Open access

Valvular heart disease

Shiro Miura,‍ ‍ 1 Takehiro Yamashita,1 Michiya Hanyu,2 Hiraku Kumamaru,3Shinichi Shirai,4 Kenji Ando4

To cite: Miura S, Yamashita T,
Hanyu M, et al. Propensity
score-matched analysis ofpatients with severe aortic
stenosis undergoing surgicalaortic valve replacement. OpenHeart 2019;6:e000992.
doi:10.1136/
openhrt-2018-000992
Received 12 December 2018
Revised 22 March 2019
Accepted 26 April 2019

© Author(s) (or theiremployer(s)) 2019. Re-use
permitted under CC BY-NC. No
commercial re-use. See rights
and permissions. Publishedby BMJ.
1

Department of Cardiology,
Hokkaido Ono Memorial
Hospital, Sapporo, Japan
2
Cardiovascular Centre, Tazuke
Kofukai Foundation Medical
Research Institute, Kitano
Hospital, Osaka, Japan
3
Graduate School of Medicine,
The University of Tokyo, Tokyo,
Japan
4
Department of Cardiology,
Kokura Memorial Hospital,
Kitakyushu, Japan
Correspondence to
Dr Shiro Miura; ​shirotan1027m@​yahoo.​co.​jp

Abstract

Objective Severe aortic stenosis (AS) is one of the mostserious valve conditions. Patient demography and theaetiology of AS have substantially changed in the past
several decades along with a drastic improvement ofsurgical aortic valve replacement (SAVR) and its associatedprocedures. Contemporary patients with severe AS havemultiple comorbidities and live much longer. We aimed
to elucidate the treatment effects of SAVR on long-term
outcome in propensity score (PS)-matched and the entire
patient populations.
Methods We retrospectively reviewed 570 patients withsevere AS defined as an aortic valve area of 1.0 cm2 orless. Systemic differences in 39 baseline characteristics
between non-SAVR and SAVR groups were adjusted using
PS matching method. The endpoints included all-cause
mortality and cardiovascular events that included heart
failure, non-fatal stroke, syncope and acute coronary
syndrome.
Results Overall, 55% of the entire population (mean age
78 years; males 41%) were symptomatic. During 3.9 yearsof the median follow-up, 210 (36%) patients underwent
SAVR and 231 (41%) died. Cumulative incidences ofmortality and both mortality and cardiovascular eventswere significantly higher in the non-SAVR group than in
the other group (p<0.001, each). Among 101 PS-matchedpairs, SAVR correlated with a lower mortality risk (HR0.35; 95% CI 0.21 to 0.59; p<0.001)) and mortality andcardiovascular events combined (HR 0.62; 95% CI 0.42
to 0.92; p=0.02). However, survival difference between
both groups was markedly smaller among asymptomaticpatients in the subgroup of matched patients.
Conclusion Patients with AS undergoing SAVR exhibit
a lower incidence of all-cause mortality and major
cardiovascular events than those not undergoing surgicalinterventions, even after the baseline characteristics arebalanced by the PS matching. The correlation between
SAVR and survival from cardiovascular events is lessevident among asymptomatic patients.

Introduction
The prevalence of aortic stenosis (AS)increases with ageing, and AS is one of
the leading valve abnormalities. Recently,

Key questions
What is already known about this subject?
►► Among patients with severe symptomatic aortic ste-nosis (AS), surgical aortic valve replacement (SAVR)
has been demonstrated to improve survival compared with that in unoperated patients. However, asubstantial imbalance in terms of baseline characteristics, for example, comorbidities, cardiovascularrisks, valve severity, performance status (frailty) andsocioeconomic background, can exist between operated and unoperated patients.

What does this study add?
►► In this contemporary study, patients undergoing

SAVR exhibited a lower incidence of death and major cardiovascular events than medically treatedpatients, even after baseline characteristics werebalanced via propensity score matching. However,further studies are warranted to appropriately debate the appropriate indications, methods andtiming of surgical intervention for asymptomatic patients or for those with renal dysfunction.

How might this impact on clinical practice?
►► These findings can have substantial implications

for informed decision-making during the management of patients with severe AS among heat teammembers and those seeking advice on prognosis of
the critical disease. Our data are also more valuable
in terms of the efficacy of surgical interventions on
long-term clinical outcomes over medical management in the new era of transcatheter aortic valve
replacement.

degenerative AS, the most prevalent aetiology,
has rapidly increased, with a prevalence of
2%–7% in the population aged ≥65 years.1 2
In the past several decades, patients’ profiles
have shifted remarkably, with the aetiology
now dominated by senile calcific AS.3 Moreover, patients are more likely to comprisemarked comorbidities, such as multiple
organ dysfunctions and concomitant cardiovascular diseases, all independently affecting

Miura S, et al. Open Heart 2019;6:e000992. doi:10.1136/openhrt-2018-000992

1

Open Heart: first published as 10.1136/openhrt-2018-000992 on 21 May 2019. Downloaded from http://openheart.bmj.com/ on 28 May 2019 by guest. Protected by copyright.

