Survival in elderly patients with severe aortic stenosis

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European Journal of Cardio-thoracic Surgery 30 (2006) 722—727
www.elsevier.com/locate/ejcts
Survival in elderly patients with severe aortic stenosis is dramatically
improved by aortic valve replacement: results from a cohort
of 277 patients aged 80 years§
Padmini Varadarajan, Nikhil Kapoor, Ramesh C. Bansal, Ramdas G. Pai *
Division of Cardiology, University of Southern California/Keck School of Medicine, 1510 San Pablo Street,
Suite 300N, Los Angeles, CA 90033, United States
Received 20 April 2006; received in revised form 24 July 2006; accepted 25 July 2006; Available online 6 September 2006
Abstract
Background: Calcific aortic stenosis (AS) is a disease of the elderly. However, there is reluctance to offer aortic valve replacement (AVR) for
elderly patients with severe AS. We investigated if AVR confers a survival benefit in elderly patients with severe AS. Methods: We screened our
echocardiographic database from 1993 to 2003 for patients with severe AS (AV area 0.8 cm2) and age 80 years. Two hundred and seventy seven
patients were identified. Complete chart reviews were performed for clinical data. Mortality data were obtained from National Death Index.
Survival curves of patients who underwent AVR during the follow-up period were compared with those managed nonsurgically. Results: Patient
characteristics were as follows: age 85 4 years, 53% male, AV area 0.68 0.16 cm2, EF 52 20%, CAD 47%, diabetes 17%. Over a mean follow-up
of 2.5 years, 55 (20%) had AVR and there were 175 deaths. One-year, 2-year and 5-year survival rates among patients with AVR were 87, 78 and 68%
respectively, compared with 52, 40 and 22%, respectively, in those who had no AVR ( p < 0.0001). Hazard ratio for death with AVR adjusted for 19
covariates including age, EF, gender, comorbidities and pharmacotherapy was 0.38 (95% CI 0.26—0.66, p < 0.0001). Conclusion: Prognosis of
medically managed severe calcific AS in the elderly patients is dismal. AVR appears to improve survival of these patients and should be strongly
considered in the absence of other major comorbidities.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Aortic stenosis; Aortic valve replacement; Survival; Echocardiography; Prognosis
1. Introduction
Aortic stenosis (AS) is the most frequent valvular lesion in
the elderly in western countries [1]. The prevalence of AS
(<1.2 cm2) in the general population increases with age from
2.5% at 75 years to 8.1% at 85 years [1,2]. With the proportion
of elderly patients rising, AS is becoming a serious clinical
issue. Indications for aortic valve replacement (AVR) are well
defined in guidelines, and there is a consensus for AVR in
patients with severe symptomatic AS [3]. Decisions to
operate the elderly patients have specific problems related
to increase in operative morbidity and mortality [4—14]. AVR
is the only effective therapy for symptomatic aortic stenosis.
Age alone is not a contraindication; several studies have, in
fact, shown that AVR can be performed in the elderly with
acceptable mortality and morbidity and postoperative
quality of life. However, there is still a reluctance to offer
AVR for patients aged 80 years and more. We investigated the
§
Presented at the 78th Annual Scientific Sessions of the American Heart
Association, Dallas, Texas, USA, November 2005.
* Corresponding author. Tel.: +1 323 442 6130; fax: +1 323 442 6133.
E-mail address: [email protected] (R.G. Pai).
1010-7940/$ — see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejcts.2006.07.028
survival patterns of octogenarians with severe AS managed
with AVR in comparison with those treated medically.
2. Methods
2.1. Patient population
This is a retrospective cohort study from a large university
medical center. Our echocardiographic database was
searched for patients with severe aortic stenosis defined
as Doppler-derived valve area 0.8 cm2. This yielded a total
of 740 patients. Of these, 277 patients were 80 years
forming the study cohort. Detailed chart reviews were then
performed on these patients (both alive and dead) by senior
medical residents.
