Main topic Herz DOI 10.1007/s00059-017-4584-z © Springer Medizin Verlag GmbH 2017

J. Ledwoch1,2 · H. Thiele1,2 1

Medical Clinic II (Medical Clinic II, Department of Cardiology, Angiology, Intensive Care Medicine), University Heart Center Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany 2 Partner Site Hamburg/Kiel/Lübeck, German Center for Cardiovascular Research (DZHK), Lübeck, Germany

Treatment of asymptomatic aortic valve stenosis Watchful waiting or early intervention?

Aortic stenosis (AS) is the leading heart valve disease in Western countries. Approximately one half of patients with severe AS are asymptomatic [28, 30]. Currentguidelines recommend medical therapy with close surveillance for the majority of these patients. Recently, however, it has been speculated that patients with asymptomatic severe AS might benefit from early aortic valve replacement (AVR) than from a watchful waiting strategy with AVR only upon symptom onset [11]. Unfortunately, there are only very few non-randomized trials with several limitations available addressing this issue [15, 28, 29, 34]. The present report gives an overview of the available data on the prognosis and management of patients with severe asymptomatic AS.

with severe AS are asymptomatic, a very large number of patients are affected by this special condition. Therefore, evidence-based treatment in asymptomatic AS is as important as in symptomatic AS.

Prognosis of asymptomatic aortic stenosis For long, asymptomatic AS was considered a benign disease and aortic valve replacement (AVR) is therefore indicated only after symptom onset in the majority of the patients [26, 36]. However, there is a growing body of evidence indicating that patients with asymptomatic severe AS have a relatively poor prognosis. The 5-year mortality ranges widely across the

studies but can be as high as 62% [23, 28, 32, 34]. In addition, a large number of patients will develop symptoms requiring AVR within a short period of time following the initial diagnosis (. Table 1). Hence, freedom of death or of AVR in asymptomatic AS is low. Pellikka et al. showed survival free of symptoms to be 82%, 67%, and 33% at 1, 2, and 5 years, respectively (. Fig. 1; [30]). Overall, the median time to symptom onset, AVR, or death ranges between only 1 and 4 years [11]. These data underline that a relevant number of asymptomatic patients with severe AS will either die or must undergo AVR relatively soon after diagnosis.

Prevalence of asymptomatic aortic stenosis The prevalence of asymptomatic AS is often higher than expected. Since the majority of asymptomatic patients are followed up as outpatients, the awareness of asymptomatic AS is biased leading to an underestimation of these patients, particularly by hospital cardiologists. Large US echocardiography databases revealed that approximately 40–50% of patients with severe AS are asymptomatic [28, 30]. In Western countries, 5% of patients over the age of 65 years suffer from AS [13]. In Germany, a total of 13,264 patients with severe AS underwent transcatheter aortic valve implantation (TAVI) in 2014 with a further increase to 16,544 patients in 2015 [10]. Since up to one half of patients

Fig. 1 8 Event-free survival of patients (pts) with severe asymptomatic aortic stenosis (with permission from Pellika et al. [30]) Herz

Main topic Table 1 stenosis

Rates of aortic valve replacement (AVR) in patients with asymptomatic severe aortic

Study

Number of patients

Age (years)

Follow-up (years)

Need for AVR (in %)

Otto et al.

123

63 ± 16

~2.5

39

Rosenhek et al.

128

60 ± 18

~2

46

Monin et al.

107

72 (63–77)

~2

54

Lancelotti et al.

163

70 ± 10

~2

35

Marechaux et al.

135

64 ± 15

~2

43

Cioffi et al.

