Evaluation of Initial Surgical Versus Conservative Strategies in Patients With Asymptomatic Severe Aortic Stenosis:

-Results from the CURRENT AS registry-

Tomohiko Taniguchi, MDKyoto 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, MDOn 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 Recommendationson 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.

Limitations1. 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.

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

Conservative group

1100 patients

Initial AVR group

905 patients

CURRENT AS registry: Flow ChartMulti-center, retrospective registry

Follow-up interval (median): 3.7 years2-year follow-up: 90%

Unknown symptomaticstatus: 2 patients

*AnginaSyncopeHeart failure

*

Baseline Characteristics in the entire cohort

Initial AVR groupConservative

groupP value

No. of patients 291 1517

Age (years) 71.6 ± 8.7 77.8 ± 9.4 <0.001

Age ≥80 years 17% 46% <0.001

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) <0.001

LVEF (%) 67 ± 10 66 ± 11 0.11

Peak aortic valve velocity (m/s)

4.8 ± 0.8 3.8 ± 0.7 <0.001

Mean aortic valve gradient (mmHg)

54 ± 20 33 ± 14 <0.001

AVA (cm2) 0.67 ± 0.16 0.79 ± 0.16 <0.001

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 <1.0cm2

Asymptomatic

1808 patients

Conservative group

1517 patients

Initial AVR group

291 patients

Symptomatic

2005 patients

Conservative group1100 patients

Initial AVR group905 patients

Main Analysis Set:

Propensity-score Matched Cohort

Initial AVR group

291 patients

Propensity-score matched cohort

Unknown symptomaticstatus: 2 patients

Initial AVR groupConservative

groupP value

No. of patients 291 291

Age (years) 71.6 ± 8.7 73.1 ± 9.3 0.047

Age ≥80 years 17% 16% 0.91

Male 43% 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 <0.001

AVA (cm2) 0.67 ± 0.16 0.75 ± 0.18 <0.001

Baseline Characteristics in the Propensity-score Matched Cohort

Se-ries1

0 20 40 60 80 100 120

Class-IIa

Other cardiac surgery

Rapid hemodynamic progres-sion

Active infective endocarditis

Class-IIa

Class-IIb

Indications for AVR in the initial AVR group

列 1

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%

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.

Surgical AVR or TAVI

Years after diagnosis

Cum

ula

tive inci

dence

(%

)

1 2 3 4 500

20

40

60

80

100

Log-rank P<0.001

Initial AVR group

Conservative group

Interval 0d 30d 180d 1y 3y 5y

Conservative group 　 　 　 　 　N of patients with at least 1 event 0 10 24 84 106

N of patients at risk 291 279 258 229 117 38Cumulative incidence 0% 3.7% 9.1% 35.8% 52.6%Initial AVR groupN of patients with at least 1 event 87 281 287

N of patients at risk 291 204 9 1Cumulative incidence 30.0% 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)

All-cause death

Interval 0d 30d 1y 3y 5y

Conservative group 　 　 　 　 　N of patients with at least 1 event 3 20 48 60N of patients at risk 291 279 252 178 72Cumulative incidence 1.1% 7.2% 17.9% 26.4%Initial AVR groupN of patients with at least 1 event 1 14 25 33N of patients at risk 291 286 266 188 75Cumulative incidence 0.3% 4.9% 9.0% 15.4%

Years after diagnosis

Cum

ula

tive in

cidence

(%)

1 2 3 4 500

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

Heart failure hospitalization

Interval 0d 30d 1y 3y 5yConservative group 　 　 　 　 　N of patients with at least 1 event 0 8 31 39N of patients at risk 291 279 246 161 63Cumulative incidence 0% 3.0% 13.0% 19.9%Initial AVR groupN of patients with at least 1 event 0 3 6 8N of patients at risk 291 286 264 185 75Cumulative incidence 0% 1.1% 2.4% 3.8%

Years after diagnosis

Cum

ula

tive inci

dence

(%

)

1 2 3 4 500

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

　Initial AVR

group(N=291)

Conservative group

(N=291)

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)<0.00

1

0.01 0.1 1 10 100

Secondary outcome measures

Initial AVR Strategy Better

Conservative Strategy Better

Cumulative 5-Year Incidence

EndpointsAdjuste

d HR

P value

All-cause death

Propensity-score matched cohort 0.64 0.02

Entire cohort 0.51<0.00

1

Heart failure hospitalizatio

n

Propensity-score matched cohort 0.19

<0.001

Entire cohort 0.21 <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

NYHA-3NYHA-2 NYHA-4Angina

Syncope

分類 1 Symptoms emerge

No Symptom

32% ( N = 492 )

NYHA unknown

Types of emerging symptoms and outcomes in the conservative group

Heart Failure

Conservative group (N=1517)

AVR

44%

NoAVR

NoAVR

AVR43%

NoAVR

AVR63%

NoAVR

AVR28%

NoAVR

NoAVR

15%

AVR Rate

AVR71%

AVR

Emergingsymptoms

Mortality

分類 1 分類 2 分類 3 分類 40

20

40

60

80

100

3850 52 48

6784

716 13 12 12 8

(%)

Angina SyncopeNo symptom NYHA-3NYHA-2 NYHA-4

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.

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.

Manuscript

Just AcceptedIn JACC!

To be coming soon !