Key Words: Prostheses Warfarin Stroke Bleeding.

Transcription

1 Low-Intensity Oral Anticoagulant Plus Low-Dose Aspirin During the First Six Months Versus Standard-Intensity Oral Anticoagulant Therapy After Mechanical Heart Valve Replacement: A Pilot Study of Low-Intensity Warfarin and Aspirin in Cardiac Prostheses (LIWACAP) Vittorio Pengo, MD, * Gualtiero Palareti, MD, Umberto Cucchini, MD, * Maurizio Molinatti, MD, Roberto Del Bono, MD, Franco Baudo, MD, ** Angelo Ghirarduzzi, MD, Cinzia Pegoraro, MD,* and Sabino Iliceto on behalf of the participating centers of Italian Federation of Anticoagulation Clinics (FCSA) *Clinical Cardiology, Thrombosis Centre, University of Padova; Department of Angiology & Blood Coagulation Marino Golinelli, University of Bologna; Division of Transfusion Medicine, Maria Vittoria Hospital, Torino; Clinical Pathology, Brescia Hospital; **Division of Hematology Niguarda Ca Granda, Milano, Department of Medicine, Reggio Emilia Hospital, Italy Summary: The objective of this study was to evaluate the safety and efficacy of low-intensity warfarin treatment plus aspirin during the first 6 months after surgery in patients undergoing heart valve substitution with mechanical prostheses. Vitamin K antagonists (VKA) are able to reduce but not eliminate thrombosis and systemic embolism in patients with mechanical heart valves. The intensity of treatment and additional use of aspirin in these patients is still controversial. Consecutive patients undergoing aortic or mitral valve replacement (or a combination of the two) with mechanical prostheses were invited to participate in the study. After stratifying for site of prosthesis, patients were randomized to receive low intensity VKA treatment (target INR 2.5) plus aspirin (100 mg/day) for the first six months (Group A) or standard-intensity (INR target 3.7) VKA treatment (Group B). Mean follow-up was 1.5 years. Principal outcome events were systemic embolism, major bleeding, and vascular death. A total of 94 patients in Group A and 104 in Group B were randomized and followed up for 144 and 163 patient years, respectively. There were 5 (5%) events in Group A (4 major bleeding events and 1 vascular death) and 4 (4%) in group B (2 major bleeding events and 2 ischemic stroke). All the events except 1 occurred within the first 6 months after surgery. Cumulative incidence of primary outcome events was 5.8% (95% CI 0.9 to 10.7) in Group A and 4.3% (95% CI 0,2 to 8.4) in Group B (p=0.6). Low-intensity treatment plus aspirin during the first six months after surgery appears to be as effective and safe as moderatehigh-intensity anticoagulation. Key Words: Prostheses Warfarin Stroke Bleeding. A list of participating centers is reported at the end of the manuscript. This study was partially supported by a grant from Bayer S.p.A (Milan, Italy), which also provided aspirin tablets (Cardioaspirin ). Address correspondence to: Vittorio Pengo, MD, Clinical Cardiology, Thrombosis Centre, University of Padova School of Medicine, Ex Busonera Hospital, Via Gattamelata 64, I Padova, Italy; vittorio.pengo@unipd.it. Clinical and Applied Thrombosis/Hemostasis Vol. 13, No. 3, July DOI: / Sage Publications The introduction of oral anticoagulants has markedly reduced thromboembolic events in patients carrying mechanical heart valves (1,2). These drugs have, however, a narrow therapeutic window, and the intensity of treatment needed to minimize thromboembolism and limit the risk of hemorrhagic complication is still a matter of debate. In the 1980s, data from a retrospective study (3) suggested the therapeutic range using the International Normalized Ratio (INR) system should be kept between 3.0 and 4.5 (2,4). 241