218

75 ± 11

~2

35

Table 2 Risk factors for adverse outcome in asymptomatic severe aortic stenosis (AS) Echocardiographic parameter Laboratory parameter Clinical parameter Severity of AS Peak velocity >5.0 m/s [15, 16] or >5.5 m/s [33] Aortic valve area [16, 30] Mean gradient [16, 23]

B-type natriuretic peptide [20, 25]

Drop in blood pressure during exercise [9, 30, 31]

Rapid progression of AS severity [15, 32] Calcification severity [6, 32] Ejection fraction [28, 29] Left ventricular hypertrophy [6, 23, 30] or left ventricular mass index [23] Left ventricular strain [19, 40] Valvuloarterial impedance [8, 19, 40] Left atrial area [18, 19]

Subgroups at increased risk One of the key questions is whether certain subgroups of patients with asymptomatic AS are at increased risk for mortality or AVR. Several studies revealed a high number of predictors for adverse outcome, which are summarized in . Table 2.

Echocardiography Among risk factors, echocardiographic parameters play a central role. Measures of AS severity were repeatedly found to predict outcome. Rosenhek et al. showed that patients with very severe AS have a dismal prognosis. They stratified 116 patients based on peak aortic jet velocity and found a clear association with eventfree (absence of guideline-based indication for AVR) survival (. Fig. 2a). The event-free survival at 3 years in patients with peak aortic jet velocity between 4.0 and 5.0 m/s was 49%, 33% in patients with jet velocity between 5.0 and 5.5 m/s, and Herz

11% in patients with jet velocity ≥5.5 m/s (p < 0.0001) [32]. Similar results were found in other trials assessing the association of peak velocity or other AS severity parameters such as aortic valve area and mean aortic valve gradient with outcome (. Table 2). Not only AS severity but also change in AS severity over time has a significant impact on prognosis. Rosenhek et al. revealed that 79% of patients with rapid progressive AS defined as an increase in peak aortic jet velocity of ≥0.3 m/s per year died or underwent AVR within 1 year of diagnosis (. Fig. 2b; [32]). There is also a range of prognostically relevant echocardiographic parameters that reflect myocardial function. Ejection fraction (EF) is one of the key measures that determine survival in severe AS. When treated medically, asymptomatic patients with severe AS and concomitant left ventricular systolic dysfunction have increased mortality [28]. Importantly, AVR may improve EF in this subset of patients [35]. Of note, in a large

cohort of asymptomatic patients with severe AS, impaired EF was only found in 3% of the cases [30]. This shows that a decline in EF occurs late during the course of the disease and patients usually become symptomatic at this point. Myocardial deformation assessment by speckle tracking has gained increasing attention in various settings and, consecutively, it was also assessed in asymptomatic AS patients. Lancellotti et al. found, in 163 patients with moderateto-severe AS, longitudinal strain to be independently associated with outcome. Those with longitudinal strain >15.9% had significantly better 4-year survival than those with <15.9% (63% vs. 22%; p < 0.001) [19]. A cut-off of 15% in longitudinal strain with respect to outcome evaluation was also seen in the report of Yingchoncharoen et al. [40]. Furthermore, they found global longitudinal strain to add incremental prognostic value in addition to risk prediction by established factors including the Society of Thoracic Surgeons (STS) score and aortic valve gradient. Another important functional assessment includes measures of left ventricular hypertrophy. The relevance of left ventricular hypertrophy was shown in 186 asymptomatic patients studied by Marcheaux et al. The authors identified ventricular hypertrophy to be independently associated with the combined endpoint of cardiovascular death or AVR (hazard ration [HR] 1.96; 95% confidence intervals [CI] 1.17–3.27; p = 0.01) [23]. Patients with inappropriately high left ventricular mass defined as left ventricular mass exceeding 10% of the expected value predicted from height, sex, and stroke work had a threefold increased risk for cardiovascular events (death, AVR, or hospital admission for myocardial infarction and/or heart failure) [6].

