Intensity of oral anticoagulation after implantation of St. Jude Medical mitral or multiple valve replacement: lessons learned from GELIA (GELIA 5)

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1 European Heart Journal Supplements () 3 (Supplement Q), Q39 Q43 Intensity of oral anticoagulation after implantation of St. Jude Medical mitral or multiple valve replacement: lessons learned from GELIA (GELIA ) D. Pruefer, M. Dahm, G. Dohmen, D. Horstkotte, R. Bergemann 3 and H. Oelert Department of Cardiothoracic and Vascular Surgery, Johannes Gutenberg-University, Mainz, Heart Center North Rhine-Westphalia, Department of Cardiology, Bad Oeynhausen, and 3 Institute for Medical Outcome Research (IMOR), Loerrach, Germany Aims The purpose of the present analysis was to determine survival rate, and risk for thromboembolic and bleeding complications after mechanical heart valve replacement with St. Jude Medical mechanical heart (bileaflet) valves under differing regimens of postoperative anticoagulation. Method In the randomized German Experience with Low Intensity Anticoagulation (GELIA) study, 3 patients after mitral valve replacement and 8 patients after double valve replacement with a St. Jude Medical prosthesis were randomly assigned to three groups for postoperative oral anticoagulation: group A, target International Normalized Ratio (INR) range 3 4 ; group B, target INR range 4 ; and group C, target INR range 3. Results The various anticoagulation regimens had no significant impact on risk for bleeding or thromboembolism, or Introduction Thrombotic and thromboembolic complications are important causes of late morbidity and mortality in patients after prosthetic heart valve replacement. Although mechanical valves confer the advantage of long-term durability, they require life-long anticoagulation because of the thrombogenicity of mechanical substitutes. However, the anticoagulation treatment itself carries an inherent complication hazard []. The optimal level of anticoagulation has not yet been sufficiently determined. Most of the current recommendations are based on clinical results with an earlier generation of mechanical prostheses, which were associated with a relatively high incidence of thromboembolism. Correspondence: Diethard Pruefer, MD, Department of Cardiothoracic and Vascular Surgery, Johannes Gutenberg- University, Langenbeck-Str., D-3, Mainz, Germany. cumulative survival rate after mitral valve replacement. However, less intensive anticoagulation (target INR range 3 ) was associated with a significant decrease in cumulative survival rate after combined valve replacement, although analysis confirmed that 4% of these deaths were not valve related. Conclusion The results suggest that in terms of low-intensity anticoagulation an INR of 3 after mitral valve replacement and of 4 after double valve replacement (aortic and mitral) may be recommended when using the St. Jude Medical bileaflet prosthetic valve. (Eur Heart J Supplements ; 3 (Suppl Q): Q39 Q43) The European Society of Cardiology Key Words: Anticoagulant regimen, bleeding, heart valve prosthesis, survival rate, thromboembolism. Previous studies have shown that a low-dose anticoagulant regimen reduces anticoagulant-related bleeding, but does not increase the incidence of thromboembolic events [,3]. In order to consolidate those findings and establish the optimal level of anticoagulation, a large, multicentre, randomized study was initiated to prospectively follow patients implanted with a St. Jude Medical (SJM; St. Jude Medical, Inc., St. Paul, MN, U.S.A.) mechanical heart valve. The SJM mechanical valve prosthesis is a bileaflet mechanical valve that is constructed from pyrolytic carbon. Its central flow design offers a low transvalvular gradient and a high degree of thromboresistance. These attributes have been substantiated and documented in previous reports [4 ]. The present report presents the intent-to-treat analysis of the German Experience with Low Intensity Anticoagulation (GELIA). Therefore, analysis is based on assigned, not actual, ranges. It describes findings regarding survival rate, and postoperative risk for thromboembolic events and -X//Q39 + $3./ The European Society of Cardiology

2 Q4 D. Pruefer et al. Table 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 Transient, reversible within h Symptoms observed and treated I Transient, reversible within 4 h by the patient himself II Prolonged, reversible within days Symptoms observed by the patient II Significantly prolonged, but completely reversible and treated in an outpatient mode Prolonged, partly reversible, minimal functional impairment persisting 3 4 Prolonged, partly reversible, but some sequelae III Prolonged, limiting functional impairment persisting Symptoms leading to hospitalization III 9 Severe permanent impairment (severe handicap, persistent hospitalization/institutional care) 9 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 [8], adapted from the Karnofsky criteria [9] for neurological symptoms. *Modified performance status scale (PSS), which allows grading of persistent disabilities. bleeding complications after SJM mechanical heart valve (mitral valve, or combined aortic and mitral valve) replacement under various regimens of postoperative anticoagulation. Method In the GELIA study, patients were randomly assigned to one of three target