Article Text

Valvular heart disease
Management of asymptomatic aortic stenosis
  1. Bernard Iung
  1. Correspondence to Professor Bernard Iung, Cardiology Department, Bichat Hospital, AP-HP, 46 rue Henri Huchard, Paris 75018, France; bernard.iung{at}bch.aphp.fr

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The management of asymptomatic patients with aortic stenosis (AS) is a frequent situation, as attested by the 23% of patients in New York Heart Association (NYHA) functional class I referred for AS in the Euro Heart Survey on valvular disease.1 This is the consequence of an increased awareness of AS, which is the most frequent heart valve disease in western countries, and of the widespread use of echocardiography. Symptomatic severe AS is a class I recommendation for surgery in guidelines.2 3 Conversely, asymptomatic AS was initially considered as justifying only follow-up. A better insight into the prognosis of asymptomatic AS now makes it possible to identify asymptomatic patients with AS in whom intervention can be considered.

Natural history of asymptomatic aortic stenosis

Overall prognosis

The landmark paper of Ross and Braunwald published in 1968 reported a dramatic increase in the mortality of patients with AS after the onset of severe symptoms. For a long time this has been the rationale for not operating on patients with asymptomatic AS. However, this study from the pre-echo era did not include any evaluation of either AS severity or its left ventricular consequences. In addition, rheumatic AS was still prevalent and mean age at death was 63 years, which does not correspond to contemporary AS epidemiology.

Prospective studies focusing on asymptomatic AS have been performed since the 1990s and these have progressively led to an individualised prognostic assessment. From nine prospective series totalling 1125 asymptomatic patients, the linearised rate of sudden death is estimated at 0.8% per year (table 1).4–12 A series of 622 patients identified retrospectively reported a 0.3% yearly rate of sudden death over a mean follow-up of 5.4 years.13

Table 1

Prospective series on the spontaneous prognosis of asymptomatic aortic stenosis

At first sight, this could be an incentive for not intervening before symptom onset, since the risk of sudden death is lower than the operative risk. However, these studies also showed that patients became rapidly symptomatic, thereby facing a yearly risk of sudden death of approximately 4%. Since symptom onset is subjective and often progressive, patients are likely not to report symptom onset at an early stage. In addition, even symptomatic patients with severe AS are not always referred for surgery.1 13 Thus, waiting for symptom onset may expose such patients to a higher risk of sudden death, which also increases when surgery is delayed because of a waiting list. These considerations, in addition to the inter-individual variability in the progression of AS, justify the attempts to identify among asymptomatic patients with AS those who are likely to become rapidly symptomatic and who, therefore, will be candidates for surgery in the near future.

Risk stratification

Echocardiographic variables

The first step towards risk stratification followed the publication of the paper by Otto et al which reported the prospective follow-up of 123 patients with AS and a peak aortic jet velocity (Vmax) ≥2.5 m/s.4 Annual stress tests ensured that patients remained truly asymptomatic. This study identified Vmax as the best predictor of events—that is, death or surgery. Patients with Vmax <3 m/s had a 5 year event-free survival rate >80%, whereas those with Vmax ≥4 m/s had a 2 year event-free survival rate <30%.

The prospective follow-up of 128 patients with Vmax ≥4 m/s enabled a subgroup of asymptomatic patients at particularly high risk to be identified. Patients who had moderate or severe valve calcification and rapid AS progression, defined as an increase in Vmax ≥0.3 m/s/year, had a 2 year event-free survival <20%. A particularly relevant finding was that those patients had a high risk of very early event, since death or surgery occurred in 30% of them at 6 months and in >65% at 1 year.5

More recently, Vmax ≥5.5 m/s was found to be associated with a high risk of events in asymptomatic patients: rates of death or surgery were 56% at 1 year, 75% at 2 years, and 89% at 3 years.9 It should be noted that very severe AS was a marker of poor outcome only when using Vmax, whereas there was no significant difference in outcome according to whether the aortic valve area was ≤ or >0.6 cm2 (figure 1).

