Porcine bioprosthesis use for surgical treatment of

Fifteen-Year Clinical Experience With the Biocor Porcine Bioprostheses in the Mitral Position Kaan Kırali, MD, Mustafa Güler, MD, Altuğ Tuncer, MD, Bahadır Dağlar, MD, Gökhan İpek, MD, Ömer Işık, MD, and Cevat Yakut, MD Department of Cardiovascular Surgery, Koşuyolu Heart and Research Hospital, Istanbul, Turkey Background. Bioprosthetic valve use represents a crucial improvement in surgical treatment of mitral valve disease. The aim of this study is to determine the long-term durability of the Biocor porcine bioprosthetic mitral valve. Methods. Between 1985 and 1989, a total of 158 Biocor porcine bioprosthetic valves were placed in the mitral position, and long-term results of these patients were investigated retrospectively in 1999. Results. Thirty-day mortality was 4.4% (7 patients). Total follow-up was 1,499 patient-years. Actuarial survival was 83.66% 3% at 5 years, 77.78% 3.36% at 13 years (1.8% patient-year). Multivariate analysis demonstrated younger age, duration of implantation, congestive heart failure, and functional class to be significant predictors of late mortality. Actuarial freedom from valverelated mortality was 98.58% 1% at 15 years (0.13% patient-year). Actuarial freedom from structural valve deterioration was 95.49% 1.8% at 5 years, 70.2% 4.12% at 10 years, and 64.82% 5.34% at 13 years (2.6% patient-year). Actuarial freedom from structural valve deterioration-related reoperation was 98.43% 1.1% at 5 years, 89.15% 2.85% at 10 years, and 76.82% 7.91% at 14 years. Multivariate analysis showed younger age and duration of implantation to be significant predictors of structural valve deterioration and its related reoperation. Conclusions. By studying a 15-year time period, it is seen that this new generation porcine bioprosthetic valve should be considered an alternative for mechanical valves in selected patients. (Ann Thorac Surg 2001;71:811 5) 2001 by The Society of Thoracic Surgeons Porcine bioprosthesis use for surgical treatment of heart valve diseases represents an important improvement in cardiac surgery. More than 30 years have passed since the first implantation of a glutaraldehydetreated valvular bioprosthesis. The most important disadvantage of mechanical valves is the requirement of indefinite anticoagulation, which exposes patients to the risk of hemorrhagic or thromboembolic complications, whereas tissue valves have limited long-term durability because of fibrocalcification and fatigue-related leaflet disruption. However, despite the limited long-term durability, some advantages of bioprostheses merit use in selected patients [1]. Improvements in valve design and preservation of bioprosthetic valves to avoid thromboembolic complications and to lengthen durability, and new techniques for management of reoperation, may change current indications for selecting these valves [2]. The Biocor (Biocor Industria e Pesguisa Ltda, Belo Horizonte, MG, Brazil) prosthesis was developed in Brazil in 1982 [3]. The leaflets are mounted on a flexible stent made of an acetyl copolymer covered by a tubular Dacron (C.R. Bard, Haverhill, PA) fabric. The main improvements of the Biocor valve, which is fixed and preserved in Accepted for publication Oct 14, 2000. Address reprint requests to Dr Kırali, Koşuyolu Heart and Research Hospital, 81020, Kadıköy, Istanbul, Turkey; e-mail: kosuyolu@ superonline.com. glutaraldehyde under resting conditions with a pressure less than 1 mm Hg (third generation), are particularly careful harvesting, tanning, and handling of the tissue. This new generation bioprosthesis has been in use more than 15 years, yet data regarding long-term results of this device are limited [4, 5]. In this study, 15-year long-term results of Biocor porcine bioprosthesis were investigated retrospectively. Material and Methods At Koşuyolu Heart and Research Hospital, isolated mitral valve replacement with a bioprosthetic artificial valve (Biocor) was used in 158 patients between January 1985 and 1989. Long-term results of these patients were investigated retrospectively in 1999. The preoperative features of the patients are given in Table 1. The etiology in young patients (85%) was