An Observational Study of Elderly Veterans With Initially Asymptomatic Severe Aortic Stenosis

Abstract: Background. The optimal timing of aortic valve replacement (AVR) among patients with asymptomatic severe aortic stenosis (AS) remains uncertain and controversial. Methods. We conducted a cohort study of consecutive patients with severe AS (mean gradient, 40 mm Hg; aortic valve area <1 cm², or peak velocity ≥4 m/s) who were asymptomatic at the time of echocardiography (2005-2015). Outcomes included mortality, AVR, or AS symptoms. Kaplan-Meier curves and the log-rank test were used to compare the outcomes of patients treated with AVR compared with conservative management. Cox proportional-hazards regression analysis was performed to identify predictors of long-term mortality. Results. Of 1181 echocardiograms and medical records reviewed, a total of 324 patients met inclusion criteria. The mean age of the study cohort was 78 ± 10 years and 97% were male. The median follow-up time was 8 years (interquartile range [IQR], 7-10 years), during which 147 patients (51%) underwent AVR and 94 patients (29%) died. The median survival for patients treated with AVR was 10 years (IQR, 9-10 years) and for patients managed conservatively was 4.8 years (IQR, 3.7-5.7 years; P<.001). A total of 47 patients (14% of the cohort and 48% of deaths) expired before AS symptoms were documented in their medical records. Independent predictors of mortality were age (hazard ratio [HR] per increase in decile, 1.14; 95% CI, 1.05-1.24; P<.01) and performance of AVR during follow-up (HR, 0.15; 95% CI, 0.9-0.28; P<.01). Conclusion. A significant proportion of elderly patients with initially asymptomatic severe AS died before symptoms were identified. Our study highlights the difficulty of relying on symptoms alone for timely referral to AVR surgery.

J INVASIVE CARDIOL 2019;31(6):166-170. Epub 2019 March 15.

Key words: aortic stenosis, natural history, prognosis

Aortic stenosis (AS) is one the most common valvular heart diseases.¹ It affects 5% of the adult population 65 years of age or older and is the most common indication for valve replacement in the United States.^2,3 Current American College of Cardiology (ACC)/American Heart Association (AHA) valvular heart disease guidelines recommend aortic valve replacement (AVR) for patients with symptomatic severe AS.³ The management of patients with severe but asymptomatic AS remains controversial.⁴ The natural history of AS involves a long asymptomatic period characterized by increased pressure overload and adaptive left ventricular hypertrophy.⁵ This latency period has traditionally been characterized by a low incidence of clinical events.^6-9 Based on these observations, ACC/AHA guidelines recommend a conservative approach for most patients with severe asymptomatic AS.³

Recent studies have challenged the notion that all patients with severe asymptomatic AS have a benign clinical course.^10-13 Taniguchi et al described a lower 5-year cumulative incidence of sudden death with AVR (0.7%/year) vs conservative management (1.5%/year).¹¹ Interestingly, 70% of sudden deaths occurred in patients without preceding symptoms.¹¹

We sought to describe the natural history of severe asymptomatic AS in a real-world cohort of elderly veterans by conducting a 10-year observational study among patients receiving medical care in a large, integrated health-care system.

Methods

Setting and patients. The Minneapolis VA Healthcare System (MVAHCS) is a tertiary, 250-bed hospital within the VA Midwest Health Care Network (Veterans Integrated Service Network VISN 23). The network serves more than 440,000 enrolled veterans residing in the states of Iowa, Minnesota, Nebraska, North Dakota, South Dakota, and portions of Illinois, Kansas, Missouri, and Wyoming. The MVAHCS is the only approved surgical and transcatheter AVR program in a nine-state area and has an academic affiliation with the University of Minnesota.

We conducted a retrospective electronic search of the echocardiographic database of the MVAHCS encompassing a 10-year period from January 1, 2005 to December 31, 2015. Echocardiograms that met at least one criterion for severe AS demonstrated a peak aortic jet velocity >4 m/s, aortic valve area (AVA) <1 cm², and/or mean gradient ≥40 mm Hg;³ these were identified and linked to a computerized patient record system. Electronic medical records were then reviewed by trained medical doctors to assess symptomatic status at the time of the echocardiogram. Patients with no reported angina, dyspnea, or syncope were deemed to be asymptomatic. Patients who were symptomatic or presumed to be symptomatic (referral to AVR within 6 months of the index echocardiogram) were excluded from the study. In cases with >1 echocardiogram during the study period, we used the first one that met criteria for severe AS. In addition to symptoms, we collected baseline demographic, clinical, medication, laboratory, and echocardiographic data. The burden of comorbidities was calculated for each patient by the Charlson comorbidity index (CCI).¹⁴ The reported CCI value represents an estimate of 10-year survival; with every increased level of the CCI, there is an increase in long-term mortality.⁴ For example, 10-year mortality is 1% for patients with a CCI of 0 and 50% for patients with a CCI of 4.⁴

