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Embolic complications of porcine heterograft cardiac valves
J THoRAc
CARDIOVASC SURG
81:626-631, 1981
Embolic complications of porcine heterograft cardiac valves From January, 1975, until August, 1978, 509 porcine valves were implanted in 465 patients. Patient follow-up was done at 6 to 45 months (mean 20.2 months), for a total observation of 713 patient-years. There were six early embolic events (mitral four, aortic two). Four of these six patients were in atrial fibrillation and none was receiving anticoagulants at the time of the embolism. There were 18 late emboli. Four occurred in patients with aortic prostheses and produced mild, transient symptoms only. Fourteen occurred in patients with mitral or multiple prostheses. These resulted in death in five patients and permanent sequelae in three. The rate of embolic events was 1.321100 patient-years for aortic prostheses. 3.27//00 patient-years for mitral prostheses, and 4.91/100 patient-years for multiple prostheses. Thirteen of the /4 patients with emboli were in atrial fibrillation and only three were receiving anticoagulants. Anticoagulation is vital in patients with mitral prostheses who remain in atrial fibrillation. but it appears unnecessary in patients with aortic prostheses and those with mitral or multiple prostheses who remain in sinus rhythm.
W. R. Eric Jamieson, M.D., Michael T. Janusz, M.D., Robert T. Miyagishima, M.D., A. Ian Munro, M.D., Hernando Tutassura, M.D., Alfred N. Gerein, M.D., Lawrence H. Burr, M.D., and Peter Allen, M.D., Vancouver, British Columbia, Canada
Thromboembolism is a serious complication of prosthetic heart valve replacement. This complication is a significant cause of morbidity and mortality in reported series of heart valve replacements. The majority of mechanical prostheses have a high potential for thrombogenicity and necessitate long-term postoperative anticoagulation to reduce the risks of thromboembolisrn.'::" This problem is more severe following mitral valve replacement than aortic valve replacement. Because of the high incidence of systemic thromboembolism and the complications of anticoagulant therapy, the porcine heterograft cardiac valve was introduced in an attempt to reduce the morbidity and mortality from these complications in our patients. In this report we review our clinical experience with the porcine heterograft cardiac valve and document the incidence and cause of thromboembolic episodes in our patients. The contributing factors to thromboembolism From the Division of Cardiothoracic Surgery, University of British Columbia. Vancouver, British Columbia, Canada. Supported in part by the British Columbia Heart Foundation. Received for publication Feb. 29, 1980. Accepted for publication Aug. 27, 1980. Address for reprints: W. R. Eric Jamieson. M.D., #410-750 West Broadway, Vancouver, British Columbia, Canada.
626
are identified and the role of anticoagulation with this prosthesis is discussed.
Patients and methods Between January, 1975, and August, 1978, 509 Carpentier-Edwards and Hancock heterograft valves were placed in 465 patients. The patients ranged in age from 11 to 85 years with a mean of 53.1 years. There were 240 men and 225 women in this series. One hundred ninety-six aortic and 216 mitral valve replacements were performed and 45 patients underwent multiple valve replacements. Twenty-one percent of the total had previous cardiac operations (45 valve replacements, 40 mitral commissurotomies, and 11 other procedures) . The indications for aortic valve replacement were congenital calcific aortic stenosis (155), rheumatic heart disease (53), failed prosthesis (14), collagen disease (10), and infective endocarditis (five). For mitral valve replacements, the indications were rheumatic heart disease (201), myxomatous degeneration (28), failed prosthesis (22), infective endocarditis (six), myocardial infarction (two), Marfan's syndrome (one), and atrial septal defect, primum type (one). Other cardiac operations were performed concomitantly with the valve replacements in 69 patients
0022-5223/81/040626+06$00.60/0 © 1981 The C. V. Mosby Co.
Volume 81
Embolic complications of porcine valves
Number 4
627
April,1981
(14.6%): concomitant aorta-coronary bypass in 54 patients (11.6%), resection of an ascending aortic aneurysm in six, and open commissurotomy of another valve in four. Prior to operation 16.5% were in Class IV, 60.5% in Class III, 22.6% in Class II, and 0.4% in Class I. Those in Class II were primarily patients with aortic valve disease. Of the total 509 valves inserted, 166 (32%) were Hancock bioprostheses and 343 (68%) were CarpentierEdwards bioprostheses. The current evaluation was obtained by direct contact with all patients, attending physicians, or both. The average duration of follow-up of surviving patients was 20.2 months (range 6 months to 44 months). The cumulative follow-up for all patients was 713 patient-years. In our center, anticoagulation takes one of three avenues at the discretion of the attending physicians: (I) anticoagulation of all patients with a mitral valve prosthesis who are in chronic atrial fibrillation until such time as they are hemodynamically stable in sinus rhythm; (2) anticoagulation of all patients with an aortic or mitral prosthesis for a period of three months, with continuation of anticoagulants for patients with mitral valve replacement who are in chronic atrial fibrillation until such time as they are hemodynamically stable and free of atrial arrhythmias; (3) anticoagulation for an indefinite period of all patients with mitral valve replacement. Patients who received anticoagulants for the first 3 months only were considered, for analysis, not to be receiving long-term anticoagulation. Results Early deaths and complications. There were 32 deaths in 465 patients (6.9%)-six following aortic valve replacement (3.1 %), 22 following mitral valve replacement (10.2%), and three following multiple valve replacements (6.7%). There were seven deaths (16%) in patients requiring reoperation for previous valve replacement and four deaths (9.5%) in the group of patients who had a previous mitral commissurotomy. Of the 32 operative and early postoperative deaths, over 50% were attributed to low output states. Of the remainder, the most frequent significant causes were hemorrhage, cerebrovascular accident, congestive heart failure, and arrhythmias. There were 44 significant nonfatal operative complications in this series. Cerebrovascular accidents occurred in 13 patients, intraoperatively in seven and postoperatively in six. Heart block occurred in 17 patients and necessitated insertion of permanent cardiac pacemakers. There were five instances of sternal dehis-
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o
6
n-465"'\... n-196 ""n-216 ' . - -•.----. n-45
12
18
24
30
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42
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Fig. 1. Patient survival up to 42 months, expressed as an actuarial curve for aortic, mitral, and multiple replacements and for all 465 patients.
