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JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 10, NO. 11, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-8798/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jcin.2017.03.030
STRUCTURAL
Outcomes of Alcohol Septal Ablation
in Younger Patients With Obstructive
Hypertrophic Cardiomyopathy
Max Liebregts, MD,a Lothar Faber, MD,b Morten K. Jensen, MD,c Pieter A. Vriesendorp, MD, PHD,d
Jaroslav Januska, MD,e Jan Krejci, MD, PHD,f Peter R. Hansen, MD, DMSC, PHD,g Hubert Seggewiss, MD,b,h
Dieter Horstkotte, MD,b Radka Adlova, MD,i Henning Bundgaard, MD, DMSC,c Jurriën M. ten Berg, MD, PHD,a
Josef Veselka, MD, PHDi
JACC: CARDIOVASCULAR INTERVENTIONS CME/MOC
This article has been selected as this issue’s CME/MOC activity, available
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5. Claim your CME/MOC credit and receive your certificate electronically
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CME/MOC Objective for This Article: At the end of the activity the reader
should be able to: 1) appraise the efficacy and safety of alcohol
Accreditation and Designation Statement
septal ablation in younger patients with hypertrophic obstructive
The American College of Cardiology Foundation (ACCF) is accredited by
cardiomyopathy; 2) identify the current age recommendations for alcohol
the Accreditation Council for Continuing Medical Education (ACCME) to
septal ablation in patients with hypertrophic obstructive cardiomyopathy
provide continuing medical education for physicians.
based on the 2011 American College of Cardiology Foundation/American
Heart Association guidelines; and 3) recognize the independent pre-
The ACCF designates this Journal-based CME/MOC activity for a
dictors of mortality in younger patients undergoing alcohol septal abla-
maximum of 1 AMA PRA Category 1 Credit(s). Physicians should only
tion for hypertrophic obstructive cardiomyopathy.
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Issue Date: June 12, 2017
Expiration Date: June 11, 2018
From the aDepartment of Cardiology, St. Antonius Hospital Nieuwegein, Nieuwegein, the Netherlands; bDepartment of Cardiology, Heart and Diabetes Centre NRW, Ruhr-University Bochum, Bad Oyenhausen, Germany; cUnit for Inherited Cardiac Diseases,
Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; dDepartment of Cardiology,
Thoraxcanter, Erasmus Medical Center, Rotterdam, the Netherlands; eCardiocentre Podlesí, Trinec, Czech Republic; f1st Department of Internal Medicine/Cardioangiology, International Clinical Research Centre, St. Anne’s University Hospital and Masaryk
University, Brno, Czech Republic; gDepartment of Cardiology, Gentofte Hospital, Copenhagen University Hospital, Hellerup,
Denmark; hDepartment of Internal Medicine, Schweinfurt, Germany; and the iDepartment of Cardiology, 2nd Medical School,
Charles University, University Hospital Motol, Prague, Czech Republic. The authors have reported that they have no relationships
relevant to the contents of this paper to disclose.
Manuscript received January 5, 2017; revised manuscript received February 21, 2017, accepted March 23, 2017.
Liebregts et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 11, 2017
JUNE 12, 2017:1134–43
Age-Specific Outcomes of ASA for Obstructive HCM
Outcomes of Alcohol Septal Ablation
in Younger Patients With Obstructive
Hypertrophic Cardiomyopathy
Max Liebregts, MD,a Lothar Faber, MD,b Morten K. Jensen, MD,c Pieter A. Vriesendorp, MD, PHD,d
Jaroslav Januska, MD,e Jan Krejci, MD, PHD,f Peter R. Hansen, MD, DMSC, PHD,g Hubert Seggewiss, MD,b,,h
Dieter Horstkotte, MD,b Radka Adlova, MD,i Henning Bundgaard, MD, DMSC,c Jurriën M. ten Berg, MD, PHD,a
Josef Veselka, MD, PHDi
ABSTRACT
OBJECTIVES The aim of this study was to describe the safety and outcomes of alcohol septal ablation (ASA) in younger
patients with obstructive hypertrophic cardiomyopathy.
BACKGROUND The American College of Cardiology Foundation/American Heart Association guidelines reserve ASA for
older patients and patients with serious comorbidities. Data on long-term age-specific outcomes after ASA are scarce.
METHODS A total of 1,197 patients (mean age 58 14 years) underwent ASA for obstructive hypertrophic cardiomyopathy. Patients were divided into young (#50 years), middle-age (51 to 64 years), and older ($65 years) groups.
RESULTS Thirty-day mortality and pacemaker implantation rates were lower in young compared with older patients (0.3%
vs. 2% [p ¼ 0.03] and 8% vs. 16% [p < 0.001], respectively). Ninety-five percent of young patients were in New York Heart
Association functional class I or II at last follow-up. During a mean follow-up period of 5.4 4.2 years, 165 patients (14%) died.
Annual mortality rates of young, middle-age, and older patients were 1%, 2%, and 5%, respectively (p < 0.01). Annual adverse
arrhythmic event rates were similar in the 3 age groups at about 1% (p ¼ 0.90). Independent predictors of mortality in young
patients were age, female sex, and residual left ventricular outflow tract gradient. Additionally, young patients treated
with $2.5 ml alcohol had a higher all-cause mortality rate (0.6% vs. 1.4% per year in patients treated with <2.5 ml, p ¼ 0.03).
