Aspirin or Coumadin as the Drug of Choice

Aspirin or Coumadin as the Drug of Choice for Valve Replacement with Porcine Bioprosthesis L. Nufiez, M.D., M. Gil Aguado, M.D., D. Celemin, M.D., A. Iglesias, M.D., and J. L. Larrea, M.D. ABSTRACT Eight hundred twenty-four patients who had cardiac valve replacement with a porcine bioprosthesis were given either Coumadin (sodium warfarin) or aspirin. No patient in sinus rhythm no matter what valve or valves were replaced had thromboembolism whether treated with Coumadin (124 patients) or aspirin (26 patients). One hundred fifty-one patients who had mitral valve replacement, were in atrial fibrillation, and were treated with Coumadin had seven embolic events (4.6%), while 135 similar patients treated with aspirin had five embolic events (3.7%). Fifty-one patients who had double-valve replacement, were in atrial fibrillation, and were treated with Coumadin had three embolic episodes (5.9%), while 86 similar patients treated with aspirin had three embolic events (3.5 /). No statistical difference was found in the incidence of thromboembolism between similar groups of patients whether treated with Coumadin or aspirin (p >.5). Hemorrhagic complications were higher and reached statistical significance (p <.1) for the group treated with Coumadin. This study shows that aspirin prevents thromboembolic complications as well as Coumadin in patients having cardiac valve replacement with a bioprosthesis, and results in a lower rate of complications. Bioprostheses have had worldwide acceptance mainly because of low thrombogenesis. Temporary postoperative anticoagulation after insertion of a porcine bioprosthesis has been recommended, and is used in most cardiovascular units. The best method of prophylactic anticoagulation is still not clear, as was pointed out in a survey of nineteen institutions in the United States [l]. The use of temporary oral an- From the Department of Cardiac Surgery, Ciudad Sanitaria La Paz Autonomous University of Madrid, Madrid, Spain. Accepted for publication June 8, 1981. Address reprint requests to Dr. Nuriez, Cardiac Surgery, C/ Otero y Delage, 58, Madrid, 35, Spain. ticoagulants in all patients and long-term anticoagulation in selected patients has been the most common method of anticoagulation. Antiplatelet agents, if effective, would decrease the risks involved with oral anticoagulants, thereby making the bioprosthesis a safer and more attractive valve substitute. The purpose of this article is to report our experience with 824 patients treated either with derivatives of Coumadin (sodium warfarin) or with aspirin as the antiplatelet agent. Material and Methods From April, 1975, through April, 198, 9 patients underwent single-valve or multiple-valve replacement with porcine bioprostheses at the Hospital Clinico, Madrid, and at the Residencia Sanitaria La Paz, Madrid. Twenty-six patients who received mixed prostheses (mechanical and bioprostheses), 48 patients who died during hospitalization, and 2 patients lost to follow-up before the sixth postoperative month were excluded from the study. This left 824 patients who were considered to be at risk and were included in the study. Follow-up was achieved by personal examination every 6 months. In October, 198, all patients were contacted either personally or by mail. Follow-up ranged from 6 to 66 months except for 16 patients who died during the first 6 postoperative months. Mean follow-up was 23 months and total follow-up, 19,637 patientmonths. Sixteen patients lost to follow-up after the second postoperative year were included in the study up to the time of the last visit. The age of the patients ranged from 7 to 78 years (mean age, 48.5 years). There were 57 female patients. Two commercially available bioprostheses were used. Hancock valves were implanted 445 times (39 in the mitral position and 136 in the aortic position) and Carpentier- Edwards, 61 times (25 mitral; 345 aortic; and 15 tricuspid) for a total of 1,55 bioprostheses. 354 3-4975/82/4354-5$1.25 @ 1981 by The Society of Thoracic Surgeons

