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Ann Thorac Surg 2006;82:2116-2122
© 2006 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Malignant Natural History of Asymptomatic Severe Aortic Stenosis: Benefit of Aortic Valve Replacement

Division of Cardiology, Loma Linda University Medical Center, Loma Linda, California

Accepted for publication July 11, 2006.

^_* Address correspondence to Dr Pai, Division of Cardiology, USC/Keck School of Medicine, 1510 San Pablo Street, Suite 322, Los Angeles, CA 90033. (Email: rpai{at}usc.edu).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
BACKGROUND: Patients with asymptomatic severe aortic stenosis (AS) are reported to have a benign prognosis and hence the American College of Cardiology/American Heart Association guidelines do not recommend aortic valve replacement (AVR) for patients with isolated asymptomatic severe AS. However, symptoms are subjective and would depend upon patient’s life style. We examined the natural and unnatural history of initially asymptomatic patients with severe AS.

METHODS: A search of our echocardiographic database between 1993 and 2003 yielded 740 patients with severe AS defined as aortic valve area 0.8 cm² or less. Thorough chart reviews were conducted to collect clinical and pharmacologic data. Of these, 338 patients were asymptomatic at the initial encounter forming the study cohort.

RESULTS: Patient characteristics were the following: age 71 ± 15 years, males 51%, aortic valve area 0.72 ± 0.17 cm², left ventricular ejection fraction 0.59 ± 0.17. Ninety-nine (29%) patients had AVR during a mean follow-up of 3.5 years. Survival at 1, 2, and 5 years in the nonoperated patients were 67%, 56%, and 38%, respectively, compared with 94%, 93%, and 90% in those who underwent AVR (p < 0.0001). The Cox regression model was used to adjust for the effect of 18 clinical, echocardiographic, and pharmacologic variables on survival. The adjusted hazard ratio for death with AVR was 0.17 (95% confidence interval [CI] 0.10 to 0.29). In the nonoperated group, renal insufficiency (risk ratio [RR] 3.1, 95% CI 1.5 to 6.6), beta blocker use (RR 0.52, 95% CI 0.31 to 0.88), statin use (RR 0.52, 95% CI 0.27 to 0.99), age (per year RR 1.03, 95% CI 1.02 to 1.05), and left ventricular ejection fraction (per % RR 0.99, 95% CI 0.98 to 1.00) were found to be the independent predictors of mortality. The benefit of AVR was further supported by sensitivity and propensity score analyses.

CONCLUSIONS: Our observational data indicate that the natural history of asymptomatic AS is not benign and that survival is dramatically improved by AVR. Survival of the asymptomatic unoperated or nonoperable patients may potentially be improved by the use of beta blockers and statins.

	Introduction

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It has been reported that patients with asymptomatic severe aortic stenosis (AS) have a benign prognosis and that events are generally preceded by cardiac symptoms [1–5]. Hence, the American College of Cardiology/American Heart Association guidelines do not recommend aortic valve replacement (AVR) for patients with isolated asymptomatic severe AS in the absence of concomitant cardiac or aortic surgery [6]. However, closer examination of the data from three of the largest published series [3–5] shows that in severe AS patients who are initially asymptomatic, the probability of remaining symptom or event-free at 2 years is 21% to 67%, with a higher probability of events in the aged, those with greater degrees of AS, and heavier aortic valve calcification. Also, symptoms are subjective and depend upon patient life style and expectations. Nearly half of the patients with severe AS who deny symptoms become symptomatic for the first time when subjected to a stress test [7, 8]. In addition, there is a concern in these patients of sudden death without symptoms and death in the waiting period from the onset of symptoms to AVR [9]. The goal of our study was to examine the natural history of asymptomatic severe AS patients, to identify high risk subgroups, and to examine the potential benefit of AVR, if any, in asymptomatic severe AS.

	Patients and Methods

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Patient Population
This is a retrospective cohort study from a large university medical center. This study was approved by our Institutional Review Board, which waived the need for patient consent because of the retrospective nature of the study. Our echocardiographic database was searched for patients with severe AS defined as a valve area 0.8 cm² or less. This yielded a total of 740 patients. Complete clinical, echocardiographic, and pharmacologic data were compiled on these patients from comprehensive chart review. Of these, 338 patients had no cardiac symptoms (exertional chest pain, shortness of breath, or syncope) at the initial encounter forming the study cohort. The following data were extracted through chart review.

Definition of clinical variables
Hypertension was defined as blood pressure greater then 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 (LVEF) 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 [10–11]. Anatomic and Doppler examinations and measurements were performed according to the recommendations of the American Society of Echocardiography [12]. The aortic valve area was calculated using the continuity equation.