CONCLUSIONS ASA in younger patients with obstructive hypertrophic cardiomyopathy was safe and effective for relief
of symptoms at long-term follow-up. The authors propose that the indication for ASA can be broadened to younger
patients. (J Am Coll Cardiol Intv 2017;10:1134–43) © 2017 by the American College of Cardiology Foundation.
A
lcohol septal ablation (ASA) for the treatment
A recent smaller study (n ¼ 217) showed that ASA in
of obstructive hypertrophic cardiomyopathy
patients #55 years of age was effective for reduction
(HCM) was introduced in 1995 as a percuta-
of symptoms at short-term follow-up and had low
neous alternative to surgical myectomy (1). The
mortality and adverse arrhythmic event (AAE) rates
American College of Cardiology Foundation/Amer-
at long-term follow-up, comparable with patients
ican Heart Association guidelines on HCM state that
with nonobstructive HCM (7). The aim of the present
ASA should be reserved for older patients and pa-
study was to further assess if ASA is safe and effective
tients with serious comorbidities and give a Class III
for younger patients by comparing complication
recommendation (Level of Evidence: C) for ASA in
rates, treatment effects, and long-term outcome of
younger patients if myectomy is a viable option (2).
young, middle-age, and older patients after ASA.
These recommendations reflected the lack of ASA
studies with long-term follow-up, whereas myectomy
METHODS
had already been proved to be safe and effective. As a
result, most studies comparing long-term outcomes
STUDY DESIGN AND PATIENT POPULATION. An in-
of ASA and myectomy have significant age differ-
ternational multicenter observational cohort design
ences (3–5). Thus, in a recent meta-analysis of long-
was used. The study population consisted of 1,197
term outcomes following septal reduction therapy,
consecutive patients with HCM (mean age 58 14
the ASA patients (n ¼ 2,013) were 9 years older than
years; range 13 to 88 years; 49% female) who under-
the myectomy patients (n ¼ 2,791) (6). Studies on
went ASA because of highly symptomatic left ven-
long-term outcome of young ASA patients are scarce.
tricular outflow tract (LVOT) obstruction despite
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Liebregts et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 11, 2017
JUNE 12, 2017:1134–43
Age-Specific Outcomes of ASA for Obstructive HCM
ABBREVIATIONS
optimal medical therapy. Procedures were
AND ACRONYMS
performed at 7 tertiary invasive centers from
sex-, and country-specific mortality rates obtained
4 European countries (Germany–Bad Oyen-
from the respective national registries (http://www.
hausen; Czech Republic–Prague, Trinec, and
destatis.de [Germany]; http://www.czso.cz [Czech
Brno;
Republic]; http://www.cbs.nl [the Netherlands]; http://
AAE = adverse arrhythmic
event
ASA = alcohol septal ablation
CI = confidence interval
HCM = hypertrophic
cardiomyopathy
HR = hazard ratio
the
Netherlands–Nieuwegein;
Denmark–Copenhagen
and
Gentofte)
compared with the general population using age-,
be-
www.dst.dk [Denmark]). Because of the controversy
tween January 1996 and August 2015. Studies
regarding the use of ASA in very young patients, the
reporting outcomes of subsets of this cohort
subgroup #35 years of age was also subjected to a
have been published before (8–11).
separate descriptive analysis.
FOLLOW-UP AND ENDPOINTS. Follow-up started at the
ICD = implantable
SEE PAGE 1144
time of ASA. There were some differences in post-ASA
cardioverter-defibrillator
Patients met the criteria for invasive treat-
LVOT = left ventricular outflow
tract
ment,
NYHA = New York Heart
including:
1)
ventricular
septal
thickness $15 mm; 2) (provocable) LVOT
Association
SCD = sudden cardiac death
VT = ventricular tachycardia
gradient $50 mm Hg; and 3) persistent New
follow-up among the centers. Conventionally, all patients had first clinical checkups 3 to 6 months after the
procedure and annual routine checkups after that.
Adverse events were retrieved from national patient
York Heart Association (NYHA) functional class
registries, from hospital patient records at the center at
III or IV dyspnea or Canadian Cardiovascular
which follow-up occurred, and from information
Society class III or IV angina (2,12). In exceptional cases,
provided
patients with documented exertional syncope were
general practitioners. All implantable cardioverter-
by
patients
themselves
and/or
their
also included. The choice of ASA instead of surgical
defibrillator (ICD) shocks were evaluated by an
myectomy was based on patient profile (age, comor-
experienced electrophysiologist, unaware and inde-
bidities, and so on) and patient preference. All patients
pendent of the study purpose and endpoints.
gave informed consent before the procedure. Details of
The primary endpoints of this study were all-cause
the ASA technique have been published before (1,10).
mortality and AAEs during long-term follow-up. AAEs
All procedures were performed by experienced inter-
consisted of sudden cardiac death (SCD), resuscitated
ventional cardiologists and guided by myocardial
cardiac arrest due to ventricular fibrillation or ven-
contrast echocardiography.
tricular
tachycardia
(VT),
and
appropriate
ICD
Patients were divided into 3 age groups: young
shock, respectively. Secondary endpoints were peri-
(#50 years), middle-age (51 to 64 years), and older
procedural (#30 days) atrioventricular block, cardiac
($65 years). Survival rates in the 3 groups were
tamponade, AAEs and mortality; pacemaker implantation, ICD implantation, (provocable) LVOT gradient,
NYHA functional class, and need for reintervention at
last clinical checkup, respectively. The study was in
T A B L E 1 Baseline Characteristics of 1,197 Patients Before
compliance with the Declaration of Helsinki.