Biomarker assessment Work on biomarker assessment and its potential prognostic implications in asymptomatic AS is still at the beginning. The only parameters adequately assessed so far in this setting are brain natriuretic peptides. Since these peptides correlate with AS grade [37] and severity of symp-

Abstract · Zusammenfassung toms [12], their value can be considered an indicator of disease stage. Brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) were both found to be predictive of symptom onset, AVR, and death in moderate-to-severe asymptomatic AS [5, 7, 12, 20, 25, 37]. Clavel et al. reported that BNP adds incremental prognostic value regarding long-term survival in asymptomatic AS above and beyond clinical risk factors [7]. The cut-off for symptom onset prediction in patients with severe asymptomatic AS was 130 pg/ml [5] and 66 pg/ml [20] for BNP and 677 pg/ml for NT-pro-BNP [5]. Whether these values may be used in a decision-making process for AVR in asymptomatic AS needs to be validated in prospective trials.

Ergometry/stress echocardiography There are data available claiming the usefulness of ergometry or stress echocardiography in unmasking patients’ symptoms [1, 17]. However, the definition of symptomatic/asymptomatic status is based on physical capacity in patients’ daily routine instead of exercise testing [36]. Approximately one third of patients with severe asymptomatic AS are unable to undergo exercise owing to limited physical mobility or they may have contraindications to pharmacological stress testing [41]. Two thirds of patients need to terminate the exercise because of fatigue, according to Das et al. [9]. This underlines that a substantial number of patients report only very unspecific symptoms, which are not clearly attributable to AS. Therefore, stress testing including ergometry or stress echocardiography is only rarely performed in clinical practice. In fact, only 5.7% of patients with severe asymptomatic AS underwent exercise testing based on a survey of 92 centers from 25 European countries [14].

Risk of sudden cardiac death One of the major issues of asymptomatic AS is the risk for sudden cardiac death. The rates vary between 0.3% and 3.1% per year [1, 27, 28, 30, 32]. Based on the largest cohort of severe asymptomatic AS

Herz DOI 10.1007/s00059-017-4584-z © Springer Medizin Verlag GmbH 2017 J. Ledwoch · H. Thiele

Treatment of asymptomatic aortic valve stenosis. Watchful waiting or early intervention? Abstract There is ongoing debate about the optimal management of severe asymptomatic aortic stenosis (AS). Thus far, current guidelines recommend a watchful waiting strategy for the majority of asymptomatic patients. However, data on the prognosis of asymptomatic AS are inconsistent. Some reports claim an increased risk of complications and even mortality in this subset of patients when treated conservatively. Several factors are considered to contribute to the impaired outcome of asymptomatic patients, such as progressive myocardial damage or sudden cardiac death, during the watchful waiting period. Indeed, a few nonrandomized studies are available in the literature showing improved survival

with early aortic valve replacement during the asymptomatic phase compared with watchful waiting. However, these studies have several limitations particularly with regard to methodology, and thus making a clear recommendation on treatment options impossible. Therefore, randomized controlled trials are urgently needed in order to treat these patients on the basis of adequate evidence. Keywords Asymptomatic aortic valve stenosis · Transcatheter aortic valve implantation · Aortic valve replacement · Watchful waiting · Outcome

Behandlung der asymptomatischen Aortenklappenstenose. „Watchful waiting“ oder frühe Intervention? Zusammenfassung Es wird nach wie vor über das optimale Management von Patienten mit schwerer asymptomatischer Aortenklappenstenose diskutiert. Bisher empfehlen die Leitlinien bei einem Großteil dieser Patienten eine „Watchful-waiting-Strategie“. Allerdings sind die Daten bezüglich der Prognose der asymptomatischen Aortenklappenstenose widersprüchlich. Einige Publikationen zeigen ein erhöhtes Risiko von Komplikationen und sogar Mortalität, wenn diese Patienten konservativ behandelt werden. Mehrere Faktoren wie beispielsweise ein progredienter Myokardschaden als Folge der permanent erhöhten Nachlast oder plötzlicher Herztod während des „watchful waiting“ tragen vermutlich zu einem schlechteren Ergebnis asymptomatischer Patienten bei. Es existieren