% 100
80 60
40
20
o
II
III
Pre-op
IV
II
III
IV
Post-op
Fig. 2. Functional classification (New York Heart Association) of surviving patients.
cence, four of periprosthetic leak, two of myocardial infarction, and three of false aneurysm of cannulation sites. Late deaths and complications. There have been 43 late deaths in the series (9.9%). The late mortality was 5.4% per patient-year. The late mortality for aortic valve replacement was 3.3% per patient-year, for mitral replacement, 6.8% per patient-year, and for multiple replacement, 13.8% per patient-year. Patient survival is expressed actuarially in Fig. I. The most common cause of late death was congestive heart failure (13 cases). Other causes include infective endocarditis (six), cerebrovascular accident (five), and periprosthetic leak (two). The postoperative functional classification improved significantly in the majority of the surviving patients, as shown in Fig. 2. Actuarial survival is expressed for
The Journal of
628
Jamieson et al.
Thoracic and Cardiovascular Surgery
% 100
90
e _ e II _ _ e~e-e-e-
IIn=61 III n 104
=
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= 29
_ e _ e _ e ""-, IV
80
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I
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I
I
12
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36
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Fig. 3. Long-term survival versus preoperative New York Heart Association class for patients with aortic valve replacement. % 100
90
e~
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.-.~
~.-.~ e~
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80 70
<,
60 \ 50
e
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Fig. 4. Long-term survival versus preoperative New York Heart Association class for patients with mitral valve replacement. each preoperative functional class for both aortic and mitral valve replacements (Figs. 3 and 4). The significant late complications were infective endocarditis, periprosthetic leak, thrombosis of the prosthesis, and systemic emboli. Infective endocarditis occurred in 10 patients, six with aortic valve prostheses (2.0 episodes per 100 patient-years), four with mitral prostheses (0.6 episodes per 100 patient-years), and two with multiple prostheses. Six of the 10 died, including three of the five patients who underwent reoperation. A periprosthetic leak occurred in seven patients, four with aortic valve replacements (1.3 episodes per 100 patient-years), and three with multiple valve replacements, two involving a mitral and one involving an aortic prosthesis (5.0 episodes per 100 patient-years). Four patients required reoperation, two
of whom died. There was one case of thrombosis of the left atrium in a patient with a mitral prosthesis. This was fatal. The reoperation rate in the aortic position was 1.9/100 patient-years, and in the mitral position the incidence was zero. For patients with multiple valve replacements the rate of a valve re-replacement was 6.7/100 patient-years. Thromboembolism. There were 24 thromboembolic events. Six occurred during the early postoperative period and 18 occurred late (Table 1). Of the 18 late episodes, five occurred within the first 3 months and the remaining 13 were distributed throughout the rest of the observation period. There were four instances of late systemic emboli after aortic valve replacement, 11 after mitral replacement, and three after multiple replacements. Five events were fatal and three produced significant permanent sequelae. Of the six early embolic events, two followed aortic valve replacement and four, mitral replacement. There were no deaths. All patients were in chronic atrial fibrillation, except for one who had aortic and one, mitral replacement. The events occurred between the first and fourteenth postoperative days. Anticoagulation had been commenced in only one patient, but therapeutic range had not been attained at the time of the cerebrovascular accident. Of the 18 late embolic events, only four occurred in patients with an aortic valve prosthesis. In each case, the events were limited to transient visual scotomata only, with no permanent deficit. Eleven episodes followed mitral valve replacement, and three followed multiple valve replacement. Two of these 14 were peripheral and 12 affected the central nervous system. Most of these produced a major deficit, most commonly a hemiparesis. Five were fatal and three left a permanent deficit. Thirteen of these 14 patients were in chronic atrial fibrillation, and only three were receiving anticoagulants at the time of embolization. The rate of embolic events was 1.32/100 patient-years for aortic valve prostheses, 3.27II 00 patient-years for mitral prostheses, and 4.91/100 patient-years for multiple prostheses. There were no deaths related to embolization in aortic valve replacement. The fatality rate for mitral valve replacement related to thromboembolism was 1.2/100 patient-years and for multiple valve replacement, 1.67/100 patient-years. For statistical analysis, embolic events occurring in the first 12 months of all patients followed for 12 months or longer were examined. Of 171 patients with aortic valve prostheses, two had clinically insignificant emboli. Of 175 patients with mitral prostheses, nine experienced an embolic event; eight of these events
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Embolic complications of porcine valves
629
April. 1981
were clinically significant and caused three deaths. There was no significant difference (p = 0.08) in the total number of emboli between patients with aortic and those with mitral prostheses, but there was a statistically significant difference (p < 0.01) when the number of clinically significant events was compared. No clear relationship could be found between the occurrence of previous cerebrovascular accidents and postoperative emboli-one early and one late embolic event in 25 patients who had experienced systemic emboli prior to valve replacement. Only 32% of these patients were maintained on anticoagulant therapy. Long-term anticoagulation was employed in 10% of patients with aortic prostheses and 45% of patients with mitral or multiple prostheses. There were 13 episodes of significant bleeding related to anticoagulants, six necessitating hospitalization. Without anticoagulation the incidence of systemic emboli in aortic valve replacement was I. I7/l 00 patient-years (three events), compared to 4.30/100 patient-years with anticoagulation (one event). With anticoagulation the incidence of emboli in mitral valve replacement was 2.09/100 patient-years (three events); without anticoagulation, it was 5.08/100 patient-years (eight events). In multiple valve replacements there were no emboli when anticoagulants were utilized, but the incidence without anticoagulation was 8.9l!100 patient-years (three events). No statistically significant difference in embolism rates was found between those taking anticoagulants and those not taking anticoagulants in the aortic, mitral, or multiple valve replacement groups. However, except for the first 100 patients, in whom no anticoagulants were utilized, all patients with known risk factors such as atrial fibrillation were placed on a long-term regimen of anticoagulants. Ninety-five percent of patients in this series are free of embolization at 36 months (Fig. 5). Discussion
Several authors have noted that the risk of thromboembolic events is lower in patients with porcine xenograft valve prostheses than in patients with mechanical valve prostheses.': 7-14 In their early experience, most authors used no anticoagulants. However, with time, embolic events was noted, particularly in patients with mitral prostheses who continued to have chronic atrial fibrillation or who had a dilated left atrium. 7-11. 15-19 In our early experience, during which we used no anticoagulants, we l 8 • 20 noted this same association of emboli with left atrial dilatation or fibrillation.
