Ann Thorac Surg 2001;71:S278-S281
© 2001 The Society of Thoracic Surgeons
Bioprosthetic valves and conduits: new developments
Medtronic intact porcine bioprosthesis experience to twelve years
W.R. Eric Jamieson, MDa,
Michel D. Lemieux, MDb,
John A. Sullivan, MDc,
A. Ian Munro, MDa,
Jacques Métras, MDb,
Paul C. Cartier, MD*,b
a Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
b Department of Surgery, Laval University, Quebec, Quebec, Canada
c Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada
Address reprint requests to Dr Jamieson, St. Paul’s Hospital, 331-332 Burrard Bldg, 1081 Burrard St, Vancouver, BC, V6Z 1Y6, Canada
e-mail: wrej{at}interchange.ubc.ca
Presented at the VIII International Symposium on Cardiac Bioprostheses, Cancun, Mexico, Nov 3–5, 2000.
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Abstract
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Background. The Medtronic Intact porcine bioprosthesis was further evaluated to determine the influence of zero-pressure glutaraldehyde fixation on structural valve deterioration (SVD).
Methods. From 1986 through 1996, at three Canadian centers, 1,272 patients had 1,296 procedures: 836 aortic valve replacement (AVR), 332 mitral valve replacement (MVR), 14 tricuspid valve replacement, 3 pulmonary valve replacement, and 111 multiple valve replacements. The mean age of the patient population was 67 years (range 9 to 91 years). The total follow-up was 8,011 patient-years (mean 6.2 years).
Results. The late mortality (overall) was 4.8% and 6.7% per patient-year for AVR with or without concomitant procedures, respectively; and 4.7% and 10.4% per patient-year for MVR, respectively. There were 51 cases of SVD (AVR 22 of 836; MVR 23 of 332; pulmonary valve replacement 1 of 3; and multiple valve replacement 5 of 111). The actuarial freedom from SVD at 12 years for AVR was 94.3% ± 3.3% for patients aged 61 to 70 years and 97.7% ± 1.1% for those more than 70 years; for MVR actuarial freedom from SVD at 12 years was 93.7% ± 3.9% for patients more than 70 years. The actual freedom at 12 years from SVD for AVR was 92.4% ± 3.1% for patients aged 51 to 60 years, 96.1% ± 2.1% for those 61 to 70 years, and 98.4% ± 0.7% for those older than 70 years; for MVR actual freedom from SVD at 12 years was 89.6% ± 3.2% for patients 61 to 70 years and 96.6% ± 3.4% for those more than 70 years.
Conclusions. The Medtronic Intact porcine bioprosthesis, formulated with tissue preservation at zero-pressure fixation, has encouraging freedom from structural failure.
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Introduction
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The Canadian experience with the Medtronic Intact porcine bioprosthesis was reported previously in 1995 and 1998 [1, 2]. This prosthesis has not been implanted in Canada since 1996. We curtailed use of the Medtronic Intact prosthesis because of the compromised hemodynamics in the aortic position resulting from its intraannular configuration and the high stent posts in the mitral position [3]. (The first-generation Hancock standard and the Carpentier–Edwards standard are also intraannular porcine bioprostheses.) Supraannular porcine bioprostheses were then formulated to improve hemodynamic performance. These prostheses include the Carpentier–Edwards supraannular, Hancock II, St. Jude Medical Biocor, and Medtronic Mosaic.
Since 1994, several centers in Canada have participated in the United States Food and Drug Administration investigational trial of the third-generation Medtronic Mosaic porcine bioprosthesis [4], which was approved by the US Food and Drug Administration in 2000. The Mosaic and Intact porcine bioprostheses both have the porcine tissue fixed with glutaraldehyde under pressure-free conditions, although different technologies are used. Because the experience with the Medtronic Intact may provide some indication of the intermediate and long-term durability of the Medtronic Mosaic porcine bioprosthesis, the Canadian experience with the Medtronic Intact porcine bioprosthesis has been followed continually to determine the influence of pressure-free glutaraldehyde fixation on the incidence of structural valve deterioration (SVD) [1, 2].
