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Abstract
Objective The management of asymptomatic severe and very severe aortic stenosis (AS) remains unestablished. This study aimed to investigate the clinical outcomes of severe versus very severe AS patients.
Design A single centre, retrospective cohort study.
Patients and Methods The study retrospectively reviewed 108 conservatively treated patients with severe AS (a maximal jet velocity ≥4.0 m/s, or mean aortic pressure gradient (MPG) ≥40 mm Hg, or an aortic valve area (AVA) <1.0 cm2) and 58 patients with very severe AS (a maximal jet velocity ≥5.0 m/s, or MPG ≥50 mm Hg or an AVA <0.6 cm2). Clinical outcomes were compared between the two groups, considering the existence of symptoms.
Main Outcome Measures All-cause mortality and valve-related event, defined by a composite of cardiac death and hospitalisation because of heart failure.
Results Mean follow-up was 5.5±3.1 years. Fifty-six patients (52%) with severe AS and 20 patients (34%) with very severe AS were asymptomatic. Very severe AS had poorer survival and valve-related event-free survival than severe AS at 3 years (77% vs 88%, p<0.01; 75% vs 88%, p<0.001, respectively). In addition, the 3-year survival and valve-related event-free survival of asymptomatic very severe AS were comparable with symptomatic severe AS, but they were significantly worse than asymptomatic severe AS (p<0.01 and p<0.001, respectively).
Conclusions Surgery should always be considered in very severe AS regardless of symptoms, and particular attention needs to be paid to their extremely poor outcomes.
- Aortic valve disease
- dissection
- mitral regurgitation
- surgery—valve
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Aortic stenosis (AS) is becoming more common with the increasing age of the population.1 2 Although aortic valve replacement (AVR) is the only effective treatment for symptomatic severe AS patients,3 4 decision making for surgical intervention is not always an easy process for reasons such as advanced age, comorbidities and patient refusal. As a result, a considerable number of patients with severe AS are managed non-surgically5–7 and the prognosis of unoperated symptomatic severe AS is very poor.4 It has recently been reported that patients with very severe AS have extremely poor clinical outcomes with conventional treatment, even if they are asymptomatic.8 9 However, it is still unclear whether very severe AS should be managed differently than severe AS. If very severe AS has a very different outcome compared with severe AS, care needs to be taken in making a decision on whether to operate for very severe AS. Therefore, we investigated and compared the clinical outcomes between very severe AS and severe AS, taking into consideration the presence or absence of symptoms and surgical risks of each patient.
Methods
Study population
A total of 304 consecutive patients was evaluated, who were diagnosed as having severe or very severe AS by transthoracic echocardiography at our institution between January 1999 and December 2009. Of these patients, 71 patients underwent AVR, whereas 233 patients were not primarily referred for AVR. We excluded 15 patients with other haemodynamically significant valve lesions, 29 patients who were considered as symptomatic severe AS but were contraindicated for surgery because of their prohibitive comorbidities and 23 patients with decreased left ventricular ejection fraction (LVEF) (<50%). A total of 166 patients was included in the final analysis.
Echocardiographic evaluation
LVEF was measured using the biplane Simpson disk method.10 Right ventricular systolic pressure was estimated by tricuspid regurgitation peak velocity.11 Maximal aortic jet velocity and mean aortic pressure gradient (MPG) were obtained with the use of the simplified Bernoulli equation, and the aortic valve area (AVA) was obtained with the use of the standard continuity equation12 and indexed to body surface area. Severe AS was defined as a maximal jet velocity of 4 m/s or greater, MPG of 40 mm Hg or greater, or AVA less than 1.0 cm2.13 Very severe AS was defined as a maximal jet velocity of 5.0 m/s or greater or MPG of 50 mm Hg or greater or an AVA less than 0.6 cm2.
Clinical data and follow-up
The clinical data shown in table 1 were obtained from medical records. In addition, we examined whether patients had symptoms due to AS, and the reason why AVR was not primarily planned.