Alcohol Septal Ablation
STATISTICAL
ANALYSIS. SPSS
version
24
(IBM,
#50 Years
(n ¼ 369)
51–64 Years
(n ¼ 423)
$65 Years
(n ¼ 405)
Armonk, New York), R version 3.1.1 (R Foundation for
41.7 7.5
58.4 4.1†
72.6 5.0†
soft Excel 2010 (Microsoft, Redmond, Washington)
114 (31)
190 (45)†
280 (69)†
were used for all statistical analyses. Categorical
293 (80)
352 (83)
363 (90)†
CCS class $III
79 (22)
95 (23)
78 (19)
LVEF (%)
71 9
70 10
69 10*
Left atrial diameter (mm)
47 7
46 7
47 7
SD and skewed data as median (interquartile range).
LVEDD (mm)
43 6
44 6
43 7
To
Basal septal thickness (mm)
21 5
20 4†
20 3†
t test or Mann-Whitney U test was used, and to
compare categorical variables, the chi-square test
Age (yrs)
Female
NYHA functional class $III
110 39
111 44
121 47†
Syncope
92 (25)
85 (20)
81 (20)
$2 RFs
57 (22)
31 (12)
11 (5)†
Pacemaker
14 (4)
17 (4)
16 (4)
ICD
31 (8)
12 (3)*
4 (1)†
LVOT gradient (mm Hg)
Values are mean SD or n (%). *p < 0.01. †p < 0.001 compared with patients #50 years
of age.
CCS ¼ Canadian Cardiovascular Society; ICD ¼ implantable cardioverter-defibrillator; LVEDD ¼
left ventricular end-diastolic diameter; LVEF ¼ left ventricular ejection fraction; LVOT ¼ left
ventricular outflow tract; NYHA ¼ New York Heart Association; RF ¼ conventional risk factor for
sudden cardiac death.
Statistical Computing, Vienna, Austria), and Micro-
variables are summarized as percentages. Normally
distributed continuous data are expressed as mean compare
continuous
variables,
the
Student
was used.
Cox proportional hazard regression was used to
identify predictors of all-cause mortality and AAEs
during long-term (>30 days) follow-up. The following
variables with a potential impact on primary endpoint
rates were evaluated, first in a univariate model:
age, sex, baseline and residual NYHA functional class,
baseline and residual LVOT gradient, conventional
risk factors for SCD (family history of SCD, history of
Liebregts et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 11, 2017
JUNE 12, 2017:1134–43
Age-Specific Outcomes of ASA for Obstructive HCM
unexplained syncope, maximum left ventricular wall
thickness $30 mm, nonsustained VT on Holter
F I G U R E 1 Distribution of Age at Alcohol Septal Ablation in 82 Very Young, 369 Young,
423 Middle-Age, and 405 Older Patients
monitoring, abnormal blood pressure response to
exercise),
volume
of
alcohol
injected
during
ASA, and need for reintervention. Variables with
p values <0.15 were then entered into a multivariate
analysis, which was performed using backward stepwise multiple Cox regression. Predictors of the primary endpoints are expressed as hazard ratios (HRs)
with 95% confidence intervals (CIs). Kaplan-Meier
graphs were used to show survival rates, and differences in survival were assessed using the log-rank
test. All tests were 2 sided, and p values <0.05 were
considered to indicate statistical significance.
RESULTS
CLINICAL CHARACTERISTICS. The baseline charac-
teristics of the young (n ¼ 369, mean age 42 8
Blue ¼ very young; green ¼ young; purple ¼ middle age; red ¼ older. ASA ¼ alcohol
septal ablation.
years), middle-age (n ¼ 423, mean age 58 4 years),
and older (n ¼ 405, mean age 73 5 years) patients
are shown in Table 1. Figure 1 depicts the distribution
kinase-MB
of age at ASA within the different age groups. More
kinase-MB 77 IU/l vs. 82 IU/l, respectively, p < 0.01).
older patients were in NYHA functional class III or IV
Complete (transient) atrioventricular block occurred
before ASA compared with young patients (90% vs.
in 32% of patients #50 years, compared with 42% of
80%, p < 0.001). More young patients had at least 2
patients $65 years (p < 0.01), resulting in permanent
conventional risk factors for SCD (22% vs. 5% of
pacemaker implantation after ASA in 8% and 16%,
older patients, p < 0.001), and more young patients
respectively (p < 0.001), at last follow-up visit.
had ICDs implanted (8% vs. 1% of older patients,
p < 0.001). In 456 patients (38%), <60% of the conventional risk factors for SCD were available. These
patients were therefore considered not to be risk
stratified at all. During the study period, 210 patients
were sent primarily to surgical myectomy.
measurements
TREATMENT
(maximum
EFFECTS. Long-term
creatinine
outcomes
are
shown in Table 3. At last checkup, 95% of the young
patients were in NYHA functional class I or II,
compared with 81% of the older patients (p < 0.001).
