Department of Cardiac Surgery, Trousseau University Hospital, Tours, France

Risk Factors for Valve-Related Complications after Mechanical Heart Valve Replacement in 505 Patients with Long-Term Follow Up Thierry Bourguignon, Eric Bergöend, Alain Mirza, Grégoire Ayegnon, Paul Neville, Michel R. Aupart, Michel Marchand Department of Cardiac Surgery, Trousseau University Hospital, Tours, France Background and aim of the study: Currently, valve thrombosis, thromboembolic events and bleeding events account for 75% of all complications that occur after mechanical heart valve replacement. The study aim was to determine the main risk factors for valverelated complications in patients undergoing mechanical heart valve replacement. Methods: Data were available from the systematic follow up of patients who had received a CarboMedics bileaflet mechanical heart valve replacement at the authors institution. Follow up examinations were conducted prospectively at twoyear intervals, via questionnaires sent to the patients general practitioners, or by telephone calls. Results: Between January 1988 and December 2005, a total of 505 consecutive patients (300 males, 205 females; mean age 52 years; range: 5 to 77 years) underwent heart valve replacement using a CarboMedics mechanical prosthesis. Aortic valve replacement (AVR) was performed in 308 patients, mitral valve replacement (MVR) in 134 patients, and double-valve replacement (DVR) in 62 patients. The follow up was 95.4% complete; the mean follow up was 7.5 years, and the total follow up 3,718 patientyears. Thromboembolic and bleeding complications represented the leading cause of valve-related events (104/195), of valve-related mortality (15/25), and of the need for repeat surgery (9/16). Valve thrombosis occurred in 12 patients. Implantation in the mitral position was identified as a risk factor (HR = 15.07; CI: 8.41-23.07; p 0.0001). Thromboembolism occurred in 32 patients; the use of antiplatelet agents was found to be a protective factor (HR = 0.23; CI: 0.08-0.70; p = 0.01). Bleeding events occurred in 52 patients; risk factors for bleeding events included a history of thromboembolic or bleeding complications (HR = 2.70; CI: 1.33-5.26; p = 0.006) and an unstable International Normalized Ratio (INR) (HR = 2.86; CI: 1.01-8.08; p = 0.05). Conclusion: After mechanical heart valve replacement, the only risk factors for bleeding complications were an unstable INR and a history of thromboembolic or bleeding events. The use of antiplatelet agents proved to be a protective factor against thromboembolic events. The Journal of Heart Valve Disease 2011;20:673-680 Over the past 50 years, considerable progress has been made in the field of heart valve replacement surgery, with many changes having been made to the design and materials of mechanical prostheses to improve their longevity, hemodynamic profile, and thrombogenicity. Nevertheless, valve thrombosis, thromboembolic events and bleeding events still account for 75% of all complications after mechanical heart valve replacement (1). Whilst bioprostheses do not require anticoagulant therapy after implantation, they are characterized by a limited lifespan and, therefore, are mainly indicated for elderly patients (2). However, no formal indications have yet been defined for each family of heart valve prostheses; in fact, at present this choice is guided in particular by the patient s age and heart rhythm. Clearly, significant insights into the performance of mechanical prosthetic valves in real-life settings would be acquired by an analysis of outcome in a large series of patients who had received these valves. The aim of the present study was to determine the main risk factors for valve-related complications in patients who had received a mechanical heart valve. Address for correspondence: Thierry Bourguignon, Department of Cardiac Surgery, Trousseau University Hospital, Tours, France e-mail: thierry-bourguignon@hotmail.fr Copyright by ICR Publishers 2011

