- Email: [email protected]
A Randomized Trial in Patients With Asymptomatic Severe Aortic Stenosis
1970
JACC VOL. 67, NO. 16, 2016
Letters
APRIL 26, 2016:1965–75
sibility of a pseudo-stenosis. Even so, the enrollment
Guillaume Marquis-Gravel, MD *Philippe Généreux, MD
been performed in these patients to rule out the posof these patients is by itself problematic. Low-flow
*Hôpital du Sacré-Coeur de Montréal
and/or low-gradient and paradoxical low-gradient AS
Université de Montréal Département d’Hémodynamie
bear pathophysiological processes, disease burdens,
5400 Boul. Gouin Ouest
and prognostic implications distinct from normal flow
H4J 1C5 Montréal, Québec
and/or high-gradient (NF/HG) AS (2). By including
Canada
patients with diverging disease states in the CURRENT
E-mail: [email protected]
AS registry, it is difficult to interpret the results and to
http://dx.doi.org/10.1016/j.jacc.2016.01.065
generalize the findings to patients with true severe asymptomatic NF/HG AS. Therefore, the investigators are strongly encouraged to provide a sensitivity analysis that includes only patients with proven true severe NF/HG AS, as well as stating whether pseudostenosis was ruled out when appropriate. Second, as outlined by the investigators, the asymptomatic state is increasingly difficult to assess in an aging patient population with low functional status. Patients without spontaneous symptoms, but who have limiting symptoms on exercise testing, have a different disease progression than patients without both spontaneous and exercise-induced symptoms (3). If a high proportion of the CURRENT AS registry is symptomatic on the treadmill, the study results are not as disruptive as they seem, because an indication to perform AVR in patients with abnormal exercise testing already exists. In that regard, if
Please note: Dr. Marquis-Gravel has received a research grant from Bayer; and consulting fees from Bayer and AstraZeneca. Dr. Généreux has reported that he has no relationships relevant to the contents of this paper to disclose.
REFERENCES 1. Taniguchi T, Morimoto T, Shiomi H, et al. Initial surgical versus conservative strategies in patients with asymptomatic severe aortic stenosis. J Am Coll Cardiol 2015;66:2827–38. 2. Eleid MF, Sorajja P, Michelena HI, Malouf JF, Scott CG, Pellikka PA. Flowgradient patterns in severe aortic stenosis with preserved ejection fraction: clinical characteristics and predictors of survival. Circulation 2013;128:1781–9. 3. Rafique AM, Biner S, Ray I, Forrester JS, Tolstrup K, Siegel RJ. Meta-analysis of prognostic value of stress testing in patients with asymptomatic severe aortic stenosis. Am J Cardiol 2009;104:972–7. 4. Holmes DR Jr., Nishimura RA, Grover FL, et al. Annual outcomes with transcatheter valve therapy. From the STS/ACC TVT Registry. J Am Coll Cardiol 2015;66:2813–23. 5. Thyregod HGH, Steinbrüchel DA, Ihlemann N, et al. Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis: 1-year results from the all-comers NOTION randomized clinical trial. J Am Coll Cardiol 2015;65:2184–94.
possible, an additional sensitivity analysis involving only patients for whom an exercise test proved negative would improve the scope of the study and allow generalizability of the findings to a truly asymptomatic patient population. A potential randomized trial of asymptomatic severe AS will need to perform a thorough patient selection process with exercise testing before enrollment.
A Randomized Trial in Patients With Asymptomatic Severe Aortic Stenosis A Future Has Begun!
Notwithstanding these 2 comments, the results provided by Taniguchi et al. further the debate of the optimal management of asymptomatic severe AS. In
We have carefully, and with great interest, read the
light of the 13.5% mortality rate while awaiting surgery
CURRENT AS (Contemporary Outcomes After Surgery
(1), these patients deserve a randomized trial to finally
and Medical Treatment in Patients with Severe Aortic
settle the question. As the learning curve of trans-
Stenosis) registry data by Taniguchi et al. (1), which
catheter AVR (TAVR) improves, procedural mortality,
was published in a previous issue of the Journal, and
major bleeding, and vascular complications rates
the editorials written by world-renowned experts,
consistently decrease according to data from the So-
Dr. Bonow (2) and Drs. Eneid and Pellikka (3). The
ciety of Thoracic Surgeons/American College of Car-
summary conclusion from all these papers is that a
diology Transcatheter Valve Therapy registry, which
prospective,
was presented in the same issue of the Journal (4).
patients with isolated severe aortic stenosis (AS) is
With recent studies justifying the expansion of the role
much needed to ascertain whether we can provide
of TAVR in lower risk populations (5), patients with
better treatment for these patients. As Dr. Bonow
asymptomatic severe AS should be the next popula-
observed, the CURRENT AS registry is “about as good
tion to be addressed in a TAVR trial. Because there is
as it gets in shedding more light on this issue.” The
currently no formal indication for surgical AVR in
subheading in the editorial by Eleid and Pellikka,
these patients, this could be an exclusive niche for the
“What Are We Waiting For?” is especially interesting.
less invasive TAVR procedure.