E
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I
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.
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~
6
12
18 24 Months
30
36
42
Fig. 5. Actuarial probability of remaining free of systemic embolism for patients with aortic prostheses, mitral prostheses, and for the total patient group (465 patients).
Table I. Time interval of thromboembolism Total
Time interval
2
4 4 3 2 2
0 0 0 2 I
6 5 4 4 5
6
15
3
24
<2 wk 2 wk-J mo 3·6 rno 6·12 rno >12 mo
I I 0
Totals
2
In patients with rheumatic heart disease who had had no cardiac operation, Szekely" reported the risk of embolic events to be 0.67/100 patient-years for those in sinus rhythm compared to 5.26/100 patient-years for those in atrial fibrillation. This report as well as one by Fleming and Bailey" showed a reduction of this risk by use of well-controlled anticoagulants. We believe, therefore, that anticoagulants will benefit patients who have an increased risk for thromboembolic events. Our present experience showed a reduced incidence of embolic events among patients with mitral or multiple prostheses who were taking anticoagulants. Although this difference did not achieve statistical significance, we consider it indicative of a beneficial effect, since the majority of "high-risk" patients were in the anticoagulant group. Most recent reports'? 19. 20. 23-27 agree that patients with mitral prostheses who have a dilated left atrium or atrial fibrillation should receive anticoagulants. The experience of Davila, 28 Cohn, 10 and their colleagues, as well as our own experience, indicates that anticoagulation can be virtually eliminated in aortic valve replacements with the porcine xenograft. Cohn's group has reported a single major embolic event in a patient who remained in atrial fibrillation following aortic valve replacement, and they recommend anticoagulation for such patients. It has been reported that the majority of embolic
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630 Jamieson et al.
Thoracic and Cardiovascular Surgery
Table II. Comparison of embolism rates for patients with mitral porcine bioprostheses reported in the literature Institution
Valve
Years of valve replacement
Emboli per 100 patient-years
University of Kansas (1976)9 Stanford University (1977)' Henry Ford Hospital (1978)2" Peter Bent Brigham (1979)31
Hancock Hancock Hancock Hancock
1970-1975 1971-1975 1971-1975 1972-1977
104 243 125 131
4.8 5.2 2.87 3.8
Pacific Medical Center (1978)24 Stanford University (1979)30 University of British Columbia (1979)
Hancock Hancock Hancock and Carpentier-Edwards
1974-1977 1971-1978 1975-1978
133 561 216
5.3 3.1 3.27
Long-term anticoagulation
If left atrial thrombus 15% of patients 75% of patients If atrial fibrillation or large left atrium present Various 3 I% of patients 45% of mitral valve replacement and multiple replacements
Table III. Comparison of embolism rates for patients with aortic porcine bioprostheses reported in the literature Institution
Palo Alto, Calif. (1976)15 Henry Ford Hospital (1978)2" Harvard Medical Hospital, Peter Bent Brigham (1979)31 Stanford University (I 979):J0 University of British Columbia
Valve
Years of valve replacement
Emboli per 100 patient-years
Long-term anticoagulation
Hancock Hancock Hancock
1971-1974 1971-1975 1972-1975
75 60 71
2.84 1.28 1.02
25% (4 to 6 wk) 20% (3 to 6 mol None
Hancock Hancock and Carpeatier-Edwards
1971-1978 1975-1978
557 196
2.1 1.32
10% 10%
events occur in the first 3 months following operation,": 27-29 and the use of anticoagulants in all patients until the Teflon ring of the prosthesis has been covered with endothelium has been recommended. In our own experience, however, 55% of thromboembolic events occurred after the first 3 months, although only a minority of patients were routinely prescribed anticoagulants for the first 3 months. Our experience with thromboembolism in patients with the porcine heterograft valve is similar to that documented in the literature. The experience with thromboembolism in patients with mitral bioprostheses is summarized in Table II. The incidence ranges between 2.87 and 5.3 episodes per 100 patient-years, depending upon the number of patients on anticoagulant coverage. Most centers have developed indications for anticoagulation as they have gained experience. Table III documents the embolism experience in the aortic position, range 1.02 to 2.84 episodes per 100 patientyears. The majority of episodes in these patients are transient and do not cause permanent neurologic sequelae. The actuarial probability of aortic replacements remaining free of thromboembolism is in the range of 95% to 96% for the majority of patients at 3 to 4 years.!" 28, 30 For mitral replacements the range is
77% to 92% between 5 and 6'4 years, and for multiple replacements, 96% at 4 years. to. 28. 30 Effective control of thromboembolism has contributed to the excellent long-term survival reported with the porcine bioprosthesis. The actuarial survival of several clinical series is as high as 91 % at 3 years for aortic replacements and 86.8% at 5 1/ 2 years for mitral replacements. 7. 10. 15. 27. :30-:32 Thromboembolism is a complication of the cardiac disease and not necessarily of the heterograft prosthesis. For the risk of thromboembolism to be reduced, anticoagulation should be utilized when factors contributing toward vascular stasis are evident. Stringent observation of continuous anticoagulant management is necessary for patients with a mitral prosthesis who remain in atrial fibrillation. No anticoagulants appear to be necessary for patients who are hemodynamically stable in sinus rhythm. REFERENCES Oyer PE, Stinson EB, Griepp RB, Shumway NE: Valve replacement with the Starr-Edwards and Hancock prostheses. Comparative analysis of late morbidity and mortality. Ann Surg 186:301-309, 1977 2 Roberts We: Prosthetic heart valves. Which ones and why. Hosp Pract 13:63-69, 1978
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Embolic complications of porcine valves
