- Email: [email protected]
Is it Time for a New Paradigm in Asymptomatic Severe Aortic Stenosis?
1968
JACC VOL. 67, NO. 16, 2016
Letters
APRIL 26, 2016:1965–75
than in patients taking clopidogrel (Figure 1A). After 30 days, the mean RHI increased slightly (mean, þ15%)
Please note: Dr. Bonello has received a research grant from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
in the clopidogrel group and greatly (þ100%) in the ticagrelor group (Figure 1B). We found a correlation
REFERENCES
between the increase in the APL and the increase in the
1. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:
RHI in the ticagrelor group. No ischemic or bleeding events were recorded within 1 month. Dyspnea was present in 7 patients in the ticagrelor group and in 5 patients in the clopidogrel group. Treatment with ticagrelor improves peripheral arterial function compared with clopidogrel. Endothelial function responds quickly to ticagrelor therapy within 30 days, long before the effects on clinical outcomes are seen. The underlying mechanism seems to be the APL increase. It was shown that clopidogrel slightly improved endothelial function (4); however, we found that these effects were not related to an
1045–57. 2. Bonello L, Laine M, Kipson N, et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 2014;63:872–7. 3. Rubinshtein R, Kuvin JT, Soffler M, et al. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J 2010;31:1142–8. 4. Willoughby SR, Luu LJ, Cameron JD, et al. Clopidogrel improves microvascular endothelial function in subjects with stable coronary artery disease. Heart Lung Circ 2014;23:534–41. 5. Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, et al. Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol 2013;61:723–7.
increase in adenosine plasma concentration. It was shown that the ticagrelor dose dependently increased adenosine-mediated coronary blood flow in healthy human subjects (5). These effects occur mostly via the activation of A2A adenosine receptors. Here, we found that ticagrelor induces an increase in the APL that correlates with the increase in the RHI. Because a low
Is it Time for a New Paradigm in Asymptomatic Severe Aortic Stenosis?
RHI is associated with a higher adverse rate during follow-up, our study led to the hypothesis that the adenosine-mediated effects of ticagrelor may explain the accuracy of the PLATO (A Comparison of Ticagrelor (AZD6140) and Clopidogrel in Patients With Acute Coronary Syndrome) mortality data (1). Finally, our study demonstrates a correlation between the increase in the APL and improvement in the RHI, but whether this increase in the APL has a direct effect on endothelial function remains to be established.
We read with interest the paper by Taniguchi et al. (1), who reported that a strategy of earlier aortic valve replacement (AVR) in patients with asymptomatic severe aortic stenosis (AS) was associated with a lower long-term risk of hospitalization for heart failure or all-cause mortality compared with the strategy currently recommended in clinical practice guidelines, which is to wait for the onset of symptoms before intervention. Two
important
issues
should
be
considered
Julien Fromonot, PhD Françoise Dignat-Georges, PhD Pascal Rossi, MD, PhD Giovanna Mottola, PhD Nathalie Kipson, BSc Jean Ruf, PhD Laurent Bonello, MD, PhD *Régis Guieu, MD, PhD Franck Paganelli, MD
regarding the clinical relevance of this study. First,
*UMR MD2
methods were robust, asymptomatic status was not
Aix Marseille University
confirmed by a treadmill exercise test; therefore, it
Institute of Biological Research of the
was possible that some symptoms were undetected or
French Army (IRBA)
unrecognized in some patients due to a sedentary
Boulevard P. Dramard
life-style. Among patients with asymptomatic severe
Marseille
AS, cardiopulmonary exercise testing (CPET) provides
France
more sensitive detection of exercise intolerance
E-mail: [email protected]
than the stress test criteria recommended in the
http://dx.doi.org/10.1016/j.jacc.2016.02.023
guidelines (3).