rheumatic fever in childhood, and was degenerative changes in older patients (15%). No patient had undergone valve surgery before, and no concomitant cardiac procedures were performed at operation. The main indications for operation was functional incapacity or echocardiographic findings. The same operative technique was used in all patients under elective conditions; cold crystalloid cardioplegia was applied every 20 minutes in additional to topical cooling. After left atriotomy, the mitral valve was resected and a bioprosthetic valve was replaced using simple sutures (2-0 Dacron polyester) including four 2001 by The Society of Thoracic Surgeons 0003-4975/01/$20.00 Published by Elsevier Science Inc PII S0003-4975(00)02516-9

812 KIRALİ ET AL Ann Thorac Surg BIOCOR IN THE MITRAL POSITION 2001;71:811 5 Table 1. Patient Data Variable Data (Patients [%]) Mean age (yr) 19 68 (48 14) Sex Women 97 (61.4%) Men 61 (38.6%) ECG (preop/postop) Sinus 90 (57%)/85 (56.3%) Atrial fibrillation 68 (43%)/66 (43.7%) NYHA (preop/late postop) Class I 8 (5%)/58 (46.75%) Class II 66 (41.8%)/58 (46.75%) Class III 72 (45.5%)/8 (6.5%) Class IV 12 (7.7%)/0 Mitral valve pathology Stenosis 52 (33%) Insufficiency 47 (29.7%) Both 59 (37.3%) Mitral valve size 27 4 29 88 31 59 33 7 ECG electrocardiogram; NYHA New York Heart Association. pledged sutures. Sixty-seven patients (42.4%) underwent left atrial thrombectomy and appendix ligation. Anticoagulation In the postoperative period, 150 mg/day acetyl salicylic acid and 2.5 mg/day warfarin sodium was started after extubation. Both drugs were discontinued in patients in sinus rhythm after 3 months, but warfarin sodium was given lifelong at 2.5 mg/day for patients with atrial fibrillation, enlarged left atrium, or a history of thromboembolism or cerebrovascular event. Definition The definitions of complications and methods of analysis were consistent with the guidelines issued by Edmunds and colleagues [6]. Results are presented as mean standard deviation. Multivariate proportional hazard regression analysis was used to assess risk factors as independent predictors of patient survival and structural valve deterioration (SVD). Survival curves were constructed using the Kaplan-Meier method. The log rank test for independent groups was used to test the significance of differences. Categorical variables were compared using the 2 test. A p value less than or equal to 0.05 was considered statistically significant for all comparisons. Follow-up Information on patients was provided by the patient or the patient s relatives, physicians, or hospital registry in 2000. Follow-up was 96.7% complete with 146 patients. Five patients were lost to follow-up. Total follow-up was 1,499 patient-years, with a mean of 9.9 3 years (range, 1 to 15 years). Results Thirty-Day and Late Mortality The 30-day mortality was 4.4% with 7 patients and late mortality was 17.9% with 27 patients. Causes of 30-day and late mortality are listed in Table 2. Actuarial survival and freedom from mortality are listed in Table 3 (Fig 1). Multivariate analysis demonstrated younger age, duration of implantation, congestive heart failure, and functional class to be significant predictors of late mortality. Frequency of valve-related mortality (VRM) was lower than non-vrm ( p 0.0008) (Fig 2). Functional Class The patients had significant improvement of their functional capacity as compared to their preoperative status ( p 0.001) (Fig 3). Thromboembolism and Anticoagulant-Related Hemorrhage Thromboembolic events were observed in 9 patients and a bleeding complication due to anticoagulation therapy was found in 1 patient (Table 3). Transient ischemic attack occurred in 5 patients (3.3%), stroke in 2 (1.3%), and reversible ischemic neurologic deficit in 2 patients (1.3%). Only 1 patient who had a stroke died. The mean time interval from operation to an embolic event was 4.2 2.6 years (range, 1 to 9 years). Structural Valve Deterioration Bioprosthetic valve deterioration was observed in 39 patients (Table 3). Sixteen patients (41%) were reoperated and the other 23 patients are being followed echocardiographically. Actuarial freedom from SVD and corrected ratios according to patient age are shown in Figure 4. For all patients, multivariate analysis demonstrated younger age and duration of implantation as significant predictors of SVD. Table 2. Causes of 30-Day and Late Mortality Causes No. of Patients (%) 30-day mortality 7 (4.4%) Heart failure 5 (3.2%) Bleeding 1 (0.6%) Cerebrovascular accident 1 (0.6%) Late mortality 27 (17.9%) Cardiac 13 (8.6%) Cardiomyopathy 7 (4.6%) Heart failure 4 (2.7%) Valve related 2 (1.3%) Prosthetic endocarditis 1 (0.65%) Stroke 1 (0.65%) Noncardiac 14 (9.3%)