Propensity score-matched analysis ofpatients with severe aortic stenosis
undergoing surgical aortic
valve replacement

Open Heart

Methods
Study design and patient enrolment
This retrospective, observational cohort study was
conducted at Kokura Memorial Hospital (Kitakyushu,
Japan). We reviewed the echocardiographic databasefor patients with severe AS who visited the hospital from
August 2009 to February 2012. We defined severe AS,
based on international guidelines, as an aortic valve area
(AVA) of ≤1.0 cm2 by transthoracic echocardiography.6
Initially, we identified 595 patients from the database.
Of these, 18 patients who underwent TAVR during thefollow-up period and 7 patients with lost follow-up data
were excluded; the remaining 570 subjects were includedin the final analysis (figure 1). The study was reviewed
and approved by the Institutional Review Board of
Kokura Memorial Hospital, Japan (Approval number:
201402210108).
2

Figure 1 A flowchart of primary findings in the study
population as severe aortic stenosis. AVA, aortic valve
area; PS, propensity score; SAVR, surgical aortic valve
replacement; TAVR, transcatheter aortic valve replacement.

Baseline characteristics and echocardiographic assessment
We collected comprehensive data, including patients’characteristics, medications and operational informationfrom chart reviews based on the definitions provided.
Activity level was defined as active if a patient lived an
independent life and as limited if a patient required
assisted care. Asymptomatic status was defined as no limitations of ordinary physical activity based on the New YorkHeart Association functional classification (NYHA class).
All patients underwent two-dimensional echocardiographic examinations, at least, once, during the study
period, by professional sonographers using commerciallyavailable cardiac ultrasound machines (Vivid 7 Dimension and Vivid E9, GE Healthcare, Horten, Norway; iE33,
Philips Medical Systems, Best, The Netherlands). Moreover, all patients who underwent SAVR received a preoperative echocardiographic examination within 1 monthof their respective operation date. We considered theserecords as the baseline characteristics of those undergoing SAVR. Doppler echocardiographic measurements
comprised the aortic mean pressure gradient using thesimplified Bernoulli equation and an AVA using a standard continuity equation;7 the severity of aortic regurgitation, mitral regurgitation and tricuspid regurgitation wasassessed per international guidelines.8
Clinical follow-up and endpoints
The primary endpoint was all-cause mortality. Cardiovascular events, including hospital admission fromworsened heart failure (HF), acute coronary syndrome,
syncope and non-fatal stroke, were defined as other end
points. We gathered information on clinical outcome
from patients, families or physicians, either in person or
by telephonic interviews. We followed all patients retrospectively until June 2015 to assess their survival status.
Perhaps, a time delay before a patient receives surgicaltreatment can account for marked survival advantages in
Miura S, et al. Open Heart 2019;6:e000992. doi:10.1136/openhrt-2018-000992

Open Heart: first published as 10.1136/openhrt-2018-000992 on 21 May 2019. Downloaded from http://openheart.bmj.com/ on 28 May 2019 by guest. Protected by copyright.

mortality, as we investigated previously.4 Surgical aortic
valve replacement (SAVR) is the most well-establishedtherapy for severe AS. Besides demographic changes inpatients with severe AS, remarkable advances in surgical
techniques and innovative equipment have facilitatedpatients with operative risks to undergo surgical procedures safely.
The last two decades have witnessed the launchingof minimally invasive transcatheter aortic valve replacement (TAVR) which was similar to SAVR with respect
to mortality in patients with severe AS at intermediate
operative risks.5 This less invasive therapy might not be acomplete alternative to SAVR, as simultaneous interventions on the mitral valve, coronary artery bypass grafting(CABG), are challenging in conjunction with TAVR,
and data on long-term device durability remain scarce.
In the modern era when aggressive interventions arerecommended to patients with severe AS, ascertaining
the efficacy and safety of surgical interventions for thecontemporary population of patients with severe AS
remains critical, as operative risks due to age and multiple
comorbidities and long-term complications, such as
structural valve deterioration, prosthetic valve endocarditis and anticoagulant-induced bleeding events, in surgically treated patients remain significant. Yet there exists,
for ethical reasons, a limited number of randomised
controlled trials. Thus, a well-organised, observational
cohort study comparing SAVR and medical management
should be designed with marked differences between
surgically treated and medically treated groups being
appropriately adjusted for their baseline risks.
Hence, this study aims to investigate the clinical impactof SAVR compared with nonsurgical treatment on
mortality and incidences of adverse cardiovascular eventsin patients with severe AS with adjustments by propensity score (PS) matching. Furthermore, the study assesses
the benefits of SAVR in various subgroups of our interest
within the matched population.