355 Nuiiez et al: Aspirin or Coumadin for Porcine Valve Replacement The operations performed were: isolated mitral valve replacement (MVR), 34 times; isolated aortic valve replacement (AVR), 261 times; double-valve replacement (AVR and MVR), 28 times; triple-valve replacement (AVR, MVR, and tricuspid valve replacement [TVR]), 11 times; AVR and TVR, 2 times; and MVR and TVR, 2 times. Associated procedures were performed in some patients. They were as follows: tricuspid annuloplasty, 196 patients; mitral commissurotomy, 24; left atrial thrombectomy, 18; aortocoronary bypass, 36; replacement of the ascending aorta, 16; and others, 21. Operations were performed by median sternotomy. Total hemodilution, cardiopulmonary bypass with a bubble oxygenator, moderate hypothermia, and aortic root cardioplegia were employed. Anticoagulation Therapy The patients were divided into two groups without regard for type of disease, age, sex, operation, or valve replaced. One group was administered Coumadin and the other, aspirin, for anticoagulation. GROUP A. This group of 328 patients was on a regimen of oral administration of Coumadin from the second postoperative day to maintain a prothrombin activity between 2 and 3% (Table 1). Patients in sinus rhythm were removed from the regimen after the sixth postoperative month. Patients in atrial fibrillation were followed on a regimen of long-term anticoagulation. GROUP B. The 496 patients in this group were given 1 gm of aspirin daily from the second postoperative day (Table 2). This regimen continued over the long-term regardless of whether sinus rhythm was present. Definitions A thromboembolic episode was considered to be any event characterized by the suggestion or evidence of acute arterial obstruction in any part of the arterial tree, whether the event was transitory, temporary, or definitive. An embolism was considered major when death, permanent damage, or vascular operation resulted; it was minor when the episode left no sequelae. Patients with any of these findings who had proved bacterial endocarditis were excluded from the study. Patients with cerebrovascular accidents in the operating room were also excluded (11 patients) because air or particulate debris explained the vascular accident in every instance. A hemorrhagic episode was considered to be any occurrence of internal or external hemorrhage, whether or not a predisposing disease was present. Major episodes were those causing death or permanent damage or necessitating operation. Results Thromboembolism Nineteen patients experienced a thromboembolic event, an incidence of 2.3% (19 out of 824 patients). Ten were major embolic events, one resulting in death, and nine were minor. Sixteen episodes occurred during the first 6 postoperative months (Figure). GROUP A. Eleven patients treated with Coumadin had a thromboembolism, an incidence of 3.4% (11 out of 328 patients); 1 of them died. No patient in sinus rhythm sustained a thromboembolic event, no matter what valve or valves had been replaced. Thromboembolism occurred in 7 patients who had undergone isolated MVR and were in atrial fibrillation 4.6% (7 out of 151), and 1 of these was the patient who died. Three patients who had had double-valve replacement and were in atrial fibrillation sustained a thromboembolism, 5.9% (3 out of 51). One patient with isolated AVR and in atrial fibrillation experienced a thromboembolic event (1 out of 2). Eight of the eleven thromboembolic events occurred during the first 6 postoperative months, and eight of the embolic episodes were major (see Table 1). GROUP B. Eight patients treated with aspirin sustained a thromboembolic event, an incidence of 1.6% (8 out of 496 patients). No patient died of this complication. No patient in sinus rhythm had thromboembolism no matter what valve or valves had been replaced. Five patients who had had isolated MVR and were in atrial fibrillation experienced a thromboembolic event, 3.7% (5 out of 135), and 3 patients with double-valve replacement had the same com-