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3 Moggio RA, Hammond GL, Stansel HC Jr, Glenn WWL: Incidence of emboli with cloth-covered Starr-Edwards valve without anticoagulation and with varying forms of anticoagulation. J THORAC CARDIOVASC SURG 75:296299, 1978 4 Limet R, Lepage G, Grondin CM: Thromboembolic complications with the cloth-covered Starr-Edwards aortic prosthesis in patients not receiving anticoagulants. Ann Thorac Surg 23:529-533, 1977 5 Tandon AP, Sengupta SM, Lukacs L, Ionescu MI: Longterm clinical and hemodynamic evaluation of the IonescuShiley pericardial xenograft and the Braunwald-Cutter and Bjork-Shiley prostheses in the mitral position. J THORAC CARDIOVASC SURG 76:763-770, 1978 6 Gray LA, Fulton RL, Srivastava TN, Flowers NC: Surgical treatment of thrombosed Bjork-Shiley aortic valve prosthesis. J THORAC CARDIOVASC SURG 71:429-431, 1976 7 Stinson EB, Griepp RB, Oyer PE, Shumway NE: Longterm experience with porcine aortic valve xenografts. J THORAC CARDIOVASC SURG 73:54-63, 1977 8 Mclntosh CL, Michaelis LL, Morrow AG, ltscoitz SB, Redwood DR, Epstein SE: Atrioventricular valve replacement with the Hancock porcine xenograft. A five year clinical experience. Surgery 78:768-775, 1975 9 Hannah HIll, Reis RL: Current status of porcine heterograft prosthesis. A five year appraisal. Circulation 54: Suppl 3:27-31, 1976 10 Cohn LH, Sanders JH, Collins 11: Aortic valve replacement with the Hancock porcine xenograft. Ann Thorac Surg 22:221-227, 1976 II Stinson EB, Griepp RB, Shumway NE: Clinical experience with a porcine aortic valve xenograft for mitral valve replacement. Ann Thorac Surg 18:391-401, 1974 12 Cevese PG: Long-term results of 212 xenograft valve replacements. J Cardiovasc Surg 16:639-642, 1975 13 Struck E, Meisner H, Schmidt-Habelmann P, Sebening F: Cardiac valve replacement with Hancock and CarpentierEdwards bioprosthesis (abstr). Symposium on Bioprosthetic Cardiac Valves, Munich, 1979 14 Jouven JC, Roux 11, Rapuzzi A, Talmoudi T, Antypas G, Malmjac C, Houel J: Early thromboembolic complications with porcine xenografts (abstr). Symposium on Bioprosthetic Cardiac Valves, Munich, 1979 15 Pipkin RD, Buch WS, Fogarty TS: Evaluation of aortic valve replacement with a porcine xenograft without longterm anticoagulation. J THORAC CARDtOVASC SURG 71: 179-186, 1976 16 Zuhdi N, Hawley W, Voehl V, Hancock W, Carey J, Greer A: Porcine aortic valves as replacements for human heart valves. Ann Thorac Surg 17:479-491, 1974 17 Cohn LH, Lambert 11, Castaneda AR, Collins 11: Cardiac valve replacement with the stabilized glutaraldehyde porcine aortic valve. Indications, operative results, and follow-up. Chest 68:162-165, 1975 18 Jamieson WRE, Munro AI, Allen P: Study of porcine xenograft replacement without long-term anticoagulants (abstr). Ann R Coli Phys Surg Can 10:36, 1977
19 Spampinato N, Gagliardi C, de Amicis V, Stassano P, Covino E: Incidence of thromboembolism on bioprosthetic cardiac valves not treated with anticoagulants (abstr). Symposium on Bioprosthetic Cardiac Valves, Munich, 1979 20 Jamieson WRE, Munro AI, Miyagishima RT, Allen P: Clinical evaluation of porcine heterograft cardiac valves in 200 patients. Can J Surg 21: 133-135, 1978 21 Szekely P: Systemic embolism and anticoagulant prophylaxis in rheumatic heart disease. Br Med J 11: 1209-1213, 1964 22 Fleming HA, Bailey SM: Mitral valve disease, systemic embolism and anticoagulants. Postgrad Med J 47:599604, 1971 23 Cohn LH, Sanders JH, Collins JJ: Actuarial comparison of Hancock porcine and prosthetic disk valves for isolated mitral valve replacement. Circulation 54:Suppl 3:60-63, 1976 24 Hetzer R, Hill JD, Kerth WJ, Ansbro J, Adappa MG, Rodvien R, Kamm B, Gerbode F: Thromboembolic complications after mitral valve replacement with Hancock xenograft. J THORAC CARDIOVASC SURG 75:651658, 1978 25 Horowitz MS, Goodman DJ, Fogarty TJ, Harrison DC: Mitral valve replacement with the glutaraldehyde-preserved porcine heterograft. Clinical, hemodynamic, and pathological correlations. J THORAC CARDIOVASC SURG 67:885-895, 1974 26 Edmiston WA, Harrison EC, Duick GF, Parnassus W, Lau FYK: Thromboembolism in mitral porcine valve recipients. Am J Cardiol 41:508-511, 1978 27 Cevese PG, Gallucci V, Morea M, Volta SD, Fasoli G, Casarotto D: Heart valve replacement with the Hancock bioprosthesis. Analysis of long-term results. Circulation 56:Suppl 3: 111-116, 1977 28 Davila JC, Magilligan OJ, Lewis JW: Is the Hancock porcine valve the best cardiac valve substitute today? Ann Thorac Surg 26:303-316, 1978 29 Poulain H, Bloch G, Cachera JP, Journet M, Loisance D, Menu P, Vouhe P, Aubry PH, Juvin AM, Galey 11: A three year experiment with bioprosthetic cardiac valves (abstr). Symposium on Bioprosthetic Cardiac Valves, Munich, 1979 30 Oyer PE, Stinson EB, Reitz BA, Miller DC, Rossiter S, Shumway NE: Long-term evaluation of porcine xenograft bioprosthesis. J THORAC CARDIOVASC SURG 78:343-350, 1979 31 Cohn LH, Collins JJ: The glutaraldehyde-stabilized porcine xenograft valve, Tissue Heart Valves, Chap 5, Toronto, 1979, Butterworth & Co., Ltd. 32 Jones EL, Craver JM, Morris DC, King SB III, Douglas JS Jr, Franch RH, Hatcher CR Jr, Morgan EA: Hemodynamic and clinical evaluation of the Hancock bioprosthesis for aortic valve replacement (with emphasis on management of the small aortic root). J THORAC CARDIOVASC SURG 75:300-308, 1978
CARDIOVASC SURG
81:626-631, 1981
Embolic complications of porcine heterograft cardiac valves From January, 1975, until August, 1978, 509 porcine valves were implanted in 465 patients. Patient follow-up was done at 6 to 45 months (mean 20.2 months), for a total observation of 713 patient-years. There were six early embolic events (mitral four, aortic two). Four of these six patients were in atrial fibrillation and none was receiving anticoagulants at the time of the embolism. There were 18 late emboli. Four occurred in patients with aortic prostheses and produced mild, transient symptoms only. Fourteen occurred in patients with mitral or multiple prostheses. These resulted in death in five patients and permanent sequelae in three. The rate of embolic events was 1.321100 patient-years for aortic prostheses. 3.27//00 patient-years for mitral prostheses, and 4.91/100 patient-years for multiple prostheses. Thirteen of the /4 patients with emboli were in atrial fibrillation and only three were receiving anticoagulants. Anticoagulation is vital in patients with mitral prostheses who remain in atrial fibrillation. but it appears unnecessary in patients with aortic prostheses and those with mitral or multiple prostheses who remain in sinus rhythm.