Ann Thorac Surg KIRALİ ET AL 2001;71:811 5 BIOCOR IN THE MITRAL POSITION 813 Table 3. Late-Term Results Actuarial Freedom (%) Actual Freedom (%) % patientyear Patient 5-Year 10-Year 15-Year 5-Year 10-Year (%) Mortality 83.66 3 77.78 3.36 77.78 3.3 84.2 78.48 1.8 34 (21.5) NVRM a 88.96 2.6 82.71 3.15 82.71 3.15 89.4 83.4 0.13 25 (16.6) VRM a 98.58 1 98.58 1 98.58 1 98.67 98.67 1.67 2 (1.3) SVD 95.65 1.74 70.2 4.12 64.82 5.34 95.3 68.64 2.6 39 (25.8) Mild/ reop 96.62 1.66 79.05 3.9 79.05 3.9 96.87 79.66 1.54 23 (15.2) Severe/ reop 98.5 1.06 87.89 3.07 82.01 5.02 98.4 89 1.06 16 (10.6) NSVD 98.65 0.95 98.65 0.95 98.65 0.95 98.43 98.3 0.14 2 (98.7) All reoperation 95.60 1.76 84.98 3.19 79.89 4.67 95.3 83.9 1.4 21 (13.9) SVD related 98.43 1.1 89.15 2.85 76.82 7.91 98.43 89 1.06 16 (10.6) Endocarditis 98.5 1.05 97.65 1.34 97.65 1.34 98.43 97.45 0.22 3 (2) PVL 98.61 0.98 98.61 0.98 98.61 0.98 98.43 98.3 0.14 2 (1.3) Thromboembolism 94.94 1.87 93.31 2.16 93.31 2.16 94.5 92.38 0.6 9 (5.9) Endocarditis 97.14 1.41 96.35 1.6 96.35 1.6 96.87 95.7 0.04 5 (3.3) Antico/hemo 99.32 0.68 99.32 0.68 99.32 0.68 99.2 99.15 0.07 1 (0.66) a For survival; confidence interval 95%. Antico/hemo anticoagulant-related hemorrhage; NSVD nonstructural valve deterioration; NVRM nonvalve-related mortality; PVL paravulvular leak; reop do not require reoperation; reop require reoperation; SVD structural valve deterioration; VRM valve-related mortality. Nonstructural Valve Dysfunction Two patients had significant paravalvular leakage and they were reoperated (Table 3). Reoperation Reoperation was performed in 21 patients (Table 3). Reoperative mortality was 4.76%, with 1 patient reoperated because of endocarditis 4 years after his first operation. Actuarial freedom from reoperation was shown in Figure 5. For all patients, multivariate analysis showed younger age and duration of implantation to be significant factors that increased the probability of reoperation. The difference for actuarial freedom from reoperation between patients with SVD and non-svd was very significant ( p 0.001). Prosthetic Valve Endocarditis Prosthetic valve endocarditis was observed in 5 patients (Table 3). Three of them were reoperated and the other 2 patients were treated medically. Comment Porcine bioprostheses have provided patients with an excellent quality of life at a low risk of major thromboembolism, essential lack of thrombosis, and freedom from hemorrhagic events related to anticoagulation. Glutaraldehyde-preserved porcine bioprostheses were widely used and their long-term results are published [7 10]. At present, more durable bioprosthetic valves are produced by using anticalcification and antimicrobial technology [11, 12]. The most significant reason for bioprosthetic valve dysfunction is valve deterioration after 5 to 6 years that requires reoperation within 8 to 12 years [13, 14]. The pathologic features of SVD are most thoroughly documented by Schoen and Levy [15]. When the long-term results of various valves were analyzed, it was shown that hospital mortality was closely related to preoperative functional capacity. Early mortality was determined to be 6% to 12% [7, 8, 10, 16 18]. In comparison, groups replaced with mechanical or biological mitral valves, early mortality was 11.2% for mechanical valves and 6.6% for bioprosthetic valves [17]. Fig 1. Overall survival of all patients. The number in the upper box shows the total number of patients who have undergone mitral valve replacement with the Biocor valve between 1985 and 1989, and the number in the lower box shows 30-day mortality. Fig 2. Actuarial freedom from valve- and nonvalve-related mortality in the following period (p 0.0008).