Taniguchi et al. (1), in the collection of baseline clinical information, reported the classic symptoms of angina, syncope, or heart failure as AS-related symptoms. These symptoms are typically the later manifestation of disease and now are seen only in patients who do not receive medical care, fail to report early symptoms, or have an inappropriate surgical delay (2). Second, although the study
JACC VOL. 67, NO. 16, 2016
Letters
APRIL 26, 2016:1965–75
The American College of Cardiology/American Heart Association guidelines provide a class IIa recommendation for AVR in asymptomatic patients with severe AS who have decreased exercise tolerance on treadmill testing (4). However, nonspecific
3. Levy F, Fayad N, Jeu A, et al. The value of cardiopulmonary exercise testing in individuals with apparently asymptomatic severe aortic stenosis: a pilot study. Arch Cardiovasc Dis 2014;107:519–28. 4. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice
dyspnea is frequently observed during exercise
Guidelines. J Am Coll Cardiol 2014;63:e57–185.
testing, and differentiating between pathological and
5. Dhoble A, Sarano ME, Kopecky SL, et al. Safety of symptom-limited cardiopulmonary exercise testing in patients with aortic stenosis. Am J Med 2012;125:704–8.
physiological
breathlessness
is
sometimes
chal-
lenging. Aging, a sedentary life-style, obesity, and/or lung disease complicate the interpretation of exercise symptoms. CPET has been proven to have diagnostic and prognostic value in heart failure, and reportedly improves the quantification of exercise cardiopulmonary capacity in valvular diseases (3). The safety of CPET in asymptomatic AS was recently studied in a cohort of 327 patients. No major
Asymptomatic Severe Aortic Stenosis Oxymoron?
adverse events during or after the test were reported
In the December 29, 2015 issue of the Journal,
(5). Compared with standard exercise testing, CPET
Taniguchi et al. (1) presented data from the CURRENT
can provide additional information about the respi-
AS (Contemporary Outcomes After Surgery and
ratory status, quality and quantity of efforts, and an
Medical Treatment in Patients with Severe Aortic
estimate of cardiac output in these patients (3). The
Stenosis) registry, which constitutes the largest study
decision-making process regarding AVR is especially
to date on the natural history of asymptomatic severe
challenging in patients who are either asymptomatic
aortic stenosis (AS), and included 1,517 patients
or have equivocal symptoms, and CPET can poten-
treated conservatively and 291 treated with aortic
tially aid in that decision process. Further research
valve replacement (AVR) (1). Their results are directly
should specifically evaluate the incremental value of
in line with a wide body of literature from smaller
CPET over standard exercise tests in a large cohort of
scale observational studies that have suggested a
asymptomatic patients with severe AS and a normal
dismal prognosis for this disease. They showed that
exercise test (3).
compared
with
patients
who
underwent
AVR,
Once severe valve obstruction is present, the most
conservatively managed patients had higher rates
important distinction is between asymptomatic and
of hard clinical endpoints, even in the subgroup of
symptomatic disease. If the symptom status is
patients without the traditional operative indications,
unclear, CPET may be helpful in revealing under-
such as left ventricular dysfunction or rapid disease
reported or underestimated symptoms and in pre-
progression. In addition, Taniguchi et al. showed
dicting the short-term occurrence of symptoms in
that nearly one-half of conservatively managed
truly asymptomatic individuals.
patients underwent AVR at 5 years, and that surgical mortality was higher in patients who developed
*Alberto Dominguez-Rodriguez, MD, PhD Pedro Abreu-Gonzalez, PhD
symptoms during that interval.
*Department of Cardiology
large multicenter cohort and for the thorough anal-
Hospital Universitario de Canarias
yses they performed, including a propensity-matched
Ofra s/n La Cuesta
cohort and relevant sensitivity analyses, which all
La Laguna, Tenerife E-38320
confirmed the results of the primary analysis. Lacking
Spain
a randomized trial, these data are, by far, the best
E-mail: [email protected]
evidence available to encourage the expansion of the
http://dx.doi.org/10.1016/j.jacc.2016.01.066
indication of AVR in asymptomatic patients with se-
Please note: Both 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. Rashedi N, Otto CM. Aortic stenosis: changing disease concepts. J Cardiovasc Ultrasound 2015;23:59–69.