2.2. Clinical variables
Hypertension (HTN) was defined as blood pressure greater
then 130/90 mmHg or a history of hypertension or being on
medications. Diabetes was defined as having a history of or
being treated with medications. Renal insufficiency was
P. Varadarajan et al. / European Journal of Cardio-thoracic Surgery 30 (2006) 722—727
723
Table 1
Characteristics of patients with and without AVR
Age (in years)
Males
Ejection fraction
Aortic valve area (cm2)
Mean aortic gradient (mmHg)
LV end diastolic dimension (cm)
LV end systolic dimension (cm)
Interventricular septum (cm)
Posterior wall (cm)
Hypertension
Diabetes
Coronary artery disease
Renal insufficiency
Congestive heart failure
Chronic obstructive
pulmonary disease
Aspirin
Beta blocker
ACE inhibitors
Statin
Digoxin
No AVR (n = 197)
AVR (n = 80)
p-value
85.3 4.1
42%
50 21%
0.68 16
39 15
4.8 0.8
3.4 1.0
1.4 0.2
1.2 0.2
40%
16%
41%
13%
51%
11%
83.0 2.3
57%
56 18%
0.68 15
44 16
4.8 0.8
3.2 0.9
1.4 0.2
1.2 0.1
60%
17%
62%
7%
45%
12%
<0.0001
0.02
0.04
ns
0.02
ns
ns
ns
ns
0.002
ns
0.001
ns
ns
ns
31%
18%
30%
15%
20%
62%
44%
30%
27%
31%
<0.0001
<0.0001
ns
0.01
0.06
defined as serum creatinine 2 mg/dl, and coronary artery
disease was defined as having a history, electrocardiographic
presence of Q-waves or being on anti-anginal medications.
3. Results
2.3. Pharmacological data
Patients characteristics were as follows: mean age 85 4
years, 53% male, mean AV area 0.68 0.16 cm2, mean aortic
gradient 40 15 mmHg, EF 52 20%, CAD 47%, diabetes
17%, HTN 46%. Over a mean follow-up of 2.5 years, there
were 175 deaths. All the 80 patients underwent aortic valve
replacement with a bioprosthetic valve. The concomitant
surgical procedures included the following: three (4%) had
aortic root enlargement, 37 (46%) coronary artery bypass
surgery and eight (10%) had mitral valve repairs.
Table 1 summarizes characteristics of elderly patients
with severe AS with and without AVR. AVR group had a
greater preponderance of males (57% vs 42%, p = 0.02),
higher EF (56 18% vs 50 21%, p = 0.04), higher prevalence of hypertension (60% vs 40%, p = 0.002), higher
prevalence of coronary artery disease (CAD)(62% vs 41%,
p = 0.001), and greater use of cardiac medications such as
Pharmacotherapy at the time of echocardiography was
recorded. This was broadly categorized into beta blockers,
calcium channel blockers, diuretics, angiotensin-converting
enzyme inhibitors, digoxin and statins.
2.4. Echocardiographic data
All patients had standard two-dimensional echocardiographic examinations. LV ejection fraction was assessed by a
level-3 trained echocardiographer and entered into a
database at the time of the examination. Anatomic and
Doppler measurements were performed according to the
recommendations of the American society of Echocardiography [15]. Aortic valve area was obtained by continuity
equation.
3.1. Patient characteristics
2.5. Mortality data
The endpoint of the study was all-cause mortality.
Mortality data were obtained from the National Death Index
using social security numbers.
2.6. Statistical analysis
Analysis was performed using Stat View 5.01 (SAS Institute
Inc., Cary, NC, USA). Characteristics of patients with and
without AVR were compared using the Student’s t-test for
continuous variables and Chi-squared test for categorical
variables. Statistical tools used for survival analysis included
the Kaplan—Meier method, Cox regression model, propensity
score analysis and sensitivity analysis as described later.
A p-value of 0.05 was considered significant.
Fig. 1. Survival of patients with severe AS with and without AVR.
P. Varadarajan et al. / European Journal of Cardio-thoracic Surgery 30 (2006) 722—727
724
Table 2
Cox regression model showing independent predictors of survival
Age (per year)
Ejection fraction (per 1%)
AVA (per cm2)
Renal insufficiency
ACE inhibitor
AVR
3.4. Propensity score analysis (PSA)
Relative risk
95% CI
p-value
1.04
0.99
0.37
1.8
1.9
0.38
0.99—1.1
0.98—1.0
0.12—1.12
1.04—3.15
1.2—3.0
0.26—0.66
0.07
0.04
0.08
0.03
0.008
<0.0001
aspirin (62% vs 31%, p < 0.0001) and beta blockers (44% vs
18%, p < 0.0001).