Outcome measures. Outcomes of interest included death, symptom development related to AS, and surgical or transcatheter AVR. Time to event was calculated using the baseline echocardiogram as time zero. For calculating time to death and AVR, we used death certificates and surgical notes, respectively. For symptoms, we used the date that angina, dyspnea, or syncope was first documented in the medical record. Outcomes were prospectively defined according to the Valve Academic Research Consortium definitions¹⁵ and obtained through review of electronic medical records, surgical notes, and death certificates when applicable.

Statistical analysis. Continuous variables are presented as mean ± standard deviation or as median with interquartile range (IQR) when appropriate. Categorical variables are reported as frequencies and percentages. Continuous variables were compared using the unpaired Student’s t-test or Mann-Whitney U-test, as appropriate. Discrete variables were compared with the Chi-square test or Fisher’s exact test, as appropriate. We used the Kaplan-Meier method to estimate cumulative incidence of events and assessed the differences with the log-rank test. Cox proportional-hazards regression analysis was performed with time to death or censoring as the dependent variable and age, performance of AVR, AVA, mean aortic valve gradient, left ventricular ejection fraction, and peak aortic jet velocity as the explanatory variables. The final model was determined by entering variables with a P-value <.05 and removing variables with a P-value >.01. The risk of an initial AVR strategy relative to a conservative strategy for the clinical endpoint of mortality was expressed as hazard ratio (HR) and 95% confidence interval (CI). A 2-sided P-value <.05 was considered statistically significant. MedCalc version 17.2 (MedCalc Software) was used for statistical analysis. This study was approved by the institutional review board of the Minneapolis VA Medical Center. Individual consent requirement was waived.

Results

A total of 1181 echocardiograms met the study inclusion criteria; 857 of these were excluded because of symptoms, referral to AVR within 6 months, or duplicate echocardiograms, leaving a total of 324 patients in the final study cohort.

The mean age of the study cohort was 78 ± 10 years and 97% were male. Baseline and echocardiographic characteristics of patients according to the performance of AVR are presented in Table 1. The group of patients that underwent AVR was younger than the group of patients that underwent a conservative approach (76 ± 9 years vs 80 ± 10 years, respectively; P<.01). Otherwise, there were no significant intergroup differences in terms of baseline characteristics.

Echocardiographic indices of AS severity were significantly more advanced in the AVR group than in the conventional group (AVA, 0.83 ± 0.13 cm² vs 0.85 ± 0.10 cm², respectively [P=.06]; peak aortic velocity, 3.73 ± 0.60 m/s vs 3.56 ± 0.65 m/s, respectively [P=.02]; mean gradient, 35 ± 11 mm Hg vs 31 ± 12 mm Hg, respectively [P<.01]) (Table 1). At least one parameter consistent with severe AS was present in 100% of patients. The mean ejection fraction was slightly lower for the conservative group (56 ± 8% than for the AVR group (58 ± 6%; P=.03). The median CCI was 4.5 (IQR, 3-6) in the conservative group and 5 (IQR, 3-6) in the AVR group (P=.96).

Clinical events during follow-up period. During a median follow-up of 8 years (IQR, 7-10 years), a total of 166 patients (51%) developed symptoms, 147 (51%) underwent AVR, and 94 (29%) died. The median time to symptoms was 3.5 years (IQR, 3-4 years) (Figure 1), median time to AVR was 4 years (IQR, 3.5-4.6 years), and median time to death was 8 years (IQR, 7-10 years). Survival for patients who underwent AVR during follow-up was significantly better relative to patients who were managed conservatively (Figure 2). The median survival time was 10 years (IQR, 9-10 years) for patients treated with AVR and 4.8 years (IQR, 3.7-5.7 years) for patients managed conservatively (P<.001). A total of 47 patients (14% of the cohort and 48% of deaths) expired before AS symptoms were documented in their medical records. A detailed analysis of their death certificates revealed that 19 of these deaths (41%) were cardiovascular, 22 (47%) were non-cardiovascular, and 6 were undetermined because they occurred in another state (Figure 3).