W. R. Eric Jamieson, M.D., Michael T. Janusz, M.D., Robert T. Miyagishima, M.D., A. Ian Munro, M.D., Hernando Tutassura, M.D., Alfred N. Gerein, M.D., Lawrence H. Burr, M.D., and Peter Allen, M.D., Vancouver, British Columbia, Canada
Thromboembolism is a serious complication of prosthetic heart valve replacement. This complication is a significant cause of morbidity and mortality in reported series of heart valve replacements. The majority of mechanical prostheses have a high potential for thrombogenicity and necessitate long-term postoperative anticoagulation to reduce the risks of thromboembolisrn.'::" This problem is more severe following mitral valve replacement than aortic valve replacement. Because of the high incidence of systemic thromboembolism and the complications of anticoagulant therapy, the porcine heterograft cardiac valve was introduced in an attempt to reduce the morbidity and mortality from these complications in our patients. In this report we review our clinical experience with the porcine heterograft cardiac valve and document the incidence and cause of thromboembolic episodes in our patients. The contributing factors to thromboembolism From the Division of Cardiothoracic Surgery, University of British Columbia. Vancouver, British Columbia, Canada. Supported in part by the British Columbia Heart Foundation. Received for publication Feb. 29, 1980. Accepted for publication Aug. 27, 1980. Address for reprints: W. R. Eric Jamieson. M.D., #410-750 West Broadway, Vancouver, British Columbia, Canada.
626
are identified and the role of anticoagulation with this prosthesis is discussed.
Patients and methods Between January, 1975, and August, 1978, 509 Carpentier-Edwards and Hancock heterograft valves were placed in 465 patients. The patients ranged in age from 11 to 85 years with a mean of 53.1 years. There were 240 men and 225 women in this series. One hundred ninety-six aortic and 216 mitral valve replacements were performed and 45 patients underwent multiple valve replacements. Twenty-one percent of the total had previous cardiac operations (45 valve replacements, 40 mitral commissurotomies, and 11 other procedures) . The indications for aortic valve replacement were congenital calcific aortic stenosis (155), rheumatic heart disease (53), failed prosthesis (14), collagen disease (10), and infective endocarditis (five). For mitral valve replacements, the indications were rheumatic heart disease (201), myxomatous degeneration (28), failed prosthesis (22), infective endocarditis (six), myocardial infarction (two), Marfan's syndrome (one), and atrial septal defect, primum type (one). Other cardiac operations were performed concomitantly with the valve replacements in 69 patients
0022-5223/81/040626+06$00.60/0 © 1981 The C. V. Mosby Co.
Volume 81
Embolic complications of porcine valves
Number 4
627
April,1981
(14.6%): concomitant aorta-coronary bypass in 54 patients (11.6%), resection of an ascending aortic aneurysm in six, and open commissurotomy of another valve in four. Prior to operation 16.5% were in Class IV, 60.5% in Class III, 22.6% in Class II, and 0.4% in Class I. Those in Class II were primarily patients with aortic valve disease. Of the total 509 valves inserted, 166 (32%) were Hancock bioprostheses and 343 (68%) were CarpentierEdwards bioprostheses. The current evaluation was obtained by direct contact with all patients, attending physicians, or both. The average duration of follow-up of surviving patients was 20.2 months (range 6 months to 44 months). The cumulative follow-up for all patients was 713 patient-years. In our center, anticoagulation takes one of three avenues at the discretion of the attending physicians: (I) anticoagulation of all patients with a mitral valve prosthesis who are in chronic atrial fibrillation until such time as they are hemodynamically stable in sinus rhythm; (2) anticoagulation of all patients with an aortic or mitral prosthesis for a period of three months, with continuation of anticoagulants for patients with mitral valve replacement who are in chronic atrial fibrillation until such time as they are hemodynamically stable and free of atrial arrhythmias; (3) anticoagulation for an indefinite period of all patients with mitral valve replacement. Patients who received anticoagulants for the first 3 months only were considered, for analysis, not to be receiving long-term anticoagulation. Results Early deaths and complications. There were 32 deaths in 465 patients (6.9%)-six following aortic valve replacement (3.1 %), 22 following mitral valve replacement (10.2%), and three following multiple valve replacements (6.7%). There were seven deaths (16%) in patients requiring reoperation for previous valve replacement and four deaths (9.5%) in the group of patients who had a previous mitral commissurotomy. Of the 32 operative and early postoperative deaths, over 50% were attributed to low output states. Of the remainder, the most frequent significant causes were hemorrhage, cerebrovascular accident, congestive heart failure, and arrhythmias. There were 44 significant nonfatal operative complications in this series. Cerebrovascular accidents occurred in 13 patients, intraoperatively in seven and postoperatively in six. Heart block occurred in 17 patients and necessitated insertion of permanent cardiac pacemakers. There were five instances of sternal dehis-
100~
.
90 I ~~
g>
'> .~
~
~
80 70
60
,, ~ . "=--~.__:--n-""338._~n-139 .... ..~ . •••-1-----·.·----·.. -n-37 -----.. - _--_ --. ..
-Total Aortic ••--- Mitral ----. Multiple
o
6
n-465"'\... n-196 ""n-216 ' . - -•.----. n-45
12
18
24
30
--.•
36
42
Months
Fig. 1. Patient survival up to 42 months, expressed as an actuarial curve for aortic, mitral, and multiple replacements and for all 465 patients.
