Download Arrhythmia/Electrophysiology

Arrhythmia/Electrophysiology
Syncope in High-Risk Cardiomyopathy Patients With
Implantable Defibrillators: Frequency, Risk Factors,
Mechanisms, and Association With Mortality
Results From the Multicenter Automatic Defibrillator Implantation
Trial–Reduce Inappropriate Therapy (MADIT-RIT) Study
Martin H. Ruwald, MD, PhD; Ken Okumura, MD; Takeshi Kimura, MD;
Kazutaka Aonuma, MD; Morio Shoda, MD; Valentina Kutyifa, MD, PhD;
Anne-Christine H. Ruwald, MD; Scott McNitt, MS; Wojciech Zareba, MD, PhD; Arthur J. Moss, MD
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Background—There is a relative paucity of studies investigating the mechanisms of syncope among heart failure patients
with implantable cardioverter-defibrillators, and it is controversial whether nonarrhythmogenic syncope is associated
with increased mortality.
Methods and Results—The Multicenter Automatic Defibrillator Implantation Trial–Reduce Inappropriate Therapy
(MADIT-RIT) randomized 1500 patients to 3 different implantable cardioverter-defibrillator programming arms: (1)
Conventional programming with therapy for ventricular tachycardia ≥170 bpm; (2) high-rate cutoff with therapy for
ventricular tachycardia ≥200 bpm and a monitoring zone at 170 to 199 bpm, and (3) prolonged 60-second delay with
a monitoring zone before therapy. Syncope was a prespecified safety end point that was adjudicated independently.
Multivariable Cox models were used to identify risk factors associated with syncope and to analyze subsequent risk of
mortality. During follow-up, 64 of 1500 patients (4.3%) had syncope. The incidence of syncope was similar across the
3 treatment arms. Prognostic factors for all-cause syncope included the presence of ischemic cardiomyopathy (hazard
ratio [HR], 2.48; 95% confidence interval [CI], 1.42–4.34; P=0.002), previous ventricular arrhythmias (HR, 2.99; 95%
CI, 1.18–7.59; P=0.021), left ventricular ejection fraction ≤25% (HR, 1.65; 95% CI, 0.98–2.77; P=0.059), and younger
age (by 10 years; HR, 1.25; 95% CI, 1.00–1.52; P=0.046). Syncope was associated with increased risk of death regardless
of its cause (arrhythmogenic syncope: HR, 4.51; 95% CI, 1.39–14.64, P=0.012; nonarrhythmogenic syncope: HR, 2.97;
95% CI, 1.07–8.28, P=0.038).
Conclusions—Innovative programming of implantable cardioverter-defibrillators with therapy for ventricular tachycardia
≥200 bpm or a long delay is not associated with increased risk of arrhythmogenic or all-cause syncope, and syncope caused
by slow ventricular tachycardias (<200 bpm) is a rare event. The clinical risk factors associated with syncope are related to
increased cardiovascular risk profile, and syncope is associated with increased mortality irrespective of the cause.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00947310. (Circulation. 2014;129:545-552.)
Key Words: heart failure ◼ implantable cardioverter-defibrillators ◼ prognosis ◼ syncope ◼ ventricular tachycardia
S
yncope in heart failure patients with or without an
implantable cardioverter-defibrillator (ICD) may be associated with a poor prognosis regardless of the cause of the
syncope, but syncope caused by life-threatening ventricular
arrhythmias is associated with an increased risk of death.1–4
Because no large study in high-risk patients with heart failure has specifically addressed syncope as a safety end point,
there is a lack of evidence on which factors are associated with
all-cause syncope, arrhythmogenic syncope, and nonarrhythmogenic syncope.
Clinical Perspective on p 552
Furthermore, it is not known whether slow ventricular
tachycardia (VT) (170–199 bpm) may induce hemodynamic
instability and syncope in high-risk heart failure patients or
whether the duration of ventricular arrhythmias until ICD
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
Received June 3, 2013; accepted October 26, 2013.
