- Email: [email protected]
Val122Ile mt-ATTR Has a Worse Survival Than wt-ATTR Cardiac Amyloidosis
JACC VOL. 69, NO. 6, 2017
Letters
FEBRUARY 14, 2017:750–9
clopidogrel in the medication stratum in our Central
significantly different severity of heart failure is
Illustration could be occupied by ticlopidine.
puzzling and warrants examination.
Pil Hyung Lee, MD, PhD *Duk-Woo Park, MD, PhD Seung-Jung Park, MD, PhD
missing data in the database, and this may have
*Department of Cardiology
time from diagnosis to enrollment, and although this
University of Ulsan College of Medicine
appeared similar, 34% of Val122Ile patients and 26%
Asan Medical Center
of wt-ATTR patients were missing the time from
388-1 Poongnap-dong, Songpa-gu
diagnosis to enrollment, information that should
Seoul, 138-736
have been easily available and whose absence raises
Republic of Korea
questions as to the reliability of other more complex
E-mail: [email protected]
data. The linearity, or otherwise, of the rate of amy-
http://dx.doi.org/10.1016/j.jacc.2016.11.046
loid deposition in the heart is not known, and too
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
short a follow-up may mask differences between
REFERENCES
a 24-month follow-up, and this could have been
The authors admit to a significant amount of
1. Lee PH, Ahn JM, Chang M, et al. Left main coronary artery disease: secular trends in patient characteristics, treatments, and outcomes. J Am Coll Cardiol 2016;68:1233–46. 2. Schomig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084–9. 3. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339:1665–71. 4. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, for Investigators C. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000;102:624–9.
influenced the outcome. Survival from database enrollment is subject to vagaries pertaining to the
groups. Their survival data were only presented over inadequate to evaluate the effect of progressive amyloid deposition on mortality in the event, for example, that the rate of death increases once a critical mass of amyloid occurs in the heart. Given the discrepancy between the reported outcome and the apparent differences in disease severity, we analyzed our own data, acquired at a single center, comparing the survival of 35 mt-ATTR patients with Val122Ile (mean age: 71.8 7.6 years old) with a randomly selected group of 85 wt-ATTR patients (mean age: 75 6.8 years old) seen within a similar time frame. Both the overall and ageadjusted survival rates (Figure 1) were significantly
Val122Ile mt-ATTR Has a Worse Survival Than wt-ATTR Cardiac Amyloidosis Maurer et al. (1) reported results from the THAOS
worse among the Val122Ile group (p ¼ 0.02 and 0.01,
F I G U R E 1 Age-Adjusted Kaplan-Meier Survival Curves
Age adjusted Kaplan–Meier survival estimates 1.00
p=0.01
0.75
(Transthyretin Amyloid Outcome Survey) registry of transthyretin cardiac amyloid (ATTR) amyloidosis, in
0.50
which they compared differences between patients carrying wild-type ATTR (wt-ATTR) cardiac amyloidosis and those carrying the mutant variant cardio-
0.25
myopathy (Val122Ile) prevalent in African American patients and the most common form of mutant ATTR (mt-ATTR) in the United States. Although patients with Val122Ile had worse New York Heart Association functional class higher B-type natriuretic peptide
0.00 0
12
24
36
48
60
72
84
96
108
120
Months WT-ATTR
Val122Ile
levels, faster heart rates, and lower quality of life, the survival of either registry enrollment or from diagnosis in patients with Val122Ile was not significantly different from that in wt-ATTR patients. The finding of an equivalent survival between 2 groups with
Kaplan-Meier curves for time to death were adjusted to median age. Survival for Val122Ile patients (median survival: 47 months) was significantly shorter than for wt-ATTR patients (59 months; hazard ratio: 2.1; 95% confidence interval: 1.2 to 3.6).
757
JACC VOL. 69, NO. 6, 2017
Letters
758
FEBRUARY 14, 2017:750–9
respectively), although the curves did not diverge
REFERENCE
until well after 24 months, the maximum duration of
1. Maurer MS, Hanna M, Grogan M, et al., and Investigators. Genotype and
follow-up reported by THAOS investigators.
phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol 2016;68:161–72.
We believe our single-center data, although smaller in numbers, have the advantage of a closer follow-up for a longer period of time, with the potential to have
REPLY: Val122Ile mt-ATTR Has a Worse
received a more uniform standard of care. Our obser-
Survival Than wt-ATTR Cardiac Amyloidosis
vation of a significantly shorter survival of patients with mt-ATTR due to the Val122Ile mutation strongly
Dr. Singh and colleagues present single-center data
suggests that Val122Ile ATTR cardiac amyloidosis is a
that demonstrate a worse survival among subjects
more aggressive disease than wild-type ATTR and ar-
with transthyretin cardiac amyloid (ATTR) cardiac
gues for caution not only in interpreting multisite
amyloid due to the Val122Ile mutation than that of
database data but also when considering the design of
those with wild-type ATTR (wt-ATTR), with differ-
future studies of ATTR cardiac amyloidosis in which
ences emerging after 2 years of follow-up. Such data
both mutant and wild-type patients are enrolled.