Figure 1

Survival free from cardiac events according to the severity of aortic stenosis as assessed by peak aortic jet velocity (AV-Vel). Reproduced with permission from Rosenhek et al.9

Exercise testing

The obvious advantage of exercise testing is its ability to overcome the subjectivity of symptom evaluation. However, the frequency and prognostic impact of objective dyspnoea occurring at exercise in patients who claim to be asymptomatic was only recently shown in 2005. In a study of 125 patients with AS of diverse severity (mean valve area ≤1.4 cm2), 29% of patients reporting no symptoms spontaneously experienced limiting symptoms during exercise testing.7 These patients had a 49% rate of 1 year symptom-free survival as compared with 89% in truly asymptomatic patients. Limiting symptoms during exercise was the strongest factor related to 1 year event-free survival in multivariate analysis. The positive predictive accuracy of limiting symptoms during exercise testing for the occurrence of symptoms was 57% in the general population, 65% in patients with severe AS, and 79% in patients aged under 70 years.

Exercise testing is also useful for risk stratification of asymptomatic AS in patients who do not experience dyspnoea. The occurrence of other symptoms (angina or near syncope), inadequate rise in blood pressure, complex ventricular arrhythmias or repolarisation abnormalities at exercise were reported in two thirds of patients with severe AS and were associated with an event-free survival rate of <20% at 2 years, whereas this rate was >80% at 5 years in those who had normal exercise tolerance.6

A meta-analysis of exercise testing in asymptomatic AS, pooling 442 patients, showed a highly significant relationship between abnormal exercise test and the risk of cardiac events (figure 2).14 Normal exercise tolerance was associated in particular with a very low risk of sudden death.

Figure 2

Meta-analysis of the predictive value of exercise testing for the occurrence of cardiac events in asymptomatic patients with aortic stenosis. Reproduced with permission from Rafique et al.14

Exercise echocardiography enables valvular function and its consequences to be assessed. The increase in aortic gradient during exercise is related to the occurrence of cardiac events in asymptomatic patients, with a threshold of 20 mm Hg increase proposed recently in a large multicentre series.12 15

Biomarkers

Serum B-type natriuretic peptide (BNP) concentration is related to NYHA functional class in AS and to event-free survival and survival. When considering specifically asymptomatic patients, serum BNP is associated with the occurrence of symptoms.8 10 A study showed that the combination of serum BNP concentration with Vmax and gender achieved a good discrimination between those patients who experienced cardiac events during a 2 year follow-up and those who did not.8 However, no consistent threshold of serum BNP concentration can be proposed to select potential candidates for surgery.

Perspectives to improve risk stratification

Other imaging variables may contribute to risk stratification in asymptomatic AS, but are in need of additional clinical validation at the present time.

Indices of diastolic function (left atrial area index, late diastolic annular velocity as assessed by tissue Doppler imaging, left ventricular diastolic filling pattern from Doppler mitral flow) were associated with occurrence of cardiac events in patients with asymptomatic AS in one series.10

Indices of left ventricular systolic function derived from stain imaging or tissue Doppler seem to be related to exercise tolerance, but their clinical prognostic value has not been proven so far.

CT enables valve calcification to be more reliably assessed and quantitated than when using echocardiography. Calcium score was related to the progression of aortic valve area in AS but its impact on clinical outcome of asymptomatic patients has not been proven.

Evaluation of the risk of surgery

By definition, the aim of surgery in asymptomatic patients is not to improve functional status, but to improve life expectancy. Therefore, the assessment of immediate and late survival after aortic valve replacement is an important component in decision-making in asymptomatic patients.

Patients in NYHA class I have a low operative mortality.16 This is partly related to less severe consequences of valvular disease itself. Low mortality is also explained by the fact that patients in NYHA class I present with favourable characteristics regarding predictive factors of operative morality—that is, younger age and less frequent comorbidities than symptomatic patients.1 17 Assessment of comorbidities, including coronary artery disease, thus has a strong impact on decision-making in asymptomatic AS. In addition, intervention is never performed in an emergency in asymptomatic patients.

Different risk scores are available to estimate the individual operative risk. There is now evidence that risk scores lack accuracy in the prediction of operative mortality in high risk patients. However, risk scores allow for a good discrimination between low risk and high risk patients and their accuracy is relatively good in low risk patients with AS.

