1. Objective Bleeding events are grave and sometimes life threatening complications after prosthetic valve replacement, especially in hemodialysis patients. This study reviewed the bleeding events experienced after valve surgery in hemodialysis patients. 1

2. Methods 76 consecutive hemodialysis(HD) patients with prosthetic valve replacement (1991 ~ 2011) were retrospectively reviewed. 2

3. Patients Characteristics Age65.9±9.3 years Male42 (55%) Preoperative HD duration11.2±8.3 years Hypertension49 (64%) Hyperlipidemia8 (11%) Diabetes mellitus14 (18%) COPD8 (11%) PAD3 (4%) CVD8 (11%) LVD ｄ 53.8±8.4mm EF58.9±16.4% Infective endocarditis6 (8%) 3 HD:Hemodialysis, COPD: Chronic obstructive pulmonary disease, PAD: Peripheral artery disease CVD: Cerebral vessel disease, LVDd:Left ventricular dimension of diastric phase, EF: Ejection fraction

4. Operation AVR59 (78%) MVR22 (29%) Bioprosthetic valve16 (21%) Concomitant procedure Valve procedures25 (33%) AVR+MV repair10 (13%) AVR+MVR5 (6.6%) AVR+TAP4 (5.6%) MVR+TAP6 (7.9%) CABG17 (22%) Aortic procedure3 (3.9%) Modified Bentall5 (6.6%) 4 AVR: Aortic valve replacement, MVR: Mitral valve replacement, TAP: tricuspid valve annuloplasty CABG: Coronary artery bypass grafting

5. Morbidities and Mortality Re-exploration for bleeding4 (5.3%) Pneumonia4 (5.3%) Cerebral infarction3 (3.9%) Mediastinitis3 (3.9%) Sepsis14 (18%) 5 In-hospital death6 (8%) Sepsis3 (3.8%) Acute Cholangitis1 (1.3%) Perioperative myocardial infarction1 (1.3%) Aspiration pneumonia1 (1.3%)

6. Long-term survivals 764528168311 No. at risk 6 Mean follow up time: 3.6±2.2 years 2 years4 years6 years 77.0%±5.1%61.6%±6.4%41.9%±7.2%

7. Freedom from hemorrhage 7640231243 No. at risk Hemorrhagic events : 4.4% per patient-years 7 2 years4 years6 years 90.1%±3.9%87.1%±4.8%78.6%±7.2% Non HD patients, under 70 years-old, mechanical valve, our hospital 0.5% per patients-year

8. Freedom from cerebral infarctions 8 2 years4 years6 years 10096.7±3.392.5±5.2 7640231243 No. at risk Cerebral infarction: 1.1% per patient-years Non HD patients, under 70 years-old, mechanical valve, our hospital 0.7% per patients-year

9. Hemorrhagic events HemorrhageDeath 10 (13%)6 /10 6 Cerebral hemorrhage4/6 4 Intestinal hemorrhage2/4 9 Hemorrhage is a life threatening complications! The 60% of patients who had hemorrhage died of bleeding. PT-INR at the hemorrhage : 3.0 (One patient with cerebral hemorrhage) 6.1 (One patietnt with intestinal hemorrhage)

10. Univariate analysis for Hemorrhage (Cox proportional hazard model) Hazard Ratio95%CIP Female0.681 0.215 ~ 2.733 0.681 Age0.945 0.877 ~ 1.019 0.1397 Mechanical Valve0.325 0.071 ~ 1.477 0.1456 AVR3.049 0.385 ~ 24.157 0.291 MVR0.227 0.028 ~ 1.811 0.1616 Warfarin0.407 0.076 ~ 2.176 0.2934 10 Valve type or warfarization did not impact the hemorrhagic incidence.