Likewise, 89% of the young patients had improved at
least 1 NYHA functional class, compared with 80% of
PROCEDURAL OUTCOMES. Periprocedural (#30 days)
older patients (p < 0.001). Residual LVOT gradient,
outcomes in the 3 age groups are shown in Table 2.
reduction
in
LVOT
gradient,
and
number
of
Periprocedural mortality was higher in older patients
compared with younger patients (2% vs. 0.3%,
p ¼ 0.03), and the incidence of AAEs was similar
T A B L E 2 Periprocedural (#30 Days) Outcomes of 1,197 Patients
(p ¼ 0.45). The AAEs within the first month all
Following Alcohol Septal Ablation
occurred in-hospital: 2 patients died of ventricular
#50 Years
(n ¼ 369)
fibrillation (day 2 in a 42-year-old man, day 9 in an
86-year-old woman), and 22 patients received suc-
Alcohol (ml)
cessful electric cardioversion for VT or ventricular
Maximum CK-MB (IU/l)
fibrillation (16 within 48 h and 2 on the 2nd, 4th, and
Complete heart block
10th days, respectively). Cardiac tamponade complicated the procedure in 3% of the older patients,
compared with 0.3% of the young patients (p < 0.01).
All cases of cardiac tamponade were thought to be
related to temporary pacing. In young patients, more
alcohol was used, compared with older patients
(mean 2.4 ml vs. 2.1 ml, p < 0.01), which did not
result in larger infarcts as assessed by creatinine
$65 Years
(n ¼ 405)
51–64 Years
(n ¼ 423)
2.0 (2.0-3.0) 2.0 (1.5-2.5)‡ 2.0 (1.5-2.5)‡
77 (52-127)
73 (54-140)
82 (55-164)*
119 (32)
161 (39)
169 (42)†
Cardiac tamponade
1 (0.3)
2 (0.5)
12 (3.0)†
AAE
7 (1.9)
6 (1.4)
11 (2.7)
Mortality
1 (0.3)
2 (0.5)
8 (2.0)*
Values are median (interquartile range) or n (%). Maximum CK-MB activity concentration was available in 72% of patients, whereas CK-MB mass concentration
measurements obtained in patients from the Czech Republic were excluded from
the analysis. *p < 0.05. †p < 0.01. ‡p < 0.001 compared with patients #50 years
of age.
AAE ¼ adverse arrhythmic event; CK-MB ¼ creatine kinase-MB.
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Liebregts et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 11, 2017
JUNE 12, 2017:1134–43
Age-Specific Outcomes of ASA for Obstructive HCM
T A B L E 3 Long-Term (>30 Days) Outcomes of 1,197 Patients Following
Alcohol Septal Ablation
reinterventions during follow-up were similar between the different age groups.
#50 Years
(n ¼ 369)
51–64 Years
(n ¼ 423)
$65 Years
(n ¼ 405)
6.2 4.6
5.3 4.1*
4.6 3.6‡
Pacemaker implantation
29 (8)
53 (13)*
65 (16)‡
rates following ASA in young, middle-age, and older
ICD implantation
21 (6)
18 (4)
11 (3)*
patients were 0.8%, 0.8%, and 1.0% per year,
NYHA functional class $III
19 (5)
36 (9)
73 (19)‡
respectively (p ¼ 0.90) (Figure 2). Approximately
Improvement of $1 NYHA
functional class
322 (89)
359 (87)
315 (80)‡
two-thirds of the AAEs were fatal in both young
Follow-up (yrs)
LONG-TERM OUTCOMES. Follow-up was complete
in 99.6% of patients. The long-term (>30 days) AAE
and older patients (Table 3). No independent pre-
LVOT gradient (mm Hg)
26 31
27 35
26 33
LVOT gradient reduction (%)
76 27
75 29
77 27
Reintervention
39 (11)
44 (10)
30 (7)
Repeat ASA
77%
82%
67%
factors
Myectomy
23%
18%
33%
term follow-up (HR: 5.26; 95% CI: 1.13 to 24.51;
p ¼ 0.03). ICD implantation following ASA was
5%
11%
3%
AAE
19 (5.1)
18 (4.3)
18 (4.4)
SCD
63%
56%
72%
Myectomy after repeat ASA
dictors of AAEs in young and middle-age patients
were found. In older patients, $2 conventional risk
for
SCD
predicted
AAEs
during
long-
more common in young compared with older patients (6% vs. 3%, p ¼ 0.04).
