1. Evaluation of Initial Surgical Versus Conservative Strategies in Patients With Asymptomatic Severe Aortic Stenosis: -Results from the CURRENT AS registry- Tomohiko Taniguchi, MD Kyoto University Graduate School of Medicine Takeshi Morimoto, MD, MPH; Hiroki Shiomi, MD; Kenji Ando, MD; Norio Kanamori, MD; Koichiro Murata, MD; Takeshi Kitai, MD; Yuichi Kawase, MD; Chisato Izumi, MD; Makoto Miyake, MD; Hirokazu Mitsuoka, MD; Masashi Kato, MD; Yutaka Hirano, MD; Shintaro Matsuda, MD; Kazuya Nagao, MD; Tsukasa Inada, MD; Tomoyuki Murakami, MD; Yasuyo Takeuchi, MD; Keiichiro Yamane, MD; Mamoru Toyofuku, MD; Mitsuru Ishii, MD; Eri Minamino-Muta, MD; Takao Kato, MD; Moriaki Inoko, MD; Tomoyuki Ikeda, MD ; Akihiro Komasa, MD; Katsuhisa Ishii, MD; Kozo Hotta, MD; Nobuya Higashitani, MD; Yoshihiro Kato, MD; Yasutaka Inuzuka, MD; Chiyo Maeda, MD: Toshikazu Jinnai, MD; Yuko Morikami, MD; Ryuzo Sakata, MD and Takeshi Kimura, MD On behalf of the CURRENT AS registry Investigators

2. Disclosure Statement of Financial Interest I have nothing to declare. This study was funded by Kyoto University graduate School of Medicine, Department of Cardiovascular Medicine.

3. Current Guidelines Recommendations on Timing of AVR in Asymptomatic Patients with Severe AS Strategy of watchful waiting for AVR until symptoms emerge, except for several subgroups of patients such as those with left ventricular dysfunction or very severe AS. Limitations 1. Based on previous small single-center studies evaluating symptoms and/or AVR, but not mortality as the outcome measures. 2. No previous large-scale multicenter study comparing the initial AVR strategy with the conservative strategy.

4. 3815 consecutive patients with severe AS (Jan 2003 - Dec 2011, 27 centers in Japan) Peak aortic jet velocity > 4.0m/s or mean aortic pressure gradient > 40mmHg, or aortic valve area < 1.0cm 2 Asymptomatic 1808 patients Conservative group 1517 patients Initial AVR group 291 patients Symptomatic 2005 patients Conservative group 1100 patients Initial AVR group 905 patients CURRENT AS registry: Flow Chart Multi-center, retrospective registry Follow-up interval (median): 3.7 years 2-year follow-up: 90% Unknown symptomatic status: 2 patients * Angina Syncope Heart failure *

5. Baseline Characteristics in the entire cohort Initial AVR group Conservative group P value No. of patients 2911517 Age (years)71.6 ± 8.777.8 ± 9.4 <0.001 Age ≥80 years17 % 46 % <0.001 Male43 % 40 % 0.27 Prior stroke (symptomatic)9%9% 15% 0.004 Coronary artery disease21 % 28% 0.01 STS score (PROM), %2.0 (1.4-3.3)3.5 (2.1-5.4) <0.001 LVEF (%)67 ± 1066 ± 11 0.11 Peak aortic valve velocity (m/s)4.8 ± 0.83.8 ± 0.7 <0.001 Mean aortic valve gradient (mmHg)54 ± 2033 ± 14 <0.001 AVA (cm 2 )0.67 ± 0.160.79 ± 0.16 <0.001

6. Conservative group 291 patients 3815 consecutive patients with severe AS (Jan 2003 - Dec 2011, 27 centers in Japan) Peak aortic jet velocity >4.0m/s or mean aortic pressure gradient >40mmHg, or aortic valve area <1.0cm 2 Asymptomatic 1808 patients Conservative group 1517 patients Initial AVR group 291 patients Symptomatic 2005 patients Conservative group 1100 patients Initial AVR group 905 patients Main Analysis Set: Propensity-score Matched Cohort Initial AVR group 291 patients Propensity-score matched cohort Unknown symptomatic status: 2 patients

7. Initial AVR group Conservative group P value No. of patients 291 Age (years)71.6 ± 8.773.1 ± 9.3 0.047 Age ≥80 years17%16% 0.91 Male43% 0.87 Prior stroke (symptomatic)9%8% 0.88 Coronary artery disease21%25% 0.20 STS score (PROM), %2.0 (1.4-3.3)2.4 (1.6-4.1) 0.007 LVEF (%)67 ± 1068 ± 8 0.06 Peak aortic valve velocity (m/s)4.8 ± 0.84.4 ± 0.9 <0.001 Mean aortic valve gradient (mmHg)54 ± 2045 ± 20 <0.001 AVA (cm 2 )0.67 ± 0.160.75 ± 0.18 <0.001 Baseline Characteristics in the Propensity-score Matched Cohort

8. Indications for AVR in the initial AVR group Formal Indications; 63 % N=184 291 patients in the initial AVR group No formal indication; 37 % N=107 Very severe AS Class-I Number of patients Formal Indications for AVR LVEF <50%

9. Outcome Measures and Analysis Primary Outcome Measures All-cause death Heart failure hospitalization Secondary Outcome Measures Cardiovascular death Non-cardiovascular death Sudden death Emerging symptoms related to AS Analysis was performed in the intention-to-treat principle regardless of the actual performance of AVR.