Given the low mortality rate of asymptomatic patients with AS, surgery is generally considered only in patients who are at high risk for cardiac events and who have a low expected operative mortality. Decision-making in asymptomatic patients should also take into account prosthetic related complications, which contribute to late cardiovascular mortality, in particular in patients who underwent valvular surgery at an early stage of their disease.

Guidelines

The European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for intervention in asymptomatic patients are summarised in table 2 and figures 3 and 4. Aortic valve replacement is considered only in selected patients who have severe AS, as defined by Vmax ≥4 m/s, mean gradient ≥40–50 mm Hg, and/or aortic valve area ≤1.0 cm2 or 0.6 cm2/m2 body surface area.2 3 Although Vmax and mean gradient are flow dependent indices, they should be checked for consistency with valve area, which is more subject to errors of measurements and inaccuracy.18

Table 2

Recommendations for aortic valvular surgery in asymptomatic patients with severe aortic stenosis

Figure 3

Management of patients with severe aortic stenosis according to the guidelines of the European Society of Cardiology. AS, aortic stenosis; BSA, body surface area; EF, ejection fraction; LV, left ventricle. Reproduced with permission from Vahanian et al.2

Figure 4

Management of patients with severe aortic stenosis according to the guidelines of the American College of Cardiology/American Heart Association. AVA, aortic valve area; BP, blood pressure; CABG, coronary artery bypass grafting; LV, left ventricle; Vmax, peak aortic jet velocity. Reproduced with permission from Bonow et al.3

Besides the need for other cardiac intervention, both guidelines recommend surgery in asymptomatic patients with left ventricular ejection fraction (LVEF) <50%, although this is not supported by the literature and concerns a small number of asymptomatic patients. Despite certain differences in criteria, intervention is also recommended in patients in whom there is a high likelihood of rapid progression of AS. The main difference between the ESC and ACC/AHA guidelines concerns the use of exercise testing, which is recommended for risk stratification of asymptomatic patients with severe AS in the ESC guidelines, and only in patients with equivocal symptoms in the ACC/AHA guidelines. The development of symptoms during exercise testing is a class I recommendation for intervention in the ESC guidelines and a class IIb recommendation in the ACC/AHA guidelines. It should be stressed that all recommendations are associated with levels of evidence C, which illustrates the low level of evidence on which they rely.

The identification of asymptomatic patients who are at high risk of cardiac events is important even in those who are not considered for surgery, since they require a frequent follow-up (≤6 months), in particular to detect symptoms which are not always reported spontaneously. Close follow-up is also important to reinforce patient education, in particular the need to report any new symptom. No medical treatment has been shown to reduce the progression of AS so far.

Evaluation of practices

An evaluation of the practices utilised in the management of asymptomatic AS was performed in the Euro Heart Survey. Of 1197 patients with AS, 809 had severe AS and 84 did not have any symptoms.17 Although there was a lower level of evidence supporting exercise testing than today, an abnormal response to exercise testing was already an indication for intervention in the 1998 ACC/AHA guidelines, which were the only international guidelines available at that time. However, exercise testing was performed in only 2.4% of asymptomatic patients with severe AS. A decision to operate was taken in 45 of the 84 patients (54%), and the decision to operate or not was in accordance with the 1998 ACC/AHA guidelines in 68% of cases. Of the 27 patients who were considered for surgery in accordance with guidelines, the most frequent reason for intervention was a valve area ≤0.6 cm2, which was a class IIb recommendation. In the light of recent studies, Vmax seems a more appropriate echocardiographic variable than aortic valve area to identify high risk asymptomatic patients with very severe AS. No patient was considered for intervention because of abnormal response to exercise. Although there was a relatively good concordance between guidelines and practice, the decision to operate was based on class IIb recommendations in 70% of cases.

Impact and limitations of different criteria of risk stratification on decision-making

Different criteria can now be used to identify asymptomatic patients with AS who are at high risk of reaching the end point of death or surgery within 1–2 years. However, the different criteria for risk stratification have been tested separately and their respective predictive value for the occurrence of cardiac events is not known. Rather than combining all criteria, a practical stepwise approach may be proposed in asymptomatic patients with AS.

  • The first step is to consider surgery in the rare asymptomatic patients with LVEF <50%.