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Patients and methods
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The Medtronic Intact porcine bioprosthesis was implanted in 1,272 patients (1,296 procedures) from 1986 through 1996, at three centers in Canada (Quebec, 654 [51.4%]; Vancouver, 356 [28%]; and Halifax, 262 [20.6%]). There were 527 women (41.4%) and 745 men (58.6%). The mean age was 67 years (range 9 to 91 years). There were 836 aortic valve replacements (AVR) (64.5%), 333 mitral valve replacements (MVR) (25.7%), 14 tricuspid valve replacements (1.1%), 3 pulmonary valve replacements (0.27%), and 110 multiple valve replacements (8.5%). The patient distribution within age groups was as follows: 20 years or younger, n = 6 (0.5%); 21 to 40 years, n = 35 (2.8%); 41 to 50 years, n = 54 (4.2%); 51 to 60 years n = 163 (12.8%); 61 to 70 years, n = 464 (36.5%); and older than 70 years, n = 550 (43.2%). The age groups more than 20 years of age were analyzed in the evaluation.
The total cumulative follow-up was 8,011.3 patient-years (mean 6.2 years, range 0 to 13.4 years). The late follow-up was 7,911.1 patient-years, follow-up more than 30 days. The total AVR follow-up was 5,208.1 patient-years (late, 5,142.5 patient-years) and the total MVR follow-up was 2,168.9 patient-years (late, 2,143.6 patient-years). The total follow-up was 94.5% complete during the closing intervals in late 1999 and early 2000 at the three universities.
The "Guidelines for reporting morbidity and mortality after cardiac valvular operations" were used for definitions of valve-related complications [5]. Structural valve deterioration was diagnosed at reoperation, echocardiography when performed for clinical indications, and autopsy. Survival analysis using the Kaplan–Meier method was used to estimate survival and the freedom from valve-related adverse events. Greenwood’s formula was used for the calculation of the standard errors of these estimates.
Cox regression models were used to assess the possible association of age at implant and concomitant procedures at implant with "time at first event" for valve-related morbidity and time to valve-related death. The relative risks (RR) and their 95% confidence limits (CL) were provided to summarize the effects of age at implant and concomitant procedures at implant.
Cumulative incidence of SVD was calculated using a method developed by Gaynor and colleagues [6]. The cumulative incidence has also been denoted in the literature as the "actual" incidence. In 1994, Grunkemeier and colleagues [7] introduced the "actual analysis" or cumulative incidence methodology to determine the percentage of patients who would experience valve-related complications during their lifetime. The reporting of valve-related complications that are often nonfatal by "actuarial analysis" means describing patient-risk, providing that patients were experiencing immortality. The standard error of the cumulative incidence is based on Greenwood’s formula. The actual freedom and its standard error are provided, as well as actuarial freedom from SVD for AVR and MVR, overall, and by the specific age groups [7].
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Results
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The early mortality was 7.2% (91 of 1,272 patients). The early mortality with concomitant procedures was 9.8% (51 of 521) and without concomitant procedures was 5.3% (40 of 751). The early mortality for AVR was 5.5% (45 of 820), with concomitant procedures it was 6.7% (24 of 358), and without concomitant procedures it was 4.5% (21 of 462). For MVR the early mortality was 7.9% (26 of 329), with concomitant procedures it was 14.5% (17 of 117) and without concomitant procedures it was 4.2% (9 of 212).
Survival at 12 years associated with AVR was 47.9% ± 4.2%; and for MVR it was 30.6% ± 9.6%. The survival by age groups for both AVR and MVR are detailed in Figure 1.
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Fig 1. Patient survival by age groups for aortic valve replacements (AVR) and mitral valve replacements (MVR).