assessed by Taniguchi et al., sudden cardiac death can be estimated to be approximately 1.5% per year [34]. However, the risk for sudden cardiac death increases significantly as soon as patients become symptomatic. Lund et al. showed that sudden cardiac death occurred in 3% of patients during the first 6 months following symptom onset [21]. Anticipating sudden cardiac death is almost impossible in this setting since roughly 70% of

einige nichtrandomisierte Studien, die tatsächlich ein verbessertes Überleben mit einem frühen Aortenklappenersatz während der asymptomatischen Phase verglichen mit „watchful waiting“ zeigen. Jedoch haben diese Studien eine Vielzahl an Limitationen, insbesondere bezüglich der Methodik. Daher kann aus diesen Daten keine eindeutige Empfehlung für eine der therapeutischen Optionen abgeleitet werden. Aus diesem Grund sind randomisierte Studien in diesem Indikationsgebiet dringend erforderlich. Schlüsselwörter Asymptomatische Aortenstenose · Kathetergestützte Aortenklappenimplantation · Aortenklappenersatz · „Watchful waiting“ · Ergebnis

sudden deaths are not preceded by any symptoms [11].

Early aortic valve replacement vs. watchful waiting AVR or watchful waiting are currently the only therapeutic strategies that can be chosen in patients with severe asymptomatic AS. Medical treatment (mainly statins and blockers of the renin–angiotensin–aldosterone system) has reHerz

Main topic

Fig. 2 8 Mortality depending on peak aortic jet velocity (a) and increase in peak aortic jet velocity of ≥0.3 m/s per year (b) (adapted from Rosenhek et al. [32])

Pros and cons of early aortic valve replacement

Fig. 3 8 Stages and associated risk depending on therapeutic strategy.AVR aortic valve replacement

peatedly failed to show outcome benefit or modification of disease progression [24].

Guideline recommendations The European Society of Cardiology (ESC) and American Heart Association (AHA) guidelines recommend Herz

AVR in patients with severe AS only after symptom onset in most of the cases. Nonetheless, based on the studies described previously, certain subgroups may benefit from early AVR in the asymptomatic phase and, thus, the guidelines advise to consider AVR in these patients (. Table 3).

There are several issues that need to be considered when opting for watchful waiting in asymptomatic AS. First, in the real world not all patients will seek medical assistance immediately when becoming symptomatic for different reasons such as adoption to limited physical activity or relating symptoms to other conditions by the patient. In this phase the risk for sudden cardiac death increases, as described earlier. Another problem can be complications that may occur during the waiting time once the decision for AVR has been made. Importantly, mortality while waiting for AVR correlates strongly with waiting time [22, 39]. Mortality was found to be 2.2% for a 10-day period with a further increase to 22.4% for a 180-day period in a TAVI population [39]. Overall, 6.5% of patients die while waiting for AVR, according to the data gathered by Lund et al. [21]. Furthermore, Taniguchi et al. found that the operative mortality of AVR was higher in symptomatic patients compared with asymptomatic patients [34]. These considerations in patient management are illustrated in . Fig. 3.

Table 3

Guidelines on AVR in severe asymptomatic AS [26, 36] ESC/EACTS

AHA/ACC

Symptoms on exercise test

I

I

Left ventricular ejection fraction <50%

I

I

Undergoing other cardiac surgery

I

I

Very severe aortic stenosis (aortic velocity ≥5.0 m/s [AHA/ACC] or >5.5 m/s [ESC/EACTS])

IIa

IIa

Fall in blood pressure during exercise

IIa

IIa

Rapid progression of aortic stenosis (aortic velocity ≥0.3 m/s/year)

IIa

IIb

Markedly elevated natriuretic peptide

IIb

–

Increase of mean pressure gradient by >20 mm Hg during exercise

IIb

–

Excessive left ventricular hypertrophy in the absence of hypertension

IIb

–

AS aortic stenosis, AVR aortic valve replacement, AHA/ACC American Heart Association/American College of Cardiology, ESC/EACTS European Society of Cardiology/European Association for Cardio-Thoracic Surgery