2 242 V. PENGO ET AL The efficacy and safety of an achieved INR between 3.0 and 4.0 was soon after confirmed by a large retrospective study conducted in the Netherlands (5). In the meantime, it was shown that moderate intensity anticoagulation was able to prevent thromboembolism with fewer hemorrhagic complications than higher intensity treatment (6,7), prompting the experts at the consensus conference of the American College of Chest Physicians to recommend reduced intensity anticoagulation in order to maintain INR between 2.5 and 3.5 in all patients with mechanical heart valve prosthesis (8). More recently, the AREVA study showed that moderate-intensity treatment may be further reduced to between 2.0 and 3.0 in patients with aortic bileaflet prosthetic valves, provided patients are in sinus rhythm with an atrial size of less than 50 mm (9). Some studies have, however, shown that low-intensity anticoagulation is also effective and safe in patients with mitral prostheses (10,11). It would seem reasonable, therefore, to posit that all the patients after heart-valve replacement should be treated at low-intensity anticoagulation. The aim of this study was to compare the effectiveness and safety of low-intensity (INR between 2.0 and 3.0) with moderate-high-intensity (INR between 3.0 and 4.5) anticoagulation in patients with mechanical heart valves. Since the first six months after surgery are at higher risk of thromboembolic event (12) and low-dose aspirin plus warfarin reduces thromboembolism (13), patients in the low-intensity group (intended INR between 2.0 and 3.0) were treated with aspirin in addition to anticoagulation during that time period. MATERIALS AND METHODS Design of the Study The LIWACAP study was a randomized, prospective, multicenter trial in centers affiliated with the Italian Federation of Anticoagulation Clinics (FCSA). The aim was to compare vascular death and thromboembolic and bleeding complications in patients treated with low-intensity warfarin plus aspirin versus standard oral anticoagulant therapy during the first six months after mechanical heart valve replacement. The protocol was approved by the local ethical committees in the participating centers. Consecutive patients undergoing heart valve replacement with mechanical prosthesis for the first time were invited to participate in the study by signing an informed consent before surgery. All patients were treated with subcutaneous unfractionated heparin (5000 IU b.i.d. first postoperative day, 5000 IU t.i.d thereafter), stopping when INR values were >2.0 for two consecutive days. Patients willing to participate in the study were stratified according to valve position (aortic or mitral) or double valve substitution. Randomization to each stratified group was carried out at first warfarin administration (usually the second day after surgery) in blocks of ten. Patients were randomized to low-intensity warfarin treatment to maintain an INR between 2.0 and 3.0 (target 2.5) or standard intensity treatment to maintain an INR between 3.0 and 4.5 (target 3.7). In the low-intensity group, aspirin (Cardioaspirin, Bayer) 100 mg was added to warfarin during the first six months after operation. Centers were advised to administer 10 mg of warfarin on days 1 and 2 with INR control on the third day. Patients All subjects over 18 years of age undergoing heart valve replacement with mechanical prosthesis for the first time were eligible for inclusion. Exclusion criteria included the need for adjunctive antiplatelet therapy, allergy or intolerance to aspirin, combined bypass surgery, emergency surgery, follow-up problems, poor compliance, renal or hepatic insufficiency, or life expectancy of less than 12 months. Outcome Events Primary end points of the study were systemic thromboembolism, major bleeding and vascular death. Systemic thromboembolism included the following: 1) Transient (TIA) or permanent (stroke) cerebral ischemic event, defined as unexpected neurologic or visual defect detected by computed tomography (CT) scan excluding intracranial bleeding; 2) peripheral, visceral, or coronary embolism, defined as acute artery occlusion detected at angiography or post-mortem; 3) valve thrombosis, detected by two-dimensional cardiac ultrasound or at surgery. Major bleeding comprised the following: 1) Intracranial bleeding at CT scan; 2) retroperitoneal bleeding at CT scan; 3) ocular bleeding with blindness; 4) articular bleeding; 5) bleeding that reduced hemoglobin concentration by 2 g/dl or more or requiring the transfusion of two or more units of blood; 6) bleeding that required surgical intervention. Vascular death included sudden demise,