  • The second step is to assess the severity of AS, combining Vmax, mean gradient, and valve area. Patients with Vmax ≥5.5 m/s may be considered for surgery without additional investigation. Although this indication relies on only one study, it may be justified by the high risk of short term cardiac events and the potential reluctance to exercise patients with very severe AS. This is likely to be applied in practice since the Euro Heart Survey showed that practitioners are prone to consider surgery for very severe AS.

  • In patients with severe AS but Vmax <5.5 m/s, the third step is to perform exercise testing if they are physically active. Patients who develop symptoms or have a fall in blood pressure should be considered for surgery. There is no reason for performing routine exercise echocardiography at this stage since conventional exercise testing is easier to perform and enables >25% of asymptomatic patients to be identified as being at high risk of cardiac events.

  • In patients who remain asymptomatic after exercise testing, the fourth step can be to search for indices whose prognostic value is less well established and/or require additional investigations:

    • rapid progression defined by an increase of Vmax ≥0.3 m/s per year in patients with moderate or severe valve calcification

    • increase in mean gradient ≥20 mm Hg during exercise echocardiography

    • a score combining Vmax, serum BNP concentration, and gender >16.8

Thus, a simple approach combining comprehensive baseline echocardiographic examination and exercise testing enables most high risk patients with severe AS to be identified.

Aortic valve replacement is considered in moderate AS only in patients who need surgery on another valve, coronary arteries or ascending aorta, which is a rare occurrence in asymptomatic patients.2 3 They should be informed of the potential for progression of moderate AS, even more so in elderly patients, in those with severe valve calcification or associated coronary artery disease who are likely to experience a more rapid progression from moderate to severe AS.

Improvement in risk stratification does not solve all the problems of the management of asymptomatic AS. The translation from the identification of a high risk of developing cardiac events to the benefit of surgery lacks supporting data. Only one prospective non-randomised study compared intervention to conservative management in patients with asymptomatic AS.11 Among 197 patients with asymptomatic AS defined by Vmax ≥4.5 m/s, mean gradient ≥50 mm Hg, or aortic valve area ≤0.75 cm2, 102 patients underwent early surgery within 3 months of evaluation and 95 were managed conservatively—that is, they underwent surgery when they became symptomatic. Six year cardiac and non-cardiac mortality rates were lower after early surgery as compared to conservative management, including in two subgroups of 57 propensity matched patients. However, the lack of exercise testing raises concerns about the absence of symptoms. This is reinforced by the high cardiac mortality (24% at 6 years) in patients managed conservatively, with the occurrence of seven deaths due to heart failure and nine sudden deaths. Such figures are unexpected in closely followed patients with asymptomatic AS, even with initial Vmax ≥4.5 m/s. In contrast, there were no cardiac deaths, including no operative mortality, in the 105 patients who underwent early surgery.

The findings of this study cannot lead to the recommendation for systematic surgery in asymptomatic patients with AS without taking into account the criteria of risk stratification. Available evidence strongly suggests that decision-making for aortic valve replacement in symptomatic AS should be individualised, and weighs the risk of cardiac events according to echocardiographic examination, exercise testing, and other investigations if needed, and the risk of surgery.

Particular situations

Bicuspid aortic valve

Bicuspid aortic valve is frequently associated with a dilatation of the ascending aorta independently of valve function. Surgery may be indicated in asymptomatic patients with a bicuspid aortic valve when the maximum diameter of the ascending aorta is ≥50 mm.2 3 Thus, echocardiographic examination should comprise standardised measurements of the ascending aorta when a bicuspid aortic valve is present or even suspected—for example, in young patients—since the diagnosis of bicuspid valve may be difficult, particularly when highly calcified. This is of particular importance when the dilatation predominates above the sinotubular junction, since it can be missed if the echocardiographer does not pay specific attention to the aorta.

Elderly

Aortic valve replacement is generally not considered in asymptomatic elderly patients with AS because of the increase in the operative risk with age. No age limit can be given and surgery may be considered in selected physically active patients without comorbidities; exercise testing is feasible and useful in these cases. Conversely, elderly patients in whom objective exercise capacity is difficult to assess because of reduced activity and/or comorbidities are generally not considered for early surgery.

