Intensity of oral anticoagulation after implantation of St. Jude Medical aortic prosthesis: analysis of the GELIA Database (GELIA 4)

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1 European Heart Journal Supplements (2001) 3 (Supplement Q), Q33 Q38 Intensity of oral anticoagulation after implantation of St. Jude Medical aortic prosthesis: analysis of the GELIA Database (GELIA 4) C. Huth, A. Friedl and A. Rost, for the GELIA Study Investigator Group Department of Cardio-Thoracic Surgery, Otto-von-Guericke-University, Magdeburg, Germany Aims No prospective studies exist that define the ideal target International Normalized Ratio (INR) with respect to anticoagulation-related complications and survival rates after valve replacement with mechanical prostheses. The purpose of the present analysis is to determine optimal levels of anticoagulation for St. Jude Medical mechanical aortic prostheses (St. Jude Medical, Inc., St. Paul, MN, U.S.A.). Method Patients who received a St. Jude Medical mechanical prosthesis were randomized to three ranges of INR for postoperative oral anticoagulation: stratum A, INR ; stratum B, INR ; and stratum C, INR This intent-to-treat analysis is based on the assigned range, not the actual range. Results In total, 2024 patients with aortic valves were included in the German Experience with Low Intensity Anticoagulation (GELIA) study, with 672, 677 and 675 patients in strata A, B and C, respectively. The percentages of patients who achieved an INR within their target range in each stratum are as follows: Introduction During the early 1960s the first mechanical aortic valve was implanted [1,2]. This achievement was followed shortly thereafter by the first homograft implantation in 1962 [3] and the first stented bioprosthesis in 1965 [4]. Since then, changes in technology have improved haemodynamic and physiologic parameters, and durability of both the mechanical and bioprosthetic heart valve prostheses [5 7]. The primary advantage of mechanical prostheses is their durability. Bioprosthetic valves do not have the durability of mechanical valves, but have the advantage of not requiring Correspondence: Prof. Dr. med. Christof Huth, Klinik für Herz- und Thoraxchirurgie, Medizinische Fakultät, Otto-von-Guericke- Universität Magdeburg, Leipziger Straße 44, D Magdeburg, Germany. 43 3% in stratum A; 62 8% in stratum B; and 75 9% in stratum C. Patients who self-managed their anticoagulation therapy achieved an INR within their target range more often than did those who were managed by conventional methods. No statistically significant differences in adverse event rates were identified between strata. Conclusion A target INR range of is preferable to the usual range in reducing the number of severe bleeding complications in patients implanted with a St. Jude Medical prosthesis. Self-management of INR may result in better achievement of target INR levels. (Eur Heart J Supplements 2001; 3 (Suppl Q): Q33 Q38) 2001 The European Society of Cardiology Key Words: Aortic valve replacement, bleeding complications, German Experience with Low Intensity Anticoagulation (GELIA) study, low-intensity oral anticoagulation, thromboembolic events, St. Jude Medical prostheses, survival rate. lifelong anticoagulation. Regardless of type of prosthetic heart valve, aortic valve replacement with artificial valves has an overall morbidity and mortality rate of 3 5% per patient-year. The reported rates of late mortality in mechanical and biological prostheses are similar, at 2 4% per patient-year [8 11]. With regard to the frequency of thromboembolic events, including prosthetic thrombosis [12 14] and bleeding complications, published reports cite 2 4% per patient-year for bioprosthetic valves, whereas the rate is 1 2% higher for mechanical prostheses. The rate of valve degeneration or destruction with consecutive reoperations is 1 5% for mechanical valves, whereas the rate is 0 1% higher for biological prostheses [15 17]. The frequency of prosthetic endocarditis is similar for both types of valves, at a linearized rate of 1% [18,19]. Until now no data regarding the incidence of these problems in a population matched for age and comorbidity have been X/01/0Q $35.00/ The European Society of Cardiology

2 Q34 C. Huth et al. available. Standard oral anticoagulation therapy with a high target International Normalized Ratio (INR) range of is usually administered to patients following mechanical heart valve replacement with first-generation heart valves, and for newer valve types an INR of is recommended [20 22]. However, no prospective studies with warfarin alone exist that define an ideal or lower target INR with respect to anticoagulation-related complications and survival rates after valve replacement with mechanical prostheses. In the literature, warfarin therapy has often been combined with aspirin and/or dipyridamole [23 25]. Before 1998, with the publication of the American College of Cardiology/American Heart Association guidelines [20], a lower target INR of was generally accepted