Patient characteristics, comorbid conditions and echocardiographic indices
Clinical follow-up data were obtained from patients either in person or by telephone interviews. Follow-up data were available for 146 patients and were obtained in person in 88 patients and by telephone in 58 patients. The remaining 20 patients could not be contacted and were lost at a mean follow-up of 3.2±1.6 years. Adverse valve-related events were defined by a composite of cardiac death and hospitalisation for congestive heart failure due to AS.
Statistical analysis
Categorical variables are presented as number and percentage, and they were compared using the χ2 test or Fisher's exact test, as appropriate. Continuous variables are described as mean±SD. Survival analysis was performed by Kaplan–Meier analysis and differences between groups were tested using the log-rank test. To determine the predictors of mortality and adverse valve-related events, the Cox proportional hazards model was used to estimate the risks associated with the following variables: age, gender, severity of AS, symptoms due to AS and ischaemic heart disease. Log (time) versus log (−log (survival)) stratified by each significant risk factor was plotted and the relative slopes of the plotted lines were evaluated. Those variables for which probability values were less than 0.20 in univariable analyses and when proportional assumptions were generally fair were included in the multivariable analysis. With regard to the parameters of AS severity, we applied univariable analysis for peak velocity, mean gradient, valve area and the criteria for very severe AS. In multivariable analysis, we only included the criteria for very severe AS. Each component of the definition was not included as variables, because these parameters are closely correlated with one another and therefore confound one another. All analyses were performed with the statistical software program JMP 7.02 (SAS Institute).
Results
Baseline patient characteristics
There were 108 patients with severe AS and 58 patients with very severe AS. A comparison of baseline clinical and echocardiographic characteristics of patients with severe AS and very severe AS are shown in table 1. There were no significant differences between the two groups in terms of age, gender, comorbid conditions, LVEF, left ventricular dimension and right ventricular systolic pressure. Fifty-six patients (52%) with severe AS and 20 patients (34%) with very severe AS were asymptomatic. Among the 90 symptomatic patients, 47 patients (52%) refused surgery and 27 patients (30%) were not recommended AVR because of physician's unrecognition.
Mortality and adverse valve-related events
The mean follow-up period was 5.5±3.1 years. There were 39 deaths including 22 cardiac deaths. Overall survival at 3 and 5 years were 77% and 69% in very severe AS, and 88% and 83% in severe AS, respectively (p<0.01, figure 1A). During follow-up, AVR was eventually performed in 64 patients, and 22 patients were admitted with severe heart failure. Operative mortality (within 30 days of surgery) of the 64 patients who underwent AVR during follow-up was 1.6%, and that of the 71 patients who underwent AVR at the time of diagnosis was 2.8%. The valve-related event-free survival was significantly lower in very severe AS than those in severe AS at 3 years (75% vs 88%; p<0.001, figure 2A). Patients were subdivided into four groups according to the severity of AS and symptoms. Patients with symptomatic very severe AS had the worst overall survival (p<0.01, figure 1B) and valve-related event-free survival (p<0.001, figure 2B). In addition, both overall survival and valve-related event-free survival of asymptomatic very severe AS were comparable with those of symptomatic severe AS, but they were significantly worse than asymptomatic severe AS.
Comparison of actuarial survival, between patients with very severe aortic stenosis (AS) and severe AS (A), and among the four subgroups; asymptomatic severe AS, symptomatic severe AS, asymptomatic very severe AS, and symptomatic very severe AS (B).
Comparison of freedom from adverse valve-related events, in patients with very severe aortic stenosis (AS) and severe AS (A), and among the four subgroups: asymptomatic severe AS, symptomatic severe AS, asymptomatic very severe AS, and symptomatic very severe AS (B). Adverse valve-related clinical events included cardiac death and admission due to heart failure.
Prognostic factors for adverse valve-related events
Table 2 shows the results of univariable and multivariable analyses for predictors of mortality and adverse valve-related events. The multivariable Cox proportional hazard model revealed that very severe AS and symptoms were independent predictors for both mortality and valve-related events.