International Normalized Ratio (INR) groups: group A, target INR range 3 4 ; group B, target INR range 4 ; and group C, target INR range 3. Patients with concomitant coronary surgery, reconstructive surgery of a second or third valve, emergency operations and valve replacement for infective endocarditis were included in this study in order to enhance the generalizability of the results. Because of the well-known greater incidence of thromboembolic events during the first 3 months after operation, patients were randomized after this time period. Immediate postoperative anticoagulation was performed according to the individual regimen of each hospital. INR measurements and complications for each patient were collected according to protocol. Cases in which it was impossible to determine whether the neurological symptoms were caused by bleeding or thromboemboli were considered separately (i.e. bleeding or thromboembolic events). The Karnofsky criteria were used to define complications (Table ). [8,9] Results Transient thromboembolic and haemorrhagic events are minor events, but are often under-reported because of their transient nature. Therefore, they are regularly overlooked by conventional follow-up techniques []. In this analysis, minor (grade I) thromboembolic and bleeding events were recorded, but are disregarded in the following discussion. The overall -year survival rates were 8 ± % after mitral valve replacement and 8 ± 4 % after combined valve replacement. The GELIA study could not demonstrate that risks for thromboembolic and bleeding events of grades II and III were related to the level of anticoagulation. Contrary to expectation, the actuarial -year survival rate (all-cause mortality) after multiple valve replacement was significantly lower in group C (target INR range 3 ) than in groups A or B. Mitral valve replacement During the follow-up period after mitral valve replacement, 4 out of 3 patients died of all causes. The cumulative - year survival rate was 8 ± %. The actuarial survival probabilities (Kaplan Meier survival analysis) after mitral valve replacement according to anticoagulation group are shown in Fig.. No statistically significant differences in survival probability were identified between groups A, B and C at the end of the follow-up period. During the -year follow-up period, 8 patients had thromboembolic events after mitral valve replacement. Of these, nine patients had severe (two grade II and eight grade III) events. The incidence of late thromboembolic and bleeding events is shown in Fig.. Linearized rates for grade II and III thromboembolic events are per patient-years and per patient-years, respectively. The incidence of severe bleeding events was 9 per patient-years for grade II and per patient-years for grade III. Comparison between the groups revealed no

3 Prosthetic valve thrombosis: lessons learned from GELIA Q4 Cumulative survival probability Patient years Figure Cumulative survival probability after St. Jude Medical mitral valve replacement (Kaplan Meier survival analysis). There was no significant difference in survival rate between the three anticoagulation regimens. INR=International Normalized Ratio. Incidence/ patient-years INR 4 significant differences between the three anticoagulation regimens with regard to bleeding or thromboembolic risk. Combined valve replacement Following the same procedure as in patients with mitral valve replacement, the actuarial survival rate at years was 8 ± 4 %. During this follow-up period, out of 8 patients died of all causes. The actuarial survival probabilities after multiple valve replacement according to anticoagulation group are shown in Fig. 3. Comparing the P > INR 3 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 9% Confidence interval INR 3 INR 4 Total Figure Incidence of major complications after St. Jude Medical mitral valve replacement. No significant differences in the risk for bleeding complications or thromboembolic events were observed between the three anticoagulation regimens. Cumulative survival probability Patient years P < Figure 3 Cumulative survival probability after St. Jude Medical combined valve replacement (Kaplan Meier survival analysis). Survival rate was significantly lower in group C (low-intensity anticoagulation group; target International Normalized Ratio [INR] range 3 ). Incidence/ patient-years INR 4 three group, we observed a significant increase in the rate for all-cause mortality in the lowest intensity anticoagulation group (group C, target INR range 3 ). The cumulative survival in group C was ± %, versus 89 ± 8% in group B and 9 9 ± 3% in group A (P < ). An additional investigation was unable to identify the cause of the differences between the groups in terms of survival rates, but did serve to confirm that more than % of the excess mortality in group C was not valve related (Table ). The incidence for late thromboembolic complications is shown in Fig. 4. Linearized rates for grade II and III thromboembolic events were per patient-years and INR 3 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 9% Confidence interval INR 4 INR 3 Total Figure 4 Incidence of major complications after St. Jude Medical combined valve replacement. No significant differences in the risk for bleeding complications or thromboembolic events were observed between the three anticoagulation regimens.

