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

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.

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. 2

CURRENT AS registry: Flow Chart Multi-center, retrospective registry 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 < 1.0cm2 Asymptomatic 1808 patients Conservative group 1517 patients Initial AVR group 291 patients Symptomatic 2005 patients 1100 patients 905 patients Unknown symptomatic status: 2 patients Angina Syncope Heart failure * * Follow-up interval (median): 3.7 years 2-year follow-up: 90% 3

Baseline Characteristics in the entire cohort Initial AVR group Conservative group P value No. of patients 291 1517 Age (years) 71.6 ± 8.7 77.8 ± 9.4 <0.001 Age ≥80 years 17% 46% Male 43% 40% 0.27 Prior stroke (symptomatic) 9% 15% 0.004 Coronary artery disease 21% 28% 0.01 STS score (PROM), % 2.0 (1.4-3.3) 3.5 (2.1-5.4) LVEF (%) 67 ± 10 66 ± 11 0.11 Peak aortic valve velocity (m/s) 4.8 ± 0.8 3.8 ± 0.7 Mean aortic valve gradient (mmHg) 54 ± 20 33 ± 14 AVA (cm2) 0.67 ± 0.16 0.79 ± 0.16 4

Main Analysis Set: Propensity-score Matched Cohort 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 <1.0cm2 Asymptomatic 1808 patients Conservative group 1517 patients Initial AVR group 291 patients Symptomatic 2005 patients 1100 patients 905 patients Unknown symptomatic status: 2 patients Propensity-score matched cohort Initial AVR group 291 patients Conservative group 291 patients 5

Baseline Characteristics in the Propensity-score Matched Cohort Initial AVR group Conservative group P value No. of patients 291 Age (years) 71.6 ± 8.7 73.1 ± 9.3 0.047 Age ≥80 years 17% 16% 0.91 Male 43% 0.87 Prior stroke (symptomatic) 9% 8% 0.88 Coronary artery disease 21% 25% 0.20 STS score (PROM), % 2.0 (1.4-3.3) 2.4 (1.6-4.1) 0.007 LVEF (%) 67 ± 10 68 ± 8 0.06 Peak aortic valve velocity (m/s) 4.8 ± 0.8 4.4 ± 0.9 <0.001 Mean aortic valve gradient (mmHg) 54 ± 20 45 ± 20 AVA (cm2) 0.67 ± 0.16 0.75 ± 0.18 6

Indications for AVR in the initial AVR group 291 patients in the initial AVR group Formal Indications for AVR Class-I LVEF <50% Very severe AS No formal indication; 37% N=107 Formal Indications; 63% N=184 Number of patients 7

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. . 8

Surgical AVR or TAVI Initial AVR group 97.5% 287/291 patients (99%) 100 Initial AVR group Conservative group 97.5% 287/291 patients (99%) AVR/TAVI interval: 44 days (median) 80 Cumulative incidence (%) 60 Log-rank P<0.001 118/291 patients (41%) AVR/TAVI interval: 780 days (median) 40 20 3.7% 0.5 1 2 3 4 5 Years after diagnosis Interval 0d 30d 180d 1y 3y 5y Conservative group N of patients with at least 1 event 10 24 84 106 N of patients at risk 291 279 258 229 117 38 Cumulative incidence 0% 3.7% 9.1% 35.8% 52.6% Initial AVR group 87 281 287 204 9 1 30.0% 97.5% 99.7% 9

Primary outcome measure All-cause death 100 80 Crude HR 0.60 (0.40-0.88), P=0.009 Adjusted HR 0.64 (0.42-0.94), P=0.02 Cumulative incidence(%) 60 Log-rank P=0.009 40 26.4% Conservative group 20 15.4% Initial AVR group 1 2 3 4 5 Years after diagnosis Interval 0d 30d 1y 3y 5y Conservative group N of patients with at least 1 event 3 20 48 60 N of patients at risk 291 279 252 178 72 Cumulative incidence 1.1% 7.2% 17.9% 26.4% Initial AVR group 1 14 25 33 286 266 188 75 0.3% 4.9% 9.0% 15.4% The results from the adjusted analysis conducted as a sensitivity analysis were fully consistent with those from the unadjusted analysis. 10

Heart failure hospitalization Primary outcome measure Heart failure hospitalization 100 80 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 60 Cumulative incidence (%) 40 19.9% Conservative group 20 3.8% Initial AVR group 1 2 3 4 5 Years after diagnosis Interval 0d 30d 1y 3y 5y Conservative group N of patients with at least 1 event 8 31 39 N of patients at risk 291 279 246 161 63 Cumulative incidence 0% 3.0% 13.0% 19.9% Initial AVR group 3 6 286 264 185 75 1.1% 2.4% 3.8% The results from the adjusted analysis conducted as a sensitivity analysis were fully consistent with those from the unadjusted analysis. 11

Secondary outcome measures Cumulative 5-Year Incidence Initial AVR group (N=291) Conservative group Adjusted HR (95% CI) P value Cardiovascular death 9.9% 18.6% 0.59 (0.35-0.96) 0.03 Aortic valve-related death 5.3% 13.5% 0.42 (0.21-0.79) 0.006 Sudden death 3.6% 5.8% 0.43 (0.17-0.99) 0.049 Non-cardiovascular death 6.1% 9.6% 0.74 (0.37-1.45) 0.38 Emerging symptoms 3.2% 46.3% 0.06 (0.03-0.11) <0.001 Initial AVR Strategy Better Conservative Strategy Better 12

Adjusted Hazard Ratio for the Primary Outcome Measures Propensity-score matched cohort and Entire cohort Endpoints Adjusted HR P value All-cause death Propensity-score matched cohort 0.64 0.02 Entire cohort 0.51 <0.001 Heart failure hospitalization 0.19 0.21 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. 13

Types of emerging symptoms and outcomes in the conservative group Conservative group (N=1517) Emerging symptoms Heart Failure NYHA unknown AVR AVR 71% AVR Rate No symptom Angina Syncope NYHA-2 NYHA-3 NYHA-4 (%) Mortality 14

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. 15

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. 16

Manuscript Just Accepted In JACC! To be coming soon ! 17