Aborted SCD
5%
6%
6%
ICD discharge
32%
39%
22%
During a mean follow-up of 5.4 4.2 years, there
Annual AAE rate >30 days
0.8%
0.8%
1.0%
were 165 deaths in total, which translates into mor-
23 (6.2)
44 (10.4)*
87 (21.5)‡
tality rates of 1% per year in young, 2% per year in
HCM-related death
70%
55%
31%
middle-age, and 5% per year in older patients
Noncardiac death
17%
43%
51%
(Table 3). The 1-, 5-, and 10-year survival rates of all
Unknown cause of death
13%
2%
18%
Annual mortality rate
1.0%
2.1%†
5.1%‡
1-yr survival
99%
98%
94%
5-yr survival
95%
92%
79%
10-yr survival
91%
80%
55%
Mortality
ASA patients were 97% (95% CI: 96% to 98%), 89%
(95% CI: 89% to 91%), and 76% (95% CI: 73% to 80%),
compared with 98%, 92%, and 80%, respectively,
in the age- and sex-matched general population
(p < 0.05) (Figure 3A). The 1-, 5-, and 10-year survival
Values are mean SD, n (%), or %. Values in italics are relative percentages. *p < 0.05.
†p < 0.01. ‡p < 0.001 compared with patients #50 years of age.
HCM ¼ hypertrophic cardiomyopathy; SCD ¼ sudden cardiac death; other abbreviations as in
Tables 1 and 2.
rates of patients #50 years were 99% (95% CI: 98% to
100%), 95% (95% CI: 92% to 97%), and 91% (95% CI:
88% to 95%), compared with 100%, 99%, and 97%,
respectively, in the age- and sex-matched general
population (p < 0.05) (Figure 3B). The 1-, 5-, and 10-
F I G U R E 2 Kaplan-Meier Graph of Survival Free of Adverse Arrhythmic Events
Following Alcohol Septal Ablation in 369 Patients #50 Years of Age,
423 Patients 51 to 64 Years of Age, and 405 Patients $65 Years of Age
year survival rates of patients 51 to 64 years were
98% (95% CI: 97% to 99%), 92% (95% CI: 89% to 95%),
and 80% (95% CI: 74% to 86%), compared with 99%,
96%, and 89%, respectively, in the age- and sexmatched general population (p < 0.05) (Figure 3C).
The 1-, 5-, and 10-year survival rates of patients $65
years were 94% (95% CI: 92% to 97%), 79% (95% CI:
74% to 84%), and 55% (95% CI: 47% to 64%),
compared with 97%, 85%, and 64%, respectively,
in the age- and sex-matched general population
(p < 0.05) (Figure 3D). The cause of death was HCM
related (SCD, heart failure, or stroke) in 70% of the
young, 55% of the middle-age, and 31% of the older
patients. The opposite pattern was the case for
noncardiac deaths (17%, 43%, and 51%, respectively).
According to multivariate analyses, independent
predictors of all-cause mortality in young patients
were age at ASA (HR: 1.09; 95% CI: 1.02 to 1.17;
p ¼ 0.02), female sex (HR: 3.03; 95% CI: 1.28 to 7.18;
p ¼ 0.01), volume of alcohol injected during ASA (HR:
AAE ¼ adverse arrhythmic event; ASA ¼ alcohol septal ablation.
1.55; 95% CI: 1.04 to 2.30; p ¼ 0.03), and LVOT
gradient at last checkup (HR: 1.01; 95% CI: 1.00 to
Liebregts et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 11, 2017
JUNE 12, 2017:1134–43
Age-Specific Outcomes of ASA for Obstructive HCM
F I G U R E 3 Kaplan-Meier Graphs of Survival Following Alcohol Septal Ablation in All 1,197 Patients, in 369 Patients #50 Years of Age, in 423 Patients 51 to
64 Years of Age, and in 405 Patients $65 Years of Age, Compared With the Age- and Sex-Matched General Population
(A) All patients; (B) patients #50 years of age; (C) patients 51 to 64 years of age; (D) patients $65 years of age. Dotted lines ¼ 95% confidence intervals.
ASA ¼ alcohol septal ablation.
1.02; p ¼ 0.02). No independent predictors of mor-
patients who received <2.5 ml (n ¼ 213). The 1-, 5-, and
tality in middle-age patients were found. Indepen-
10-year survival rates of patients who received <2.5 ml
dent predictors of all-cause mortality in older
alcohol were 99% (95% CI: 99% to 100%), 98% (95% CI:
patients were age at ASA (HR: 1.14; 95% CI: 1.07 to
95% to 100%), and 94% (95% CI: 90% to 99%),
2.21; p < 0.001), and $2 conventional risk factors for
compared with 98% (95% CI: 96% to 100%), 91% (95%
SCD (HR: 3.13; 95% CI: 1.40 to 7.00; p < 0.01).