In patients who had aortic valve replacement, 13% had
cerebrovascular accident compared with 12% in those who
did not undergo valve replacement during the entire followup period.
3.2. Survival with AVR
Of the 277 patients, 80 underwent AVR during follow-up.
Survival in patients who underwent AVR was significantly
better than those managed medically using Kaplan—Meier
analysis with log-rank statistic (Fig. 1). One-year, 2-year and
5-year survival rates among patients with AVR were 87, 78
and 68%, respectively, compared to 52, 40 and 22%,
respectively in those who had no AVR ( p < 0.0001).
In addition to Cox regression, PSA was used to address the
effect of covariate imbalance between the treatment and
control groups. Probability of receiving AVR (propensity
score) for each patient was modeled by using logistic
regression conditioned on covariate values for that individual. Effect of AVR on survival in each of the four strata of
equal size was analyzed on the basis of propensity score.
Fig. 2a—d shows the Kaplan—Meier survival curves in the four
individual strata. Patients who underwent AVR had a
significant survival benefit in all four strata.
3.5. Sensitivity analysis (SA)
Sensitivity analysis was carried out by serially eliminating
observations within 30 days, 90 days, 1 year and 2 years,
respectively, to minimize the effect of unmeasured and
unmeasurable variables on mortality and the nonproportional early mortality hazard in the nonsurgical arm. Fig. 3a—
d shows the Kaplan—Meier survival curves for observations
eliminated before 31 days, 91 days, 1 year and 2 years,
respectively. Survival with AVR was superior compared to the
non-AVR group in each of the strata. These analyses strongly
suggest that AVR conferred survival benefit.
3.6. Survival benefit with AVR in subsets
3.3. Survival adjusted for confounding variables
Hazard ratio for death with AVR adjusted for 19 covariates
including age, EF, gender, comorbidities and pharmacotherapy was 0.38 (95% CI 0.26—0.66, p < 0.0001). Table 2 shows
the independent predictors of mortality by Cox regression
analysis.
Fig. 4a shows the Kaplan—Meier survival curves in patients
with ejection fraction 30% (n = 60). Five-year survival rate
was 10% in patients who did not undergo AVR compared with
52% who underwent AVR ( p = 0.003). In patients with EF 30%
and a mean aortic gradient 30 mmHg (n = 25), only two
patients had underwent AVR (Fig. 4b). Survival benefit with
Fig. 2. (a—d): Survival with and without AVR based on propensity score analysis. Stratum 1 least likely to receive AVR and stratum 4 most likely to receive AVR.
P. Varadarajan et al. / European Journal of Cardio-thoracic Surgery 30 (2006) 722—727
725
Fig. 3. (a—d): Results of sensitivity analysis by serially eliminating observations before 30 days, 90 days, 1 year and 2 years, respectively.
AVR could not be assessed because of low number of patients
with AVR in this subgroup, but in those patients with no AVR in
this subgroup with severe AS, 1-year survival rate was dismal
at 18%. Analysis of patients with CRI (n = 32) shows that only
six patients had AVR, 5-year survival rate was 12% in those
who did not undergo AVR compared with 42% in those who
underwent AVR ( p = 0.13) (Fig. 4c).
4. Discussion
The elderly population of 65 years and more is the fastest
growing segment of population in western countries [16]. AVR
has been shown to be safe in the elderly population [4—14]. In
a study conducted by Lung et al. [2] in the Euro Heart Survey,
it was found that 33% of elderly patients with severe
symptomatic AS were denied surgery. Old age and LV
dysfunction were the most striking reasons for denial of
surgery. In our patients, nonsurgical management was
associated with older age, female gender and lower ejection
fraction. Presence of CAD was a trigger for AVR in many of
these patients.