674 Risk factors for valve-related complications Clinical material and methods Patient population Between December 1988 and December 2005, a total of 505 consecutive patients (300 males, 205 females; mean age 52 ± 13 years; range: 5 to 77 years) underwent heart valve replacement at the Tours University Hospital cardiac surgery unit, using a CarboMedics bileaflet mechanical prosthesis (CarboMedics Inc., Austin, Texas, USA). The patients were regularly reviewed, and a final survey was performed between January and December 2006. Postoperatively, each patient was requested to complete a questionnaire, following an echocardiographic examination carried out during the previous three months. No patient was excluded from the study because of concomitant lesions. Any patient who underwent repeat surgery and required the implantation of a further CarboMedics prosthesis was considered to be a new case. Surgical approach All valve replacements were performed via a midline vertical sternotomy, under cardiopulmonary bypass. Myocardial protection was provided using crystalloid or cold blood cardioplegia. After implantation, the CarboMedics prosthesis was sutured in place using interrupted sutures composed of a woven, nonresorbable polyester material. Anticoagulation During the immediate postoperative period, patients received anticoagulation (via continuous intravenous infusion) of unfractionated heparin to achieve an International Normalized Ratio (INR) within the therapeutic range. Oral anticoagulation using a vitamin K antagonist (VKA) was initiated from postoperative day 2. The target INR for aortic valve replacement (AVR) was between 3 and 4.5 until December 1995, and between 2 and 3 after this date (2-2.5 if the patient was in sinus rhythm, and 2.5-3 if in atrial fibrillation), in line with European guidelines (3). The target INR for mitral valve replacement (MVR) and double valve replacement (mitral and aortic valves; DVR) was between 3 and 4.5 before 1995, and between 2.5 and 3.5 after this date (2.5-3 if in sinus rhythm, and 3-3.5 if in atrial fibrillation (AF)). The VKA dosing was regulated by the surgeon during hospitalization and the early follow up, and thereafter by the referring physician (no home self-testing anticoagulation was used). Plateletaggregation inhibitors were administered only when justified by a cardiological indication (ischemic heart disease) or a vascular indication (ischemic vascular accident, occlusive arterial disease of the lower limbs). Data acquisition Mortality and valve-related events were reported according to the recommendations of the American Association of Thoracic Surgery (4,5). The long-term results were compared between patients aged <60 years or 60 years at the time of surgery. Statistical analyses All data were imported and then analyzed using Statview 4.57 software (Abacus-Concept, Inc., Berkeley, CA, USA). Continuous variables were expressed as mean ± SD, while qualitative variables were compared using the chi-square test, and quantitative variables using Student s t-test. Probabilities were expressed as a percentage, with a 95% confidence interval (CI) (6). The limit of statistical significance was set at p <0.05. Survival and valve-related complications were described using Kaplan-Meier analysis and linear rates, while survival curves were compared using the log-rank test. The Cox model was used as a multiple regression model for multivariate analyses. Results J Heart Valve Dis Patient population During the study period, a total of 568 CarboMedics mechanical heart valves was implanted in 505 patients; this represented 19% of all valve prostheses implanted (including 2,368 bioprostheses) at the authors institution during this period. Of these 505 patients, 117 presented preoperatively with arrhythmias; the mean NYHA class was 2.3 ± 0.7. The surgical procedures performed included 308 AVRs, 134 MVRs, and 63 DVRs. Of these patients, 23 (4.6%, mean age 42 ± 17 years) were lost to follow up. The mean follow up period was 7.5 ± 5 years (CI: 0.01-17.6), and the total follow up was 3,718 patient-years (pt-yr). Short-term results An analysis of the 30-day postoperative mortality rates revealed 11 deaths (three cases of multiple organ failure, three of low cardiac output, three of sepsis, and two of disseminated intravascular coagulation). None of these deaths was attributed to the implanted prosthesis. The overall operative mortality rate was 2.2%. Long-term results At the time of follow up, the mean NYHA functional class was 1.3 ± 0.6 (10 patients were in NYHA class III). A total of 359 patients was included in the long-term study (there were 112 late deaths), among whom 60 (16.7%) had AF. Details of mortality and valve-related events are listed in Table I. No case of structural deterioration of the valve was

