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J Thorac Cardiovasc Surg 2007;133:614-622
© 2007 The American Association for Thoracic Surgery
Surgery for Acquired Cardiovascular Disease |
Bristol Heart Institute, Bristol Royal Infirmary, Bristol, United Kingdom.
Read at the Eighty-sixth Annual Meeting of The American Association for Thoracic Surgery, Philadelphia, Pa, April 29-May 3, 2006.
Received for publication May 22, 2006; revisions received June 22, 2006; accepted for publication August 25, 2006. * Reprint requests: Gianni D. Angelini, MD, MCh, FRCS, Bristol Heart Institute, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW. (Email: g.d.angelini{at}bristol.ac.uk).
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Abstract |
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Methods: Between 1992 and 1996, 485 patients undergoing mechanical heart valve replacement were randomized to receive CarboMedics (n = 234) or St. Jude Medical (n = 251) prostheses for aortic (n = 288), mitral (n = 160), or double (n = 37) valve replacements. Patients were followed annually to the end of 2004.
Results: Demographic, preoperative, and operative characteristics were similar between the 2 groups. The median follow-up was 10 years in both groups (CarboMedics 99% complete, St. Jude Medical 98% complete; 3879 patient-years of follow-up). Overall, 165 patients died, 25 of valve-related causes. Ten-year survivals were 66.4% (95% confidence interval: 59.6%-72.3%) and 64.7% (95% confidence interval: 58.0%-70.6%) in the CarboMedics and St. Jude Medical groups, respectively (P = .94). Freedom at 10 years from valve-related mortality was 95.0% (95% confidence interval: 90.8%-97.3%) in the CarboMedics group and 93.0% (95% confidence interval: 88.3%-95.9%) in the St. Jude Medical group. During follow-up, 34 patients had a thromboembolic event, 79 patients had at least 1 bleeding event, and 14 patients required reoperation. There were no significant differences between the groups with respect to freedom from complications (P 
.12); freedom from thromboembolism at 10 years (CarboMedics: 91.5%, 95% confidence interval: 86.5%-94.7%; St. Jude Medical: 92.2%, 95% confidence interval: 87.5%-95.2%); freedom from bleeding events (CarboMedics: 83.0%, 95% confidence interval: 76.6%-87.8%; St. Jude Medical: 77.5%, 95% confidence interval: 71.1%-82.7%); and freedom from death or valve-related complication (CarboMedics: 51.6%, 95% confidence interval: 44.7%-58.0%; St. Jude Medical: 46.2%, 95% confidence interval: 39.7%-52.4%). Linearized rates per patient-year were 1.1% in the CarboMedics group and 0.8% in the St. Jude Medical group for thromboembolism; 2.3% in the CarboMedics group and 3.2% in the St. Jude Medical group for bleeding events; and 0.72% in the CarboMedics group and 0.47% in the St. Jude Medical group for nonstructural valve dysfunction. International normalized ratio values were similar between the 2 groups throughout the study period.
Conclusion: At 10 years, the clinical outcome was similar with respect to these 2 mechanical bileaflet prostheses.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduced in 1977, the St. Jude Medical (SJM) (St. Jude Medical Inc, St. Paul, Minn) mechanical bileaflet prosthesis was the first bileaflet pyrolytic carbon prosthesis. The CarboMedics (CM) (CarboMedics Inc., Austin, Tex) mechanical bileaflet prosthesis was introduced as an investigational prosthesis in 1986 and received Food and Drug Administration approval in 1993. Both prostheses have been widely used, and there are extensive observational studies describing their clinical performance.1-4 There are differences in the design of the 2 prostheses,5 which could conceivably confer differences in thromboembolic risk and other aspects of clinical performance. However, Akins6 concluded that rates for valve-related complications were essentially comparable between CM and SJM valves, although data for the CM valve from a smaller study population did show a slightly higher rate of thromboembolic complications in the mitral position, despite adequate anticoagulation. This finding has been supported by others.7,8 In contrast, Jamieson and colleagues7,9 found no significant differences in thromboembolic tendency between the CM and SJM prostheses in isolated mitral valve replacement (MVR) or double valve replacement (DVR). A recent meta-analysis of these 2 prostheses found comparable thromboembolism and bleeding rates, but differing thrombosis rates (lower with the CM aortic valve and higher with the CM mitral valve compared with the corresponding SJM valves). However, whether the differences observed were of any clinical importance was doubtful.10 Long-term randomized studies to evaluate experiences with these prostheses have been lacking to date, although an interim analysis of this study at 5 years has been presented.11 Although some argue that randomized controlled trials are not essential in evaluating prostheses, the conflicting and occasionally worrisome outcomes reported in observational studies make randomized controlled studies an important contribution to the assessment of the clinical performance of particular valve prostheses.