Valvular heart disease

Statistical analysis
Although we compared the distributions of continuous
variables using Student’s t-test or Wilcoxon rank-sum test,
χ² test was used for categorical variables. Continuous data
are presented as mean±SD for normally distributed variables or median values with 25th and 75th percentiles for
non-normally distributed variables, and categorical data
are presented as absolute numbers and percentages. For
survival analyses in both the entire population and thematched group, the Kaplan-Meier method was used toestimate the cumulative incidence of all-cause mortality
and cardiovascular events in three ways: mortality,
mortality and HF requiring admission and mortality
and cardiovascular events. Using the log-rank test, we
compared the survival and cumulative event-free survival
between both groups.
We evaluated patients’ PS, defined as the conditional
probability that a patient is assigned to the SAVR group
given the patient’s demographics, and measured thedisease status and comorbidities.9 We selected 39 baseline covariates: age, sex, body mass index, body surface
area, underweight, NYHA class III or IV, estimatedglomerular filtration rate (eGFR), hypertension, diabetes
mellitus, hyperlipidaemia, coronary artery disease,
peripheral vascular disease, previous myocardial infarction, peripheral vascular disease, previous HF admission,prior heart surgery, chronic lung disease, malignancy,
chronic liver disease, atrial fibrillation, haemodialysis
treatment, peptic ulcer disease, limited activity, current
smoker, aortic aneurysm or dissection, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker,
calcium channel blocker, antiplatelet therapy, anticoagulant, β-blocker, corticosteroid, AVA, mean aortic pressure
gradient, peak aortic velocity ≥4.0 m/s, left ventricularejection fraction, aortic regurgitation, mitral regurgitation, tricuspid regurgitation and EuroSCORE II. Then,
we matched non-SAVR and SAVR patients using PS anda greedy matching technique with a calliper of 0.2 SD of
the logit (PS).10 Furthermore, we assessed the balanceof the baseline characteristics’ distribution between thetwo groups by evaluating the standardised mean difference (SMD) as SMD ≤0.1 suggests a balanced distribution of factors between the two groups.11 By performing
subgroup analyses, we assessed the correlation between
treatment and mortality and cardiovascular events in thegroups of patients with prespecified risk factors at baseline of interests—advanced age (≥80 years), asymptomatic status, renal insufficiency (eGFR ≤30 mL/min/1.73cm2)) and a history of HF.
All statistical analyses were performed using STATA
V.14 (STATA, College Station, Texas, USA) and R Statistical Software (V.3.3.2; R Foundation for Statistical
Miura S, et al. Open Heart 2019;6:e000992. doi:10.1136/openhrt-2018-000992

Computing, Vienna, Austria). Furthermore, we considered p<0.05 (two-sided) as statistically significant.
Results
Clinical characteristics
During the observation period up to June 2015, 210
patients finally underwent SAVR and 360 were medically managed. The median interval between the enrolment and SAVR date was 121 days (IQR: 35–624 days).
Table 1 summarises the patients’ baseline characteristics. At enrolment, the average age was 79 years, 236
were males (41%), 314 (55%) were symptomatic and97 (17%) presented severe daily symptoms (NYHA class
III or IV). Regarding the AS severity assessments, SAVR
patients exhibited a more severe valve status at the preoperative period concerning the AVA (non-SAVR vs SAVR,
0.76 vs 0.67 cm2, p<0.001). For surgical intervention,
bioprosthetic valves were more frequently used (n=161,77%) than mechanical valves (n=44, 21%) and, notably,
49% of SAVR procedures were concomitant, including
CABG (20%), mitral valve replacement or repair (24%),
tricuspid valve replacement or repair (8%) and ascending
aorta replacement (6%).
Clinical outcomes
During the follow-up (median 3.9 years; IQR, 1.8–5.2
years), 231 (41%) patients died. The median follow-up
period was 3.5 years (IQR, 1.2–5.2 years) for the
non-SAVR group and 4.1 years (IQR, 2.7–5.1 years) for
the SAVR group. Based on the Kaplan–Meier survival
analysis (figure 2), SAVR patients exhibited 1-year, 3-year
and 5-year estimated survival rates (from each operationdate) of 91%, 87% and 84%, respectively, compared with
81%, 57% and 43% in the non-SAVR group. Overall,survival and event-free survival rates were significantly
higher in the SAVR group compared with the non-SAVR
group during the follow-up period (p<0.001). Table 2
presents detailed clinical outcome data between the twogroups. The rate of patients with HF admission was higher
in the non-SAVR group within a 3-year period, whereas
rates were similar during the complete follow-up period(non-SAVR, 38% and SAVR, 36%). We observed a gradualincrement in the percentage of non-SAVR patients whodeveloped syncope during the follow-up compared with
<1% of SAVR patients having syncope following SAVR.
Clinical outcome and subgroup analysis in PS-matchedpatients
The distribution of created PS is presented in figure 3A,
and PS matching yielded 101 matched pairs of patientsfrom both groups with a c-statistic of 0.90. Furthermore,
SMD was demonstrated in the unmatched and matchedpatients, highlighting that PS matching successfully
decreased the SMD for 34 variables to an absolute valueof ≤0.1 (figure 3B). In the non-SAVR group, 101 patients
exhibited a markedly lower survival and cumulative
event-free survival than 101 patients in the SAVR group(figure 4). In addition, these risks were significantly
3

Open Heart: first published as 10.1136/openhrt-2018-000992 on 21 May 2019. Downloaded from http://openheart.bmj.com/ on 28 May 2019 by guest. Protected by copyright.

the SAVR group. Hence, we defined the operation dateas day 1 for the follow-up of the SAVR group, whereas thefollow-up started on the day of index echocardiography(enrolment) for the non-SAVR group.