J Heart Valve Dis Risk factors for valve-related complications 675 reported. Non-structural dysfunction (87 events) included a minimal periprosthetic leak in 68 patients, and a moderate leak in 12. A severe periprosthetic leak, either isolated or associated with hemolytic anemia, required repeat surgery in five patients, while two patients required repeat surgery due to a blocked leaflet secondary to the development of pannus. The linear non-structural dysfunction rate was 2.3 per 100 pt-yr. Valve thrombosis All 12 events of valve thrombosis occurred in MVR patients (five females, seven males; mean age 57 ± 11 years). Three of these patients presented with AF, but none was treated with platelet-aggregation inhibitors. The INR was considered difficult to stabilize during follow up for two patients. During hospitalization, five of the 12 patients with valve thrombosis had an INR outside the target range (mean INR 3.2 ± 0.8), while four presented with additional risk factors for thrombosis (changes of anticoagulant therapy in three cases, one pregnancy, one case of polycythemia, one case of dilated cardiomyopathy secondary to pulmonary hypertension). Three of the patients had a history of stroke, and three also presented with a major bleeding event. Nine patients were reoperated on, and two patients died as a result of valve thrombosis before they could receive repeat surgery. One patient was treated successfully with effective anticoagulation. In the nine repeat-surgery patients, the CarboMedics mechanical prosthesis was replaced with a Carpentier- Edwards Perimount pericardial bioprosthesis. The mean time to onset of valve thrombosis was 3.4 ± 3.1 years, and the linear valve-thrombosis rate was 0.3 per 100 pt-yr. The results of the multivariate analysis relating to valve thrombosis are listed in Table II. The only identified risk factor was MVR (hazard ratio (HR) = 15.07; p <0.0001). Thromboembolic events No patient experienced a non-cerebral embolic event that was identified. In total, 31 patients (13 females, 18 males; mean age 54 ± 11.9 years) experienced 35 cerebral embolic events (one patient experienced two events, and one patient experienced four events) that included 11 transient ischemic attacks (TIAs) and 24 strokes. Seven patients died as a result of the stroke. Among the 31 patients, 19 had undergone AVR and 12 MVR. Nine patients (30%) presented with AF, but none had any history of thromboembolic disease. Four patients were treated with a combination of VKA and platelet-aggregation inhibitors. The INR was considered difficult to stabilize during follow up in eight patients. On admission to the emergency department, five of the 31 patients had an INR outside the target range (mean INR for AVR = 2.6 ± 0.3; mean INR for MVR and DVR = 3.1 ± 0.7). Twenty patients (65%) presented with a thromboembolic risk factor, including AF (n = 9), neoplasm (n = 3), aneurysm of the ascending aorta (n = 3), immediate postoperative period (n = 2), valve thrombosis (n = 2), change of anticoagulant therapy (n = 2), recent myocardial infarction (MI) (n = 1), left atrial myxoma (n = 1), and left atrial dilatation >50 mm (n = 1). None of the thromboembolic events required surgical treatment. The mean interval between mechanical heart valve replacement and onset of the embolic event was 4.2 ± 4.0 years (median 3.3 years). The linear embolic event rate was 0.9 per 100 pt-yr. The results of the multivariate analysis concerning embolic events are listed in Table III. The only protective factor identified was the use of platelet-aggregation inhibitors (HR = 0.23; CI: 0.08-0.70; p = 0.01), with no statistically significant difference between aspirin, clopidogrel, or a combination of the two. Table I: Survival (%) after five, 10, and 15 years in the absence of valve-related events. Event Survival period 5 years 10 years 15 years Valve thrombosis 97 ± 0.7 97 ± 0.9 96 ± 1.1 Thromboembolic event 96 ± 1 92 ± 1.6 90 ± 1.9 Bleeding event 92 ± 1 86 ± 2 83 ± 3 Reoperation 98 ± 0.7 97 ± 0.9 95 ± 2 Overall survival 87 ± 2 73 ± 3 58 ± 4 Valve-related mortality 97 ± 0.8 94 ± 1 89 ± 3 Valve-related mortality* 96 ± 1 91 ± 2 83 ± 3 Values are mean ± SD. *Including deaths of unknown cause. Table II: Multivariate analysis of valve thromboses. Parameter Hazard 95% CI p-value ratio Patient age at surgery 1.03 0.98-1.09 0.25 Age <60 years 0.45 0.14-1.40 0.17 MVR vs. AVR 15.07-0.0001 Prosthesis size 1.41 0.94-1.65 0.15 Platelet-aggregation inhibitor 0.39 0.07-3.71 0.53 History of thromboembolism 0.69 0.09-5.43 0.73 CI: Confidence interval; MVR/AVR: Mitral valve replacement/aortic valve replacement.