% 100
80 60
40
20
o
II
III
Pre-op
IV
II
III
IV
Post-op
Fig. 2. Functional classification (New York Heart Association) of surviving patients.
cence, four of periprosthetic leak, two of myocardial infarction, and three of false aneurysm of cannulation sites. Late deaths and complications. There have been 43 late deaths in the series (9.9%). The late mortality was 5.4% per patient-year. The late mortality for aortic valve replacement was 3.3% per patient-year, for mitral replacement, 6.8% per patient-year, and for multiple replacement, 13.8% per patient-year. Patient survival is expressed actuarially in Fig. I. The most common cause of late death was congestive heart failure (13 cases). Other causes include infective endocarditis (six), cerebrovascular accident (five), and periprosthetic leak (two). The postoperative functional classification improved significantly in the majority of the surviving patients, as shown in Fig. 2. Actuarial survival is expressed for
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Jamieson et al.
Thoracic and Cardiovascular Surgery
% 100
90
e _ e II _ _ e~e-e-e-
IIn=61 III n 104
=
-m-e",-
e",-
e_
IV n
__..
= 29
_ e _ e _ e ""-, IV
80
"'
e_
I
6
I
I
12
18
24
30
36
42
Months
Fig. 3. Long-term survival versus preoperative New York Heart Association class for patients with aortic valve replacement. % 100
90
e~
II
.-.~
~.-.~ e~
III
80 70
<,
60 \ 50
e
e_e_e
"'-e_
= IV n =39
II n 31 IIIn=l46
e-,'e__ IV
Months
Fig. 4. Long-term survival versus preoperative New York Heart Association class for patients with mitral valve replacement. each preoperative functional class for both aortic and mitral valve replacements (Figs. 3 and 4). The significant late complications were infective endocarditis, periprosthetic leak, thrombosis of the prosthesis, and systemic emboli. Infective endocarditis occurred in 10 patients, six with aortic valve prostheses (2.0 episodes per 100 patient-years), four with mitral prostheses (0.6 episodes per 100 patient-years), and two with multiple prostheses. Six of the 10 died, including three of the five patients who underwent reoperation. A periprosthetic leak occurred in seven patients, four with aortic valve replacements (1.3 episodes per 100 patient-years), and three with multiple valve replacements, two involving a mitral and one involving an aortic prosthesis (5.0 episodes per 100 patient-years). Four patients required reoperation, two
of whom died. There was one case of thrombosis of the left atrium in a patient with a mitral prosthesis. This was fatal. The reoperation rate in the aortic position was 1.9/100 patient-years, and in the mitral position the incidence was zero. For patients with multiple valve replacements the rate of a valve re-replacement was 6.7/100 patient-years. Thromboembolism. There were 24 thromboembolic events. Six occurred during the early postoperative period and 18 occurred late (Table 1). Of the 18 late episodes, five occurred within the first 3 months and the remaining 13 were distributed throughout the rest of the observation period. There were four instances of late systemic emboli after aortic valve replacement, 11 after mitral replacement, and three after multiple replacements. Five events were fatal and three produced significant permanent sequelae. Of the six early embolic events, two followed aortic valve replacement and four, mitral replacement. There were no deaths. All patients were in chronic atrial fibrillation, except for one who had aortic and one, mitral replacement. The events occurred between the first and fourteenth postoperative days. Anticoagulation had been commenced in only one patient, but therapeutic range had not been attained at the time of the cerebrovascular accident. Of the 18 late embolic events, only four occurred in patients with an aortic valve prosthesis. In each case, the events were limited to transient visual scotomata only, with no permanent deficit. Eleven episodes followed mitral valve replacement, and three followed multiple valve replacement. Two of these 14 were peripheral and 12 affected the central nervous system. Most of these produced a major deficit, most commonly a hemiparesis. Five were fatal and three left a permanent deficit. Thirteen of these 14 patients were in chronic atrial fibrillation, and only three were receiving anticoagulants at the time of embolization. The rate of embolic events was 1.32/100 patient-years for aortic valve prostheses, 3.27II 00 patient-years for mitral prostheses, and 4.91/100 patient-years for multiple prostheses. There were no deaths related to embolization in aortic valve replacement. The fatality rate for mitral valve replacement related to thromboembolism was 1.2/100 patient-years and for multiple valve replacement, 1.67/100 patient-years. For statistical analysis, embolic events occurring in the first 12 months of all patients followed for 12 months or longer were examined. Of 171 patients with aortic valve prostheses, two had clinically insignificant emboli. Of 175 patients with mitral prostheses, nine experienced an embolic event; eight of these events
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were clinically significant and caused three deaths. There was no significant difference (p = 0.08) in the total number of emboli between patients with aortic and those with mitral prostheses, but there was a statistically significant difference (p < 0.01) when the number of clinically significant events was compared. No clear relationship could be found between the occurrence of previous cerebrovascular accidents and postoperative emboli-one early and one late embolic event in 25 patients who had experienced systemic emboli prior to valve replacement. Only 32% of these patients were maintained on anticoagulant therapy. Long-term anticoagulation was employed in 10% of patients with aortic prostheses and 45% of patients with mitral or multiple prostheses. There were 13 episodes of significant bleeding related to anticoagulants, six necessitating hospitalization. Without anticoagulation the incidence of systemic emboli in aortic valve replacement was I. I7/l 00 patient-years (three events), compared to 4.30/100 patient-years with anticoagulation (one event). With anticoagulation the incidence of emboli in mitral valve replacement was 2.09/100 patient-years (three events); without anticoagulation, it was 5.08/100 patient-years (eight events). In multiple valve replacements there were no emboli when anticoagulants were utilized, but the incidence without anticoagulation was 8.9l!100 patient-years (three events). No statistically significant difference in embolism rates was found between those taking anticoagulants and those not taking anticoagulants in the aortic, mitral, or multiple valve replacement groups. However, except for the first 100 patients, in whom no anticoagulants were utilized, all patients with known risk factors such as atrial fibrillation were placed on a long-term regimen of anticoagulants. Ninety-five percent of patients in this series are free of embolization at 36 months (Fig. 5). Discussion
Several authors have noted that the risk of thromboembolic events is lower in patients with porcine xenograft valve prostheses than in patients with mechanical valve prostheses.': 7-14 In their early experience, most authors used no anticoagulants. However, with time, embolic events was noted, particularly in patients with mitral prostheses who continued to have chronic atrial fibrillation or who had a dilated left atrium. 7-11. 15-19 In our early experience, during which we used no anticoagulants, we l 8 • 20 noted this same association of emboli with left atrial dilatation or fibrillation.