11. Incidence of hemorrhage Non-HD patients – 1.20 ～ 1.60% per patient-year – Chan et. al: JTCS 2010;140:1053-8 – 0.36% per patient-year (22 cases/ 6180 patients-year) – Aupart MR et.al: J Heart Valve Dis. 2006 Nov;15(6):768-75 – 0.5% per patient-year (Under 70years old, Mechanical valve, Kumamoto Central hospital) HD patients – 4.4% per patient-years (in this study) 3~10 time higher than in non-HD patients. 11

12. Incidence of cerebral infarction Non-HD patients – 0.7% per patient-year (Under 70years old, Mechanical valve, our hospital) HD patients – 1.1% per patient-year (in this study) There seems to be no differences about incidence of cerebral infarction between Non-HD patients and HD patients. 12

13. Discussion PT-INR variability was significantly higher in HD patients than non-HD patients on warfarin. – Phelan PJ et al: Clin Nephrol. 2011;75(3):204-11 HD patients has higher risk of hemorrhage than non- HD patients after valve replacement. And the hemorrhages for HD patients are life threatening events. HD patients have similar risk of cerebral infarction to non-HD patients. HD patients after valve replacement might be controlled in mild anticoagulation with warfarin. 13

14. Conclusions HD patients had hemorrhagic risk of 4.4% per patient-years after valve replacement. This was 3~10 time higher than in non-HD patients. The hemorrhage was the life threatening events for HD patients after valve replacement. The incidents of cerebral infarction about HD patients were similar to those of Non-HD patients. HD patients after valve replacement might be controlled in mild anticoagulation with warfarin. 14

15. Bleeding events Sex Age (Operation) Operation Post operative duration (years) Valve typeWarfarin Bleeding sight Prognosis Male59 MVR 9.9Mechanical Yes IntestinalDead Male57 AVR 4.4Mechanical Yes CerebralDead Male54 AVR +Splenectomy 4.6Mechanical Yes IntestinalDead Female56 AVR 0.5Mechanical Yes CerebralAlive Male76 AVR 1.2Bioprosthesis No CerebralDead Female76 AVR+ MAP 0.1Bioprosthesis Yes IntestinalAlive Male54 Bentall 0.3Mechanical Yes CerebralDead Male58 AVR 3.1Mechanical Yes CerebralAlive Female69 AVR+ MAP 1.7Bioprosthesis No IntestinalAlive Female49 Bentall 0.3Mechanical Yes CerebralDead 15

16. Bleeding events HemorrhageDeath 10 /76 (13%)6 /10 6 Cerebral hemorrhage4/6 4 Intestinal hemorrhage2/4 16 Hemorrhage is a life threatening complications! The 60% of patients who had hemorrhage died of bleeding. Valve typeHemorrhage Bioprosthesis2/16 (13%) Mechanical valve8/60 (11%) WarfarinHemorrhage No2/12 (17%) Yes8 /64(13%) ・ There were no differences of hemorrhage frequencies observed between patients with bioprostheses and mechanical valves. ・ There were also no differences of hemorrhage observed between patients with warfarin and without that.

17. Bleeding events 10 cases (13%) were observed Cerebral bleedings 6 cases (4 cases → Dead) Gastrointestinal bleedings 4 cases (2 cases→ Dead) 60% of mortality : 6 patients of the 10 hemorrhagic cases were dead 17

18. Discussion Warfarization should be avoided among the hemodialysis patients – Clinical Guidelines for the Evaluation and the Treatment of Cardiovascular Complications in Hemodialysis Patients – : The Japanese society for dialysis therapy Bioprosthesis 18

19. Discussion Bioprosthesis : – Short time follow up, Small number No differences were observed in this study Bioprosthesis vs Mechanical valves Patients with warfarin vs patients without warfarin 19

20. Freedom from hemorrhage 7640231243 No. at risk Bleeding events : 4.4% per patient-years 20 2 years4 years6 years 90.1%±3.9%87.1%±4.8%78.6%±7.2%

21. Freedom from hemorrhage curve Warfarin vs Non warfarin 6437231343 123 No. at risk P=0.276 21

22. Freedom from hemorrhage curve Bioprosthesis vs Mechanical valves 4833211343 1561 No. at risk P=0.125 22