are consistent with those of other single-center reports (1), as well as the small multicenter TRACS
Avinainder Singh, MBBS Hallie I. Geller, BS *Rodney H. Falk, MD
(Transthyretin Amyloidosis Cardiac Study) study (2) in 29 subjects, but differ from data reported in international multicenter THAOS (Transthyretin Amy-
*Cardiac Amyloidosis Program
loid Outcome Survey) in a larger cohort (3). In THAOS,
Brigham and Women’s Hospital
survival from time of enrollment rather than survival
75 Francis Street
from diagnosis was reported as defining onset of the
Boston, Massachusetts 02115
disease retrospectively, which is difficult given the
E-mail: [email protected]
association of ATTR cardiac amyloid with common
http://dx.doi.org/10.1016/j.jacc.2016.09.987
age-related conditions. Concerns were raised about
Please note: Dr. Singh is supported by the Janet and Stanley Cohen Cardiac Amyloidosis Fellowship. Dr. Falk has received support from the Friends of Burt Glazov Cardiac Amyloidosis Fund and the Demarest Lloyd Jr. Foundation; serves as a consultant for Ionis Pharmaceuticals and Alnylam Pharmaceuticals; and has received research support from GlaxoSmithKline. Ms. Geller has reported she has no relationships relevant to the contents of this paper to disclose.
the completeness of follow-up, and we acknowledged that this could confound our reported results. Prompted by the analyses of Singh and colleagues, we evaluated survival from enrollment in THAOS over
F I G U R E 1 Survival Post Enrollment in THAOS in ATTRwt Compared to Val122Ile
A
B 100% Cumulative Mortality Percentage
Cumulative Mortality Percentage
100% 90% 80% 70% 60% 50% 40% 30% 20% 10%
90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
0% 0 Number at risk Wild–type 170 Val122Ile 82
6
12
18
24
30
36
112 57
77 41
55 32
38 22
0
6
12
18
24
30
36
Time from Enrollment (Months)
Time from Enrollment (Months) 24 15
20 10
Age–adjusted Cumulative Mortality Estimate Wild–type
Val122Ile
Cumulative Mortality Estimate Wild–type (n = 170)
Val122Ile (n = 82)
Survival from enrollment in THAOS over 3 years (A: overall survival in which 36-month estimate SE is 47.5% 6.1% for Wild-type and 55.1% 8.0% for Val122Ile) and age adjusted (B: age-adjusted hazard ratio for Val122Ile versus Wild-type ¼ 1.947; Wald chi-square p value ¼ 0.0132).
Letters
FEBRUARY 14, 2017:750–9
clopidogrel in the medication stratum in our Central
significantly different severity of heart failure is
Illustration could be occupied by ticlopidine.
puzzling and warrants examination.
Pil Hyung Lee, MD, PhD *Duk-Woo Park, MD, PhD Seung-Jung Park, MD, PhD
missing data in the database, and this may have
*Department of Cardiology
time from diagnosis to enrollment, and although this
University of Ulsan College of Medicine
appeared similar, 34% of Val122Ile patients and 26%
Asan Medical Center
of wt-ATTR patients were missing the time from
388-1 Poongnap-dong, Songpa-gu
diagnosis to enrollment, information that should
Seoul, 138-736
have been easily available and whose absence raises
Republic of Korea
questions as to the reliability of other more complex
E-mail: [email protected]
data. The linearity, or otherwise, of the rate of amy-
http://dx.doi.org/10.1016/j.jacc.2016.11.046
loid deposition in the heart is not known, and too
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
short a follow-up may mask differences between
REFERENCES
a 24-month follow-up, and this could have been
The authors admit to a significant amount of
1. Lee PH, Ahn JM, Chang M, et al. Left main coronary artery disease: secular trends in patient characteristics, treatments, and outcomes. J Am Coll Cardiol 2016;68:1233–46. 2. Schomig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084–9. 3. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339:1665–71. 4. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, for Investigators C. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000;102:624–9.