CI: 86% to 96%), and 89% (95% CI: 83% to 94%),
The role of alcohol volume in young ASA patients
respectively, in patients who received a higher alcohol
was further explored by dividing the cohort into a high
volume (p ¼ 0.03) (Figure 4). The annual HCM-related
and low alcohol dose groups. A cutoff of 2.5 ml was
mortality rate was found to be 0.2% in the <2.5 ml
chosen because in a previous analysis, a volume be-
alcohol group, compared with 1.2% in the higher
tween 1.5 and 2.5 ml was found to be well balanced in
alcohol volume group (p < 0.01). Furthermore, pa-
terms of efficacy and risk for conduction disturbances
tients who received the higher volume of alcohol
(11). Six patients (1.6%) were excluded from this anal-
developed
ysis because data regarding the volume of alcohol
kinase-MB 89 IU/l vs. 69 IU/l, p < 0.001), whereas there
could not be retrieved. Patients who received $2.5 ml
were no differences in LVOT gradient or NYHA func-
alcohol (n ¼ 150) had a significantly higher all-cause
tional class at long-term follow-up between the 2
and HCM-related mortality rate compared with
groups (Table 4).
larger
infarcts
(maximum
creatinine
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Liebregts et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 11, 2017
JUNE 12, 2017:1134–43
Age-Specific Outcomes of ASA for Obstructive HCM
patients (16%) underwent repeat ASA, and only 1
F I G U R E 4 Kaplan-Meier Graph of Survival Following Alcohol Septal Ablation in
213 Young (#50 Years) Patients Treated With <2.5 ml of Alcohol Compared With
patient (1%) remained in NYHA functional class III
or IV at last follow-up. Nine patients had received
150 Young Patients Treated With $2.5 ml of Alcohol
ICDs before ASA, and 6 patients were implanted
with ICDs after the ASA procedure. Of these 15 patients (18%), 3 received an appropriate ICD shocks
during follow-up. Combined with 2 SCDs (4 years
after ASA in a 25-year-old man, 10 years after ASA
in a 24-year-old woman) and 1 resuscitated cardiac
arrest (9 years after ASA in a 35-year-old man), this
translated to an AAE rate of 1.0% per year during
long-term follow-up. With no other deaths in the
very young, this made for an all-cause mortality
rate of 0.3% per year.
DISCUSSION
With almost 1,200 patients from 4 European countries, this is the largest ASA cohort to date. The
principal findings of this 5.4-year follow-up study
were that: 1) young (#50 years) patients had
OUTCOMES IN THE VERY YOUNG. Of the young pa-
tients, 82 (21%) were #35 years of age and therefore
considered to be “very young” (Figure 1). None of
these patients died in relation to the procedure or
within the first 30 days post-ASA. One patient
(1.2%) experienced in-hospital VT requiring electric
cardioversion. Twenty-one patients (26%) developed (transient) complete atrioventricular block,
resulting in permanent pacemaker implantation in 4
patients
(5%)
at
last
follow-up
visit.
Thirteen
favorable long-term survival following ASA, with an
all-cause mortality rate of 1% per year; 2) despite
more risk factors for SCD, young patients had a
similar AAE rate (0.8% per year) compared with
middle-age and older patients; 3) symptom alleviation following ASA in young patients was excellent,
with 95% of patients functioning in NYHA functional class I or II at long-term follow-up; 4) the 30day mortality rate in young patients undergoing
ASA was very low (0.3%); 5) young patients had
one-half the risk for permanent pacemaker implantation compared with older patients; 6) the use of
<2.5 ml alcohol for ASA was associated with an
T A B L E 4 Outcomes of 363 Patients #50 Years of Age Following
Alcohol Septal Ablation
improved survival rate in young patients; and 7)
ASA in very young (#35 years) patients was safe
<2.5 ml
(n ¼ 213)
$2.5 ml
(n ¼ 150)
and effective as well.
5.0 4.1
8.0 4.8†
Maximum CK-MB (IU/l)
69 (52)
89 (93)†
Pacemaker implantation
18 (8%)
11 (7%)
NYHA functional class $III
10 (5%)
9 (6%)
LVOT gradient (mm Hg)
28 31
23 32
Mortality
6 (2.8)
17 (11.3)†
with a median follow-up of 5 years (13). Survival free
Follow-up (yrs)
PREVIOUS
AGE-SPECIFIC
ASA
STUDIES. Studies
reporting on long-term outcomes of young patients
following ASA are scarce. In 2014, a study was conducted that included 75 patients #50 years of age
Periprocedural mortality
17%
0%
of all-cause mortality following ASA at 10 years was
HCM-related death
17%
82%
found to be 94%. In 2016, a study was reported that
Noncardiac death
33%
12%
included 217 ASA patients who were divided into
Unknown cause of death
33%
6%
young (#55 years) and older (>55 years) groups and
Annual mortality rate
0.6%
1.4%*
1-yr survival
99%
98%
5-yr survival
98%
91%
10-yr survival
94%
89%
followed for 7.6 4.6 years (7). ASA was similarly
effective in both age groups for reduction of symptoms at short-term follow-up, and young patients
were found to have a lower risk for procedure-
Values are mean SD, n (%), or %. Values in italics are relative percentages.
*p < 0.05. †p < 0.001 compared with patients receiving <2.5 ml alcohol.
Abbreviations as in Table 1.
related
atrioventricular
conduction
disturbances.