4.1. Benefit of AVR
Our study shows that in octogenarians with severe AS,
survival is dramatically improved with AVR. AVR had
significant survival benefit with 1-year, 2-year and 5-year
survival rates of 87, 78 and 68%, respectively, compared with
52, 40 and 22%, respectively, in those who had no AVR
( p < 0.0001). On multivariate analysis, lower ejection
fraction and, renal insufficiency were predictors of increased
mortality. Old age and smaller aortic valve area showed a
trend towards increased mortality, which was not statistically significant. AVR was a strong independent predictor of
improved survival. There is a paucity of studies in the
literature comparing survival with and without AVR for severe
aortic stenosis in those aged 80 years. Gilbert et al. [11]
reported that 103 patients from a single center in the UK with
severe AS underwent AVR. Median age in this study was 82
years. The 50% actuarial survival in this study was 62 months.
Early postoperative mortality was related to increasing age,
renal impairment and peripheral vascular disease. Patients
who survived the surgery had good long-term prognosis. Oneyear, 2-year and 5-year survival rates were 78, 75 and 58%,
respectively, in all patients undergoing AVR (by examining the
published Kaplan—Meier survival curves). Bouma et al. [14]
evaluated the decision-making process leading to medical or
surgical treatment for aortic stenosis in elderly patients.
There were 67 patients aged 80 years. This study showed 3year survival rates of 80% in the surgical group compared with
49% in the non-AVR group. Our study is the largest study
evaluating the survival pattern with and without AVR in
patients aged 80 and more with severe AS and shows similar
survival patterns.
4.2. Outcomes after AVR in patients aged 80 and more
There are studies reporting good outcomes after AVR in
the elderly. Gehlot et al. [8] studied 322 patients with a
mean age of 82.2 years who underwent AVR. On multivariate analysis, the most important independent predictors
726
P. Varadarajan et al. / European Journal of Cardio-thoracic Surgery 30 (2006) 722—727
Fig. 4. (a—c): Kaplan—Meier survival curves in patients with EF 30%, EF 30% and mean gradient 30 mmHg and chronic renal insufficiency, respectively.
of mortality included female gender, renal impairment,
EF < 35%, bypass grafting and chronic obstructive pulmonary
disease. Age and year of operation did not influence
mortality. Five-year survival rates for all patients and for
operative survivors were 60.2 3.2% and 70.3 3.4%.
Asimakopoulos et al. [10] reported on data collected from
1100 patients >80 years undergoing AVR from the UK Heart
Valve Registry. Actuarial survival rates were 89, 79, 69% and
46% at 1, 3, 5 and 8 years, respectively. Survival in the
operated patients in our series was practically identical to
this. Sundt et al. [17] retrospectively evaluated 133 patients
between the age of 80 and 91 years undergoing AVR.
Actuarial survival rates at 1 and 5 years were 80 and 55%, respectively. Urgent or emergent surgery, aortic insufficiency,
perioperative stroke or renal dysfunction were significant
risk factors for operative death by multivariate analysis.
4.3. Strengths of our study
Ours is the largest study addressing this issue, and our
patients are well characterized in terms of clinical,
pharmacologic and echocardiographic data. We used robust
statistical tools like propensity score analysis and sensitivity analysis in addition to the standard Kaplan—Meier
analysis. Propensity score analysis was used to correct
covariate imbalances. Modeling based on propensity scores
is estimated to remove up to 90% of inherent bias of a
retrospective study [18]. Propensity score analysis reveals
strong survival benefit with AVR in octogenarians with
severe AS. As there is a nonproportionate mortality hazard
during the first 30 days, sensitivity analysis was carried out
to serially eliminate these initial observations and determine the survival benefit of AVR. By serial elimination of
observations before 30 days, 90 days, 1 year and 2 years,
AVR continues to show a very strong survival benefit.
4.4. Limitations
This is a retrospective, observational study and hence is
prone to inherent bias of a retrospective study. Though
various statistical tools were used to attempt to remove
effect of selection of bias on survival, a prospective
randomized study is the only way to answer this clinical
question in unequivocal terms.
4.5. Conclusions
Our study shows that medically managed octogenarians
with severe aortic stenosis have a dismal prognosis, and AVR
improves survival. Hence, strong consideration should be
given for aortic valve replacement in octogenarians in the
absence of serious comorbidities.
P. Varadarajan et al. / European Journal of Cardio-thoracic Surgery 30 (2006) 722—727
Acknowledgement
The authors acknowledge the statistical expertise of Dr
Daniel O. Stram PhD, Professor, Department of Preventive
Medicine and Biostatistics, University of Southern California,
Los Angeles, CA.
[8]
[9]
[10]
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