3 LOW WARFARIN IN PROSTHETIC HEART VALVES 243 defined as unexpected death occurring within 1 hour of the first symptom and that was not provoked by a nonvascular cause (14). Events occurring during the first week after surgery were not counted as primary end points. All events were reviewed by an adjudication committee that was unaware of the treatment group and independent of the investigating centers. Follow-up INR calculation and clinical evaluation were performed at Italian Anticoagulation Clinics following the guidelines of the Italian Federation (15). Maximum follow-up for each patient was 2 years. Statistical Analysis A sample size calculation to test the benefit of low-intensity treatment plus aspirin during the first six months should have involved 350 patients in each arm (assuming a cumulative event rate of 5% in 2 years in the moderatehigh intensity group and considering a reduction of 50%, with power of 80% (β=0.20) and an α error of 0.05). We decided to perform a pilot study considering 100 patients in each arm. This was based on the difficulties in performing a big nonsponsored trial and on the concern that low-intensity treatment may not be safe and effective. Baseline variables were compared by Student s t-test for continuous and by chi-square and Fisher s exact tests for categorical variables. Primary analysis was based on first occurrence of an event among primary end points. The groups were compared on the basis of originally assigned treatment (intention-to-treat analysis). Survival analysis by the Kaplan-Meier method (16) was used to analyze the difference in the proportion of event-free patients in the two groups with censored cases. The two groups were compared by the log-rank test according to Mantel-Cox (17). Person-time data in the two groups during the first six months after surgery were expressed as difference between incidence rates (18). The method of Rosendaal et al. (19) was used to evaluate the achieved intensity of anticoagulation in both groups. This method is based on the assumption that INR values will vary linearly between two measurements; using the dates of all prothrombin time determinations, it allows calculation of percentage of time spent at different INR intervals. RESULTS In total, 239 patients were considered for this study. Forty-one were excluded for the following reasons: Unavailability for regular follow up (n=18); previous heart valve replacement surgery (n=7); need for simultaneous coronary bypass (n=6) or emergency surgery (n=4); renal failure (n=3); aged below 18 years (n=3). After giving their informed consent to the study, the remaining 198 patients were randomly assigned to low-intensity oral anticoagulant treatment (OAT) (INR target 2.5) plus 100 mg aspirin or to moderate-high intensity OAT (INR target 3.7) for the first six months. Patients baseline characteristics were similar as reported in Table 1. Patients were followed up for a maximum of two years, mean follow-up being 1,5 years in both groups. Most of the replaced valves were bileaflet mechanical valves in the aortic position though about one in four patients had valves replaced in the mitral area as well as atrial fibrillation. A total of 31 patients terminated the study early: 18 (7 in low intensity group) for INR check-ups and clinical controls performed outside the anticoagulation clinic, 8 (3 in low intensity group) for new heart valve substitution unrelated to valve thrombosis, 3 for allergy to aspirin and 2 for major deviations from the study protocol (change of target INR and continuation of aspirin beyond six months, both in low intensity group). Two patients (one in each group) withdrew their consent to participate in the study and other two patients (both in the moderatehigh intensity group) were lost to follow up and censored at the time of their last visit. Principal outcome events occurred in 5 (5%) patients of low intensity group (4 major bleeding events and 1 vascular death) and 4 (4%) patients in moderate-high intensity group (2 major bleeding events and 2 systemic thromboembolism). The cumulative incidence of outcome events was 5.8% (95% CI 0.9 to 10.7) in the low intensity plus aspirin group and 4.3% (95% CI 0,2 to 8.4) in the moderate-high intensity group (p=0.6, Fig. 1). No patient in the low intensity group and 2 patients (1.2% pt/yrs) in moderateintensity group had thromboembolic events. Major bleeding occurred in 4 patients (2.8% pt/yrs) in the low-intensity group and in 2 patients (1.2%pt yrs) in the moderate intensity group (Rate Ratio 2.3, 95% CI , p=0.3). All primary events except one stroke occurred during the first six months after surgery. During this period the incidence of major bleeding was

