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a Division of Cardiology, Loma Linda University Medical Center, Loma Linda, California
b Division of Cardiothoracic Surgery, Loma Linda University Medical Center, Loma Linda, California
Accepted for publication August 4, 2008.
* Address correspondence to Dr Pai, Division of Cardiology, Loma Linda University School of Medicine, 11234 Anderson Street, #4414, Loma Linda, CA 92354 (Email: rpai{at}llu.edu).
| Adult cardiac surgery:
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| Abstract |
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Methods: Our echocardiographic database for the period of 1993 to 2003 was screened for severe AS (aortic valve area [AVA]
0.8 cm2) with LVEF 0.35 or less or a mean transvalvular gradient of 30 mm Hg or less. Chart reviews were performed for clinical, pharmacologic, and surgical details. Survival data were obtained from the Social Security Death Index and analysis was performed using Kaplan-Meier, Cox regression, sensitivity, and propensity score analysis.
Results: Of the 740 patients with severe AS, 194 (26%) had severe LV dysfunction defined as EF 0.35 or less and 168 (23%) a mean transvalvular gradient of 30 mm Hg or less. Low ejection fraction was not a prerequisite for a low gradient. The Univariate predictors of higher mortality in both groups included higher age, lower ejection fraction, renal insufficiency, and lack of aortic valve replacement. Lack of aortic valve replacement was a strong predictor of mortality after adjusting for 18 clinical, echocardiographic, and pharmacologic variables. There were 72 patients with EF 0.20 or less, of whom 18 had AVR, which was associated with a large survival benefit similar to the entire cohort. In the 52 patients with EF 0.55 or less and mean gradient less than 30 mm Hg, the 5-year survival with AVR was 90% compared with 20% without AVR (p < 0.0001) which was supported by propensity score analysis as well.
Conclusions: Severe LV dysfunction or a low transvalvular gradient is seen in about a quarter of patients with severe AS and there is a reluctance to offer AVR in these patients. Aortic valve replacement is associated with a large mortality benefit in these patients.
Aortic stenosis (AS) is the most common cause of valve replacement and its prevalence increases with age and the aging population [1]. Nearly a quarter of the severe AS patients have reduced left ventricular (LV) ejection fraction (EF) and a substantial subset have a low transvalvular gradient despite normal LVEF [1, 2]. Though the American College of Cardiology/American Heart Association guidelines recommend aortic valve replacement (AVR) for severe AS patients with LV dysfunction, the recommendations are not clear in those with low transvalvular gradient [1].
There are limited outcome studies in severe AS patients with low EF. Connolly and colleagues have reported that AVR can be performed in such patients with acceptable mortality [2, 3]. Monin and colleagues [4] showed a mortality benefit with AVR in the 32 patients with contractile reserve despite low EF and low gradient in the setting of severe AS [4]. Using propensity score matching, Pereira and colleagues [5] showed a survival benefit of AVR in severe AS patients with EF 0.35 or less and mean aortic valve gradient 30 mm Hg or less.
Low transaortic gradient despite normal EF is another issue where limited data exist. It occurs not only in the setting of low EF, but many with normal EF as well, and as shown by Hachicha and colleagues [6] portends a poor prognosis if treated medically. Many times these patients are misjudged to have milder degrees of AS and AVR is not offered.
Hence, we investigated the clinical implications and outcomes with AVR in two separate groups of severe AS patients from our Loma Linda AS Study database: (1) a contemporary group of 194 patients with severe AS and a LVEF of 0.35 or less; and (2) 168 patients with severe AS with low mean transvalvular gradient (
30 mm Hg) with special emphasis on those with normal EF.
| Patients and Methods |
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Definition of Clinical Variables
Hypertension was defined as blood pressure greater than 130/90 mm Hg or a history of hypertension and being on antihypertensive medications. Diabetes mellitus was defined as fasting blood sugar greater than 125 mg/dL or being on antidiabetic agents. Renal insufficiency was defined as serum creatinine 2 mg/dL or greater. Coronary artery disease was deemed to be present if any of the following were present: a history of angina pectoris, myocardial infarction, a positive stress test, angiographic evidence of coronary artery disease, coronary intervention, coronary artery bypass surgery, or presence of significant Q-waves on the surface electrocardiogram.
Pharmacologic Data
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.
Echocardiographic Data
All patients had complete two-dimensional echocardiographic examinations. Left ventricular ejection fraction was assessed visually by a level 3 trained echocardiographer and entered into a database at the time of the examination. This has been shown to be reliable and has been validated against contrast and radionuclide LV angiography [11, 12]. Anatomic and Doppler examinations and measurements were performed according to the recommendations of the American Society of Echocardiography [13]. The transvalvular velocities were obtained from at least two views aligning parallel to the flow and using the nonimaging continuous wave transducer. The aortic valve area was calculated using the continuity equation.