356 The Annals of Thoracic Surgery Vol 33 No 4 April 1982 Table 1. Thromboembolism in Patients Treated with Coumadin No. of No. of Follow-up Procedure Patients Emboli (mo) Percent AVR + SR 58 AVR + AF 2 MVR + SR 35 MVR+ AF 151 DVR + SR 31 DVR + AF 51 1,383 31 836 3,644 74 1,22 Total 328 11 7,854 3.4 AVR = aortic valve replacement; SR = sinus rhythm; AF = atrial fibrillation; MVR = mitral valve replacement; DVR = double-valve replacement. 5 4.6 5.9 Table 2. Thromboembolism in Patients Treated with Aspirin No. of No. of Follow-up Procedure Patients Emboli (mo) Percent AVR + SR 186 4,48 AVR + AF 15 355 MVR+ SR 3 81 MVR+ AF 135 5 3,13 3.7 DVR + SR 44 1,42 DVR + AF 86 3 2,38 3.5 Total 496 8 11,783 1.6 AVR = aortic valve replacement; SR = sinus rhythm; AF = atrial fibrillation; MVR = mitral valve replacement; DVR = double-valve replacement. plication, 3.5% (3 out of 86). All instances of thromboembolism occurred during the first 6 postoperative months, and two were considered major (see Table 2). Hemorrhage GROUP A. Eighteen hemorrhagic episodes occurred in the group treated with Coumadin, 5.4% (18 out of 328 patients) (see Figure). Four patients died of hemorrhage, 1.2%, and 6 more had major hemorrhagic events, 1.8%. The risk of severe or mortal hemorrhage was higher during the third, fourth, and fifth postoperative months. Patients with TVR had a higher risk of bleeding (4 out of 11 patients). GROUP B. Two patients experienced mild gastrointestinal bleeding. This was the only recorded complication of aspirin treatment (see Figure). Comparative Results THROMBOEMBOLISM. No statistical significance (p >.5) was found between Groups A and B as a whole, or between subgroups made according to the valve or valves replaced and the presence or absence of sinus rhythm. No difference in the rate of thromboembolic events was found in patients undergoing cardiac valve replacement with a bioprosthesis when they were treated with either Coumadin or aspirin. The period of maximal risk for both groups was the first 6 months after operation. Patients in either group who were in sinus rhythm were free from embolic complications. HEMORRHAGE. Patients given Coumadin were subject to the risks of hemorrhage and death. The risk was highest during the third, fourth, and fifth postoperative months. Hemorrhagic events in patients treated with aspirin were

, ~~. 357 Nuiiez et al: Aspirin or Cournadin for Porcine Valve Replacement I :. qo: + nq, -, ",,,, ~, 2 d 6 6 1 12 14 16 16 2 22 74 56 MONTHS Timing of hemorrhage and embolism in the postoperative period. negligible. Statistical significance for hemorrhage was found for the group of patients treated with Coumadin ( p <.1). Comment Follow-up data on our patients confirm the results of previous studies with regard to the low incidence of thromboembolism in patients who underwent valve replacement with a porcine bioprosthesis [2-41. The main advantage of porcine bioprostheses is their low incidence of thromboembolism. This advantage is blurred in some studies because of permanent oral anticoagulation [2, 51. In 198, two articles reported a low incidence of thromboembolism in patients with bioprostheses and without long-term anticoagulation [6, 71. Temporary oral anticoagulation for every patient with a bioprosthesis has been recommended by the commercial producers and has proved to be effective in preventing thromboembolism in several surgical series [5, 8, 91. Oral anticoagulation is associated with an objective risk of hemorrhage and inconvenience for the patients [lo]. Evidence of the contribution of platelets to the pathogenesis of thrombus formation exists in patients with atherosclerosis [ll], patients with rheumatic heart disease [12], and patients with prosthetic heart valves [131. Aspirin has been shown to be effective in prophylaxis of stroke and venous thrombosis in males [14, 151. The role of antiplatelet agents in the prevention of thromboembolism in patients with bioprostheses is not known. In this study, patients in sinus rhythm ex- perienced no episode of thromboembolism regardless of which valve was replaced or which anticoagulation treatment was used. We agree with Cohn and co-workers [8] that patients in sinus rhythm with bioprostheses are free from this complication. Patients in atrial fibrillation had a low incidence of embolism. Most thromboembolic events happened during the first 6 postoperative months. Neither Coumadin nor aspirin was able to prevent embolism completely. However, the incidence of this complication was acceptably low, as reported by others [2,5]. No statistical difference in the rate of thromboembolism was found in patients