only for those patients with a high risk for suffering thromboembolic events without an artificial valve. Indeed, many European practitioners prefer a target INR range of , as recommended by the European Society of Cardiology in 1995 [21] for second-generation mechanical prosthetic heart valves. Anticoagulation therapy requires a careful balance. High INRs may result in complications such as gastrointestinal bleedings and intracerebral haemorrhages. In contrast, low INRs may result in thromboembolic events such as vascular complications caused by small thrombotic formations at the surface of an artificial valve, or haemodynamic problems associated with large thrombotic formations on the valve [12 14]. Anticoagulant-related complications and degeneration remain areas of concern for physicians and patients. Criteria for optimal valve selection remains controversial, and recommendations for both types of valve prostheses have constantly changed over the past 20 years because of technological developments (e.g. from ball, to tilting disc and to bileaflet prostheses; from stented to stentless bioprostheses; various fixation and preparation procedures) and identification of mid-term and long-term results and complications. In Germany the number of aortic valve implants increased from 974 in 1978 to 9644 in 1999 (Table 1) [26], during which time the proportion of implanted bioprostheses fluctuated between 20% and 30% of total. The use of bioprostheses during the past 5 6 years increased to 45% and is attributed to patients being older [26 28]. If an optimal INR range could be defined for mechanical heart valve patients ( optimal being defined as the range associated with the lowest incidence of complications and best long-term survival), then concerns regarding implantation of a mechanical valve would be minimized. The aim of the German Experience with Low Intensity Anticoagulation (GELIA) study was to define an optimal target INR range following routine implantation of a St. Jude Medical (SJM) prosthesis (St. Jude Medical, Inc., St. Paul, MN, U.S.A.) in patients with aortic, mitral, or combined aortic and mitral valve diseases. Methods The protocol for the GELIA study is described elsewhere [29]. Because the purpose of the GELIA study was to Table 1 Increase of aortic valve replacement and developments in the use of bioprostheses in Germany between 1978 and 1999 Mechanical % Year prostheses Bioprostheses Bioprostheses Data from Kalmar and Irrgang [26]. examine the most appropriate long-term anticoagulation regimen for SJM mechanical heart valve patients, it was necessary to include a generalizable patient sample. Therefore, patients with concomitant coronary surgery, reconstructive surgery of a second or third valve, emergency operations and valve replacement for infective endocarditis were eligible for randomization. Patients were randomized 3 months postoperatively when they were stabilized. Until then, anticoagulation was managed according to the individual regimen employed at each hospital. In the GELIA study, 2024 patients (71 3%) were randomized after aortic valve replacement with the SJM mechanical valve. Patients were randomized to three target ranges of INR for postoperative oral anticoagulation: stratum A, INR ; stratum B, INR ; and stratum C, INR Numbers of patients in each group and their characteristics are summarized in Table 2. INR measurements and complications were collected every 3 months per protocol. Complications were defined by Karnofsky criteria for neurological symptoms, and these criteria were adapted for other organ symptoms (Table 3) [29 31] because they are more sensitive than the traditionally used American Association of Thoracic Surgeons/Society of Thoracic Surgeons guidelines [15,16,32]. Cases in which it was impossible to determine whether the neurological symptoms were caused by bleeding or thromboemboli were considered as a separate group, termed bleeding or thromboembolism [29,33]. Males constituted approximately 69% of the aortic valve replacement patients in the GELIA study. Altogether, patients had a mean age of 60 4 years, mean weight of

3 Intensity of oral anticoagulation Q35 Table 2 Patient strata and characteristics Postoperative anticoagulation Stratum A Stratum B Stratum C Patient characteristic (INR ) (INR ) (INR ) n Male sex (%) Age (years) Weight (kg) Height (cm) Body mass index (kg. m 2 ) History of congestive heart failure (NYHA class IV [%] History of thromboemboli (%) Prior cardiac surgery (%) Preoperative anticoagulation (%) Concomitant ACB (%) Concomitant valve reconstruction (%) Emergency operation (%) Problems with prosthesis (%) Mean valve diameter (mm) Use of CAVG (%) Intraoperative complications (%) Postoperative bleeding (%) Permanent pacemaker implantation (%) Sinus rhythm at discharge (%) Postoperative complications total (%) Pre-, peri- and postoperative patient characteristics, and targeted International Normalized Ratio (INR) for oral anticoagulation after aortic valve replacement in the German Experience with Low