Open Heart

Variables

Entire cohort

Non-SAVR

SAVR

N=570

N=360

N=210

P value*

Clinical demographics Age, years

78.6 (9.0)

80.9 (8.3)

74.6 (8.8)<0.001 Age >80 years

297 (52)

224 (62)63 (30)<0.001 Male sex

236 (41)142 (39)

94 (45)0.22 BMI, kg/m2

22.1 (3.4)

21.6 (3.4)

22.8 (3.2)<0.001 Underweight (BMI <18.5 kg/m2)

83 (15)72 (20)11 (5)<0.0011.47 (0.17)

1.44 (0.16)

1.51 (0.18)<0.001<0.001

2 BSA, m Symptom at enrolment NYHA class I

256 (45)167 (46)

61 (29) NYHA class II

217 (38)

121 (34)

123 (59) NYHA class III

85 (15)63 (18)23 (11) NYHA class IV

12 (2)

9 (3)

3 (1)

 Hypertension

175 (31)251 (70)

144 (69)

0.78 Diabetes

155 (27)

95 (26)60 (29)0.63 Dyslipidaemia

229 (40)133 (37)

96 (46)0.04 Hyperuricaemia

63 (11)40 (11)23 (11)

1.00 Prior heart failure

205 (36)

117 (33)

88 (42)0.03 Coronary artery disease

230 (40)155 (43)

75 (36)0.09 Old myocardial infarction

78 (14)60 (17)18 (9)

0.01 Previous heart surgery

100 (18)73 (20)27 (13)0.03 eGFR (mL/min/1.73 cm2)

32 (20)27 (19)40 (20)<0.001  Renal insufficiency

270 (47)

211 (59)

59 (28)<0.001  
Haemodialysis

69 (12)49 (14)20 (10)0.18 Chronic lung disease

61 (11)39 (11)22 (11)

1.00 Previous stroke77 (14)54 (15)24 (11)0.26 Atrial fibrillation

105 (18)68 (19)37 (18)0.74 Peripheral vascular disease

83 (15)66 (18)17 (8)0.001 Aortic aneurysm or dissection

40 (7)

27 (8)

13 (6)

0.61 Malignancy

78 (14)61 (17)17 (8)

0.003 Chronic liver disease

25 (4) Peptic ulcer disease

43 (8) Limited activity

110 (19) Current smoker

36 (6) EuroSCORE II (%)† STS score (PROM) (%)†

16 (4)

9 (4)

1.00

13 (6)

0.41

103 (29)7 (3)<0.00122 (6)

14 (7)

0.86

3.3 (2.0–5.4)

3.8 (2.6–6.2)

2.3 (1.5–3.9)<0.0014.2 (2.8–6.6)

4.9 (3.4–7.5)

3.1 (1.9–4.1)<0.00130 (8)

Medication use Antiplatelet

290 (51)

192 (53)

98 (47)0.14 
β-blocker

144 (25)

88 (24)56 (27)0.55 ACE inhibitor or ARB

324 (57)

145 (40)101 (48)0.08 Statins

202 (35)

118 (33)

84 (40)0.09 Calcium channel blockers

246 (43)

165 (46)

81 (39)0.10 Anticoagulant

132 (23)82 (23)50 (24)0.84 Corticosteroids
Echocardiographic assessment

14 (3)

11 (3)3 (1)0.27
Continued

4

Miura S, et al. Open Heart 2019;6:e000992. doi:10.1136/openhrt-2018-000992

Open Heart: first published as 10.1136/openhrt-2018-000992 on 21 May 2019. Downloaded from http://openheart.bmj.com/ on 28 May 2019 by guest. Protected by copyright.

Table 1 Baseline characteristics of the study patients according to the treatment

Valvular heart disease

Variables

Entire cohort

Non-SAVR

SAVR

N=570

N=360

N=210

P value* Left ventricular ejection fraction (%)

61 (12)60 (13)62 (11)

0.04 Aortic valve area (cm2)0.73 (0.18)

0.76 (0.18)

0.67 (0.15)<0.001 Peak aortic velocity (m/s)

3.7 (0.9)

3.4 (0.9)

4.3 (0.8)<0.001 Peak aortic velocity >4.0 m/s

233 (41)90 (25)143 (68)<0.001 Mean aortic gradient (mm Hg)

34 (19)29 (18)45 (19)<0.001 Aortic regurgitation (grade III–IV)

35 (6)

17 (5)

18 (9)

0.14 Mitral regurgitation (grade III–IV)

44 (8)

23 (6)

21 (10)0.87 Tricuspid regurgitation (grade III–IV)

44 (8)

28 (9)

16 (9)

1.00

Surgical procedure Valve profile Bioprosthetic valve, n (%)

161 (77) Mechanical valve, n (%)

44 (21) Unknown

5 (2) Associated procedures, n (%)