814 KIRALİ ET AL Ann Thorac Surg BIOCOR IN THE MITRAL POSITION 2001;71:811 5 Fig 3. Pre- and postoperative functional capacity of patients. (NYHA New York Heart Association functional class). The early mortality of Biocor bioprostheses was 6.1% in the study by Vrandecic and coworkers [4] and 13% in the one by Myken and coworkers [5]. In our series, early mortality was 4.43% with 7 patients, and valve-related early mortality was zero. In addition, our late mortality rate was lower than in other studies [4, 5]. The reason may be that the patients preoperative functional capacity was better in our study, or that our patients did not have any additional cardiac disease and were younger. Overall survival for several types of first generation porcine bioprosthetic valves in the mitral position was found to be between 70% and 87% at 5 years, between 44% and 76% at 10 years, and between 23% and 65% at 15 years [8, 18, 19]. Overall survival for new generation bioprostheses were 55% and 57% at 10 years [5, 10]. Myken and coworkers [2] compared bioprosthetic and mechanical valves in their study and found that the actuarial survival was 65.5% versus 55.2% at 10 years. In our experience, we found cumulative survival to be 83.66% 3% at 5 years and 77.78% 3.36% at 13 years. The causes of long-term mortality were noncardiac factors in our study, contrary to other series. We believe that our patients condition (younger age, higher functional capacity) is the most important reason for this long-term survival. One of the most important criterion of prosthetic valves in long-term observation is actuarial freedom from VRM, which is reported in different series as between 88% and 98% at 5 years, and between 60% and 95% at 10 years [8, 16 19]. For new generation bioprostheses, the freedom from VRM was 97% at 8 years [4], and 89% at 9 years [12]. In our series, the actuarial freedom from VRM was 98.58% 1% at 15 years. Deterioration shows rapid advance and requires prompt reoperation. Knowledge of the average time to failure for a specific porcine valve is important when counseling patients about valve selection. Tissue valve use in elderly patients should be expanded because of a low incidence of SVD, slow rate of deterioration, and a low VRM risk, in contrast to the use of mechanical valves. Freedom from SVD of different types of bioprosthetic valves implanted in the mitral position is between 45% and 84% at 10 years, and between 21% and 45% at 15 years [8, 16 18]. This ratio is between 75% and 95% at 8 to 10 years for Biocor [4, 5, 10]. In our series, actuarial Fig 4. Actuarial freedom from structural valve deterioration (SVD) and freedom from structural valve deterioration in different age groups. freedom from SVD was 95.49% 1.8% at 5 years, 70.2% 4.12% at 10 years, and 64.82% 5.34% at 13 years. Myken and coworkers found freedom from SVD to be 61.1% 18.4% at 10 years for the under 50-year-old age group [5]. In the literature, the freedom from SVD for the under 50-year-old age group was determined to be 10% to 40% for a 15-year period [7, 8]. This ratio for patients older than 50 years changed to between 75% and 85% [5, 10]. When we analyzed the age groups, we observed that the reoperation ratio was significantly higher in the younger age group than in the older age group (Fig 4). Another factor in valve deterioration is the duration of implantation. Bioprosthetic abnormalities in terms of calcification and cusp rupture (or both) and their hemodynamic consequences develop gradually and permit selection of the optimum time for reoperation [9]. Bioprosthetic failure progresses slowly in most patients with a porcine valve, allowing elective reoperation, but, in a few patients, an emergency reoperation that carries a high mortality risk, may be necessary [20]. Late deterioration should not be a contraindication for the use of bioprostheses in adults because of improvements in reoperation and myocardial protection techniques. Although the rate of asymptomatic SVD is improved, reoperation can be performed without damage to the patient s cardiac functions [21]. Myken and coworkers determined freedom from reoperation to be 78.9% 9.2% at 10 years, and freedom from valve-related reoperation to be 85.3% 9.6% at 10 years [5]. More recent Fig 5. Actuarial freedom from reoperation.