Our answer is that we are not waiting any more.
randomized
trial
in
asymptomatic
JACC VOL. 67, NO. 16, 2016
Letters
APRIL 26, 2016:1965–75
A group of cardiologists and cardiac surgeons from several European countries have started the AVATAR (Aortic
Valve
Replacement
versus
Conservative
Treatment in Asymptomatic Severe Aortic Stenosis) trial, which is a randomized, multicenter-controlled,
3. Eleid MF, Pellikka P. Asymptomatic severe aortic stenosis. What are we waiting for? J Am Coll Cardiol 2015;66:2842. 4. Banovic M, Iung B, Bartunek J, et al. Rationale and design of the Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR trial): a randomized, multicenter, controlled, eventdriven trial. Am Heart J 2016;174:147–53.
event-driven trial. The study has been registered at clinicaltrials.gov (NCT02436655) and has already started. The first 10 randomized patients have already been included in the study. We believe that the AVATAR trial (4), which is to the best of our knowledge, the first prospective randomized trial in asymptomatic patients with isolated severe AS and with normal left ventricular ejection fraction (>50%),
Might Outcome of Patients With Asymptomatic Severe AS Be Improved by an Initial Surgical Strategy?
will overcome all the drawbacks identified in the useful and well-designed Japanese registry (1), that is, its retrospective nature, reliance on aortic valve
We read with interest the recent publication by
area as a main parameter to diagnose severe AS, and
Taniguchi et al. (1) in a previous issue of the Journal,
the large disproportion between patients who un-
which reported that the long-term outcome of
derwent electively surgery and patients who under-
asymptomatic patients with severe aortic stenosis
went surgery after symptom onset. The advantages of
(AS) was dismal when managed conservatively,
the AVATAR trial include randomization, stress
and that this outcome might be substantially im-
testing to prove the asymptomatic status of the pa-
proved by an initial surgical strategy. We recognize
tient, comprehensive analysis to confirm the absence
the strengths of a study that sheds light on this issue.
of serious comorbidities and the absence of coronary
However, the study raises a number of concerns.
close
Patients in the conservative group were more often
follow-up that will enable all patients that are
included in the study on the basis of aortic valve
randomized to “watchful waiting” to be promptly
area <1 cm 2 alone (peak aortic jet velocity #4 m/s and
referred to surgery after symptom onset, and a safety
mean aortic pressure gradient #40 mm Hg) compared
analysis that will compare the results of elective
with patients in the initial aortic valve replacement
surgery
group. Among patients with low gradient severe AS,
artery
disease
needing
(treatment
revascularization,
group)
versus
surgery
after
symptom onset (watchful waiting group).
those with a low transvalvular flow seem to have a
Regardless of the AVATAR trial results, we believe
worse prognosis (2). Therefore, it would have been
this study will be an important step forward in add-
interesting to evaluate a measure of transvalvular
ressing the question of whether early aortic valve
flow (i.e., stroke volume index by Doppler echocar-
replacement is preferable to a watchful waiting
diography), and to incorporate this variable into the
strategy.
regression function to calculate the propensity score or into the adjusted analysis using Cox proportional
*Marko Banovic, MD, PhD Serge D. Nikolic, PhD Svetozar Putnik, MD, PhD
hazard models if this variable had not been well
*Belgrade Medical School
of contemporary patients with AS, information about
University of Belgrade
frailty would have helped to reduce uncertainty
11000 Belgrade
regarding selection bias and residual confounding in
Serbia
the comparison between the groups, provided that
E-mail: [email protected]
frailty is a pivotal feature related to both the man-
http://dx.doi.org/10.1016/j.jacc.2016.01.068
agement strategy and prognosis (3).
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
REFERENCES 1. Taniguchi T, Morimoto T, Shiomi H, et al. Initial surgical versus conservative strategies in patients with asymptomatic severe aortic stenosis. J Am Coll Cardiol 2015;66:2827–38. 2. Bonow R. Asymptomatic aortic stenosis. It is not simple any more. J Am Coll Cardiol 2015;66:2839–41.