Mortality Data
The endpoint of the study was all cause mortality. Mortality data were obtained from the National Death Index using the Social Security numbers.
Statistical Analysis
The data were imported into Stat View 5.01 (SAS Institute Inc, Cary, NC) program for statistical analysis. Group comparisons were made using the Student t test for continuous variables and
2 test for categoric variables. Survival analysis was performed using various statistical tools such as Kaplan-Meier analysis, Cox regression models, propensity score analysis, and sensitivity analysis, as discussed later in the Results section. A p value of 0.05 or less was considered significant.
| Results |
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Severe AS Patients With LVEF 0.35 or Less
Baseline patient characteristics
The baseline patient characteristics are summarized in Table 1. In the low EF group, the mean age was 75 years, 58% were men, the aortic valve area (AVA) was 0.67 ± 0.18 cm2, and the LVEF was 0.25 ± 0.07. The mean aortic regurgitation grade was 1.1 on a scale of 0 to 4; only 4 had 3+ and none had 4+ aortic regurgitation. The LV outflow tract velocity was 0.8 ± 0.2 m/s, transvalvular velocity was 3.8 ± 0.7 m/s, and their ratio was 0.21. Over a mean follow-up period of 2.4 ± 2.7 years, there were 58 (30%) AVRs and 127 deaths; 28 deaths in the AVR group and 99 in the non-AVR group. The mean interval between diagnosis of severe AS and AVR was 34 days.
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AVR and survival
By Kaplan-Meier analysis, patients undergoing AVR had 30 day, 1 year, and 5 year survival rates (from the initial diagnosis of severe AS) of 91%, 80%, and 58%, respectively, compared with 79%, 47%, and 23% for those who had no AVR (p < 0.0001) (Fig 1).
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Other univariate predictors of survival
Other univariate predictors of higher mortality included lower EF (p = 0.04), lower mean transvalvular gradient (p = 0.01), renal insufficiency (p = 0.01), and higher age (p = 0.06). Gender, coronary artery disease (CAD), hypertension, diabetes mellitus, AVA, MR, and medication use had no effect on survival. The LV dimensions were not a predictor of survival and did not add to the predictive model.
Comparison of patients with and without AVR
As shown in Table 2, patients not undergoing AVR were older (p = 0.02), and had a lower prevalence of hypertension (p = 0.001) and diabetes mellitus (p = 0.04). They had similar LVEF, AVA, and degree of MR. The prevalence of stroke and renal insufficiency were similar in both groups.
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Propensity score analysis
Probability of receiving AVR for each patient was calculated based on the 13 preoperative covariate characteristics including age, gender, hypertension, diabetes, renal insufficiency, chronic obstructive pulmonary disease, stroke, CAD, EF, pulmonary artery pressure, presence of MR, AVA, and aortic mean gradient. Logistic regression analysis was used to calculate this propensity score. Adjusted for the propensity score developed based on the low EF subset, AVR was associated with a mortality hazard of 0.44 (95% CI 0.26–0.74, p = 0.002) using the Cox regression model. We also adjusted for propensity score developed based on all the 740 severe AS patients as well; the hazard ratio with AVR was 0.42 (p = 0.002). Adjusting for propensity score has been reported to eliminate 85% to 90% of the treatment bias in observational cohorts [14–16].
Severe AS Patients With Transaortic Mean Gradients of 30 mm Hg or Less
Patient characteristics
In the low gradient group, the mean age was 72 years and 50% were men, the aortic valve area (AVA) was 0.76 ± 0.18 cm2 and the LVEF was 0.41 ± 0.20. Of the 47 patients who underwent AVR, 7 had mitral valve repair and 6 had mitral valve replacement. Only 49% of these had an LVEF 0.35 or less and 31% (52) had an LVEF 0.55 or greater indicating that low EF is not a prerequisite for low gradient, as commonly thought.
Comparison of severe AS patients with mean aortic gradient less than 30 mm Hg and greater than 30 mm Hg
Table 3
summarizes the characteristics of severe AS patients with and without a low transvalvular gradient defined as 30 mm Hg or less. Compared with those with a higher gradient, they had a lower LVEF (0.41 ± 0.20 vs 0.58 ± 0.18%, p < 0.0001), lower stroke volume (p < 0.0001), greater prevalence of 3 or 4+ MR (34 vs 20%, p = 0.0002), greater prevalence of CAD (53 vs 29%, p = 0.002), and a slightly larger aortic valve area (0.76 ± 0.18 vs 0.69 ± 0.15 cm2, p < 0.0001).