102 (49) Coronary artery bypass grafting

43 (20) Mitral valve replacement or repair

50 (24) Tricuspid valve replacement or repair Ascending aorta replacement

17 (8)
13 (6)*P value refers to comparisons between the non-SAVR group at enrolment and the SAVR group at operation.
†Median and IQR. Data are mean (SD) or n (%).
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; BSA, body surface area; NYHA
class, New York Heart Association functional classification; PROM, predicted risk of mortality; SAVR, surgical aortic valve replacement; STS,
Society of Thoracic Surgery; eGFR, estimated glomerular filtration rate.

higher in the non-SAVR group compared with the SAVR
group (HR 0.35, 95% CI 0.21 to 0.59, p<0.001, for all-cause
mortality; HR 0.53, 95% CI 0.34 to 0.82, p=0.004, for HF
hospitalisation and mortality; HR 0.62, 95% CI 0.42 to
0.92, p=0.02, for cardiovascular events and mortality).
We performed a subgroup analysis for the PS-matched
population (table 3). Patients aged ≥80 years (non-SAVR
vs SAVR: HR 0.35; 95% CI 0.21 to 0.34; p<0.001), withcardiac symptoms (NYHA class II–IV; HR 0.19; 95% CI
0.10 to 0.37; p<0.001) or a history of admission due to
HF (HR 0.38; 95% CI 0.19 to 0.78; p=0.009) exhibiteda significant correlation with the survival benefit during

Figure 2 Cumulative event-free survival curves between
the non-SAVR (n=360) and SAVR (n=210) groups in the entire
population regarding (A) all-cause mortality, (B) all-cause
mortality and heart failure hospitalisation and (C) all-cause
mortality and cardiovascular events. SAVR, surgical aortic
valve replacement.
Miura S, et al. Open Heart 2019;6:e000992. doi:10.1136/openhrt-2018-000992

the follow-up period, although it was not significant in
the population without cardiac symptoms (HR 0.83; 95%
CI 0.38 to 1.84; p=0.66) or with renal insufficiency (HR0.60; 95% CI 0.33 to 1.07; p=0.09).
Discussion
This study established that SAVR markedly correlatedwith the survival improvement and prevention of major
cardiovascular events compared with medical treatments
during the follow-up period in both the entire severe AS
and PS-matched populations. In a few recent studies,
researchers attempted to more precisely investigate thetreatment effect of SAVR on long-term outcome withina well-balanced sample. Pai et al reported that SAVR
correlated with a survival benefit in three of the four
strata produced by the PS stratification method.12 Theirfindings are consistent with those of the present study,
although approximately 55% of our population was symptomatic and there was a delay between the diagnosis and
SAVR along with a possible baseline characteristic imbalance between the two groups. In addition, we observedthat the overall survival rates of both groups were higher
than a prior study in which the 1-year, 2-year and 5-year
survival rates among 277 patients with severe AS were87%, 78% and 68% in the SAVR group and 52%, 40%
5Open Heart: first published as 10.1136/openhrt-2018-000992 on 21 May 2019. Downloaded from http://openheart.bmj.com/ on 28 May 2019 by guest. Protected by copyright.

Table 1 Continued

Open HeartTime (years)
Clinical events

1 (%)

2 (%)

3 (%)

Total in group (%)

Total

P
value*

All-cause death

Non-SAVR
SAVR

18.9
8.6

31.7
11.9

42.5
12.4

55.6
14.8

40.5%

<0.001

HF admission

Non-SAVR

15.6

24.7

32.8

37.8

37.0%

<0.001

SAVR

5.7

7.1

8.6

35.7

Non-SAVR

2.5

6.1

7.5

9.7

8.6%

0.49

SAVR

3.3

4.3

5.7

6.7

Non-SAVR

1.7

2.8

4.2

5.0

3.3%

0.002

SAVR

0.0

0.0

0.0

0.5

Non-SAVR
SAVR

0.8
0.5

0.8
0.5

1.4
0.5

1.4
1.4

1.4%

0.42

Nonfatal stroke
SyncopeACS*P value refers to comparisons of event rates between the non-SAVR and SAVR groups at 3 years. Data are % values.
ACS, acute coronary syndrome; HF, heart failure; SAVR, surgical aortic valve replacement.

and 22% in the non-SAVR group, respectively; notably,
their population comprised an older population (averageage, 85 years) and more advanced stenosis (defined as
AVA≤0.8 cm2).13 Bach and his colleagues reported thatthe mortality rate of symptomatic patients with severe AS
and relatively low-operative risk based on the EuroSCORE
II who did not undergo SAVR was 53% at 3 years.14 The
long-term outcome in this study seemed more reassuring
at the 3-year mark, with a mortality of approximately
17% in the SAVR group. Regarding short-term mortality,
SAVR-related operative risks have declined over the lasttwo decades, although patients receiving SAVR are now
much older and with a higher prevalence of comorbidities.15 Studies have estimated a 30-day mortality of <3%
for isolated SAVR and <4.5% for combined SAVR and
CABG.16 Our study obtained a remarkable achievement
rate for 30-day mortality as only 5 (2%) of 210 patientsdied within 30 days of SAVR, in which 49% of SAVR
patients underwent concomitant surgical procedures,such as mitral valve replacement or CABG.
Limited data are currently available on detailed clinical events in patients with severe AS, especially among
those who underwent SAVR.17 Our study elucidated thebreakdown of cardiovascular events during the follow-up
period less optimistically. In fact, admission for HF was
the leading adverse event in both groups and was markedly different at 3 years. However, during the entire
follow-up period, the admission rate for HF in the SAVR
group reached 36%, which corroborated the non-SAVR
group (38%). The findings of a few previous studies12
are consistent with this study, although almost 55% of
our population was symptomatic and there was a delay
between the diagnosis and SAVR along with a possible
baseline characteristics imbalance between the twogroups. These remarkable findings of high readmission
rates in SAVR patients may be explained by two primary
6