676 Risk factors for valve-related complications Table III: Multivariate analysis of thromboembolic events (Cox model). Parameter Hazard 95% CI p-value ratio Patient age at surgery 1.02 0.99-1.05 0.25 Age <60 years 0.6 0.21-1.71 0.34 MVR vs. AVR 1.09 0.43-1.98 0.84 Platelet-aggregation inhibitor 0.23 0.08-0.70 0.01 Aspirin 0.36 0.11-1.22 0.1 Clopidogrel 0.33 0.04-2.56 0.29 Difficulty stabilizing INR 0.58 0.26-1.32 0.2 History of valve thrombosis 0.74 0.10-5.68 0.77 CI: Confidence interval; INR: International Normalized Ratio; MVR/AVR: Mitral valve replacement/aortic valve replacement. Table IV: Multivariate analysis of bleeding events (Cox model). J Heart Valve Dis Parameter Hazard 95% CI p-value ratio Patient age at surgery 1.02 1.00-1.06 0.09 Age <60 years 0.87 0.38-1.96 0.73 Female gender 1.01 0.55-1.86 0.97 AVR vs. MVR 0.57 0.32-1.03 0.06 Difficulty stabilizing INR 2.86 1.01-8.08 0.05 History of AC-related 2.7 1.33-5.26 0.006 complications AC: Anticoagulant; CI: Confidence interval; INR: International Normalized Ratio; MVR/AVR: Mitral valve replacement/aortic valve replacement. Bleeding events A total of 52 patients (27 females, 25 males; mean age 55 ± 10 years) experienced 57 bleeding events (five patients experienced two events) that required hospitalization and/or transfusion. The various sites were intracranial (three extradural hematomas, four intracerebral hematomas, two subdural hematomas), pericardial (n = 2), pleural (n = 3), ear/nose/throat (n = 5), urological (n = 4), gynecological (n = 4), gastrointestinal (n = 13), parietal (n = 4), orthopedic (n = 5) and three deep hematomas. Among these patients, 23 had undergone AVR and 29 MVR. Twelve patients presented with AF, and two were treated with platelet-aggregation inhibitors. The INR was considered difficult to stabilize in four patients. Eleven patients had a history of previous bleeding events. Figure 1: Kaplan-Meier survival curves in the absence of bleeding events, comparing groups aged <60 years and 60 years at the time of surgery (log-rank test) for the first five postoperative years. On admission to the emergency department, 45 of the 52 patients had an INR outside the target range (mean INR for AVR = 3.6 ± 0.4; mean INR for MVR and DVR = 4.1 ± 0.8). No patient presented with any comorbidity that was likely to predispose to bleeding (e.g., renal failure, liver failure, clotting disorder). Four of these patients had also experienced a thromboembolic event, while another two had experienced an episode of valve thrombosis. Eight patients underwent further heart surgery. Five patients died as a result of the bleeding event before they could receive repeat surgery. The mean time to onset of a bleeding event was 4.3 ± 4.0 years (median 3.7 years), and the linear bleeding event rate was 1.5 per 100 pt-yr. A Kaplan-Meier survival analysis showed that bleeding events occurred significantly more often during the first five postoperative years in patients who were aged 60 years at the time of surgery (log-rank = 5.09; p = 0.02; Fig. 1). The results of the multivariate analysis relating to bleeding events are listed in Table IV. A history of adverse events related to anticoagulants, and an INR that was difficult to stabilize, were identified as risk factors for bleeding complications. For the overall study period, the patient s age at the time of surgery tended to be a risk factor for bleeding complications (HR = 1.02 for each additional year). Typically, AVRs tend to be associated with a lower bleeding risk than other sites. Repeat surgery The mean interval between the first operation and the 16 repeat operations was 4.6 ± 4.4 years (median 5.5 years). Repeat operations were performed for a periprosthetic leak (in five patients), valve thrombosis (nine patients), and a blocked leaflet (two patients). The linear reoperation rate was 0.4 per 100 pt-yr.