The 5- and 10-year survival of young patients was
95% and 90%, respectively, which was comparable
Liebregts et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 11, 2017
JUNE 12, 2017:1134–43
Age-Specific Outcomes of ASA for Obstructive HCM
with age- and sex-matched patients with non-
(6). Of the 50 studies examined in the systematic re-
obstructive HCM. These results are in line with those
view that accompanied this meta-analysis, only 7
of the present study, except that along with a dif-
compared survival rates of their patients with HCM
ference in (transient) atrioventricular block, we also
with the sex- and age-matched general population:
found a 50% lower need for pacemaker implantation
Smedira et al. (17) (n ¼ 323, Cleveland Clinic) and
in young patients (8% vs. 16% in older patients).
Ommen et al. (18) (n ¼ 289, Mayo Clinic) found sur-
Furthermore, periprocedural cardiac tamponade and
vival rates following myectomy to be comparable
death were less frequent in young patients compared
with the general population; Schaff et al. (19)
with older patients (0.3% vs. 3% and 0.3% vs. 2%,
(n ¼ 749, Mayo Clinic), Woo et al. (20) (n ¼ 388,
respectively). Symptom alleviation was excellent in
Toronto General Hospital), and Sedehi et al. (5)
young patients, with improvement of at least 1 NYHA
(n ¼ 171, Stanford University Medical Center) found
functional class in 89% of patients to an NYHA
survival rates following myectomy to be worse than
functional class of I or II in 95% of patients at long-
the general population; Jensen et al. (8) (n ¼ 279, 4
term follow-up. Of the older patients, only 81%
Scandinavian centers), Veselka et al. (9) (n ¼ 178, 2
were in NYHA functional class I or II at last checkup.
Czech centers), and Sedehi et al. (5) (n ¼ 52, Stanford
However, residual LVOT gradient, reduction in LVOT
University Medical Center) found survival rates
gradient, and number of reinterventions were com-
following ASA to be comparable with the general
parable in both groups, and clearly other factors
population; and Sorajja et al. (16) (n ¼ 342, Mayo
can cause exertional dyspnea, especially in older
Clinic) found post-ASA survival to be comparable
patients.
with the general population and with sex- and
Outcomes of very young patients following ASA
age-matched myectomy patients. What primarily
were favorable as well, with 99% of them functioning
differentiates these studies is that the ones with post-
in NYHA functional class I or II at last checkup and a
intervention survival rates comparable with the
further decline in the need for permanent pacemaker
general population had <1,700 patient-years of
implantation to 5%. Moreover, the AAE rate was
follow-up, whereas the studies with a significant
similar to the other age groups, and the all-cause
survival difference had follow-up of >2,300 patient-
mortality rate was only 0.3% per year.
years. The present study, with about 6,500 patientyears of follow-up, belongs to the second category.
ASA AND SURGICAL MYECTOMY. The American Col-
Consequently, our results support that irrespective of
lege of Cardiology Foundation/American Heart Asso-
septal
ciation guidelines on HCM from 2011 state that ASA
symptomatic obstructive HCM have reduced long-
should be reserved for older patients and patients
term survival compared with the general popula-
with serious comorbidities and give a class III
tion. Apart from comparisons with the general
reduction
therapy,
patients
with
severe
recommendation (Level of Evidence: C) for ASA in
population, Ommen et al. (18) also reported specif-
younger patients if myectomy is a viable option (2).
ically on survival of patients #45 years of age and
These recommendations reflected the lack of ASA
found 92% of these to be alive 10 years post-
studies with long-term follow-up, whereas myectomy
myectomy. Woo et al. (20) did the same for
had been proved to be safe and effective. Despite
patients <50 years of age and found a 10-year survival
these recommendations, recent reports show that
of about 90% following myectomy. These results
about 43% of U.S. patients undergo ASA instead of
correlate well with the 91% 10-year survival of young
myectomy (14), and these numbers are known to be
ASA patients found in the present study. Because
even higher in Europe (15). Most of the studies
symptom improvement was excellent and long-
comparing long-term outcomes of ASA and myectomy
lasting in young ASA patients as well, we therefore
were reported after publication of the 2011 HCM
propose that the indication for ASA can be broadened
guidelines (3–5,10,16). These more recent studies all
to younger patients.
showed similar mortality rates following ASA and
myectomy, which clearly supports the long-term
ASA AND ALCOHOL VOLUME. To date, there has
safety of ASA, especially considering that most of
been only 1 other study that showed a significant
the ASA cohorts were on average older than their
survival benefit from the use of a lower alcohol vol-
surgical counterparts. A recent meta-analysis of long-
ume for ASA. This study, by Kuhn et al. (21),
term outcomes of septal reduction therapy found an
comprised 2 series: 329 patients treated in a dose-
all-cause mortality rate of 1.5% per year following
finding study with decreasing amounts of alcohol
ASA compared with 1.4% per year following myec-
until 2001 (on average 2.9 to 0.9 ml) and 315 patients
tomy, and similar annual (aborted) SCD rates as well
in the subsequent “low alcohol dose era” treated until
1141
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Liebregts et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 11, 2017
JUNE 12, 2017:1134–43
Age-Specific Outcomes of ASA for Obstructive HCM
2005 (mean volume 0.8 ml). In the first group, pa-
has no complicating factors, the advice should be that
tients treated with >2 ml of alcohol showed a higher
ASA and surgical myectomy are both safe and effec-
mortality rate than patients treated with #2 ml. The
tive for relief of symptoms. However, ASA has a 5% to
mean follow-up period for this cohort was only 2
16% (depending on the patient’s age) risk for perma-
years, however, and the patients treated with a higher
nent pacemaker implantation, compared with about
alcohol volume were by definition the first patients to
4% after myectomy (6). Furthermore, there is a higher
undergo ASA at this center.