Mortality data
The end point 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 then imported into the 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 the ² test for categoric variables. Survival analysis was performed using various statistical tools such as Kaplan-Meier analysis, Cox regression models (including time varying Cox regression), propensity score matching, 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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Baseline Patient Characteristics
The baseline patient characteristics are shown in Table 1. The mean age was 71 years and 51% were men. The aortic valve area was 0.72 ± 0.17 cm² and the LVEF was 0.59 ± 0.17. Over a mean follow up period of 3.5 years, there were 99 (29%) AVRs and 157 (46%) deaths. The precise AVR time was known in 69 patients. The mean interval between diagnosis of severe AS and AVR was 232 days, delay was greater than 3 years in 3 patients and 2 to 3 years in 4 patients.

View larger version (17K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival curves comparing asymptomatic severe aortic stenosis patients with and without aortic valve replacement (AVR).

Propensity Score Analysis
Patients were divided into four strata, based on the probability of receiving AVR for each patient based on the 18 covariate characteristics. Logistic regression analysis was used to calculate this propensity score. Stratum 1 was least likely to receive AVR and the stratum 4 was most likely to receive AVR. Aortic valve replacement was associated with a survival benefit in three of the four strata (Fig 2). As can be expected, the survival curves for the non-AVR group was the worst in stratum 1, but AVR seemed to offer a larger survival benefit in these patients. It is also interesting that the survival curves in the AVR groups were very similar across all four strata.

View larger version (24K): [in this window] [in a new window]   Fig 2. Kaplan-Meier survival curves of asymptomatic severe aortic stenosis patients with and without aortic valve replacement (AVR) stratified by the propensity scores. Patients in stratum 1 are least likely to and patients in stratum 4 are most likely to receive AVR.

View larger version (29K): [in this window] [in a new window]   Fig 3. Results of sensitivity analysis by serially eliminating patients with durations of observations 30 days or less, 90 days or less, 1 year or less, and 2 years or less. Kaplan-Meier survival curves of patients with and without aortic valve replacement (AVR) are shown.

Surgical Mortalities
Of the 287 patients with AVR in the whole cohort, the 30 day mortalities were 2% in the 99 patients with no symptoms, 4% in the 188 with symptoms, 2% in the 80 patients 80 or greater years of age and 11% in the 46 patients who had an LVEF of 0.30. The 1 and 5 year survivals were 94% and 90% in the asymptomatic compared with 88% and 67%, respectively, in the symptomatic patients (p < 0.0001).

Mechanical Versus Bioprosthetic Valves in the Asymptomatic Patients
Of the 99 AVRs, 34 were mechanical and 65 were bioprosthetic. Both groups were similar in terms of EF and gender. However, the mechanical AVR group was younger compared with the bioprosthetic group (60 ± 14 vs 71 ± 15 years, p < 0.05). There were only 17 deaths in the AVR group with no difference in survival between the two AVR types (p = 0.91).

	Comment

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Benefit of AVR in Asymptomatic Severe AS
Our study shows that AVR may benefit asymptomatic patients with severe AS in terms of improved survival. This effect was independent of all the clinical, pharmacologic, and echocardiographic variables that were evaluated in this study. Our data are more comprehensive compared with other published studies and include pharmacological data that were not available in earlier studies. The influence of unmeasured or unmeasurable variables on mortality cannot be fully excluded despite the confirmation of the results with propensity and sensitivity analyses. These can only be eliminated in a randomized study. We are not aware of any randomized study addressing this question either in progress or in planning. Hence, we believe our data should help the clinicians in decision making in these patients until results from randomized studies become available. We believe AVR should be strongly considered in all patients with severe AS in the absence of severe comorbidities which may limit survival or impair quality of life post-AVR. Results of propensity score analysis indicates that even the patients who are least attractive for AVR based on covariate characteristics do benefit from AVR and, as a matter of fact, to a greater extent compared with the most attractive surgical candidates. Lack of a difference in survival between the groups receiving a mechanical or bioprosthetic valve is attributable to a small sample size with low event rates in those receiving AVR.

Role of Beta Blockers and Statins
The other important finding is the survival benefit from statins and beta blockers in the nonsurgically managed patients. We suggest that consideration should be given to the use of these agents in this group of patients and possibly in all with severe AS. The exact mechanism of this benefit is not clear, but it can be speculated that beta blockers may prevent or attenuate atrial fibrillation and other tachyarrhythmias that are poorly tolerated by AS patients. Statins, on the other hand, reduce the risk of a myocardial infarction, which could be disastrous in AS patients who also have coronary artery disease risk factors and are at elevated risk for acute coronary syndromes. There may also be potential beneficial effects on the LV myocardial function and the pulmonary arterioles attenuating the development of pulmonary hypertension (13, 14).