Ann Thorac Surg KIRALİ ET AL 2001;71:811 5 BIOCOR IN THE MITRAL POSITION 815 results shows that Biocor porcine bioprosthetic valves need fewer deterioration-related reoperations and provide greater freedom from SVD-related reoperations than other porcine valves [8, 16, 18, 19]. In particular, improvement in surgical reoperation techniques reduce the mortality and morbidity rates of bioprosthetic dysfunction-related reoperations [22, 23]. Improved results of reoperation using bioprosthetic valves, as published in recent years, complements the reduced incidence of SVD and should broaden indications for using those valves [12, 22]. The reoperation mortality of dysfunctional bioprosthetic valves in the mitral position was 10% [5]. The mortality ratio in this study was 5.3% (1 patient) and is similar to the rate of early mortality for initial operations. We performed reoperation in a way to not hurt cardiac function or functional capacity. The absence of a stent is believed to reduce mechanical stress on valvular tissue and result in better valve durability; thus, a new generation of bioprostheses was produced [24]. Use of a stentless mitral valve has the potential to maintain valvuloventricular interaction and to preserve left ventricular function. This new generation valve is an option for reoperation. In conclusion, valve type for mitral replacement is the most significant factor affecting the patient s life after operation. Furthermore, factors like patient age, sociocultural situation, quality of life, VRM, and morbidity must be taken into account. Because the selected valve should not limit quality of life, valve durability is an important long-term concern. In addition, an earlier investigation found that geographic and socioeconomic parameters should be taken into account during selection of a valve [25]. In developing countries, factors such as lack of definitive solutions for health problems; rheumatic fever, and rheumatic heart valve disease; lack of follow-up; and a young prolific population desiring children should be considered. These considerations limit use of mechanical valves for replacing the mitral valve. Because of these factors in developing countries, valve repair, if it is possible, should be the first choice. Freedom from anticoagulant use or anticoagulant-related complications is an important advantage of bioprosthetic valves. Longterm results indicate that SVD is often nonfatal because of its slow progress, and patients have almost always a chance for reoperation, whereas mechanical valverelated complications are often fatal. Because mortality after reoperation is similar to that of the primary operation, we recommend a new generation bioprosthetic valve for the adult age group. References 1. Carabello BA, Crawford FA. Valvular heart disease. N Engl J Med 1997;337:32 41. 2. Myken PSU, Caidahl K, Larsson P, Larsson S, Wallentin I, Berggren HE. Mechanical versus biological valve prosthesis: a ten-year comparison regarding function and quality of life. Ann Thorac Surg 1995;60:S447 52. 3. Vrandecic MO, Gontijo FB, Rabelo S. Clinical experience with a new generation of porcine bioprostheses. In: Bodnar E, Yacoub M, eds. Bioprosthetic valves. New York: Yorke Medical Books, 1986:659 65. 4. Vrandecic MO, Gontijo FB, Paula e Silva JA, et al. Clinical results with the Biocor porcine bioprosthesis. J Cardiovasc Surg (Torino) 1991;32:807 13. 5. Myken PSU, Caidahl K, Larsson S, Berggren HE. 10-year experience with the Biocor porcine bioprosthesis in the mitral position. J Heart Valve Dis 1995;4:63 9. 