Univariable and multivariable analysis of predictors of mortality and valve-related events
Discussion
The main findings of this study were as follows: (1) very severe AS had a significantly poorer outcome than severe AS; (2) the outcome of asymptomatic very severe AS was comparable with symptomatic severe AS, in which the guidelines recommend surgical intervention as class I indication;13 14 and (3) the severity of AS and symptoms were significant predictors of adverse valve-related events.
Aortic stenosis is the most common valvular heart disease and is the leading indication for valve surgery. It is generally accepted that symptomatic severe AS requires an operation because of the dismal natural history under medical therapy,3 4 13–15 whereas early surgery for asymptomatic severe AS remains controversial.3 7–9 16–18 Some reports suggested a benefit of early surgery for asymptomatic severe AS,6 7 16 and it has been recommended that the threshold for AVR in patients with severe AS would be lowered to include asymptomatic patients. However, these studies might have included a considerable number of patients with asymptomatic very severe AS. The present study clearly showed that very severe AS had a significantly worse outcome than severe AS patients. In addition, asymptomatic very severe AS had comparably worse outcomes with symptomatic severe AS, which is generally known as a class I indication for AVR. Based on previous reports8 9 and our own results, we propose that the decision for treatment should take into account that very severe AS and severe AS are distinctive conditions, and early surgical intervention should be indicated in patients with asymptomatic very severe AS rather than watchful waiting.
AVR is a standard and relatively low-risk procedure for severe AS, and a good surgical outcome can be expected even in patients in their 80s.1 19–21 However, a substantial number of patients are not referred for surgical consideration because of an operative risk that is presumed to be too high.1 5 Particularly for elderly patients, advanced age per se is not a contraindication to surgery,13 14 and the prognosis of unoperated patients in their 80s with severe AS is very poor.22 Preoperative risk assessment can be difficult in patients with multiple comorbidities, because they form a pathologically heterogeneous group. We used both the European system for cardiac operative risk evaluation (EuroSCORE) and the Society of Thoracic Surgeons (STS) risk score to obtain risk quantification in the current study, because operative risk may be overestimated in the EuroSCORE and underestimated in the STS risk score in high-risk AVR patients.20 21 23 Indeed, patients who primarily underwent medical management but eventually had AVR had a clear survival benefit compared with patients who were not treated surgically. We need to avoid overestimating the perioperative risk and potentially denying patients access to surgery because of a lack of familiarity with current operative risks.
Echocardiography is currently the most widely used diagnostic modality for determining the severity of AS using an aortic pressure gradient and aortic valve area. However, inconsistent grading of AS severity is common, such as an AVA less than 1.0 cm2 and maximal jet velocity less than 4.0 m/s or MPG less than 40 mm Hg, especially when stroke volume is decreased.24 In addition, Lancellotti et al25 reported the importance of valvular, arterial and ventricular interplay on the clinical outcomes of AS patients. It is important to ensure that all measurements are integrated with clinical findings. Therapeutic decisions should always be based on the balance between risks and benefits, considering the results of intervention and the risk of adverse outcomes without intervention. The results of the present study support the idea of early intervention in patients with the diagnosis of very severe AS when there is low institutional perioperative mortality.
Limitations
The main limitation of the present study is the retrospective design, which is prone to inherent bias. Although various statistical tools were used to attempt to minimise the effect of selection bias, it is not possible to remove all biases. A prospective randomised study between surgery and medical therapy in asymptomatic very severe AS would be the only way to answer this clinical question.
Conclusions
Very severe AS had a distinctively poorer clinical outcome among severe AS. Surgery should always be considered in patients with very severe AS regardless of symptoms, and particular attention needs to be paid to their extremely poor outcomes.
Key message
The results of the present study support the idea of early intervention in patients with very severe AS.
References
Footnotes
↵* TK and SH contributed equally to this study.
Competing interests None.
Patient consent Written informed consent from patients was waived because the study subjects were enrolled retrospectively.
Ethics approval The study was approved by the Institutional Review Board of Kobe City Medical Center General Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.