Intensity Anticoagulation (GELIA) study. ACB=aorto-coronary bypass; CAVG=collagen-impregnated aortic valve graft; NYHA=New York Heart Association kg and mean height of cm, with a body mass index of 26 5 kg. m 2. Background medical history indicated congestive heart failure of New York Heart Association class IV in 21 5%, a history of preoperative thromboembolic events in 3 9%, prior cardiac surgery in 4 8% and preoperative anticoagulation therapy in 2 9%. No significant differences in these measures were identified between the three strata (Table 2). In addition, there were no significant differences with regard to perioperative data between the three strata (Table 2). Preliminary analysis consisted of three parts. First, the targeted, or assigned, INR range was compared with the actual INR range achieved by each patient. Second, a comparison was done according to the type of anticoagulation monitoring, either self-management by the patient or under the management of the physician. Finally, survival curves were established for each stratum. Results During the interval between preoperative inclusion of 2024 patients with aortic valves in the GELIA study and randomization into three oral anticoagulation groups 3 months postoperatively, 90-day mortality (including operative mortality) of 1 0% (n = 21) was observed. The first part of the oral anticoagulation assessment was the assessment of the difference between the intended and achieved INR by randomized group. In stratum A (target INR range ), only 43 3% of INR measurements were within the target range, with 4 1% above and 52 7% below the target range. In stratum B the results were significantly better; only 6 0% of INR results were above, 31 2% were below and 62 8% were within the target range. Stratum C exhibited further significant improvement; 13 8% of measurements were above, 10 8% were below and 75 9% were within the target range. Patients who undertook self-management of their anticoagulation achieved an INR within the target range a greater percentage of the time than did the physicianmanaged patients. For those patients who self-managed their anticoagulation, time in which INR was within the target range was 59 2%, 72 0%, and 83 1% in strata A, B and C, respectively. This was significantly better than the results with physician monitoring, at only 38 3%, 59 5% and 73 3% for strata A, B and C, respectively (Fig. 1). Frequency and the severity of bleeding and thromboembolic complications in each of the three strata were also analyzed according to the adapted Karnofsky criteria (Table 3) [29 31]. Bleeding complications (grade II) occurred at a linearized rate of %, with no statistically significant differences between the three groups. However, the frequency of severe bleeding complications (grade III) decreased from 0 75% to 0 25% with decreasing target range, without increase in thromboembolic events (grade II and III) or undetermined events (bleeding or thromboembolic events, grades II and III; Fig. 2). Finally, an analysis of survival rates for each of the three strata was conducted. No increase in late mortality was

4 Q36 C. Huth et al. Table 3 Grading of thrombotic, thromboembolic and haemorrhagic complications, and Karnofsky criteria for neurological symptoms Karnofsky criteria Adapted GELIA grading Score PSS score* Criteria for neurological symptoms Criteria for other organs Grade I 00 Transient, reversible within 6 h Symptoms observed and treated I 00 Transient, reversible within 24 h by the patient himself II 00 Prolonged, reversible within 10 days Symptoms observed by the patient II 00 Significantly prolonged, but completely reversible and treated in an outpatient mode Prolonged, partly reversible, minimal functional impairment persisting Prolonged, partly reversible, but some sequelae III Prolonged, limiting functional impairment persisting Symptoms leading to hospitalization III Severe permanent impairment (severe handicap, persistent hospitalization/institutional care) Direct/indirect fatal complication (as well as any prosthetic valve thrombosis or thromboembolic/bleeding complication necessitating surgical intervention) or blood transfusion, regardless of PSS score Grading of thrombotic, thromboembolic and haemorrhagic complications used in the German Experience with Low Intensity Anticoagulation (GELIA) study [29], adapted from the Karnofsky criteria [31] for neurological symptoms. *Modified performance status scale (PSS), which allows grading of persistent disabilities. INR results 100% 80% 60% 40% 20% 0% Physician Patient Stratum A INR Above target range Within target range Below target range Physician Patient Figure 1 International Normalized Ratio (INR) measurements for oral anticoagulation after aortic valve replacement with a St. Jude Medical prosthesis, according to target INR range. identified in patients with moderate (stratum B) or lower (stratum C) level of oral anticoagulation in comparison with the generally accepted higher anticoagulation level (stratum A). A tendency toward better