This is the second and final report of a randomized controlled trial comparing the clinical outcome of patients who received either CM or SJM standard mechanical heart valves implanted at a single institution with a median follow-up of 10 years.
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Materials and Methods |
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Surgery and Postoperative Management
All operations were performed through a median sternotomy with cardiopulmonary bypass and mild systemic hypothermia (28°C-32°C). Myocardial protection consisted of intermittent antegrade ± retrograde cold (6°C) St. Thomas crystalloid or blood cardioplegia. The prostheses used in both the CM and SJM groups were of standard design. Interrupted or continuous suturing technique was used at the discretion of the operating surgeon. All patients received postoperative subcutaneous heparin until the international normalized ratio (INR) was greater than 2 with warfarin administration. On discharge, anticoagulation was managed in the community by general medical practitioners or at local hospitals according to the British Society of Haematology guidelines.12 For the initial part of the study, these guidelines recommended a target INR of 3.0 to 4.5 for all patients with mechanical heart valves. Subsequent revisions of this advice have acknowledged that modern bileaflet prostheses may be anticoagulated at a lower level.13
Clinical and Study Follow-up
Patients were seen at 6 weeks for a clinical review and thereafter referred to their cardiologist for annual review. Study follow-up was primarily by postal questionnaire sent to each patient on the anniversary of his or her operation. Patients were contacted directly only when clarification of details was necessary. The family practitioner and/or hospital cardiologist was contacted, and hospital health records were used where appropriate to clarify clinical events.
When a death occurred, the postmortem report was requested. The death registry of the UK Office of National Statistics was used to provide details of deaths that were otherwise unobtainable.
Adverse events, when reported, were categorized by a clinician blinded to valve type. Anticoagulation data (last 10 INR values) and drug dosages were obtained from the anticoagulant history booklet carried by the patient and filled out by the physician responsible for the patient’s care. Data collection was terminated at the end of December 2004, the planned end of the study.
Statistical Analysis and Data Reporting
The original "Guidelines for Reporting Morbidity and Mortality after a Cardiac Valvular Operation"14 and its subsequent revision15 were followed for definitions of valve-related complications, analysis, and presentation of data and results. The data were collected using a standard proforma and stored in a computerized database. Continuous data are presented as a mean and standard deviation or median and interquartile range as appropriate, and categoric data are presented as a number and percentage. Event-free survival was estimated using the Kaplan–Meier method and compared across CM and SJM groups using the Wilcoxon test. Mortality estimates, including linearized rates of percentage events per patient-year, include in-hospital deaths. Age and gender standardized mortality ratios (SMRs) were calculated using UK Office of National Statistics mortality rates for England and Wales in 2001. Multiple logistic regression, adjusting for baseline New York Heart Association (NYHA), valve position, and follow-up year, was used to compare the proportion of patients in NYHA functional classes III/IV between the 2 study groups. Robust standard errors, clustered by patient, were used to take account of the non-independence between annual NYHA assessments from the same patient. Potential interactions were examined and retained if significant at the 5% level. The results are presented as odds ratios.