E
n-330
100~1:.: .: : : : : :t: :
_.._
o 90
_
n-123 ::::.~:r::.::..
I
n-30
~
:::::
~
- - Total n-465 ..•....·.... Aorticn-196 .----. Mitral n-216
~ w
'0
CIl
e
u..
80
...,
.
70
~
6
12
18 24 Months
30
36
42
Fig. 5. Actuarial probability of remaining free of systemic embolism for patients with aortic prostheses, mitral prostheses, and for the total patient group (465 patients).
Table I. Time interval of thromboembolism Total
Time interval
2
4 4 3 2 2
0 0 0 2 I
6 5 4 4 5
6
15
3
24
<2 wk 2 wk-J mo 3·6 rno 6·12 rno >12 mo
I I 0
Totals
2
In patients with rheumatic heart disease who had had no cardiac operation, Szekely" reported the risk of embolic events to be 0.67/100 patient-years for those in sinus rhythm compared to 5.26/100 patient-years for those in atrial fibrillation. This report as well as one by Fleming and Bailey" showed a reduction of this risk by use of well-controlled anticoagulants. We believe, therefore, that anticoagulants will benefit patients who have an increased risk for thromboembolic events. Our present experience showed a reduced incidence of embolic events among patients with mitral or multiple prostheses who were taking anticoagulants. Although this difference did not achieve statistical significance, we consider it indicative of a beneficial effect, since the majority of "high-risk" patients were in the anticoagulant group. Most recent reports'? 19. 20. 23-27 agree that patients with mitral prostheses who have a dilated left atrium or atrial fibrillation should receive anticoagulants. The experience of Davila, 28 Cohn, 10 and their colleagues, as well as our own experience, indicates that anticoagulation can be virtually eliminated in aortic valve replacements with the porcine xenograft. Cohn's group has reported a single major embolic event in a patient who remained in atrial fibrillation following aortic valve replacement, and they recommend anticoagulation for such patients. It has been reported that the majority of embolic
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630 Jamieson et al.
Thoracic and Cardiovascular Surgery
Table II. Comparison of embolism rates for patients with mitral porcine bioprostheses reported in the literature Institution
Valve
Years of valve replacement
Emboli per 100 patient-years
University of Kansas (1976)9 Stanford University (1977)' Henry Ford Hospital (1978)2" Peter Bent Brigham (1979)31
Hancock Hancock Hancock Hancock
1970-1975 1971-1975 1971-1975 1972-1977
104 243 125 131
4.8 5.2 2.87 3.8
Pacific Medical Center (1978)24 Stanford University (1979)30 University of British Columbia (1979)
Hancock Hancock Hancock and Carpentier-Edwards
1974-1977 1971-1978 1975-1978
133 561 216
5.3 3.1 3.27
Long-term anticoagulation
If left atrial thrombus 15% of patients 75% of patients If atrial fibrillation or large left atrium present Various 3 I% of patients 45% of mitral valve replacement and multiple replacements
Table III. Comparison of embolism rates for patients with aortic porcine bioprostheses reported in the literature Institution
Palo Alto, Calif. (1976)15 Henry Ford Hospital (1978)2" Harvard Medical Hospital, Peter Bent Brigham (1979)31 Stanford University (I 979):J0 University of British Columbia
Valve
Years of valve replacement
Emboli per 100 patient-years
Long-term anticoagulation
Hancock Hancock Hancock
1971-1974 1971-1975 1972-1975
75 60 71
2.84 1.28 1.02
25% (4 to 6 wk) 20% (3 to 6 mol None
Hancock Hancock and Carpeatier-Edwards
1971-1978 1975-1978
557 196
2.1 1.32
10% 10%
events occur in the first 3 months following operation,": 27-29 and the use of anticoagulants in all patients until the Teflon ring of the prosthesis has been covered with endothelium has been recommended. In our own experience, however, 55% of thromboembolic events occurred after the first 3 months, although only a minority of patients were routinely prescribed anticoagulants for the first 3 months. Our experience with thromboembolism in patients with the porcine heterograft valve is similar to that documented in the literature. The experience with thromboembolism in patients with mitral bioprostheses is summarized in Table II. The incidence ranges between 2.87 and 5.3 episodes per 100 patient-years, depending upon the number of patients on anticoagulant coverage. Most centers have developed indications for anticoagulation as they have gained experience. Table III documents the embolism experience in the aortic position, range 1.02 to 2.84 episodes per 100 patientyears. The majority of episodes in these patients are transient and do not cause permanent neurologic sequelae. The actuarial probability of aortic replacements remaining free of thromboembolism is in the range of 95% to 96% for the majority of patients at 3 to 4 years.!" 28, 30 For mitral replacements the range is
77% to 92% between 5 and 6'4 years, and for multiple replacements, 96% at 4 years. to. 28. 30 Effective control of thromboembolism has contributed to the excellent long-term survival reported with the porcine bioprosthesis. The actuarial survival of several clinical series is as high as 91 % at 3 years for aortic replacements and 86.8% at 5 1/ 2 years for mitral replacements. 7. 10. 15. 27. :30-:32 Thromboembolism is a complication of the cardiac disease and not necessarily of the heterograft prosthesis. For the risk of thromboembolism to be reduced, anticoagulation should be utilized when factors contributing toward vascular stasis are evident. Stringent observation of continuous anticoagulant management is necessary for patients with a mitral prosthesis who remain in atrial fibrillation. No anticoagulants appear to be necessary for patients who are hemodynamically stable in sinus rhythm. REFERENCES Oyer PE, Stinson EB, Griepp RB, Shumway NE: Valve replacement with the Starr-Edwards and Hancock prostheses. Comparative analysis of late morbidity and mortality. Ann Surg 186:301-309, 1977 2 Roberts We: Prosthetic heart valves. Which ones and why. Hosp Pract 13:63-69, 1978