Evidence of early aortic valve replacement vs. watchful waiting

Table 4 Pros and cons for early aortic valve replacement (AVR) vs.watchful waiting Pro early AVR Contra early AVR Operative mortality is lower in asymptomatic compared with symptomatic patients

Watchful waiting may avoid/delay procedural complications and mortality

Early AVR may lower/avoid the risk of sudden Close follow-up and adequate patient behavior cardiac death without preceding symptoms, can contribute to timely detection of sympparticularly after silent onset of symptoms, and toms and AVR complications during the waiting phase for AVR Early AVR may lower/prevent irreversible myocardial damage

Mortality may be low in truly asymptomatic patients without risk factors for complications

Early AVR can possibly reduce/prevent complications that might occur if AVR is performed too late

Watchful waiting may reduce long-term complications of AVR such as endocarditis, pacemaker dependency, bleeding, thrombosis etc

Early AVR may avoid urgent heart failure hospitalizations with the associated risk for nosocomial complications and mortality

Watchful waiting may reduce the risk for aortic prosthesis degeneration due to AVR at a later stage of the disease

Table 5 Secondary endpoints of early aortic valve replacement (AVR) vs.watchful waiting at 5 years (according to Taniguchi et al. [34]) Early AVR Watchful Adjusted HR p (in %) waiting (in %) (95% CI) Cardiovascular death

9.9

18.6

0.59 (0.35–0.96)

0.03

Aortic valve-related death

5.3

13.5

0.42 (0.21–0.79)

0.006

Sudden death

3.6

5.8

0.43 (0.17–0.99)

0.049

Noncardiovascular death

6.1

9.6

0.74 (0.37–1.45)

0.38

19.9

0.19 (0.09–0.36)

<0.001

Heart failure hospitalization 3.8

A relevant disadvantage that comes along with watchful waiting is myocardial damage caused by permanent high afterload in the setting of severe AS. From cardiac magnetic resonance data it was shown that 61% of patients with severe symptomatic AS have myocardial fibrosis prior to AVR [38]. One third even had severe fibrosis, which had a significant impact on outcome. Patients with

managed by watchful waiting were hospitalized with urgent symptoms (NYHA class ≥III). This subset of patients had a clearly worse prognosis than those presenting with NYHA class ≤II (4-year mortality 44% vs. 88%; p = 0.002) [41]. On the other hand, there are possible limitations also with early AVR. Since the aortic prostheses will usually remain longer in the patient with AVR performed at an earlier stage, they may be potentially at increased risk for prosthetic valve-related complications such as endocarditis, pacemaker dependency, bleeding, thrombosis etc. The pros and cons for early AVR are summarized in . Table 4.

severe fibrosis had a decrease in EF and no improvement in New York Heart Association (NYHA) class during follow-up despite AVR. Moreover, Azevedo et al. showed the severity of myocardial fibrosis to be significantly associated with mortality (. Fig. 4; [3]). A report by Zilberszac et al. revealed that 43% of patients with severe asymptomatic AS who were initially

There are no prospective randomized trials available that assess the outcome dependent on the strategy chosen in severe asymptomatic AS. However, a number of registry data were gathered in this setting. Recently, Taniguchi et al. performed a large retrospective analysis including a total of 1808 patients with 291 patients undergoing early AVR and 1517 patients treated conservatively [34]. After adjustment for baseline risk factors, the HR for 5-year all-cause mortality was 0.64 (95% CI = 0.40–0.99; p = 0.009) of early AVR compared with conservative treatment (. Table 5; . Fig. 5). However, after an observational period of 2 years, approximately 40% of the patients in the conservative arm had a class I indication for AVR but did not undergo surgery. Pai et al. presented the second largest analysis with a total of 338 patients [28]. After adjustment for baseline risk factors, the HR for 5-year all-cause mortality was 0.17 (95% CI = 0.10–0.29) for early AVR compared with conservative treatment. A major limitation of the trial was absence of deferred AVR in the conservative group despite symptom onset. In the report by Kang et al. assessing 197 patients, the adjusted HR for all-cause mortality after 6 years was 0.14 (95% CI = 0.03–0.65) [15]. Pellikka et al. showed an unadjusted risk ratio for all-cause mortality after 2 years of 0.54 (95% CI = 0.13–2.24) in their analHerz