J Heart Valve Dis Risk factors for valve-related complications 677 Late overall mortality The total late overall mortality was 112 deaths. Causes of death were valve-related for 25 patients, cardiac for 26 patients, and other for 61 patients. Valve-related mortality The mean interval between surgery and valve-related death was 5.9 ± 4.5 years. The only independent risk factor for valve-related death was age at the time of surgery (HR = 1.55 for each additional year, CI: 1.01-1.10; p = 0.02). The linear valve-related mortality rate was 0.7 per 100 pt-yr. Discussion At 50 years after the first implantations of mechanical heart valves, the complications caused by oral anticoagulants remain the major drawback of these procedures, and represent the leading cause of valverelated complications (104/195 in the present series). The aim of the present study was to examine the valverelated complications in patients who received CarboMedics valves, in order to determine the main risk factors for these complications. Assessing the impact of a patient s age at the time of surgery is of paramount importance, as this largely determines whether a bioprosthesis or a mechanical prosthesis is to be implanted. Valve thrombosis In the present study, valve thromboses accounted for about 12% of all oral anticoagulant-related complications (12/104), but were associated with a poor prognosis, and caused death in two of the 12 patients concerned. In five of these 12 patients, the INR was outside the target range during their hospitalization (mean INR = 3.2 ± 0.8), thus confirming the results obtained by Aagaard, who showed that mechanicalvalve thromboses are generally caused by an inadequate anticoagulation, without the formation of a pannus (7). However, seven patients developed valve thrombosis despite receiving anticoagulation that complied with international guidelines, as reported previously by Jamieson et al. (8). Apart from the degree of anticoagulation, the pathogenesis of valve thrombosis may also involve other factors, such as the thrombogenicity of the valve surface, the turbulence of the intraprosthetic blood flow, and the geometry and contractile function of the left atrium (including AF), as well as the other possible causes of hypercoagulability (9). The only risk factor to be identified in the present series was MVR. In a meta-analysis, Cannegieter et al. showed the risk of valve thrombosis to be twofold higher in the mitral position than in the aortic position (10). This was partly explained by the fact that thrombotic risk is proportional to the valve surface in contact with blood (11), as the mitral orifice has a larger surface area than the aortic orifice. Another explanation is related to the valve geometry since, in the mitral position, the valve leaflets can impinge on the posterior mitral valvule, when it is conserved. Thromboembolic events Embolic events accounted for one-third of all oral anticoagulant-related complications (35/104), and for one-third of the valve-related deaths (8/25). The only protective factor identified in the present study was the use of platelet-aggregation inhibitors, though there was no statistically significant difference between aspirin, clopidogrel, or a combination of the two. In a randomized trial, Turpie et al. (12) showed that a combined treatment with aspirin (100 mg daily) and oral anticoagulation (with a target INR of 3-4.5) was associated with a reduction in thromboembolic events and cardiovascular mortality compared to treatment with oral anticoagulants alone (1.9% per year versus 8.5% per year; p <0.001). The bleeding event rate of 8.5% per year with combined treatment compared to 6.6% per year with oral anticoagulants alone, was not statistically different (12). Nevertheless, the risk of bleeding events appears to increase significantly at aspirin doses above 660 mg per day (13). Thus, the combination of aspirin and oral anticoagulants should be reserved for patients at high risk of thromboembolism (history of thromboembolism with anticoagulants alone, hypercoagulability), and those who present with an indication for aspirin independently to that for a mechanical valve (ischemic heart disease, stroke, occlusive arterial disease of the lower limbs). Low-dose aspirin (80-100 mg daily) should be recommended in all of these situations (14). The results of the present study were unable to define clearly the impact of poorly adjusted anticoagulant therapy on the development of thromboembolic events, because INR values were available only for urgently admitted patients. Only five of the 31 patients (16%) who experienced a thromboembolic event had an INR outside the target range. This confirmed the findings of Mutlu et al., which showed thromboembolic events to be possible, even in the context of anticoagulation therapy that complies with international guidelines (15). Age was shown not to be a risk factor for thromboembolic events in the present study, in contrast to data reported by Aagaard (7). This difference most likely occurred because of the particularly low mean age of the population (52 ± 13 years) compared to that