6. Edmunds LH, Clark RE, Cohn LH, Grunkemeier GL, Miller DC, Weisel RD. Guidelines for reporting morbidity and mortality after cardiac valvular operations. Ann Thorac Surg 1996;62:932 5. 7. Jamieson WRE, Burr LH, Munro AI, Miyagishima RT. Carpentier Edwards standard porcine bioprosthesis: a 21-year experience. Ann Thorac Surg 1998;66:S40 3. 8. Fann JI, Miller DC, Moore KA, et al. Twenty-year clinical experience with porcine bioprostheses. Ann Thorac Surg 1996;62:1301 2. 9. Myken PS, Berggren HE, Larsson S, Roberts B, Wallentin I, Caidahl K. Long-term Doppler echocardiographic results of aortic or mitral valve replacement with Biocor porcine bioprosthesis. J Thorac Cardiovasc Surg 1998;116:599 608. 10. Jamieson WR, Lemieux MD, Sullivan JA, Munro AI, Metras J, Cartier PC. Medtronic intact porcine bioprosthesis: 10 years experience. Ann Thorac Surg 1998;66:S118 21. 11. Abolhada A, Yu S, Oyarzun R, et al. Biocor No-React detoxification process: a superior anticalcification method for bioprostheses. Ann Thorac Surg 1996;62:1724 30. 12. Langanki D, Ogle MF, Cameron JD, Lirtzman RA, Schroeder RF, Mirsch MW. Evaluation of a novel bioprosthetic heart valve incorporating anticalcification and antimicrobial technology in a sheep model. J Heart Valve Dis 1998;7:633 8. 13. Gong G, Seifter E, Lyman WD, Factor SM, Blau S, Frater RWM. Bioprosthetic cardiac valve degeneration: role of inflammatory and immune reactions. J Heart Valve Dis 1993;2:684 93. 14. Deiwick M, Glasmacher B, Baba HA, et al. In vitro testing of bioprostheses: influence of mechanical stresses and lipids on calcification. Ann Thorac Surg 1998;66:S206 11. 15. Schoen FJ, Levy RJ. Pathology of substitute heart valves: new concept and developments. J Card Surg 1994;9(Suppl 2):222. 16. Neville PH, Aupart MR, Diemont FF, Sirinelli AL, Lemoine EM, Marchand MA. Carpentier Edwards pericardial bioprosthesis in aortic and mitral position: a 12-year experience. Ann Thorac Surg 1998;66:S143 7. 17. Vitale N, Giannolo B, Nappi GA, et al. Long-term follow-up of different models of mechanical and biological mitral prostheses. Eur J Cardiothorac Surg 1995;9:181 9. 18. Yamak B, Kener E, Kiziltepe U, Mavitas B, Tasdemir O, Beyazit K. Late results of mitral valve replacement with Carpentier Edwards high profile bioprosthesis in young adults. Eur J Cardiothorac Surg 1995;9:335 41. 19. Glover DD, Landolfo KP, Cheruvu S, et al. Determinants of 15-year outcome with 1119 standard Carpentier-Edwards porcine valves. Ann Thorac Surg 1998;66:S44 8. 20. Mazzucco A, Milano A, Mazzaro E, Bortolotti U. Reoperation in patients with a bioprosthesis in the mitral position: indications and early results. J Heart Valve Dis 1993;2:646 8. 21. Antunes MJ. Reoperations on cardiac valves. In: Acar J, Bodnar E, eds. Textbook of acquired heart valve disease. London: ICR Publishers, 1995:867 92. 22. Spaminato N, Gagliardi C, Pantaleo D, et al. Bioprosthetic replacement after bioprosthesis failure: a hazardous choice? Ann Thorac Surg 1998;66:S68 72. 23. Tyers GFO, Jamieson WRE, Munro AI, et al. Reoperation in biological and mechanical valve populations: fate of the reoperative patient. Ann Thorac Surg 1995;60:S464 9. 24. Morea M, De Paulis R, Galloni M, Gastaldi L, di Summa M. Mitral valve replacement with the Biocor stentless mitral valve: early results. J Heart Valve Dis 1994;3:476 82. 25. Rabago G. Comparison of mechanical and biological prosthesis. In: Rabago G, Cooley DA, eds. Heart valve replacement. New York: Futura Publishing, 1988:245 56.