matched in the 2 groups. Due to the aging and increasingly complex nature
Cumulative
incidence
of
all-cause
death
in
the conservative group was much higher than that observed in a recent prospective series of asymptomatic severe AS, in particular when the absence of symptoms was confirmed by exercise testing (2,4). Finally, we would have appreciated information on the proportion of patients who underwent Doppler echocardiography at intervals of 6 months to 1 year during
1971
JACC VOL. 67, NO. 16, 2016
Letters
APRIL 26, 2016:1965–75
sibility of a pseudo-stenosis. Even so, the enrollment
Guillaume Marquis-Gravel, MD *Philippe Généreux, MD
been performed in these patients to rule out the posof these patients is by itself problematic. Low-flow
*Hôpital du Sacré-Coeur de Montréal
and/or low-gradient and paradoxical low-gradient AS
Université de Montréal Département d’Hémodynamie
bear pathophysiological processes, disease burdens,
5400 Boul. Gouin Ouest
and prognostic implications distinct from normal flow
H4J 1C5 Montréal, Québec
and/or high-gradient (NF/HG) AS (2). By including
Canada
patients with diverging disease states in the CURRENT
E-mail: [email protected]
AS registry, it is difficult to interpret the results and to
http://dx.doi.org/10.1016/j.jacc.2016.01.065
generalize the findings to patients with true severe asymptomatic NF/HG AS. Therefore, the investigators are strongly encouraged to provide a sensitivity analysis that includes only patients with proven true severe NF/HG AS, as well as stating whether pseudostenosis was ruled out when appropriate. Second, as outlined by the investigators, the asymptomatic state is increasingly difficult to assess in an aging patient population with low functional status. Patients without spontaneous symptoms, but who have limiting symptoms on exercise testing, have a different disease progression than patients without both spontaneous and exercise-induced symptoms (3). If a high proportion of the CURRENT AS registry is symptomatic on the treadmill, the study results are not as disruptive as they seem, because an indication to perform AVR in patients with abnormal exercise testing already exists. In that regard, if
Please note: Dr. Marquis-Gravel has received a research grant from Bayer; and consulting fees from Bayer and AstraZeneca. Dr. Généreux has reported that he has no relationships relevant to the contents of this paper to disclose.
REFERENCES 1. Taniguchi T, Morimoto T, Shiomi H, et al. Initial surgical versus conservative strategies in patients with asymptomatic severe aortic stenosis. J Am Coll Cardiol 2015;66:2827–38. 2. Eleid MF, Sorajja P, Michelena HI, Malouf JF, Scott CG, Pellikka PA. Flowgradient patterns in severe aortic stenosis with preserved ejection fraction: clinical characteristics and predictors of survival. Circulation 2013;128:1781–9. 3. Rafique AM, Biner S, Ray I, Forrester JS, Tolstrup K, Siegel RJ. Meta-analysis of prognostic value of stress testing in patients with asymptomatic severe aortic stenosis. Am J Cardiol 2009;104:972–7. 4. Holmes DR Jr., Nishimura RA, Grover FL, et al. Annual outcomes with transcatheter valve therapy. From the STS/ACC TVT Registry. J Am Coll Cardiol 2015;66:2813–23. 5. Thyregod HGH, Steinbrüchel DA, Ihlemann N, et al. Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis: 1-year results from the all-comers NOTION randomized clinical trial. J Am Coll Cardiol 2015;65:2184–94.
possible, an additional sensitivity analysis involving only patients for whom an exercise test proved negative would improve the scope of the study and allow generalizability of the findings to a truly asymptomatic patient population. A potential randomized trial of asymptomatic severe AS will need to perform a thorough patient selection process with exercise testing before enrollment.
A Randomized Trial in Patients With Asymptomatic Severe Aortic Stenosis A Future Has Begun!
Notwithstanding these 2 comments, the results provided by Taniguchi et al. further the debate of the optimal management of asymptomatic severe AS. In
We have carefully, and with great interest, read the
light of the 13.5% mortality rate while awaiting surgery
CURRENT AS (Contemporary Outcomes After Surgery
(1), these patients deserve a randomized trial to finally
and Medical Treatment in Patients with Severe Aortic
settle the question. As the learning curve of trans-
Stenosis) registry data by Taniguchi et al. (1), which
catheter AVR (TAVR) improves, procedural mortality,
was published in a previous issue of the Journal, and
major bleeding, and vascular complications rates
the editorials written by world-renowned experts,
consistently decrease according to data from the So-
Dr. Bonow (2) and Drs. Eneid and Pellikka (3). The
ciety of Thoracic Surgeons/American College of Car-
summary conclusion from all these papers is that a
diology Transcatheter Valve Therapy registry, which
prospective,
was presented in the same issue of the Journal (4).
patients with isolated severe aortic stenosis (AS) is
With recent studies justifying the expansion of the role
much needed to ascertain whether we can provide
of TAVR in lower risk populations (5), patients with
better treatment for these patients. As Dr. Bonow
asymptomatic severe AS should be the next popula-
observed, the CURRENT AS registry is “about as good
tion to be addressed in a TAVR trial. Because there is
as it gets in shedding more light on this issue.” The
currently no formal indication for surgical AVR in
subheading in the editorial by Eleid and Pellikka,
these patients, this could be an exclusive niche for the
“What Are We Waiting For?” is especially interesting.
less invasive TAVR procedure.