4 Q4 D. Pruefer et al. Table Causes of death for patients with combined valve replacement and randomized to low-intensity anticoagulation Description n % Non-valve-related Cardiac 3 3 Other Valve-related Bleeding 3 3 Unknown cause 3 3 Total 3 Patients were from group C, with a target International Normalized Ratio range of 3. per patient-years, respectively. The incidences of severe bleeding events were 8 per patient-years for grade II and 3 per patient-years for grade III. There was no statistically significant difference between the three groups with regard to the incidence of thromboembolic events or bleeding complications. Discussion Thromboembolism and anticoagulant-related haemorrhage are concerning late complications following mechanical heart valve replacement. It was previously recommended that oral anticoagulation should be managed to maintain an INR between 3 and 4 in patients who have undergone mechanical heart valve replacement []. More recent studies do not corroborate those recommendations [3,,3]. Those studies suggest that a lower level of anticoagulation reduces bleeding events, but does not increase the incidence of thromboembolism. On the basis of those observations, we assumed that an INR range of 3 would be the optimal after mitral valve replacement and that a range of 4 would be prudent after combined valve replacement [4]. The majority of these findings are from retrospective studies at a single centre. The method of data collection plays an important role. Studies conducted by Bodnar and Horstkotte [] demonstrated the inadequacy of data collected from retrospective questionnaires sent to patients. The most effective method of follow-up is a regular examination by a physician (cardiologist and/or neurologist) in order to reduce the number of false-negatives and -positives in the assessment of transient ischaemic attacks. Furthermore, the study population should be sufficiently large to achieve statistical significance in relation to the small number of thromboembolic and bleeding events. In the GELIA study the incidence of thromboembolic and bleeding events in both mitral and combined valve replacement was particularly low. The good anticoagulation management of the patients, particularly for those patients on self-management (3% of all GELIA patients), may account for this, as well as the favourable clinical performance of the SJM valve. The GELIA study was unable to detect significant differences in the risk for bleeding or thromboembolism between the three anticoagulation regimens. These data are very reliable, because the GELIA study was a prospective, large-scale, multicentre study. Furthermore, we found that low-level anticoagulation (target INR range 3 ) was associated with an increased all-cause mortality rate during the -year follow-up period for patients with double valve replacement. Additional statistical tests did not identify any impact of dependent factors (i.e. age, sex, left ventricular ejection fraction, arrhythmias) other than the surgical procedure itself. The resulting data indicate that the bleeding risk and the risk for thromboembolic events did not differ among the anticoagulation regimens, including group C (target INR range 3 ). The significantly higher mortality rate in group C is inexplicable. Nevertheless, this low level of anticoagulation should not be recommended after SJM multiple valve replacement. Conclusion Thrombosis, embolism and bleeding are still the most important late complications after heart valve replacement. The findings of the present prospective study suggest that the previous general recommendation of a target INR range of 3 4 is unnecessary after SJM mitral or combined valve replacement. The low thrombogenicity of the SJM prosthesis may permit the use of lower intensity anticoagulation. For patients who receive a mitral prosthesis, oral anticoagulation should be managed to maintain INR within the range 3, whereas after combined valve replacement a target INR range of 4 should be recommended. References [] Levine MN, Hirsh J, Landefeld S, Raskob G. Hemorrhagic complications of anticoagulant treatment. Chest 99; (suppl): 3S 3S. [] Katircioglu SF, Yamak B, Ulus AT, Tasdemir O, Bayazit K. Mitral valve replacement with St. Jude Medical prosthesis and low-dose anticoagulation in patients aged over years. J Heart Valve Dis 998; : 4 9. [3] Horstkotte D, Schulte H, Bircks W, Strauer B. Unexpected findings concerning thromboembolic complications and anticoagulation after complete year follow up of patients with St. Jude Medical Prostheses. J Heart Valve Dis 993; : 9 3. [4] Arom KV, Nicoloff DM, Kersten TE, Lindsay WG, Northrup WF. St. Jude Medical prosthesis: valve-related deaths and complications. Ann Thorac Surg 98; 43: 9 8. 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