4 244 V. PENGO ET AL TABLE 1. Baseline Characteristics of Studied Patients Characteristic INR Target 2.5* (n=94) INR Target 3.7 (n=104) p Age, yr 60.2 ± ± Male sex, no. (%) 46 (49) 47 (45) 0.7 Follow-up, yr 1.52 ± ± Valve position, no.(%): Aortic 59 (63) 65 (63) Mitral 27 (28) 26 (25) 0.6 Aortic and mitral 8 (9) 13 (12) Type of mechanical valve (%) Sorin Bicarbon St Jude Medical Carbomedics Others Risk Factors: Atrial fibrillation, no. (%) 23 (24) 32 (31) 0.3 Left atrial size, mm 45 ± 6 46 ± Left ventricle ejection fraction 0.57 ± ± Previous thromboembolism, no. (%) 4 (4) 2 (2) 0.4 *Plus aspirin 100 mg/day for the first 6 months; plus-minus values are means± SD. TABLE 2. Rate of Events Among the Studied Groups During the First 6 Months Patients (N) Follow-up (pt/yrs) TE Major Bleeding Vascular Death INR target 2.5* (0) 4(9.3) 1(2.3) INR target (2.3) 2(4.6) 0(0) *Plus aspirin 100 mg/day for the first 6 months; Number (number/100patient/years). 9.3% pt/yrs in group A and 4.6% pt/yrs, in group B (P=0.4) (Table 2). Of the major bleeding events, hemopericardium occurred within the first month after surgery in 2 patients (one in each group) with INR values above 3.5; in one case this resulted in nonfatal cardiac tamponade. All the remaining 4 major bleeding events were gastrointestinal and occurred within the desired INR range. One 64-year-old man in the INR 3.7 target group carrying a prosthetic heart valve in the mitral position had an ischemic stroke 12 days after surgery, anticoagulation intensity being in the therapeutic range (INR=3.2). A CT scan showed a large cerebral ischemia and the patient died after 1 week. The only event to occur after the first six months from operation was an ischemic stroke in the moderate-high intensity group. This was the case of a 52-year-old man with aortic and mitral valve replacement and atrial fibrillation. The stroke occurred 19 months after surgery and the intensity of anticoagulation was within the appropriate range (INR=3.1). As far as the achieved intensity of anticoagulation in the two groups is concerned, the allocation of INR specific person-time of the patients is shown

5 LOW WARFARIN IN PROSTHETIC HEART VALVES 245 FIG. 1. Cumulative proportion of events in the two study groups. Patients in the INR target 2.5 group received additional 100 mg/d aspirin for the first six months. FIG. 2. Percentage of time among the INR categories in the two treatment groups.

6 246 V. PENGO ET AL in Fig. 2. Patients in the INR 2.5 target group spent most of the time in the INR 2.0 to 2.4 and 2.5 to 2.9 ranges, whereas patients in the 3.7 target group showed a wider distribution across INR categories with most of the time spent at INR 3.0 to 3.4. DISCUSSION The present pilot study was designed on the basis of data showing that low intensity anticoagulant treatment may reduce hemorrhagic complications without increasing thromboembolic events in patients with mechanical heart prostheses (5,6,9 11). This rationale was further supported by the knowledge that modern mechanical valves are less thrombogenic and possess a better hemodynamic profile (5). Nevertheless, evidence that the majority of thromboembolic events occurs soon after surgery (12) prompted us to add aspirin on top of low-intensity anticoagulant treatment for the first six months after surgery. This decision was taken on the basis of the study by Turpie and associates (13), which showed that 100 mg/d aspirin in combination with oral anticoagulants at an INR of 3.0 to 4.5 reduces mortality, vascular mortality, and systemic embolism compared to oral anticoagulants alone. As expected from the results of previous studies (7,20,21), the trial by Turpie and associates showed there was a nonstatistically significant increase in the rate of major bleeding in the group of patients treated with aspirin (8.5% pt/yr vs 6.6% pt/yr). This figure is similar to what we found in the first six months of treatment (9.3% pt/yr in