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The overall valve-related complications for AVR and for MVR are detailed in Table 1. The table details the overall events for endocarditis, SVD, nonstructural dysfunction, valve-related reoperation, and valve-related mortality.
There were a total of 51 SVD events after the 1,296 procedures. The number of cases of SVD by position were the following: AVR 22 of 836; MVR 23 of 332; pulmonary valve replacements 1 of 3; and multiple valve replacements 5 of 111.
The adverse event rates (predominantly thromboembolism and hemorrhage) and mortality are detailed in Table 1 for AVR and MVR. The major overall thromboembolism rate for AVR was 1.3% per patient-year and for MVR was 1.2% per patient-year. The hemorrhage rates were 0.8% per patient-year and 1.6% per patient-year, respectively, for AVR and MVR.
The predictors of performance for valve-related complications (thromboembolism (TE) and SVD) and composites of complications (reoperation and valve-related mortality) were determined. The significant predictors of performance for AVR were as follows: major thromboembolism (age RR 1.04, CL 1.01 to 1.07, p = 0.01), SVD (age RR 0.96, CL 0.93 to 0.99, p < 0.01) and valve-related reoperation (age RR 0.96, CL 0.94 to 0.98, p < 0.01). Concomitant procedure(s) were not predictive. Neither were predictive of valve-related mortality.
The significant predictor of performance for MVR was as follows: SVD (age RR 0.96, CL 0.93 to 0.99, p < 0.01), reoperation (age RR 0.94, CL 0.91 to 0.97, p < 0.01), and valve-related mortality (age RR 1.07, CL 1.02 to 1.12, p < 0.01). Concomitant procedure(s) were not predictive. Neither were predictive of major thromboembolism.
The actual and actuarial freedom from SVD by age groups for both AVR and MVR are illustrated in Figures 2 and 3. The actuarial freedom at 12 years from SVD for AVR was 90.5% ± 3.8% for patients aged 51 to 60 years, 94.3% ± 3.3% for 61 to 70 years, and 97.7% ± 1.1% for more than 70 years; and for MVR was 93.7% ± 3.9% for age group more than 70 years. The actual freedom at 12 years from SVD for AVR was 92.4% ± 3.1% for patients aged 51 to 60 years, 96.1% ± 2.1% for 61 to 70 years, and 98.4% ± 0.7% for more than 70 years; and for MVR was 89.6% ± 3.2% for 61 to 70 years and 96.6% ± 3.4% for more than 70 years.
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Fig 2. Freedom from structural valve deterioration (actuarial and actual) for aortic valve replacement.
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Fig 3. Freedom from structural valve deterioration (actuarial and actual) for mitral valve replacement.
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The actuarial freedom at 12 years from SVD, overall, was 92.3% ± 2.2% for AVR and 77.9% ± 5.5% for MVR. The actual freedom at 12 years from SVD, overall, was 95.1% ± 1.3% for AVR and 87.1% ± 3.0% for MVR.
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Comment
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The second-generation Medtronic Intact porcine bioprosthesis was introduced in 1984 with extended tissue preservation technology to address the SVD of biological valvular substitutes. The Medtronic Intact prosthesis has an intraannular configuration similar to that of the first-generation porcine bioprostheses, formulated with an acetyl-copolymer (Celcon) stent with flexible posts. The porcine tissue is fixed with glutaraldehyde in pressure-free conditions and treated with the calcium mitigation agent toluidine blue.