having MVR or double-valve replacement who were in atrial fibrillation whether they were treated with aspirin or Coumadin. Patients who underwent AVR and were in atrial fibrillation represent a very small group of patients in this series, and no valid conclusion could be obtained. Thromboembolism in patients with valve replacement by a bioprosthesis happens mainly during the first 6 postoperative months 13, 5, 161. During this period in our study, aspirin was as effective as Coumadin in the prevention of embolism. The incidence of Coumadinrelated hemorrhage is higher in our patients than that reported by others [5, 171. Oral anticoagulation has been the treatment used to prevent embolism after cardiac valve replacement. The routine use of Coumadin after valve replacement with a bioprosthesis may not be the most acceptable drug for that purpose. Antiplatelet agents seem to offer the same protection against thromboembolism at a lesser risk. References 1. Cohn LH: Bioprosthetic cardiac valves: anticoagulation or not? In Sebening F (ed): Bioprosthetic Cardiac Valves. Munich, Deutsches Herzzentrum, 1979, p 17 2. Oyer PE, Stinson EB, Reitz BA, et al: Long-term evaluation of the porcine xenograft bioprosthesis. J Thorac Cardiovasc Surg 78:343, 1979 3. Cevese PG, Galluci V, Morea M, et al: Heart valve replacement with the Hancock bioprosthesis: analysis of long-term results. Circulation 56:Suppl 3:111, 1977

358 The Annals of Thoracic Surgery Vol 33 No 4 April 1982 4. Cohn LH, Sanders JH, Collins JJ: Actuarial comparison of Hancock porcine and prosthetic disc valves for isolated mitral valve replacement. Circulation 54:Suppl 3:6, 1976 5. Angell WW, Angell JD, Sywak A: The Angell- Shiley porcine xenograft. Ann Thorac Surg 28: 537, 1979 6. Williams JB, Karp RB, Kirklin JW, et al: Considerations in selection and management of patients undergoing valve replacement with glutaraldehyde-fixed porcine bioprostheses. Ann Thorac Surg 3:247, 198 7. Grehl TM, Naifeh JG, Broda J, et al: Heterograft cardiac valve prosthesis: a five-year follow-up. Ann Thorac Surg 3:173, 198 8. Cohn LH, Kaster JK, Lee RBB, et al: Long-term follow-up of the Hancock bioprosthetic heart valve: a six-year review. Circulation 6O:Suppl 1:I-87, 1979 9. Davila JC, Magilligan DJ Jr, Lewis JW Jr: Is the Hancock porcine valve the best cardiac valve substitute today? Ann Thorac Surg 26:33, 1978 1. Stinson EB, Griepp RB, Oyer PE, Shumway NE: Long-term experience with porcine aortic valve xenografts. J Thorac Cardiovasc Surg 73:54, 1977 11. Didisherm P, Kazmier FJ, Fuster V: Platelet inhibition in the management of thrombosis. Thromb Diath Haemorrh 32:21, 1974 12. Steele PP, Weily HS, Davies H, Genton E: Platelets in patients with rheumatic heart disease. N Engl J Med 29:537, 1974 13. Harker LA, Slichter SJ: Studies of platelet and fibrinogen kinetics in patients with prosthetic heart valves. N Engl J Med 283:132, 197 14. Canadian Cooperative Study Group: A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med 299:53, 1978 15. Harris WH, Salzman EW, Athanasoulis CA, et al: Aspirin prophylaxis of venous thromboembolism after total hip replacement. N Engl J Med 297:1246, 1977 16. Hetzer R, Hill JD, Kerth WJ, et al: Thromboembolic complications after mitral valve replacement with Hancock xenograft. J Thorac Cardiovasc Surg 75:651, 1978 17. Oyer PE, Stinson EB, Griepp RB, et al: Valve replacement with the Starr-Edwards and Hancock prostheses. Ann Surg 186:31, 1977 Notice from the American Board of Thoracic Surgery The American Board of Thoracic Surgery now requires that candidates pass both the written and oral portions of the certifying examination. In 198 and thereafter, a written examination will be given prior to the oral examination. It will be necessary to pass the written examination before the oral examination can be taken. The closing date for registration for 1983 is August 1,1982. The exact times and places of these examinations will be announced later. A candidate applying for admission to the 1983 certifying examination must fulfill all the requirements for the Board in force at the time the application is received. Please address all communications to the American Board of Thoracic Surgery, 1464 E Seven Mile Road, Detroit, MI 4825.