survival rates was found for patients in strata B and C (Fig. 3). Discussion Changes in prosthesis design from ball valve and tilting disc valve to bileaflet valve, and changes in the blood contact Stratum B INR Physician Patient Stratum C INR Events per patient-year Stratum A INR Stratum B INR Stratum C INR Grade II bleeding events Grade III bleeding events Grade II bleeding or thromboembolic events* Grade III bleeding or thromboembolic events* Grade II thromboembolic events Grade III thromboembolic events *Not determined Figure 2 Frequency of thromboembolic and bleeding complications after aortic valve replacement with a St. Jude Medical prosthesis, according to target International Normalized Ratio (INR). surface material from titanium, silicon, delrin and dacron to carbon have not been able to counter the disadvantage of lifelong anticoagulation with mechanical heart valves [34 39]. Prospective studies in which anticoagulation was replaced by various platelet active drugs have shown that anticoagulation is the main factor in preventing thromboembolic complications [23 25]. The possibility of lowering the target INR safely was demonstrated in retrospective evaluations [40 42]. In a cohort of 600 consecutive patients who had undergone aortic, mitral, aortic and mitral, or triple

5 Intensity of oral anticoagulation Q37 Percentage Years Figure 3 Kaplan Meier survival curve after aortic valve replacement with a St. Jude Medical prosthesis, according to target range of International Normalized Ratio (INR). valve replacement with a SJM mechanical prosthesis, a lower rate of bleeding complications (without increased incidence of thromboembolic events) was observed in patients given moderate (INR ) anticoagulation in comparison with those on a strict (INR ) regimen [30]. Risk of degeneration requiring reoperation has been a disadvantage of bioprostheses, despite minor improvements in durability due to many changes in design, material, fixation, sterilization and antimineralization treatment [43 51]. This improvement qualifies bioprostheses for more frequent use in older patients, but the limited durability of bioprostheses with consequent need for reoperation remains a problem in younger patients. All preoperative thromboembolic events, bleeding complications and indications for anticoagulation are related to both patient and disease. Postoperatively, these events are related only to the implanted valve prostheses irrespective of the rhythm status, ventricular function or other non-valve-related indications for anticoagulation. No information is available regarding the incidence of thromboembolic and bleeding complications in a population of matched age and comorbidity without an artificial heart valve. In the GELIA study 3 9% of patients with aortic valve replacement had also suffered preoperative thromboembolic events, and 2 9% were orally anticoagulated with warfarin. In addition, that the postoperative percentage of patients in stable sinus rhythm at discharge was only 61 1% is noteworthy. In our opinion, all of these patients have a relative indication for oral anticoagulation, irrespective of the type of prosthesis. Conclusion We conclude that, in patients with single aortic valve replacement with a SJM bileaflet artificial valve, reducing anticoagulation therapy to a target INR range of decreases the number of severe bleeding complications in Stratum B INR Stratum C INR Stratum A INR comparison with the recommended INR range of The reduction in target INR range did not result in more severe thromboembolic complications following aortic valve replacement, irrespective of its origin, operative technique, prosthesis, rhythm disturbances or ventricular function [52], and did not affect the survival rate during the period of observation. A tendency toward better survival with moderate (INR ) and low (INR ) anticoagulation regimens following aortic valve replacement is possible. The problem with this first evaluation is the difference between the targeted and achieved INR range. The present evaluation is based on the targeted INR only. Patient selfmonitoring of anticoagulation therapy yielded better results than did physician monitoring, because self-managed patients in all three groups more often achieved an INR within the target range [53]. Irrespective of the type of monitoring, the best correlation between targeted and achieved INR occurred in stratum C (INR ). References [1] Harken DE, Soroff HS, Taylor WJ. Partial and complete prostheses in aortic insufficiency. J Thorac Cardiovasc Surg 1960; 40: [2] Starr A, Edwards ML, McCord CW, Grisworld HE. Aortic replacement: clinical experience with a semirigid ball-valve prosthesis. Circulation 1963; 27: [3] Ross DN. Homograft replacement of the aortic valve. Lancet 1962; 2: 487. [4] Binet JP, Duran CG, Carpentier A, Langlois J. Heterologous aortic valve transplantation. Lancet 1965; 2: [5] Aris A, Padro JM, Camara ML et al. The Monostrut Björk-Shiley valve. Seven years experience. 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