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 Watchful waiting strategy 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.

CURRENT AS registry: Flow Chart Multi-center, retrospective registry Follow-up interval (median): 3.7 years 2-year follow-up: 90% Symptom related to AS  Angina  Syncope  Heart failure including dyspnea Symptom related to AS  Angina  Syncope  Heart failure including dyspnea

Baseline Characteristics in the entire cohort Initial AVR groupConservative groupP value No. of patients Age (years)71.6 ± ± 9.4<0.001 Age ≥80 years17%46%<0.001 Male43%40%0.27 Prior stroke (symptomatic)9%15%0.004 Coronary artery disease21%28%0.01 STS score (PROM), %2.0 ( )3.5 ( )<0.001 LVEF (%)67 ± 1066 ± Peak aortic valve velocity (m/s)4.8 ± ± 0.7<0.001 Mean aortic valve gradient (mmHg)54 ± 2033 ± 14<0.001 AVA (cm 2 )0.67 ± ± 0.16<0.001 CURRENT AS registry

Main Analysis Set: Propensity-score Matched Cohort CURRENT AS registry Symptom related to AS  Angina  Syncope  Heart failure including dyspnea Symptom related to AS  Angina  Syncope  Heart failure including dyspnea Conservative group 291 patients Initial AVR group 291 patients Propensity-score matched cohort

Initial AVR groupConservative groupP value No. of patients291 Age (years)71.6 ± ± 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 ( )2.4 ( )0.007 LVEF (%)67 ± 1068 ± Peak aortic valve velocity (m/s)4.8 ± ± 0.9<0.001 Mean aortic valve gradient (mmHg)54 ± 2045 ± 20<0.001 AVA (cm 2 )0.67 ± ± 0.18<0.001 Baseline Characteristics in the Propensity-score Matched Cohort CURRENT AS registry

Indications for AVR in the initial AVR group Formal Indications; 63%N= patients in the initial AVR group No formal indication; 37% N=107 Very severe AS AVR (I) Number of patients Formal Indications for AVR CURRENT AS registry

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. CURRENT AS registry

Surgical AVR or TAVI Years after diagnosis Cumulative incidence (%) 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. CURRENT AS registry Initial AVR group 287/291 patients (99%) AVR/TAVI interval: 44 days (median) Conservative group 118/291 patients (41%) AVR/TAVI interval: 780 days (median) Interval0 day30 days180 days1 year3 years5 years Conservative group N of patients with at least 1 event N of patients at risk Cumulative incidence0%3.7%9.1%35.8%52.6% Initial AVR group N of patients with at least 1 event N of patients at risk Cumulative incidence30.0%97.5%99.7% 97.5% 3.7% 0.5

All-cause death Interval0 day30 days1 year3 years5 years Conservative group N of patients with at least 1 event N of patients at risk Cumulative incidence1.1%7.2%17.9%26.4% Initial AVR group N of patients with at least 1 event N of patients at risk Cumulative incidence0.3%4.9%9.0%15.4% Years after diagnosis Cumulative incidence (%) % Conservative group 15.4% Initial AVR group Crude HR 0.60 ( ), P=0.009 Adjusted HR 0.64 ( ), P=0.02 Log-rank P=0.009 The results from the adjusted analysis conducted as a sensitivity analysis were fully consistent with those from the unadjusted analysis. Primary outcome measure CURRENT AS registry

Heart failure hospitalization Interval0 day30 days1 year3 years5 years Conservative group N of patients with at least 1 event N of patients at risk Cumulative incidence0%3.0%13.0%19.9% Initial AVR group N of patients with at least 1 event0368 N of patients at risk Cumulative incidence0%1.1%2.4%3.8% Years after diagnosis Cumulative incidence (%) % Conservative group 3.8% Initial AVR group Crude HR 0.18 ( ), P<0.001 Adjusted HR 0.19 ( ), 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 CURRENT AS registry

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

Endpoints Adjusted HR P value All-cause death Propensity-score matched cohort 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 BetterConservative 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. CURRENT AS registry Propensity-score matched cohort and Entire cohort

NYHA unknown Types of emerging symptoms Types of emerging symptoms and outcomes in the conservative group Conservative group N=1517 Angina Syncope NYHA class 4 AVR71% Proportion of patients who died with and without AVR No symptom CURRENT AS registry Heart Failure (%) Proportion of patients who underwent AVR SyncopeNo symptomAnginaNYHA class 2NYHA class 3NYHA class 4 NYHA class 3 NYHA class 2

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. CURRENT AS registry

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. CURRENT AS registry

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, Kitano Hospital 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 CURRENT AS registry