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Propensity score analysis
In addition to Cox regression, propensity score analysis was carried out 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 analysis conditioned on covariate values for that individual. Logistic regression model was used to create propensity scores, where AVR was the dependent variable and various preoperative characteristics including age, gender, CAD, hypertension, diabetes mellitus, chronic renal insufficiency, EF, MR, pulmonary artery pressure, AVA, and mean transaortic gradient were independent variables. The AVR remained a strong predictor of survival after adjusting for the propensity scores (RR 0.55, 95% CI 0.42–0.72, p < 0.0001). Of the 47 patients who had AVR, 38 were propensity score matched with 38 patients who did not have AVR. One-year, 2-year, and 5-year survivals were 89%, 86%, and 78% with AVR compared with 58%, 45%, and 35% with no AVR using the propensity score matched cohorts (p = 0.0008).
Sensitivity analysis
In view of nonproportional mortality hazard in the non-AVR group, sensitivity analysis was carried out to minimize biases leading to AVR decisions. This was carried out by serially eliminating patients with events within 30 days, 90 days, 1 year, and 2 years, respectively. Figures 6
(A) through 6(D) show the Kaplan Meier survival curves for these patients. Survival with AVR was superior compared to no AVR in all of these analyses suggesting a strong survival benefit with AVR.
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| Comment |
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AVR in Severe AS Patients With Low EF
Connolly and colleagues [2, 3] have reported that AVR can be performed in severe AS patients with LV dysfunction or low gradient with an acceptable mortality and that this leads to an improvement in LV function and symptoms, but there were no control groups to assess the mortality benefit of AVR. There are two studies which evaluated the potential benefit of AVR in severe AS patients with a LVEF 0.35 or less and a transaortic gradient 30 mm Hg or less [4, 5]. Monin and colleagues [4] studied 45 severe AS patients with low EF and low gradient. Benefit of AVR was assessed as a function of LV contractile reserve with dobutamine. In the 32 patients with contractile reserve 24 had AVR and there was a mortality benefit. Pereira and colleagues [5] compared the survival of 39 patients with severe AS, EF 0.35 or less, and mean aortic gradient 30 mm Hg or less undergoing AVR with 56 propensity score matched patients treated medically. The adjusted mortality risk ratio with AVR was 0.19 suggesting a large mortality benefit with AVR. Unlike our study, they did not assess the impact of comorbidities and pharmacologic therapy on survival. The low EF, low gradient AS group is made up of 3 subsets of patients: those with true severe AS with contractile reserve, where the gradient goes up with dobutamine; those with no contractile reserve; and those with pseudo-severe AS, where the valve opens better with a higher stroke volume. We did not perform dobutamine stress in our patients.
Benefit of AVR with Low Gradient and Preserved EF
There is a paucity of studies in the literature comparing survival with and without AVR for severe aortic stenosis with low gradient and EF greater than 0.35. Hachicha and colleagues [6] investigated the effects of low gradient severe AS on survival with preserved LVEF. They studied a group of 181 patients with severe AS, low gradient, and low flow output defined as a stroke volume index of less than 35 mL/m2 and preserved EF. They demonstrated that patients can have low flow, low gradient severe AS despite a normal EF. Advanced age, greater valvulo-arterial impedance, and medical therapy were independent predictors of mortality. Our study confirms a mortality benefit with AVR in this population and indicates that AVA is the most important measure of AS severity and the gradient, which is flow dependent, is less important.
Unique Aspects of Our Study
This is the largest study, to our knowledge, addressing the effect of AVR on survival in severe AS patients with EF 0.35 or less and those with low gradient. In addition, the patients are comprehensively characterized, especially including all pharmacologic data such as statins, aspirin, beta blockers, and angiotensin-converting enzyme inhibitors, which can potentially impact survival in these patients. Also, the study addresses more contemporary patients (years 1993 to 2003). This is important in view of the fact that surgical techniques and medical management have dramatically changed compared with the 1980s. Because of the size of the population, we were also able to assess AVR benefit in various clinical subsets. Sensitivity and propensity score analysis make the findings fairly robust despite the observational nature.
Study Limitations
The main limitation of our study is its retrospective nature and that treatment assignment was not randomized. Sensitivity and propensity score analysis are reported to help minimize the impact of treatment of bias by 80% to 90% [14–16]. As there are no randomized studies addressing this issue, our data should be helpful in clinical decision making.
Clinical Implications of Our Study
Based on our study results and until results of randomized trials become available, we suggest that patients with severe AS and severe LV dysfunction should be offered AVR unless a contraindication exists, irrespective of age, EF, aortic gradient, CAD status, or MR. Findings of our study show that low transvalvular gradient despite severe AS is not uncommon and occurs in about a quarter of the patients, and that low EF is not a prerequisite. Severe AS is the main driving force behind mortality, which is markedly diminished by AVR. Despite this, there is reluctance to offer AVR in these patients.
| Acknowledgments |
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| References |
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