factors: increases in valve-related events and establishedmyocardial damage affecting postoperative outcomes.
There are clinical issues with valve deterioration anddurability and increased risk of valve-related events suchas prosthetic valve endocarditis and thrombosis. Andrew
and colleagues18 reported that patients with AS withsevere diastolic dysfunction have more diffuse myocardial
fibrosis detected on equilibrium contrast cardiovascular
MRI, indicating that the regression of left ventricular
hypertrophy 6 months following SAVR is due to cellularrather than ﬁbrosis resolution. Therefore, we can speculate that a complete reversible change in the cardiac
function before and after SAVR cannot be expectedin patients with AS in whom myocardial damage hascompletely developed. Further studies are warranted
to explore the potential mechanisms of HF in patients
undergoing SAVR.
Additionally, our subgroup analysis with createdPS-matched samples added new findings that these positive correlations remained substantial among patients
aged ≥80 years, even in symptomatic patients or those witha history of HF admission. Likewise, this study revealed
that a correlation between SAVR and survival decreased
among asymptomatic patients and those with renal insufficiency. It is typically accepted from the current guidelines that the symptom development is a vital indication
for intervention, whether surgical or transcatheter. A
recent comprehensive study using the Japanese population recommended early intervention in selected asymptomatic subjects with AS because long-term outcomes ofsymptomatic patients were worse than those of asymptomatic patients.19 In fact, some groups of patients with AS
processed the decompensation without any complaints
at daily practice because of frailty, cognitive disorder orworkload avoidance. Of note, an appropriate assessmentof the symptomatic status can be challenging, especially
Miura S, et al. Open Heart 2019;6:e000992. doi:10.1136/openhrt-2018-000992

Open Heart: first published as 10.1136/openhrt-2018-000992 on 21 May 2019. Downloaded from http://openheart.bmj.com/ on 28 May 2019 by guest. Protected by copyright.

Table 2 Yearly rates according to clinical events during the follow-up period between the non-SAVR (n=360) and SAVR
(n=210) groupsValvular heart diseasein elderly patients who commonly have impaired physicalmobility and cognitive impairment.20 Thus, a systematic
strategy to assess symptoms among elderly patients with
AS is warranted to avoid underestimation. Moreover,Figure 4 Cumulative event-free survival curves between
the non-SAVR (n=101) and SAVR (n=101) groups in the PSmatched population regarding (A) all-cause mortality, (B)all-cause mortality and heart failure hospitalisation and (C)all-cause mortality and cardiovascular events. PS, propensity
score; SAVR, surgical aortic valve replacement.
Miura S, et al. Open Heart 2019;6:e000992. doi:10.1136/openhrt-2018-000992

some studies reported that patients with AS and preoperative renal dysfunction exhibited an increased operativerisk for SAVR,21 with acute kidney injury following SAVR
occurring in 3.4%–43% of SAVR cases. Reportedly, the30-day mortality for these patients was 5.5%–46%.22 In
patients with pre-existing renal dysfunction, valve replacement with mechanical prostheses poses a higher risk for
anticoagulation-related complications, whereas bioprosthetic replacement might be complicated by accelerationin structural valve deterioration.23 Hence, further studies
are warranted to elucidate the appropriate indications,
methods and timing of intervention for patients withsevere AS and renal dysfunction.
Study limitations
This relatively large cohort study holds several limitations. First, selection bias should be considered in thisnon-randomised study which could account for massive
7

Open Heart: first published as 10.1136/openhrt-2018-000992 on 21 May 2019. Downloaded from http://openheart.bmj.com/ on 28 May 2019 by guest. Protected by copyright.

Figure 3 Distributions of PS between the non-SAVR (n=360) and SAVR (n=210) groups (A). The SMD of the 39 selectedbaseline variables before and after PS matching (B). AAD, aortic aneurysm or dissection; ACEI, angiotensin-converting enzyme
inhibitor; ARB, angiotensin II receptor blocker; AF, atrial fibrillation; AR, aortic regurgitation; ASA, antiplatelet; AVA, aortic valve
area; BB, β-blocker; BMI, body mass index; BSA, body surface area; CAB, calcium channel blocker; CAD, coronary arterydisease; CLD, chronic lung disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HD, haemodialysis;
HTN, hypertension; HLP, hyperlipidaemia; HF, heart failure; HS, prior history of cardiac surgery, HU, hyperuricaemia; LA, limited
activity; LVEF, left ventricular ejection fraction; MPG, mean aortic gradient; MR, mitral regurgitation; NYHA34, New York Heart
Association class III or IV; OMI, old myocardial infarction; PVD, peripheral vascular disease; PS, propensity score; PUD, peptic
ulcer disease; SAVR, surgical aortic valve replacement; SMD, standardised mean differences; SMK, current smoker; TR,
tricuspid regurgitation; Vmax4, peak aortic velocity >4.0 m/s.