Comparison With Other Published Series
Our data are not totally inconsistent with the other published series. Otto and colleagues reported on the event rates in 123 initially asymptomatic AS patients of all grades of severity, with a mean AVA of 1.3 cm² [3]. Of these a smaller subset with a transaortic velocity of greater than 4 m/second suggesting severe AS had a 2 year probability of remaining alive without AVR was only 21%. Rosenhek and colleagues [4] described the survival pattern of 128 patients with severe asymptomatic AS. The mean age of the patients was only 60 years, indicating many had bicuspid aortic valves. In the patients aged greater than 50 years and those with moderate or severe aortic valve calcification the two year event free survival was 49% and 47%, respectively, indicating severe calcific AS may have a more malignant course. Pellikka and colleagues [5] reported the survival patterns of 622 patients with initially asymptomatic significant AS patients with a mean valve area of 0.9 cm². The two year probability of developing symptoms and getting AVR or death were 33% and 37%, respectively. Interestingly, 145 of the 325 patients who remained asymptomatic received AVR and in this group the mortality was substantially lower than those who remained asymptomatic and did not receive AVR. The severity of AS in our patients (mean AVA 0.72 cm²) is comparable with those reported by Rosenhek and colleagues [4] (but older) and more severe than those reported by Otto and colleagues [3] and Pellikka and colleagues [5]. Age of our patients (mean age, 71 years), which has a bearing on both mortality and probability of having degenerative calcific AS, was similar to those of Pellikka and colleagues [5], but substantially older than those of Rosenhek and colleagues [4].

Reliability of Symptoms as a Risk Stratifier to Triage for AVR
It is not uncommon that patients with chronic disease learn to live within their symptoms and claim lack of symptoms. Symptoms are subjective and depend upon patient expectations and life style and other morbidities which may limit exercise tolerance. In our series, 4% of the patients had an EF of 0.2 or less and 12% had an EF of 0.3 or less; 10% had a pulmonary artery PA systolic pressure 60 mm Hg or greater and claimed no symptoms. This illustrates the unreliability of symptoms as an index of hemodynamic impact of AS and as the most important criterion for surgery. This was supported by other studies. Amato and colleagues [7] reported that 67% of these patients have an abnormal exercise stress test with 2 mm ST segment depression or a flattened blood pressure response. Das and colleagues [8] found that a large number of patients with severe asymptomatic AS had symptoms on the stress test and stress-induced symptoms were the best predictor of a need for AVR in the next 12 months. Hence, use of symptom status as the sole criterion for AVR in patients with severe AS seems imperfect.

Risk of Mortality From Symptom Onset to AVR
After the onset of symptoms, inevitable delays may occur for the patient to seek medical attention, to get the appropriate testing done, to be referred for AVR, and to get AVR. Depending upon the practice setting, each of these delays could be substantial, leading to mortality. A mortality of 7% has been reported while on a surgical waiting list for an AVR [9].

Implications for Percutaneous Valve Therapy
It is difficult to speculate if the benefit from surgical AVR in asymptomatic severe AS patients can be extrapolated to percutaneous valve replacement. Benefit is likely to be dependent on the technical safety of percutaneous valve replacement, durability of such valves, size of the valve, and age at which therapy is delivered. If the valves can be safely and durably delivered, it can be speculated that high risk individuals who are traditionally denied surgery may become candidates for percutaneous AVR; only a randomized study can address this.

Study Limitations
One of the main limitations of this study is its retrospective, observational nature. Hence, the treatment assignment is not randomized but was at the discretion of the patient and the physician. Other drawbacks of the retrospective study include reliability of symptom assessment and the influence of unmeasurable and unmeasured prognostic variables. We employed propensity score analysis, which would eliminate 80% to 90% of the selection bias. Other strengths of this study include the large cohort and a comprehensively characterized study population, especially with pharmacologic data. We obtained the clinical, echocardiographic, and pharmacologic variables that were clearly measurable. Chart review did not allow us to understand clearly the thought process behind clinical decisions whether to or not to offer AVR. There has not been a randomized study in this area and none in progress to our knowledge. Hence, the results of our study should be helpful in clinical decision making.

Clinical Implications
In the absence of a randomized study, we suggest that the threshold for AVR should be lowered in patients with severe AS even in the absence of symptoms. Higher risk asymptomatic patients, such as older individuals who are still acceptable candidates, those with severe valve calcification (because of rapid progression), subnormal LVEF, excessive LV hypertrophy, significant mitral regurgitation, elevated PA pressure, and small valve areas should be seriously considered for surgery. In the absence of these, a stress test is acceptable to establish a true asymptomatic status. Those chosen for nonsurgical follow-up should be closely followed for symptoms, LV dysfunction, new MR, or echocardiographic features of hemodynamic decompensation. Medical therapies with beta blockers and statins are potentially useful. A randomized study is warranted to confirm if AVR is truly beneficial in all asymptomatic patients with severe AS.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
The authors want to thank Dr Daniel Stram, PhD, for statistical review and advice.

	References

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

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