The investigators have to be commended for their
vere AS. However, 2 points should be clarified. First, a significant proportion of the patients in the conservative
group
(62%)
had
an
aortic
valve
area <1 cm 2 without a mean gradient of >40 mm Hg or a maximal transaortic velocity >4 m/s compared with the AVR group (17%). Although not stated explicitly in the paper, it is assumed that appropriate advanced testing such as dobutamine echocardiography had
1969
JACC VOL. 67, NO. 16, 2016
Letters
APRIL 26, 2016:1965–75
than in patients taking clopidogrel (Figure 1A). After 30 days, the mean RHI increased slightly (mean, þ15%)
Please note: Dr. Bonello has received a research grant from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
in the clopidogrel group and greatly (þ100%) in the ticagrelor group (Figure 1B). We found a correlation
REFERENCES
between the increase in the APL and the increase in the
1. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:
RHI in the ticagrelor group. No ischemic or bleeding events were recorded within 1 month. Dyspnea was present in 7 patients in the ticagrelor group and in 5 patients in the clopidogrel group. Treatment with ticagrelor improves peripheral arterial function compared with clopidogrel. Endothelial function responds quickly to ticagrelor therapy within 30 days, long before the effects on clinical outcomes are seen. The underlying mechanism seems to be the APL increase. It was shown that clopidogrel slightly improved endothelial function (4); however, we found that these effects were not related to an
1045–57. 2. Bonello L, Laine M, Kipson N, et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 2014;63:872–7. 3. Rubinshtein R, Kuvin JT, Soffler M, et al. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J 2010;31:1142–8. 4. Willoughby SR, Luu LJ, Cameron JD, et al. Clopidogrel improves microvascular endothelial function in subjects with stable coronary artery disease. Heart Lung Circ 2014;23:534–41. 5. Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, et al. Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol 2013;61:723–7.
increase in adenosine plasma concentration. It was shown that the ticagrelor dose dependently increased adenosine-mediated coronary blood flow in healthy human subjects (5). These effects occur mostly via the activation of A2A adenosine receptors. Here, we found that ticagrelor induces an increase in the APL that correlates with the increase in the RHI. Because a low
Is it Time for a New Paradigm in Asymptomatic Severe Aortic Stenosis?
RHI is associated with a higher adverse rate during follow-up, our study led to the hypothesis that the adenosine-mediated effects of ticagrelor may explain the accuracy of the PLATO (A Comparison of Ticagrelor (AZD6140) and Clopidogrel in Patients With Acute Coronary Syndrome) mortality data (1). Finally, our study demonstrates a correlation between the increase in the APL and improvement in the RHI, but whether this increase in the APL has a direct effect on endothelial function remains to be established.
We read with interest the paper by Taniguchi et al. (1), who reported that a strategy of earlier aortic valve replacement (AVR) in patients with asymptomatic severe aortic stenosis (AS) was associated with a lower long-term risk of hospitalization for heart failure or all-cause mortality compared with the strategy currently recommended in clinical practice guidelines, which is to wait for the onset of symptoms before intervention. Two
important
issues
should
be
considered
Julien Fromonot, PhD Françoise Dignat-Georges, PhD Pascal Rossi, MD, PhD Giovanna Mottola, PhD Nathalie Kipson, BSc Jean Ruf, PhD Laurent Bonello, MD, PhD *Régis Guieu, MD, PhD Franck Paganelli, MD
regarding the clinical relevance of this study. First,
*UMR MD2
methods were robust, asymptomatic status was not
Aix Marseille University
confirmed by a treadmill exercise test; therefore, it
Institute of Biological Research of the
was possible that some symptoms were undetected or
French Army (IRBA)
unrecognized in some patients due to a sedentary
Boulevard P. Dramard
life-style. Among patients with asymptomatic severe
Marseille
AS, cardiopulmonary exercise testing (CPET) provides
France
more sensitive detection of exercise intolerance
E-mail: [email protected]
than the stress test criteria recommended in the
http://dx.doi.org/10.1016/j.jacc.2016.02.023
guidelines (3).