Open Heart

Death

Death and HF

Subgroup

NonSAVRSAVR

HR (95% CI)

P valueHR (95% CI)

All matched patients

101

101

0.35 (0.21 to 0.59)<0.001

Over 80 years

46

42

0.13 (0.05 to 0.34)<0.001

Symptomatic

56

62

0.19 (0.10 to 0.37)

Asymptomatic

45

390.83 (0.38 to 1.84)

Renal insufficiency

49

37

Prior HF admission

34

38

Death and cardiovascular events
P value HR (95% CI)

P value

0.53 (0.34 to 0.82)

0.004

0.62 (0.42 to 0.92)

0.02

0.31 (0.16 to 0.60)<0.0010.42 (0.23 to 0.77)

0.01<0.0010.34 (0.20 to 0.59)<0.0010.37 (0.23 to 0.62)<0.001

0.66

0.99 (0.48 to 2.03)

0.97

1.17 (0.60 to 2.28)

0.65

0.60 (0.33 to 1.07)

0.09

0.72 (0.42 to 1.24)

0.24

0.74 (0.44 to 1.25)

0.26

0.38 (0.19 to 0.78)

0.01

0.44 (0.23 to 0.82)

0.01

0.42 (0.23 to 0.76)

0.004

HF, heart failure; SAVR, surgical aortic valve replacement.

confounding by indication between both groups. Thus,
besides a crude comparison, we applied the PS-mediated analysis to adjust for selection bias and potential
confounding factors rigorously, although a room still
remains for discussion regarding the variable selection
and manipulation for a fairer comparison of the processof obtaining these findings. Second, the matching
method, while attaining a more well-balanced matching,decreased the matched sample population by almost 50%
in the SAVR group, that might affect its generalisability.
Finally, being a single-centre, retrospective, observational
study, our findings might, therefore, not be generalised
to other facilities within or outside of Japan. However,
our heart centre is the only largest cardiovascular facility
in the area, and almost all patients with diseased valvespotentially warranting surgical intervention are referred
to us for the comprehensive examination and follow-up
without much selection. Consequently, a relatively large
number of patients with severe AS were successfully
reviewed in a short period along with comprehensive
records of patients’ characteristics.
Conclusion
This study establishes a correlation between SAVR and alower incidence of both all-cause mortality and adverse
cardiovascular events during the total follow-up periodof 3.9 years in the 570 patients with severe AS and thePS-matched population. The patients with severe AS
undergoing SAVR and concomitant surgical procedures
were related to a 65% risk reduction of mortality and 38%
risk reduction of adverse cardiovascular events comparedwith the medically treated cohort following rigorous
adjustment for baseline characteristics. Notwithstanding,sufficient room exists to consider surgical indications,procedure types and timing for severe AS in asymptomatic patients. These findings have significant implications for informed decision-making during the management of patients with severe AS.
Acknowledgements The authors would like to thank Dr Alan Kimber for his
guidance and interest in this study along with the continued support of the staff
from Faculty of Social, Human and Mathematical Sciences in the University ofSouthampton.

8

Contributors SM had full access to all the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data analysis.
Acquisition, analysis or interpretation of data: all authors. Drafting of themanuscript: SM. Critical revision of the manuscript for important intellectual
content: HK, TY. Administrative, technical or material support: SS, MH. Studysupervision: KA.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-for-profit sectors.
Competing interests HK is affiliated with the Department of Healthcare Quality
Assessment at the University of Tokyo, a social collaboration department supportedby the National Clinical Database, Johnson & Johnson K.K. and Nipro Co. The
remaining authors have no conflicts of interest to declare.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in thearticle or uploaded as supplementary information.
Open access This is an open access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non-commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/.

References

1. Lindroos M, Kupari M, Heikkilä J, et al. Prevalence of aortic valve
abnormalities in the elderly: an echocardiographic study of a random
population sample. J Am Coll Cardiol 1993;21:1220–5.
2. Dweck MR, Boon NA, Newby DE. Calcific aortic stenosis: adisease of the valve and the myocardium. J Am Coll Cardiol
2012;60:1854–63.
3. Matsumura T, Ohtaki E, Misu K, et al. Etiology of aortic valve disease
and recent changes in Japan:a study of 600 valve replacementcases. Int J Cardiol 2002;86:217–23.
4. Miura S, Arita T, Kumamaru H, et al. Causes of death and mortality
and evaluation of prognostic factors in patients with severe aortic
stenosis in an aging Society. J Cardiol 2015;65:353–9.
5. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgicalaortic-valve replacement in intermediate-risk patients. N Engl J Med
2016;374:1609–20.
6. Bonow RO, Carabello BA, Chatterjee K, et al. Focused update
incorporated into the ACC/AHA 2006 guidelines for the managementof patients with valvular heart disease: a report of the American
College of cardiology American Heart Association Task Force onpractice guidelines (writing Committee to revise the 1998 guidelines
for the management of patients with valvular heart disease):endorsed by the Society of cardiovascular Anesthesiologists,
Society for cardiovascular angiography and interventions, andSociety of thoracic surgeons. J Am Coll Cardiol 2008;2008:E1–142.
7. Oh JK, Taliercio CP, Holmes DR, et al. Prediction of the severityof aortic stenosis by Doppler aortic valve area determination:
prospective Doppler-catheterization correlation in 100 patients. J Am
Coll Cardiol 1988;11:1227–34.