influenced the outcome. Survival from database enrollment is subject to vagaries pertaining to the
groups. Their survival data were only presented over inadequate to evaluate the effect of progressive amyloid deposition on mortality in the event, for example, that the rate of death increases once a critical mass of amyloid occurs in the heart. Given the discrepancy between the reported outcome and the apparent differences in disease severity, we analyzed our own data, acquired at a single center, comparing the survival of 35 mt-ATTR patients with Val122Ile (mean age: 71.8 7.6 years old) with a randomly selected group of 85 wt-ATTR patients (mean age: 75 6.8 years old) seen within a similar time frame. Both the overall and ageadjusted survival rates (Figure 1) were significantly
Val122Ile mt-ATTR Has a Worse Survival Than wt-ATTR Cardiac Amyloidosis Maurer et al. (1) reported results from the THAOS
worse among the Val122Ile group (p ¼ 0.02 and 0.01,
F I G U R E 1 Age-Adjusted Kaplan-Meier Survival Curves
Age adjusted Kaplan–Meier survival estimates 1.00
p=0.01
0.75
(Transthyretin Amyloid Outcome Survey) registry of transthyretin cardiac amyloid (ATTR) amyloidosis, in
0.50
which they compared differences between patients carrying wild-type ATTR (wt-ATTR) cardiac amyloidosis and those carrying the mutant variant cardio-
0.25
myopathy (Val122Ile) prevalent in African American patients and the most common form of mutant ATTR (mt-ATTR) in the United States. Although patients with Val122Ile had worse New York Heart Association functional class higher B-type natriuretic peptide
0.00 0
12
24
36
48
60
72
84
96
108
120
Months WT-ATTR
Val122Ile
levels, faster heart rates, and lower quality of life, the survival of either registry enrollment or from diagnosis in patients with Val122Ile was not significantly different from that in wt-ATTR patients. The finding of an equivalent survival between 2 groups with
Kaplan-Meier curves for time to death were adjusted to median age. Survival for Val122Ile patients (median survival: 47 months) was significantly shorter than for wt-ATTR patients (59 months; hazard ratio: 2.1; 95% confidence interval: 1.2 to 3.6).
757
JACC VOL. 69, NO. 6, 2017
Letters
758
FEBRUARY 14, 2017:750–9
respectively), although the curves did not diverge
REFERENCE
until well after 24 months, the maximum duration of
1. Maurer MS, Hanna M, Grogan M, et al., and Investigators. Genotype and
follow-up reported by THAOS investigators.
phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol 2016;68:161–72.
We believe our single-center data, although smaller in numbers, have the advantage of a closer follow-up for a longer period of time, with the potential to have
REPLY: Val122Ile mt-ATTR Has a Worse
received a more uniform standard of care. Our obser-
Survival Than wt-ATTR Cardiac Amyloidosis
vation of a significantly shorter survival of patients with mt-ATTR due to the Val122Ile mutation strongly
Dr. Singh and colleagues present single-center data
suggests that Val122Ile ATTR cardiac amyloidosis is a
that demonstrate a worse survival among subjects
more aggressive disease than wild-type ATTR and ar-
with transthyretin cardiac amyloid (ATTR) cardiac
gues for caution not only in interpreting multisite
amyloid due to the Val122Ile mutation than that of
database data but also when considering the design of
those with wild-type ATTR (wt-ATTR), with differ-
future studies of ATTR cardiac amyloidosis in which
ences emerging after 2 years of follow-up. Such data
both mutant and wild-type patients are enrolled.
are consistent with those of other single-center reports (1), as well as the small multicenter TRACS
Avinainder Singh, MBBS Hallie I. Geller, BS *Rodney H. Falk, MD
(Transthyretin Amyloidosis Cardiac Study) study (2) in 29 subjects, but differ from data reported in international multicenter THAOS (Transthyretin Amy-
*Cardiac Amyloidosis Program
loid Outcome Survey) in a larger cohort (3). In THAOS,
Brigham and Women’s Hospital
survival from time of enrollment rather than survival
75 Francis Street
from diagnosis was reported as defining onset of the
Boston, Massachusetts 02115
disease retrospectively, which is difficult given the
E-mail: [email protected]
association of ATTR cardiac amyloid with common
http://dx.doi.org/10.1016/j.jacc.2016.09.987
age-related conditions. Concerns were raised about
Please note: Dr. Singh is supported by the Janet and Stanley Cohen Cardiac Amyloidosis Fellowship. Dr. Falk has received support from the Friends of Burt Glazov Cardiac Amyloidosis Fund and the Demarest Lloyd Jr. Foundation; serves as a consultant for Ionis Pharmaceuticals and Alnylam Pharmaceuticals; and has received research support from GlaxoSmithKline. Ms. Geller has reported she has no relationships relevant to the contents of this paper to disclose.
the completeness of follow-up, and we acknowledged that this could confound our reported results. Prompted by the analyses of Singh and colleagues, we evaluated survival from enrollment in THAOS over
F I G U R E 1 Survival Post Enrollment in THAOS in ATTRwt Compared to Val122Ile
A
B 100% Cumulative Mortality Percentage
Cumulative Mortality Percentage
100% 90% 80% 70% 60% 50% 40% 30% 20% 10%
90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
0% 0 Number at risk Wild–type 170 Val122Ile 82
6
12
18
24
30
36
112 57
77 41
55 32
38 22
0
6
12
18
24
30
36
Time from Enrollment (Months)
Time from Enrollment (Months) 24 15
20 10
Age–adjusted Cumulative Mortality Estimate Wild–type
Val122Ile
Cumulative Mortality Estimate Wild–type (n = 170)
Val122Ile (n = 82)
Survival from enrollment in THAOS over 3 years (A: overall survival in which 36-month estimate SE is 47.5% 6.1% for Wild-type and 55.1% 8.0% for Val122Ile) and age adjusted (B: age-adjusted hazard ratio for Val122Ile versus Wild-type ¼ 1.947; Wald chi-square p value ¼ 0.0132).