Taniguchi et al. (1), in the collection of baseline clinical information, reported the classic symptoms of angina, syncope, or heart failure as AS-related symptoms. These symptoms are typically the later manifestation of disease and now are seen only in patients who do not receive medical care, fail to report early symptoms, or have an inappropriate surgical delay (2). Second, although the study
JACC VOL. 67, NO. 16, 2016
Letters
APRIL 26, 2016:1965–75
The American College of Cardiology/American Heart Association guidelines provide a class IIa recommendation for AVR in asymptomatic patients with severe AS who have decreased exercise tolerance on treadmill testing (4). However, nonspecific
3. Levy F, Fayad N, Jeu A, et al. The value of cardiopulmonary exercise testing in individuals with apparently asymptomatic severe aortic stenosis: a pilot study. Arch Cardiovasc Dis 2014;107:519–28. 4. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice
dyspnea is frequently observed during exercise
Guidelines. J Am Coll Cardiol 2014;63:e57–185.
testing, and differentiating between pathological and
5. Dhoble A, Sarano ME, Kopecky SL, et al. Safety of symptom-limited cardiopulmonary exercise testing in patients with aortic stenosis. Am J Med 2012;125:704–8.
physiological
breathlessness
is
sometimes
chal-
lenging. Aging, a sedentary life-style, obesity, and/or lung disease complicate the interpretation of exercise symptoms. CPET has been proven to have diagnostic and prognostic value in heart failure, and reportedly improves the quantification of exercise cardiopulmonary capacity in valvular diseases (3). The safety of CPET in asymptomatic AS was recently studied in a cohort of 327 patients. No major
Asymptomatic Severe Aortic Stenosis Oxymoron?
adverse events during or after the test were reported
In the December 29, 2015 issue of the Journal,
(5). Compared with standard exercise testing, CPET
Taniguchi et al. (1) presented data from the CURRENT
can provide additional information about the respi-
AS (Contemporary Outcomes After Surgery and
ratory status, quality and quantity of efforts, and an
Medical Treatment in Patients with Severe Aortic
estimate of cardiac output in these patients (3). The
Stenosis) registry, which constitutes the largest study
decision-making process regarding AVR is especially
to date on the natural history of asymptomatic severe
challenging in patients who are either asymptomatic
aortic stenosis (AS), and included 1,517 patients
or have equivocal symptoms, and CPET can poten-
treated conservatively and 291 treated with aortic
tially aid in that decision process. Further research
valve replacement (AVR) (1). Their results are directly
should specifically evaluate the incremental value of
in line with a wide body of literature from smaller
CPET over standard exercise tests in a large cohort of
scale observational studies that have suggested a
asymptomatic patients with severe AS and a normal
dismal prognosis for this disease. They showed that
exercise test (3).
compared
with
patients
who
underwent
AVR,
Once severe valve obstruction is present, the most
conservatively managed patients had higher rates
important distinction is between asymptomatic and
of hard clinical endpoints, even in the subgroup of
symptomatic disease. If the symptom status is
patients without the traditional operative indications,
unclear, CPET may be helpful in revealing under-
such as left ventricular dysfunction or rapid disease
reported or underestimated symptoms and in pre-
progression. In addition, Taniguchi et al. showed
dicting the short-term occurrence of symptoms in
that nearly one-half of conservatively managed
truly asymptomatic individuals.
patients underwent AVR at 5 years, and that surgical mortality was higher in patients who developed
*Alberto Dominguez-Rodriguez, MD, PhD Pedro Abreu-Gonzalez, PhD
symptoms during that interval.
*Department of Cardiology
large multicenter cohort and for the thorough anal-
Hospital Universitario de Canarias
yses they performed, including a propensity-matched
Ofra s/n La Cuesta
cohort and relevant sensitivity analyses, which all
La Laguna, Tenerife E-38320
confirmed the results of the primary analysis. Lacking
Spain
a randomized trial, these data are, by far, the best
E-mail: [email protected]
evidence available to encourage the expansion of the
http://dx.doi.org/10.1016/j.jacc.2016.01.066
indication of AVR in asymptomatic patients with se-
Please note: Both 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. Rashedi N, Otto CM. Aortic stenosis: changing disease concepts. J Cardiovasc Ultrasound 2015;23:59–69.
The investigators have to be commended for their
vere AS. However, 2 points should be clarified. First, a significant proportion of the patients in the conservative
group
(62%)
had
an
aortic
valve
area <1 cm 2 without a mean gradient of >40 mm Hg or a maximal transaortic velocity >4 m/s compared with the AVR group (17%). Although not stated explicitly in the paper, it is assumed that appropriate advanced testing such as dobutamine echocardiography had
1969