With respect to morbidity, significant bleeding events were those resulting in transfusion, hospitalization, or death, and thromboembolic events were any event, either transient or permanent, where there was clinical corroboration. Multiple events during follow-up were included in the calculation of linearized rates for thromboembolism and bleeding events. The composite end point of valve-related complications included (1) thromboembolic events, (2) bleeding events, (3) reoperation, and (4) death due to any cause. INR values are displayed graphically. Standard errors are adjusted to take account of the multiple INR readings per patient per year. The data were analyzed using Stata version 8.2. (Stata Corp, College Station, Tex).
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Results |
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In patients undergoing AVR the most common cause was calcific, compared with a rheumatic cause in the MVR and DVR groups. No differences between the CM and SJM groups with respect to any operative variables or factors relating to additional procedures or the cause of valve dysfunction were found.
Patient Survival
The early (30-day) mortality was 5.2% (n = 25, CM 14, SJM 11, P = .43). A detailed description of the causes of early death is given in our 5-year interim report.11 The median follow-up was 10 years (interquartile range 9-11 years) and was 99% and 98% complete for the CM and SJM groups, respectively. During the total of 3879 patient-years of follow-up (CM, 1897 patient-years; SJM, 1983 patient-years), there were 165 deaths (CM 81, SJM 84). The overall survival at 10 years was 66.4% in the CM group (95% confidence interval [CI] 59.6%-72.3%) and 64.7% in the SJM group (95% CI 58.0%-70.6%) (P = .94) (Figure 1, A). The death rate was 4.3% per patient-year (95% CI 3.4%-5.3%) in the CM group and 4.2% per patient-year (95% CI 3.4%-5.2%) in the SJM group. Postmortem diagnoses were available in 36% of cases (CM 37%, SJM 35%). In cases without a postmortem diagnosis, the cause of death was assigned by the clinical diagnosis. In 109 cases, death was due to cardiac causes, 25 of which were considered valve-related (CM 11, SJM 14). The specific causes of valve-related death are presented in Table 1. At 10 years, freedom from valve-related death was 95.0% in the CM group (95% CI 90.8%-97.3%) and 93.0% in the SJM group (95% CI 88.3%-95.9%) (P = .58).
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Analysis by valve position showed that survival at 10 years differed significantly among the 3 valve positions (P = .005). Overall, survival was 72.1% after AVR, 54.4% after MVR, and 62.3% after DVR (see Figure 1 for a breakdown by prosthesis). Within each subgroup, no statistically significant difference between the 2 prostheses was found (P .53) (Figure 1, B-D).
Anticoagulation
For the assessment of anticoagulation status, 28,518 INR readings were available in 425 patients. The cumulative distribution of INR measurements, pooled over all patients and follow-up periods, by prosthesis and valve position is shown in Figure E2. No differences between the groups were found; the mean INR was 3.13 (standard error 0.023) in the CM group and 3.12 (standard error 0.025) in the SJM group. There were no obvious trends in anticoagulation during the 10 years of follow-up.
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At 10 years, 91.5% of patients (95% CI 86.5%-94.7%) in the CM group and 92.2% of patients (95% CI 87.5%-95.2%) in the SJM group were free of thromboembolism (P = .63, Figure 2). Thromboembolism-free survival after 10 years in relation to valve position was predictably higher in the aortic position at 94.8% (95% CI 91.1%-97%) compared with the mitral position at 85.5% (95% CI 77.7%-90.7%) (P = .003) (Figure 2).