A relatively frequent situation is the need for non-cardiac surgery in an asymptomatic patient with severe AS. Non-cardiac surgery can be performed in most asymptomatic patients without prior valvular surgery. Indications for valvular surgery before non-cardiac surgery are restricted to selected patients when non-cardiac surgery is at high risk and if the risk of aortic valve replacement is low.2

At present, the use of transcatheter aortic valve implantation (TAVI) is targeted towards symptomatic patients who are at high risk for conventional valvular surgery.19 In the future, it is possible that TAVI will expand the indications of interventions for AS to low risk patients, including asymptomatic patients. Such extension of indications could be considered only when the long term durability of devices has been demonstrated, and when TAVI is proven to be feasible with a very low risk in asymptomatic patients.

Low flow, low gradient AS

Low flow, low gradient AS due to impairment of LVEF is unlikely to be encountered in asymptomatic patients. Patient management relies on risk stratification including low dose dobutamine stress echocardiography.2 3

Low flow, low gradient AS with preserved LVEF has been identified more recently and is associated with an increase in valvuloarterial impedance. Valvuloarterial impedance reflects the global haemodynamic load of the left ventricle and has an impact on survival in asymptomatic patients with moderate or severe AS.20 However, indications for interventions are not well defined in patients with low flow, low gradient AS and preserved LVEF, and surgery is thus currently not considered in asymptomatic patients.

Conclusion

Prospective series on asymptomatic AS confirm that the risk of sudden death is low, but not zero, and consistently show that certain patients have a high risk of becoming symptomatic in the short term and, thus, of being put at high risk of cardiac complications. Most high risk patients can be identified using comprehensive echocardiographic examination and exercise testing. Patients with normal exercise tolerance are particularly at low risk of sudden death. Decision-making for aortic valve replacement should be individualised in asymptomatic patients with severe AS, weighing the risk of cardiac events against the operative risk to select patients for early surgery or closer follow-up.

Management of asymptomatic aortic stenosis: key points

  • Decision-making for intervention in asymptomatic patients with aortic stenosis (AS) should be individualised and based on risk stratification.

  • In asymptomatic patients with severe AS, comprehensive echocardiographic examination and exercise testing identify those who are at high risk of experiencing cardiac events in the short term.

  • Serum BNP concentrations and increases in aortic gradient at exercise echocardiography are also related to the risk of cardiac events, but rely on less evidence.

  • Aortic valve replacement can be considered in asymptomatic patients with severe AS who are at high risk of cardiac events, provided their operative risk is expected to be low.

  • Risk scores are reliable in identifying patients at low risk for valvular surgery.

  • Aortic valve replacement is seldom considered in asymptomatic elderly patients with AS because of their operative risk.

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References

  1. These ESC guidelines summarise indications for valve surgery in asymptomatic patients with AS.

  2. The recent update of the ACC/AHA guidelines summarise indications for valve surgery in asymptomatic patients with AS.

  3. This paper shows that patients who claim to be asymptomatic but had limiting symptoms during exercise testing have a poor spontaneous 1 year outcome.

  4. A well designed predictive multifactorial approach to risk stratification of asymptomatic AS on the basis of gender, peak aortic jet velocity, and serum BNP concentration.

  5. Although very severe AS is often a reason for considering surgery in asymptomatic AS, this is the first study to demonstrate the poor spontaneous outcome of these patients, which can be easily identified.

  6. This multicentre series shows the impact of exercise echocardiography in risk stratification of asymptomatic patients with severe AS.

  7. The largest series of asymptomatic patients with severe AS with a mean follow-up >5 years.

  8. This meta-analysis further confirms the strong prognostic value of exercise testing in risk stratification of asymptomatic AS, including for the risk of sudden death.

  9. The comparison of practice and guidelines shows a relatively good concordance of decisions on whether or not to operate on asymptomatic patients with severe AS, although most decisions to operate were based on class IIb recommendations.

  10. Recent combined US and European recommendations detailing the value and limitations of different echocardiographic indices to assess the severity of aortic stenosis.

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Footnotes

  • Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. Consultancy: Servier, Boehringer Ingelheim. Speaker's fee from Edwards Lifesciences, St Jude Medical, Sanofi Aventis.

  • Provenance and peer review Commissioned; internally peer reviewed.

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