By Cox proportional-hazard analysis, independent predictors of mortality were age (HR per increase in decile, 1.14; 95% CI, 1.05-1.24; P<.01) and performance of AVR during follow-up (HR, 0.15; 95% CI, 0.9-0.28; P<.01) (Table 2). Echocardiographic indices of AS severity were not independently associated with survival time.

Discussion

In this 10-year observational study of elderly veterans with initially asymptomatic severe AS, we found a high cardiovascular event rate (2.3% per year) among patients treated conservatively and a strong association between performance of AVR and long-term survival. Our study results add to the emerging literature on the topic of asymptomatic AS in the elderly and support a role for early intervention in selected patients.

Current ACC/AHA guidelines recommend surgical or transcatheter AVR for patients with severe symptomatic AS.³ However, 50% of patients with severe AS report no symptoms at the time of diagnosis and the optimal timing of intervention in these patients is uncertain.⁴ Up to 43% of elderly patients present with abrupt deterioration (functional class III-IV symptoms) despite close follow-up in a valve clinic every 6 months.¹⁰ Patients with advanced functional class at the time of AVR have increased operative mortality and worse long-term outcomes.¹⁰

Traditionally, severe asymptomatic AS has been considered a low-risk clinical entity, with a reported risk of sudden death of 1.0%-1.5% per year.^6-9 However, recent reports have highlighted the difficulty of interpreting symptoms and optimal timing of AVR in elderly patients with reduced mobility and increased frailty.^{4,10-13,16,17} Risk stratification of patients with severe asymptomatic AS using exercise stress test,^18-20 biological markers,²¹ and advanced imaging²² has been advocated to overcome some of the limitations associated with early symptom recognition. However, exercise testing has limited predicted value in patients >70 years old.²⁰ Furthermore, none of these tests received a level I recommendation in current guidelines, and periodic clinical and echocardiographic follow-up exams remain the preferred approach.³

Physicians caring for patients with asymptomatic severe AS should consider and balance two competing risks when deciding optimal timing of AVR: the risk(s) associated with an AVR procedure and the risk(s) associated with the natural history of the disease. For some patients at low surgical risk (ie, STS score <3), early AVR may offer a reasonable alternative to watchful waiting when the naturally occurring event rate exceeds a predetermined threshold (ie, >2% per year). This individualized approach to patient management based on risk assessment is already part of the ACC/AHA guidelines. For example, AVR has a class I recommendation in asymptomatic patients with very severe AS (peak velocity >5 m/s) at low surgical risk.³

The emergence of transcatheter AVR, with its low procedural mortality rate and rapid recovery,²⁴ may alter the risk/benefit assessment in the future. This strategy is currently being evaluated in a large, prospective, randomized clinical trial (Evaluation of Transcatheter Aortic Valve Replacement Compared to Surveillance for Patients with Asymptomatic Severe Aortic Stenosis [the EARLY TAVR trial; NCT03042104]).

Study limitations. Our study has important limitations. First, this is a single-center, observational study and included mostly male patients. Second, treatment assignments were not randomly allocated. The association between early AVR and improved long-term survival should be considered hypothesis-generating rather than confirmatory. Third, we did not systematically collect information on frequency of appointments. ACC/AHA guidelines recommend clinic visits every 6 to 12 months for patients with severe asymptomatic AS. A recent report found an association between guideline adherence and improved clinical outcomes.²³

Conclusion

Among elderly patients with severe asymptomatic AS, a significant proportion of fatal events occurred before symptom onset and were cardiovascular in origin. Valve replacement was strongly associated with improved long-term survival. Our study highlights the difficulty of relying on symptoms alone for timely referral to AVR surgery.

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From the ¹University of Minnesota Medical School, Minneapolis, Minnesota; ²Minneapolis VA Medical Center, Minneapolis, Minnesota; and ³Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis, Minnesota.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Garcia reports a grant from Edwards Lifesciences and personal fees from Medtronic. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted December 5, 2018, and accepted December 18, 2018.

Address for correspondence: Santiago Garcia, MD, Minneapolis Heart Institute, 920 E. 28th Street, Suite 300, Minneapolis, MN 55407. Email: garci205@umn.edu