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3 Moggio RA, Hammond GL, Stansel HC Jr, Glenn WWL: Incidence of emboli with cloth-covered Starr-Edwards valve without anticoagulation and with varying forms of anticoagulation. J THORAC CARDIOVASC SURG 75:296299, 1978 4 Limet R, Lepage G, Grondin CM: Thromboembolic complications with the cloth-covered Starr-Edwards aortic prosthesis in patients not receiving anticoagulants. Ann Thorac Surg 23:529-533, 1977 5 Tandon AP, Sengupta SM, Lukacs L, Ionescu MI: Longterm clinical and hemodynamic evaluation of the IonescuShiley pericardial xenograft and the Braunwald-Cutter and Bjork-Shiley prostheses in the mitral position. J THORAC CARDIOVASC SURG 76:763-770, 1978 6 Gray LA, Fulton RL, Srivastava TN, Flowers NC: Surgical treatment of thrombosed Bjork-Shiley aortic valve prosthesis. J THORAC CARDIOVASC SURG 71:429-431, 1976 7 Stinson EB, Griepp RB, Oyer PE, Shumway NE: Longterm experience with porcine aortic valve xenografts. J THORAC CARDIOVASC SURG 73:54-63, 1977 8 Mclntosh CL, Michaelis LL, Morrow AG, ltscoitz SB, Redwood DR, Epstein SE: Atrioventricular valve replacement with the Hancock porcine xenograft. A five year clinical experience. Surgery 78:768-775, 1975 9 Hannah HIll, Reis RL: Current status of porcine heterograft prosthesis. A five year appraisal. Circulation 54: Suppl 3:27-31, 1976 10 Cohn LH, Sanders JH, Collins 11: Aortic valve replacement with the Hancock porcine xenograft. Ann Thorac Surg 22:221-227, 1976 II Stinson EB, Griepp RB, Shumway NE: Clinical experience with a porcine aortic valve xenograft for mitral valve replacement. Ann Thorac Surg 18:391-401, 1974 12 Cevese PG: Long-term results of 212 xenograft valve replacements. J Cardiovasc Surg 16:639-642, 1975 13 Struck E, Meisner H, Schmidt-Habelmann P, Sebening F: Cardiac valve replacement with Hancock and CarpentierEdwards bioprosthesis (abstr). Symposium on Bioprosthetic Cardiac Valves, Munich, 1979 14 Jouven JC, Roux 11, Rapuzzi A, Talmoudi T, Antypas G, Malmjac C, Houel J: Early thromboembolic complications with porcine xenografts (abstr). Symposium on Bioprosthetic Cardiac Valves, Munich, 1979 15 Pipkin RD, Buch WS, Fogarty TS: Evaluation of aortic valve replacement with a porcine xenograft without longterm anticoagulation. J THORAC CARDtOVASC SURG 71: 179-186, 1976 16 Zuhdi N, Hawley W, Voehl V, Hancock W, Carey J, Greer A: Porcine aortic valves as replacements for human heart valves. Ann Thorac Surg 17:479-491, 1974 17 Cohn LH, Lambert 11, Castaneda AR, Collins 11: Cardiac valve replacement with the stabilized glutaraldehyde porcine aortic valve. Indications, operative results, and follow-up. Chest 68:162-165, 1975 18 Jamieson WRE, Munro AI, Allen P: Study of porcine xenograft replacement without long-term anticoagulants (abstr). Ann R Coli Phys Surg Can 10:36, 1977
19 Spampinato N, Gagliardi C, de Amicis V, Stassano P, Covino E: Incidence of thromboembolism on bioprosthetic cardiac valves not treated with anticoagulants (abstr). Symposium on Bioprosthetic Cardiac Valves, Munich, 1979 20 Jamieson WRE, Munro AI, Miyagishima RT, Allen P: Clinical evaluation of porcine heterograft cardiac valves in 200 patients. Can J Surg 21: 133-135, 1978 21 Szekely P: Systemic embolism and anticoagulant prophylaxis in rheumatic heart disease. Br Med J 11: 1209-1213, 1964 22 Fleming HA, Bailey SM: Mitral valve disease, systemic embolism and anticoagulants. Postgrad Med J 47:599604, 1971 23 Cohn LH, Sanders JH, Collins JJ: Actuarial comparison of Hancock porcine and prosthetic disk valves for isolated mitral valve replacement. Circulation 54:Suppl 3:60-63, 1976 24 Hetzer R, Hill JD, Kerth WJ, Ansbro J, Adappa MG, Rodvien R, Kamm B, Gerbode F: Thromboembolic complications after mitral valve replacement with Hancock xenograft. J THORAC CARDIOVASC SURG 75:651658, 1978 25 Horowitz MS, Goodman DJ, Fogarty TJ, Harrison DC: Mitral valve replacement with the glutaraldehyde-preserved porcine heterograft. Clinical, hemodynamic, and pathological correlations. J THORAC CARDIOVASC SURG 67:885-895, 1974 26 Edmiston WA, Harrison EC, Duick GF, Parnassus W, Lau FYK: Thromboembolism in mitral porcine valve recipients. Am J Cardiol 41:508-511, 1978 27 Cevese PG, Gallucci V, Morea M, Volta SD, Fasoli G, Casarotto D: Heart valve replacement with the Hancock bioprosthesis. Analysis of long-term results. Circulation 56:Suppl 3: 111-116, 1977 28 Davila JC, Magilligan OJ, Lewis JW: Is the Hancock porcine valve the best cardiac valve substitute today? Ann Thorac Surg 26:303-316, 1978 29 Poulain H, Bloch G, Cachera JP, Journet M, Loisance D, Menu P, Vouhe P, Aubry PH, Juvin AM, Galey 11: A three year experiment with bioprosthetic cardiac valves (abstr). Symposium on Bioprosthetic Cardiac Valves, Munich, 1979 30 Oyer PE, Stinson EB, Reitz BA, Miller DC, Rossiter S, Shumway NE: Long-term evaluation of porcine xenograft bioprosthesis. J THORAC CARDIOVASC SURG 78:343-350, 1979 31 Cohn LH, Collins JJ: The glutaraldehyde-stabilized porcine xenograft valve, Tissue Heart Valves, Chap 5, Toronto, 1979, Butterworth & Co., Ltd. 32 Jones EL, Craver JM, Morris DC, King SB III, Douglas JS Jr, Franch RH, Hatcher CR Jr, Morgan EA: Hemodynamic and clinical evaluation of the Hancock bioprosthesis for aortic valve replacement (with emphasis on management of the small aortic root). J THORAC CARDIOVASC SURG 75:300-308, 1978