Main topic

Fig. 4 8 Association of myocardial fibrosis and mortality (with permission from Azevedo et al. [3])

Fig. 5 8 Kaplan–Meier estimates for 5-year mortality (with permission from Taniguchi et al. [34]). AVR aortic valve replacement

Fig. 6 8 Meta-analysis with pooled adjusted hazard ratios (HR) for all-cause mortality (with permission from Genereux et al. [11]). AVR aortic valve replacement, CI confidence interval

ysis of 143 patients [29]. A recent metaanalysis confirmed the aforementioned evidence (. Fig. 6; [11]). In all these trials no randomization was performed. Therefore, a strong bias must be assumed of relatively young and healthy patients referred for early AVR. By contrast, older patients were characterized by high comorbidity and frailty and, thus, they were probably denied surgery. These “no-option for surgery” candidates were not excluded from the analyses and thus make the validity of these trials questionable. Furthermore, there was no close follow-up of the patients. Timely detection of any symptoms is crucial so as to refer patients for AVR at the beginning of their symptomatic phase. Otherwise, their outcome without invasive therapy is markedly impaired.

The need for a trial

Fig. 7 9 Study flow of the EVETAVI trial (“Early Versus Deferred Transcatheter Aortic Valve Implantation in Patients with Asymptomatic Severe Aortic Stenosis”) Herz

As previously described there are no prospective randomized data that guide us in the decision of whether AVR should be performed on asymptomatic AS [26, 36]. No conclusion can be drawn from the non-randomized studies comparing early AVR with watchful waiting because of the aforementioned issues regarding trial design and patient management. Also, the indication for early AVR in certain subgroups as mentioned in both the US and European valvular guidelines must be questioned. All these recommendations only have a level of evidence C because of the weak methodology of the studies (limited number of patients, retrospective design, question-

able inclusion criteria such as aortic valve area <1.5 cm2 or peak velocity >3 m/s [9, 17, 23, 27], lack of predefined criteria for AVR during follow-up, and nonuniform endpoints). Currently, two small randomized trials are recruiting asymptomatic AS patients to early surgical AVR vs. medical treatment [2, 4]. However, the trials do not use a transfemoral TAVI approach, which is superior to surgical AVR in moderate- and high-risk patients. Therefore, the authors are currently designing the “Early Versus Deferred Transcatheter Aortic Valve Implantation in Patients with Asymptomatic Severe Aortic Stenosis” (EVETAVI) trial in order to prove whether early AVR using transfemoral TAVI is beneficial in severe asymptomatic AS. Here, patients with severe asymptomatic AS, STS score ≥3%, and EF ≥ 50% will be assigned to one of the two therapeutic strategies in a 1:1 ratio (. Fig. 7). Patients randomized to the control group will undergo AVR as soon as they become symptomatic or develop a reduction in EF below 50%. Primary endpoint is the composite of all-cause mortality and hospitalization for decompensated heart failure at 3 years following randomization.

Conclusion Early AVR in patients with severe asymptomatic AS remains controversial. Owing to the limitations of the available data, no clear recommendation can be given on how to proceed with this subset of patients. Since a large number of patients are currently affected by this condition, prospective randomized trials are urgently needed.

Corresponding address Prof. Dr. med. H. Thiele Medical Clinic II (Medical Clinic II, Department of Cardiology, Angiology, Intensive Care Medicine), University Heart Center Lübeck, Universitätsklinikum Schleswig-Holstein Ratzeburger Allee 160, 23538 Lübeck, Germany [email protected]

Compliance with ethical guidelines Conflict of interest. J. Ledwoch and H. Thiele declare that they have no competing interests. This article does not contain any studies with human participants or animals performed by any of the authors.

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