Our answer is that we are not waiting any more.
randomized
trial
in
asymptomatic
JACC VOL. 67, NO. 16, 2016
Letters
APRIL 26, 2016:1965–75
A group of cardiologists and cardiac surgeons from several European countries have started the AVATAR (Aortic
Valve
Replacement
versus
Conservative
Treatment in Asymptomatic Severe Aortic Stenosis) trial, which is a randomized, multicenter-controlled,
3. Eleid MF, Pellikka P. Asymptomatic severe aortic stenosis. What are we waiting for? J Am Coll Cardiol 2015;66:2842. 4. Banovic M, Iung B, Bartunek J, et al. Rationale and design of the Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR trial): a randomized, multicenter, controlled, eventdriven trial. Am Heart J 2016;174:147–53.
event-driven trial. The study has been registered at clinicaltrials.gov (NCT02436655) and has already started. The first 10 randomized patients have already been included in the study. We believe that the AVATAR trial (4), which is to the best of our knowledge, the first prospective randomized trial in asymptomatic patients with isolated severe AS and with normal left ventricular ejection fraction (>50%),
Might Outcome of Patients With Asymptomatic Severe AS Be Improved by an Initial Surgical Strategy?
will overcome all the drawbacks identified in the useful and well-designed Japanese registry (1), that is, its retrospective nature, reliance on aortic valve
We read with interest the recent publication by
area as a main parameter to diagnose severe AS, and
Taniguchi et al. (1) in a previous issue of the Journal,
the large disproportion between patients who un-
which reported that the long-term outcome of
derwent electively surgery and patients who under-
asymptomatic patients with severe aortic stenosis
went surgery after symptom onset. The advantages of
(AS) was dismal when managed conservatively,
the AVATAR trial include randomization, stress
and that this outcome might be substantially im-
testing to prove the asymptomatic status of the pa-
proved by an initial surgical strategy. We recognize
tient, comprehensive analysis to confirm the absence
the strengths of a study that sheds light on this issue.
of serious comorbidities and the absence of coronary
However, the study raises a number of concerns.
close
Patients in the conservative group were more often
follow-up that will enable all patients that are
included in the study on the basis of aortic valve
randomized to “watchful waiting” to be promptly
area <1 cm 2 alone (peak aortic jet velocity #4 m/s and
referred to surgery after symptom onset, and a safety
mean aortic pressure gradient #40 mm Hg) compared
analysis that will compare the results of elective
with patients in the initial aortic valve replacement
surgery
group. Among patients with low gradient severe AS,
artery
disease
needing
(treatment
revascularization,
group)
versus
surgery
after
symptom onset (watchful waiting group).
those with a low transvalvular flow seem to have a
Regardless of the AVATAR trial results, we believe
worse prognosis (2). Therefore, it would have been
this study will be an important step forward in add-
interesting to evaluate a measure of transvalvular
ressing the question of whether early aortic valve
flow (i.e., stroke volume index by Doppler echocar-
replacement is preferable to a watchful waiting
diography), and to incorporate this variable into the
strategy.
regression function to calculate the propensity score or into the adjusted analysis using Cox proportional
*Marko Banovic, MD, PhD Serge D. Nikolic, PhD Svetozar Putnik, MD, PhD
hazard models if this variable had not been well
*Belgrade Medical School
of contemporary patients with AS, information about
University of Belgrade
frailty would have helped to reduce uncertainty
11000 Belgrade
regarding selection bias and residual confounding in
Serbia
the comparison between the groups, provided that
E-mail: [email protected]
frailty is a pivotal feature related to both the man-
http://dx.doi.org/10.1016/j.jacc.2016.01.068
agement strategy and prognosis (3).
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
REFERENCES 1. Taniguchi T, Morimoto T, Shiomi H, et al. Initial surgical versus conservative strategies in patients with asymptomatic severe aortic stenosis. J Am Coll Cardiol 2015;66:2827–38. 2. Bonow R. Asymptomatic aortic stenosis. It is not simple any more. J Am Coll Cardiol 2015;66:2839–41.
matched in the 2 groups. Due to the aging and increasingly complex nature
Cumulative
incidence
of
all-cause
death
in
the conservative group was much higher than that observed in a recent prospective series of asymptomatic severe AS, in particular when the absence of symptoms was confirmed by exercise testing (2,4). Finally, we would have appreciated information on the proportion of patients who underwent Doppler echocardiography at intervals of 6 months to 1 year during
1971