Miura S, et al. Open Heart 2019;6:e000992. doi:10.1136/openhrt-2018-000992

Open Heart: first published as 10.1136/openhrt-2018-000992 on 21 May 2019. Downloaded from http://openheart.bmj.com/ on 28 May 2019 by guest. Protected by copyright.

Table 3 Correlation between SAVR and the three types of clinical events in the selected subgroups of the propensity scorematched population

Valvular heart disease

Miura S, et al. Open Heart 2019;6:e000992. doi:10.1136/openhrt-2018-000992

15. Lee R, Li S, Rankin JS, et al. Fifteen-year outcome trends for valve
surgery in North America. Ann Thorac Surg 2011;91:677–84.
16. Brown JM, O'Brien SM, Wu C, et al. Isolated aortic valve
replacement in North America comprising 108,687 patients in 10
years: changes in risks, valve types, and outcomes in the Societyof thoracic surgeons national database. J Thorac Cardiovasc Surg
2009;137:82–90.
17. Auensen A, Hussain AI, Bendz B, et al. Morbidity outcomes after
surgical aortic valve replacement. Open Heart 2017;4:e000588.
18. Flett AS, Sado DM, Quarta G, et al. Diffuse myocardial fibrosis
in severe aortic stenosis: an equilibrium contrast cardiovascularmagnetic resonance study. Eur Heart J Cardiovasc Imaging
2012;13:819–26.
19. Shirai S, Taniguchi T, Morimoto T, et al. Five-year clinical outcomeof asymptomatic vs. symptomatic severe aortic stenosis after aortic
valve replacement. Circ J 2017;81:485–94.
20. Zilberszac R, Gabriel H, Schemper M, et al. Asymptomatic
severe aortic stenosis in the elderly. JACC Cardiovasc Imaging
2017;10:43–50.
21. Thourani VH, Keeling WB, Sarin EL, et al. Impact of preoperative
renal dysfunction on long-term survival for patients undergoing aortic
valve replacement. Ann Thorac Surg 2011;91:1798–807.
22. Najjar M, Salna M, George I. Acute kidney injury after aortic valve
replacement: incidence, risk factors and outcomes. Expert Rev
Cardiovasc Ther 2015;13:301–16.
23. Ju MH, Jung S-H, Choo SJ, et al. Valve replacement surgery insevere chronic kidney disease. Int J Cardiol 2017;241:115–9.

9Open Heart: first published as 10.1136/openhrt-2018-000992 on 21 May 2019. Downloaded from http://openheart.bmj.com/ on 28 May 2019 by guest. Protected by copyright.

8. Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines
for the management of patients with valvular heart disease: areport of the American College of Cardiology/American Heart
Association Task Force on practice guidelines (writing Committee
to revise the 1998 guidelines for the management of patients with
valvular heart disease): developed in collaboration with the Societyof cardiovascular Anesthesiologists: endorsed by the Society for
cardiovascular angiography and interventions and the Society ofthoracic surgeons. Circulation 2006;114:e84–231.
9. Horwitz RI, Viscoli CM, Clemens JD, et al. Developing improved
observational methods for evaluating therapeutic effectiveness. Am
J Med 1990;89:630–8.
10. Austin PC. Optimal caliper widths for propensity-score matchingwhen estimating differences in means and differences in proportions
in observational studies. Pharm Stat 2011;10:150–61.
11. —————–. The relative ability of different propensity score methods
to balance measured covariates between treated and untreatedsubjects in observational studies. Med Decis Making 2009;29:661–77.
12. Pai RG, Kapoor N, Bansal RC, et al. Malignant natural historyof asymptomatic severe aortic stenosis: benefit of aortic valve
replacement. Ann Thorac Surg 2006;82:2116–22.
13. Varadarajan P, Kapoor N, Bansal RC, et al. Survival in elderly patientswith severe aortic stenosis is dramatically improved by aortic valve
replacement: Results from a cohort of 277 patients aged > or =80
years. Eur J Cardiothorac Surg 2006;30:722–7.
14. Bach DS, Siao D, Girard SE, et al. Evaluation of patients withsevere symptomatic aortic stenosis who do not undergo aortic
valve replacement: the potential role of subjectively overestimatedoperative risk. Circ Cardiovasc Qual Outcomes 2009;2:533–9.