10. Surgical AVR or TAVI Years after diagnosis Cumulative incidence (%) 12 34 5 0 0 20 40 60 80 100 Log-rank P<0.001 Initial AVR group Conservative group Interval0d30d180d1y3y5y Conservative group N of patients with at least 1 event0102484106 N of patients at risk29127925822911738 Cumulative incidence0%3.7%9.1%35.8%52.6% Initial AVR group N of patients with at least 1 event87281287 N of patients at risk29120491 Cumulative incidence30.0%97.5%99.7% 97.5 % 3.7 % 0.5 287 /291 patients (99 % ) AVR/TAVI interval: 44 days (median) 118 /291 patients ( 41 % ) AVR/TAVI interval: 780 days (median)

11. All-cause death Interval0d30d1y3y5y Conservative group N of patients with at least 1 event3204860 N of patients at risk29127925217872 Cumulative incidence1.1%7.2%17.9%26.4% Initial AVR group N of patients with at least 1 event1142533 N of patients at risk29128626618875 Cumulative incidence0.3%4.9%9.0%15.4% Years after diagnosis Cumulative incidence(%) 12 34 5 0 0 20 40 60 80 100 26.4 % 15.4 % Crude HR 0.60 (0.40-0.88), P=0.009 Adjusted HR 0.64 (0.42-0.94), P=0.02 The results from the adjusted analysis conducted as a sensitivity analysis were fully consistent with those from the unadjusted analysis. Primary outcome measure Conservative group Initial AVR group Log-rank P=0.009

12. Heart failure hospitalization Interval0d30d1y3y5y Conservative group N of patients with at least 1 event083139 N of patients at risk29127924616163 Cumulative incidence0%3.0%13.0%19.9% Initial AVR group N of patients with at least 1 event0368 N of patients at risk29128626418575 Cumulative incidence0%1.1%2.4%3.8% Years after diagnosis Cumulative incidence (%) 12 34 5 0 0 20 40 60 80 100 19.9 % 3.8 % Crude HR 0.18 (0.09-0.35), P<0.001 Adjusted HR 0.19 (0.09-0.36), P<0.001 Log-rank P<0.001 The results from the adjusted analysis conducted as a sensitivity analysis were fully consistent with those from the unadjusted analysis. Primary outcome measure Conservative group Initial AVR group

13. (N=291) Conservative group (N=291) Adjusted HR (95% CI) P value Cardiovascular death9.9%18.6% 0.59 (0.35-0.96)0.03 Aortic valve-related death5.3%13.5% 0.42 (0.21-0.79)0.006 Sudden death3.6%5.8% 0.43 (0.17-0.99)0.049 Non-cardiovascular death6.1%9.6% 0.74 (0.37-1.45)0.38 Emerging symptoms3.2%46.3% 0.06 (0.03-0.11)<0.001 Secondary outcome measures Initial AVR Strategy Better Conservative Strategy Better Cumulative 5-Year Incidence

14. Endpoints Adjusted HR P value All-cause death Propensity-score matched cohort 0.640.02 Entire cohort 0.51<0.001 Heart failure hospitalization Propensity-score matched cohort 0.19<0.001 Entire cohort0.21<0.001 Adjusted Hazard Ratio for the Primary Outcome Measures Initial AVR Strategy Better Conservative Strategy Better The favorable effect of the initial AVR compared with the conservative strategy was seen in both propensity-score matched cohort and the entire cohort. Propensity-score matched cohort and Entire cohort

15. NYHA unknown Types of emerging symptoms and outcomes in the conservative group Heart Failure Conservative group (N=1517) AVR Rate AVR 71 % AVR Emerging symptoms Mortality (%) AnginaSyncopeNo symptomNYHA-3NYHA-2NYHA-4

16. Limitations 1. Retrospective study design and variable patient follow-up We were unable to exclude the possibility of ascertainment bias for symptoms related to AS at the baseline. Patient follow-up might have been variable among participating centers. 2. Selection bias and residual confounding Propensity-score matching did not completely eliminate the impact of differences in the two groups. However, the results from the adjusted analysis were fully consistent with those from unadjusted analysis.

17. Conclusion The long-term outcome of asymptomatic patients with severe AS was dismal when managed conservatively in the real clinical practice, which might be substantially improved by the initial AVR strategy.

18. 27 Participating Centers Kyoto University Hospital Kokura Memorial Hospital Shimada Municipal Hospital Shizuoka City Shizuoka Hospital Kobe City Medical Center General Hospital Kurashiki Central Hospital Tenri Hospital Nara Hospital, Kinki University Faculty of Medicine Mitsubishi Kyoto Hospital Kinki University Hospital Kishiwada City Hospital Osaka Red Cross Hospital Koto Memorial Hospital Shizuoka General Hospital Nishikobe Medical Center Japanese Red Cross Wakayama Medical Center National Hospital Organization Kyoto Medical Center The Tazuke Kofukai Medical Research Institute, KitanoHospital Hikone Municipal Hospital Kansai Electric Power Hospital Hyogo Prefectural Amagasaki General Medical Center Rakuwakai Otowa Hospital Saiseikai Noe Hospital Shiga Medical Center for Adults Hamamatsu Rosai Hospital Japanese Red Cross Otsu Hospital Hirakata Kohsai Hospital

19. Manuscript Just Accepted In JACC! To be coming soon !