aspirin plus warfarin group and 4.6 pt/yr in control group). In contrast, another study (22) showed that major bleeding events occurred in 2.33% pt/yr in the combination group and in 1.13% pt/yr in the control group. These differences are not related to the amount of aspirin administered (100 mg in all cases) but probably depend on time lapses between randomization and surgery. Indeed, in the study by Turpie and in our study, patients were enrolled very soon after surgery, which was not the case for the patients in the study by Meschengieser and colleagues (22). As bleeding complications are more frequent at the beginning of anticoagulant treatment (23), this tendency is probably reinforced by a combination therapy with aspirin (24,25). Looking at our results in more detail, it appears that all hemorrhagic events in the combination group tend to occur soon after surgery. Thereafter low-intensity anticoagulation is safe without increasing the risk of thromboembolic events. Overall, the linearized rate of thromboembolic events in our series was 0% and 1.2% pt/yr, a figure in line with many studies on bileaflet mechanical heart valves in aortic or mitral position (26 29), but not all (25,30). However, many results from antithrombotic treatment in the literature come from nonrandomized studies without controls, and the effectiveness and safety of a given intensity of anticoagulation is reported only in reference to the intended INR range without giving details on the intensity of anticoagulation actually achieved. In analyzing the achieved intensity of anticoagulation in our study, it is evident there was a clear distinction between the two groups. The low-intensity group patients spent little time in INR categories below 1.5 or above 3.5, and this suggest a low rate of thromboembolic events if these patients are maintained in this range. On the other hand, it is well known that an increase in the intended range of anticoagulation determines more unstable results with repeated changes in drug dosage (14) and possibly more risk for the patients. It is possible, therefore, to conclude that in patients with bileaflet heart valves, a well-conducted low-intensity anticoagulation appears to be safe and sufficient to prevent thromboembolic events. After this pilot study, it may be worth organizing a randomized controlled trial with a sufficient number of patients to test the hyppothesis that all patients bearing prosthetic heart valves may receive low-intensity anticoagulant treatment. Whether or not we could safely start treating patients soon after valve substitution at low-intensity anticoagulation without adding aspirin during the first six months remains to be established. PARTICIPATING CENTERS MILANO: Divisione di Ematologia (Dott. Franco Baudo) e Divisione di Cardiochirurgia (Prof. Alessandro Pellegrino, Prof. Ezio Panzeri) Ospedale Niguarda Ca Granda MILANO: IRCCS S. Raffaele: Servizio di Coagulazione Centro per Io Studio della Trombosi e la Sorveglianza del Paziente Anticoagulato (Dott. Armando D Angelo, Dott. Luciano Crippa); Divisione di Cardiochirurgia (dott. Ottavio Alfieri, dott. F. Maisano) BRESCIA: Centro Sorveglianza Anticoagulati II Lab. Analisi (Dott. Roberto Del Bono), II

7 LOW WARFARIN IN PROSTHETIC HEART VALVES 247 Divisione di Cardiochirurgia (dott. Turumello) Osp. Civile BOLOGNA Istituto di Cardiologia, Università di Bologna (Prof. Bruno Magnani, Dott. Carlo Magelli) e Istituto di Cardiochirurgia, Università di Bologna (Prof. Angelo Pierangeli, Dott. Franco Dozza, dott. Nocchi) Policlinico S. Orsola ROMA: Centro Trombosi (Dott. Giuseppe Awisati, Dott. Paolo Arcieri) e Istituto di Cardiochirurgia, Università di Roma (Prof. Benedetto Marino, Dott. Giandomenico Di Nucci), Policlinico Umberto I TORINO: Centro Sorveglianza Anticoagulati, SIT Ospedale Maria Vittoria (Dott. Maurizio Molinatti) e Clinica Villa Maria Pia, Strada Mongreno n. 180 Torino (Sez. di Cardiochirurgia Dott. Marco Diena, Dott. Mario Bobbio; Cardiologo Dott. Bruno Maugeri) BOLOGNA: Servizio di Angiologia e Malattie della Coagulazione (Prof. Sergio Coccheri, Dott. Gualtiero Palareti) e Istituto di Cardiochirurgia, Università di Bologna (Prof. Angelo Pierangeli, Dott. 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