, Lewis S, Rodger RA, Bain WH. Fourteen years’ experience with the Björk-Shiley tilting disc prosthesis. J Thorac Cardiovasc Surg 1986; 91: 350-61
• 32 Vogt S, Hoffmann A, Roth J, Dubach P, Bertschmann W, Hasse J, Gradel E, Stulz P, Burckhardt D. Heart valve replacement with the Björk-Shiley and St. Jude Medical prostheses: a randomized comparison in 178 patients. Eur Heart J 1990; 11: 583-591
• 33 DiSesa VJ, Collins Jr JJ, Cohn LH. Hematological complications with the St. Jude valve and reduced-dose coumadin. Ann Thorac Surg 1989; 48: 280-283
• 34 Kopf GS, Hammond GL, Geha AS, Elefteriades J, Hashim SW. Long-term performance of the St. Jude Medical valve: low incidence of thromboembolism and hemorrhagic complications with modest doses of warfarin. Circulation 1987; 76 (Suppl. 03) 132-136
• 35 Altman R, Rouvier J, Gurfmkel E, D’Ortencio O, Manzanel R, de LaFuente L, Favaloro RG. Comparison of two levels of anticoagulant therapy in patients with substitute heart valves. J Thorac Cardiovasc Surg 1991; 101: 427-431
• 36 Turpie AGG, Gent M, Laupacis A, Latour Y, Gunstensen J, Basile F, Klimek M, Hirsh J. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med 1993; 329: 524-529
• 37 Grunkemeier GL, Rahimtoola SH. Artificial heart valves. Annu Rev Med 1990; 41: 251-263
• 38 Pleigh PS, DiSesa DJ, Cohn LH, Collins JJ. Neurological and ophthalmo-logical phenomena after aortic conduit surgery. Circulation 1990; 82 (Suppl. 04) 47-50
• 39 Wilson DB, Dunn MI, Hassanein K. Low intensity anticoagulation in mechanical cardiac prosthetic valves. Chest 1991; 100: 1553-1557
• 40 Levine NM, Hirsh J, Landefeld S, Raskob G. Hemorrhagic complications of anticoagulant treatment. Chest 1992; 102 (Suppl. 04) 352-363
• 41 Lancaster TR, Singer DE, Sheehan MA, Oertel LB, Maraventano SW, Hughes RA, Kistler JP. The impact of long-term warfarin therapy on quality of life. Evidence from a randomized trial. Arch Intern Med 1991; 151: 1944-1949
• 42 Fihn SD, McDonell M, Martin D, Henikoff J, Vermes D, Kent D, White RH. Risk factors for complication of chronic anticoagulation. Ann Intern Med 1993; 118: 511-520
• 43 Cannegieter SC, Rosendaal FR, Wintzen AR, van derMeer FJM, Vandenbroucke JP, Briët E. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333: 11-17