The three-center Canadian series of the Medtronic Intact porcine bioprosthesis was previously reported in 1995 and 1998 [1, 2]. The Medtronic Intact has not been used since the early to mid-1990s in Canada, but interest remains in the influence of zero-pressure glutaraldehyde preservation of the porcine tissue. The other second-generation porcine bioprostheses were formulated with less than zero-pressure fixation. The Carpentier–Edwards supraannular porcine prosthesis has the porcine tissue fixed with glutaraldehyde at 2 mm Hg and treated with the calcium mitigation agent polysorbate 80. The Hancock II prosthesis includes tissue fixed with glutaraldehyde at low pressure for approximately 30 minutes and then high pressure for the remainder of the fixation period. The prosthesis is treated with the surfactant agent sodium dodecyl sulfate. The zero-pressure fixed Medtronic Intact is also of interest to Canadian centers because of the participation of several centers in investigations into the Medtronic Mosaic valve, which has the tissue preserved with an alternative zero-pressure differential technique.
The 1995 report by Lemieux and colleagues [1] on the Canadian three-center experience documented freedom from SVD at 7 years of 97% for both AVR and MVR. The 1998 publication reported an actuarial freedom from SVD at 8 years of 93% for AVR and 91% for MVR [2].
The current study has revealed extended freedom from SVD to 12 years. For AVR the actuarial freedom was 92% and for MVR was 78%, whereas the actual freedom for AVR was 95% and for MVR 87%.
Experience with the Medtronic Intact prosthesis has been reported on several occasions from Green Lane Hospital, Auckland, New Zealand [8–10]. Barratt-Boyes and colleagues [11] reported in 1998 the 10-year freedom from SVD for AVR was 81%, with the 10-year freedom for patients older than 40 years of age being 92% and for those older than 60 years, 100%. In the mitral position the freedom from SVD was 65% at 8 years with no significant difference in age groups. Of the 26 cases of SVD, Barratt-Boyes and colleagues [10] documented six cases of commissural dehiscence (stent-post dehiscence): five mitral and one aortic prostheses.
In the 1998 publication Jamieson and colleagues [2] documented three cases of commissural dehiscence, all with mitral prostheses, in the overall 36 cases of SVD (AVR, 16; MVR, 15; tricuspid, 2; and multiple, 3). The current extended experience revealed 51 cases of SVD (AVR, 22; MVR, 23). The pathologic and operative reports were not reviewed on this occasion to determine if there were more cases of commissural dehiscence.
The literature has reported freedom from SVD with other second-generation porcine bioprostheses. Jamieson and coinvestigators [11] reported on the Carpentier–Edwards supraannular porcine bioprosthesis in 1998, revealing AVR freedom at 12 years of 93% for 61 to 70 years and 95% for more than 70 years, and MVR freedom at 12 years of 66% for more than 70 years. David and colleagues [12, 13], reporting on the Hancock II porcine bioprosthesis, identified actuarial freedom at 15 years from SVD of 81% for aortic prostheses and 66% for mitral prostheses, and actual freedom of 90% and 83%, respectively. For AVR the actual freedom from SVD was 100% for patients 65 years or older and 76% for those less than 65 years; for MVR it was 89% and 76%, respectively. Mykén and coworkers [14] reported on the St. Jude Medical Biocor porcine bioprosthesis, with near total freedom of SVD identified at reoperation for AVR in patients more than 70 years, and for MVR in patients more than 60 years.
In the present study, the actual freedom from or cumulative incidence of SVD for the Medtronic Intact porcine bioprosthesis at 12 years was 95% for AVR and 87% for MVR. The actual freedom from SVD at 12 years was 96% in the AVR age group 61 to 70 years and 98% for the group older than 70 years; in the MVR age group older than 70 years the actual freedom was 97%.
The Medtronic Intact porcine bioprosthesis experience has revealed excellent freedom from structural failure for AVR in patients older than 50 years and for MVR in patients older than 60 years. The influence of pressure-free tissue preservation with glutaraldehyde may be the major determinant factor.
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Acknowledgments
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We thank the research coordinators at all three Canadian centers, and Judy Maxwell for her assistance in the preparation of the manuscript.
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Footnotes
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* Doctor Paul C. Cartier passed away on January 2, 2001. 
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References
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Abstract
Introduction