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Valve-related complication-free survival
Overall, 248 patients had at least 1 complication (thromboembolic event, bleeding event, reoperation, or death from any cause) during follow-up. The complication-free survival at 10 years was similar for the 2 prostheses (P = .37). At 10 years, 51.6% of patients in the CM group (95% CI 44.7%-58.0%) and 46.2% of patients in the SJM group (95% CI 39.7%-52.4%) were free from valve-related complications (Figure 4, A). In contrast, a difference with valve position was seen, with the AVR group having a significantly higher event-free survival than the MVR and DVR groups (overall comparison, stratified by prosthesis, P = .0006, P 
.012 for pairwise comparisons among AVR, MVR, and DVR groups) (Figure 4, B). At 10 years the event-free survival in the AVR group was 56.7% (95% CI 50.6%-64.2%) compared with 37.0% (95% CI 29.1%-44.9%) in the MVR group and 37.5% (95% CI 22.2%-52.8%) in the DVR group.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The strengths of this study were that it was prospective and randomized and to our knowledge remains the only randomized controlled trial of these 2 heart valves. Although our randomization was simplistic by today’s standards,16 careful scrutiny of our study groups revealed no apparent differences with respect to any important variables. In addition, follow-up information was collected on an annual basis in a consistent manner by the same observers during the 12-year study period.
However, we must question to what extent our finding of no difference in the clinical performance of these 2 prostheses can be considered a definitive conclusion and to what extent this outcome may have been predictable based on the study size and duration. Akins17 calculated in his learned discussion of our interim report that to definitively rule out any difference in performance between these 2 prostheses, taking into account the published ranges of complications, would require some 10,000 patient-years of follow-up with a study size of perhaps 1400 patients in each group. We therefore must consider this study an important further contribution to the information already available on the clinical performance of these heart valves and accept that the power of the study means it cannot conclusively be considered to demonstrate equivalent clinical performance.
In the study as a whole, we found that survival after AVR (72.1%) was better than after MVR (54.4%) or DVR (62.3%). These differences were more apparent when overall survival and valve-related complications were considered. For this combined end point, survival after AVR was significantly higher than after both MVR and DVR (P .012). This has been a common but not entirely consistent finding in studies after mechanical valve replacement, and we know that late survival is as much a function of the risk profile of the starting population as a reflection of prosthetic valve function. Nevertheless, the late survival and freedom from clinical events of patients after prosthetic MVR or DVR were disappointing and further support the application of mitral valve repair whenever possible.
The only difference in outcome we identified was a suggested difference in NYHA class during follow-up, with fewer patients in the CM group in NYHA class III/IV. This difference did not seem to reflect preoperative status, which was similar in the 2 groups. Echocardiographic analysis of left ventricular function may have been helpful in clarifying whether there were any differences in left ventricular function between the 2 groups, but this was not part of the study.
The rates of thromboembolism and bleeding are at the lower end of those recorded for these prostheses and consistent with previous observations.6 In particular, despite the relatively small sample size there was no evidence of an increased thromboembolic risk associated with the CM mitral valve. With reference to the anticoagulation data, it is interesting that there was no difference in the management of these mechanical prostheses with respect to the position or type of prosthesis. Despite this study being conducted during the 1990s and early 2000s, with increasing understanding of prosthesis-specific anticoagulation, we found little evidence of any adaptation of the anticoagulation to the lower demands of (1) bileaflet prostheses and (2) prostheses in the aortic position. This may simply represent the rather crude management of anticoagulation in the community.
To improve outcome for our patients, we must aim to lower the levels of anticoagulation to reduce bleeding events without increasing the thromboembolic rate, which has been shown to be effective.18 In addition, early institution of INR self-management can allow close control of prosthesis-specific anticoagulation and consequently low thromboembolic (0.21%/patient-year) and bleeding rates (0.56%/patient-year).19
It is at this point customary to suggest further possible research to elucidate further the problem under study. A study with more power would require a multicenter design with a large sample size. However, the increasing prevalence of mitral repair and the elderly surgical population dictating implantation of biological valves make this less and less likely. It is probably far more realistic to acknowledge that increasing information from observational studies and this randomized study provide an extensive basis on which to base a reasoned hypothesis that there is little to choose with respect to clinical performance between these 2 bileaflet prostheses.
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Acknowledgments |
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Footnotes |
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