678 Risk factors for valve-related complications of other series (57 years for Tominaga et al. (16); 64 years for Emery et al. (17)). This situation arose due to the age-limit of 60 years that was enforced by the present authors for the implantation of a bioprosthesis. Likewise, neither the role of AF nor the size of the left atrium in the pathogenesis of thromboembolic events, could be demonstrated in the present study. Bleeding events Bleeding events accounted for 55% of all oral anticoagulant-related complications (57/104), and for 20% of the valve-related deaths (5/25). Bleeding events were treated surgically in 14% of cases (8/57). The two risk factors identified in the present study were a history of bleeding events and an INR that was difficult to stabilize. Although the latter criterion is subjective (based on the attending physician s opinion), it has important practical implications: a more strict clinical and laboratory (INR) surveillance is required for patients with an unstable INR. The influence of the site of valve replacement was not clearly demonstrated in the present study, although AVR tended to be associated with a lower bleeding risk (HR = 0.57; CI: 0.32-1.03; p = 0.06). This can be explained by differences in the levels of anticoagulation recommended for MVR and AVR. In the present study, the influence of the patient s age at the time of surgery on the development of bleeding events was mainly demonstrated during the first five postoperative years (HR = 1.03 for each additional year; CI: 1.00-1.06; p = 0.06). Consequently, the risk of bleeding events was seen to be increased 1.8-fold for each 20-year increase in age. Among the 52 patients that experienced a bleeding event, 45 (86%) presented with an INR outside the target range at the time of admission to the emergency department (mean INR for AVR = 3.6 ± 0.4; mean INR for MVR and DVR = 4.1 ± 0.8). Although an overdose of anticoagulants will obviously predispose to bleeding events, fluctuations in the INR also play a major role; indeed, Casais et al. (18) have shown this association to be independent of the mean INR. These INR fluctuations are extremely frequent, and Dauphin et al. (19) reported that, during oral anticoagulant therapy, the INR was within the target range for only 53% of the time. J Heart Valve Dis Influence of anticoagulation In the present study, one-third (35/104) of all anticoagulant-related complications occurred during the first year, and one-half of these events occurred during the first postoperative month. This highlighted the importance of monitoring anticoagulation therapy during the immediate postoperative period. Although INR variability is essentially observed during the first postoperative month (20), Butchart et al. have reported that it also determines long-term survival (21). The importance of regular follow up ( follow up diary ) during long-term anticoagulant therapy, and the complementary roles of the laboratory, attending physician, cardiologist, anesthetist and surgeon, must therefore be stressed. Horstkotte et al. first noted that bleeding and thromboembolic events occurred when the INR was out of range and not in the target zone (22). According to many groups, the self-management of INR by the patient can help to maintain INR within the recommended range more easily than surveillance by the doctor. In a randomized, prospective study, Dauphin et al. (19) showed that INR self-management significantly decreased the INR variability. In addition, the ESCAT1 trial (Early Self-Controlled Anticoagulation Trial 1), a randomized, prospective study conducted in 930 patients with a mechanical heart valve, showed that the self-management of anticoagulation significantly improved the percentage of INR values within the target range, reduced thromboembolic events, and improved long-term survival compared to the management of oral anticoagulants by a general practitioner (23,24). More recently, the results of the ESCAT2 trial showed that low-dose INR self-management (target INR range of 1.8 to 2.8 for aortic valve recipients and of 2.5 to 3.5 for mitral or double-valve recipients) did not increase the risk of thromboembolic events compared to conventional-dose INR self-management (target INR range 2.5-4.5) (25). An interim analysis of the ESCAT3 trial, which compared low-dose and very low-dose INR self-management (INR range 1.6-2.1 for AVR and 2.0-2.5 for MVR or DVR) showed, at six months, a similar incidence of thromboembolic and bleeding events (26). Thus, INR self-management would appear to be a promising approach to reduce the rate of anticoagulant-related complications. Influence of age Consistent with the results of Toole et al. (27), in the present study age was identified as an independent risk factor for valve-related death. Compared to a 50- year-old patient, a 70-year-old patient, at the time of mechanical heart valve replacement surgery, has a 2.7- fold higher risk of dying from a valve-related event (p = 0.02). Age at the time of surgery also tended to be an independent risk factor for embolic events, and for bleeding events during the first five postoperative years. It must be taken into account that the background population also have bleeding and embolic episodes, and that the risk of such an event increases with increasing age. Horstkotte et al. (28) reported a background incidence for spontaneous bleeding in patients aged 64 years and without anticoagulation of approximately 0.8% per year, while for transient plus non-transient cerebral ischemic attacks the rate is