risk for the need for reintervention following ASA (9%
In the present study, the use of a higher volume of
in the present study) compared with myectomy (6).
alcohol was found to predict all-cause mortality in
Patients can subsequently weigh these higher risks
young patients. In a recent analysis, alcohol volume
following ASA against the somewhat higher burden of
of 1.5 to 2.5 ml was found to be well balanced in
(rehabilitation from) open heart surgery and make a
terms of efficacy and risk for conduction distur-
measured decision.
bances (11). After we divided our young cohort
accordingly, the patients who received <2.5 ml
STUDY
alcohol were found to have a significantly lower
randomized nature of the present study has several
all-cause and HCM-related mortality rate compared
limitations. In the analysis concerning the role of
with patients who received $2.5 ml (Figure 4).
alcohol volume in young patients, there was a
Furthermore,
group
potential for bias by indication, because patients who
developed larger infarcts, the LVOT gradient and
received a higher alcohol volume for ASA might have
NYHA functional class at last checkup were compa-
had different coronary artery anatomy and/or septal
rable between the 2 groups. Of note, patients who
pathology
received $2.5 ml alcohol were treated on average 5
patients who received less alcohol. However, a Cox
years earlier than those treated with <2.5 ml. This
proportional regression analysis in young patients
trend of decreasing volumes of alcohol over the years
with use of basal septal thickness data in millimeters
is seen in most ASA studies and may thus further
(as opposed to the binary conventional risk factor of
improve survival rates in young patients following
maximum left ventricular wall thickness $30 mm)
ASA in the future.
found the same results (not shown). Similar to other
PATIENT SELECTION AND SPECIALIZED CARE. In a
in the very young patients and young patients treated
previous analysis, a higher residual LVOT gradient
with <2.5 ml of alcohol were underpowered. There-
after ASA was found to predict long-term mortality
fore, no comparisons with the general population
(11). The present study documented the same asso-
were made, and the results of these analyses should
ciation, but only in young patients, with an approxi-
be interpreted with caution. Finally, we did not cor-
mate 1% increase in all-cause mortality for each
rect for individual or local alterations of percutaneous
millimeter of mercury residual LVOT gradient. This
technique. However, all procedures were performed
emphasizes the importance of proper selection
by experienced interventional cardiologists, and this
of patients suitable for ASA, especially in patients
implies that our findings are more generalizable than
#50 years of age.
those of single-center investigations.
although
the
high-volume
LIMITATIONS. The
(e.g.,
more
retrospective,
fibrosis)
compared
non-
with
reported studies (5,8,9,16–18), the survival analyses
In line with the 2011 American College of Cardiology and 2014 European Society of Cardiology HCM
guidelines (1,12), we recommend that all patients
CONCLUSIONS
undergoing septal reduction therapy should be dis-
ASA in young patients with obstructive HCM is safe
cussed by a multidisciplinary heart team (consisting
and effective for relief of symptoms at long-term
of an imaging cardiologist, an interventional cardiol-
follow-up. We propose that the indication for ASA
ogist experienced with ASA, and a surgeon experi-
can be broadened to younger patients.
enced with myectomy) to determine the optimal
therapy, by taking into account not only age but also
ACKNOWLEDGMENT The authors thank J. C. Kelder,
factors such as mitral valve anatomy, coronary anat-
MD, PhD, Department of Cardiology, St. Antonius
omy, existing conduction disturbances, septal thick-
Hospital Nieuwegein, for his statistical assistance.
ness, comorbidities, and so on. When all of these
factors have been weighted against one another, the
ADDRESS FOR CORRESPONDENCE: Dr. Max Liebregts,
heart team can provide optimal advice, leaving the
St. Antonius Hospital, Koekoekslaan 1,3430 EM, Nieuwegein,
final decision up to the patient. When an adult patient
the Netherlands. E-mail: [email protected]
Liebregts et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 11, 2017
JUNE 12, 2017:1134–43
Age-Specific Outcomes of ASA for Obstructive HCM
PERSPECTIVES
WHAT IS KNOWN? The American College of Cardiology
we propose that the indication for ASA can be broadened
Foundation/American Heart Association guidelines
to younger patients.
reserve ASA for older patients and patients with serious
comorbidities. Data on long-term age-specific outcomes
WHAT IS NEXT? In the smaller subgroup of very young
(#35 years) patients, ASA was found to be safe and effec-
after ASA are scarce.
tive as well. However, more studies with long-term followWHAT IS NEW? We found that ASA in younger (#50
up of very young patients with HCM undergoing ASA are
years) patients with obstructive HCM is safe and effective
warranted to confirm these findings.
for relief of symptoms at long-term follow-up. Therefore,
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KEY WORDS alcohol septal ablation,
hypertrophic cardiomyopathy, septal
reduction therapy
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