J Heart Valve Dis Risk factors for valve-related complications 679 approximately 1.3% per year if unselected men aged 65-74 years are taken into account (28). Among factors involved in the choice between a mechanical prosthesis and a bioprosthesis when heartvalve replacement is indicated - including patient age, contraindications to anticoagulant therapy, comorbidities, life expectancy (compared to the lifespan of the prosthesis), lifestyle and patient preference - the most controversial criterion remains the patient age. International guidelines have proposed a 65-70-year age range as being the lower age limit for bioprosthesis implantation (3,14). Nevertheless, recent reports have described excellent results with bioprostheses implanted in patients aged <65 years. For example, Khan et al. (29) did not find any significant difference in terms of survival between bioprostheses and mechanical prostheses implanted in patients aged <65 years. More recently, Ruel et al. (30) drew the same conclusions with patients aged <60 years. At the present authors unit, the age of 60 years was adopted as the lower limit for bioprosthesis implantation, in view of the excellent long-term results obtained with the Perimount valve (Carpentier-Edwards) with regards to valve deterioration and reoperation in patients aged >60 years (31). This explains the relatively small number of patients with mechanical-valve replacement who were aged >60 years at the time of surgery. A review of published series of aortic (31) or mitral (2) pericardial bioprostheses implanted in the present authors department revealed that 93% of patients undergoing AVR were aged 60 years at the time of surgery (mean age 72 years) compared to 86% (mean age 67 years) for MVR. The actuarial survival in the absence of bleeding events at 18 years after bioprosthesis implantation was 95 ± 2% after AVR, and 90 ± 3% after MVR, compared to a 15-year actuarial survival rate of 72 ± 10% for patients aged >60 years undergoing mechanical-valve replacement. The actuarial survival after an embolic event was 92 ± 2% for aortic bioprostheses, 92 ± 3% for mitral bioprostheses, and 86 ± 4% for mechanical prostheses, while the actuarial survival after reoperation was 62 ± 11%, 43 ± 9%, and 96 ± 2%, respectively. No deaths occurred among a series of 28 reoperations involving the aortic position, and only one death occurred in a series of 48 reoperations (2%) involving the mitral position. Although no conclusions can be drawn from the two different populations in the present study, the long-term results suggest that 60 years might be a relevant age limit for the implantation of a mechanical valve. Study limitations The main limitations of the present study were its retrospective nature, the limited sample size, and the relatively low mean age of the patients (52 ± 13 years; range: 5 to 77 years) compared to that of other reported series (e.g., 58 ± 13 years (8)). The low age can be explained by the need for an age limit of 60 years when choosing between a bioprosthesis and a mechanical prosthesis, compared to the 65- or even 70-year age limit defined by some surgical teams. The study also presented an intervention bias, as all patients were not operated on by the same surgeon. In addition, the mode of follow up by questionnaire also introduced a risk of bias related to loss of data, although very few patients were lost to follow up (4.6%) and the maximum follow up was 18 years. The absence of INR values during follow up, except in cases where complications required hospitalization, might constitute a measurement bias. Computed tomography of the head was not performed systematically to detect clinically silent strokes, and cardiologic follow up was insured by office cardiologists for the majority of patients, though some observations were performed by various physicians. However, all events were reported as before or after 30 days, in strict compliance with American and European guidelines. In conclusion, an unstable INR after mechanical heart valve replacement, and a history of bleeding or thromboembolism, were the only risk factors for bleeding complications. Concomitant treatment with a plateletaggregation inhibitor was a protective factor for thromboembolic events. References 1. Koertke H, Zittermann A, Minami K, et al. Lowdose International Normalized Ratio self-management: A promising tool to achieve low complication rates after mechanical heart valve replacement. Ann Thorac Surg 2005;79:1909-1914 2. Marchand M, Aupart M, Norton R, et al. Fifteen year experience with the mitral Carpentier- Edwards Perimount pericardial bioprosthesis. Ann Thorac Surg 2001;71:S236-S239 3. Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the management of valvular heart disease. ESC Guidelines. The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 2007;28:230-268 4. Edmunds LH, Jr., Clark RE, Cohn LH, et al. Guidelines for reporting morbidity and mortality after cardiac valvular operations. Ad hoc Liaison Committee for Standardizing Definitions of Prosthetic Heart Valve Morbidity of the American Association for Thoracic Surgery and the Society of Thoracic Surgeons. J Thorac Cardiovasc Surg 1996;112:708-711

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