From the Heart Research Follow-up Program, University of Rochester Medical Center, Rochester, NY (M.H.R., V.K., A.-C.H.R., S.M., W.Z., A.J.M.);
Department of Cardiology, Gentofte Hospital, Hellerup, Denmark (M.H.R., A.-C.H.R.); Department of Cardiology, Hirosaki University Hospital, Hirosaki,
Japan (K.O.); Department of Cardiology, Kyoto University Hospital, Kyoto, Japan (T.K.); Department of Cardiology, Tsukuba University Hospital,
Tsukuba, Japan (K.A.); and Department of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan (M.S.).
Correspondence to Martin H. Ruwald, MD, PhD, Heart Research Follow-up Program, University of Rochester Medical Center, 265 Crittenden Blvd,
Rochester, NY 14642. E-mail [email protected]
© 2013 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.113.004196
545
546 Circulation February 4, 2014
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treatment is initiated affects the frequency of syncope. The
design of the Multicenter Automatic Defibrillator Implantation
Trial–Reduce Inappropriate Therapy (MADIT-RIT)5 allowed
us to answer these questions.
In MADIT-RIT, syncope was a prespecified safety end
point, because life-threatening ventricular arrhythmias may
precipitate syncope before termination/conversion of the
rhythm by device therapy and thereby compromise patient
safety. It was anticipated that the rate of syncope might be
increased in the treatment arms that were programmed with
a high-rate cutoff before therapy or programmed to delayed
therapy. There was a similar incidence of all-cause syncope
across the treatment arms5; however, the origin and cause of
syncope were not analyzed separately for the safety end point.
In heart failure patients with defibrillators who experience syncope, the ICD device is interrogated to establish
­rhythm-symptom correlation. If no appropriate ICD therapy
is given or no malignant ventricular rhythm is recorded in
relation to the syncopal event, the syncope may be deemed
nonarrhythmic. For both the physician and the patient, it is
important to know whether nonarrhythmogenic syncope is
related to an adverse outcome. Furthermore, it is unclear
whether appropriate ICD therapy is associated with subsequent arrhythmogenic syncope.
In the present study, we aimed to evaluate (1) the effects
of innovative ICD programming with either a high-rate cutoff VT zone or delayed therapy on risk of syncope compared
with conventional programming; (2) the independent prognostic factors associated with syncope; and (3) the association
between syncope, the cause of syncope, and the risk of death
in patients enrolled in MADIT-RIT.
Methods
with a pacemaker, ICD, or CRT-D; or if they had a recent myocardial infarction or revascularization procedure (within 3 months).
Other exclusion criteria were described in the protocol publication.
Follow-up continued until trial termination on July 10, 2012. Patients
were randomly assigned to 1 of 3 ICD programming configurations for
the detection and initiation of therapy for VT or ventricular fibrillation.
Device Programming and Monitor Zones
Standard transvenous implantation methods were followed and commercially available ICD and CRT-D dual-chamber devices (Boston
Scientific, Natick, MA) were used in this trial. Briefly, the ICD
programming configurations were set as follows. The conventional
configuration (arm A) had a VT zone (first) at 170 to 199 bpm and
a 2.5-second delay before antitachycardia pacing (ATP) and shock
delivery, with a second zone at ≥200 bpm with a 1-second delay before
ATP or shock. The high-rate programming configuration (arm B) had
a first monitoring-only zone between 170 and 199 bpm and a second
zone at ≥200 bpm with a 2.5-second delay before ATP or shock. The
duration-delay configuration (arm C) had a first zone at ≥170 bpm
with a 60-second delay and monitoring zone before therapy, a second
zone at ≥200 bpm with a 12-second delay and monitoring zone before
therapy, and a third zone at ≥250 bpm with a 2.5-second delay and
monitoring zone before ATP or shock. For all VT zones, the first programmed therapy was ATP followed by shock therapies.
Bradycardia pacing was programmed as DDD with a lower rate
of 40 bpm and hysteresis off. For CRT-D, pacing optimization was
described in detail previously.6
Interrogation and Follow-Up
Patients were followed up every 3 months within the first year and
then at 6-month intervals until trial termination. Device reprogramming was possible after the first occurrence of inappropriate therapy.
All device interrogations were independently reviewed by the
interrogation adjudication committee, which was blinded to the programming arm assignments. The events were adjudicated on the basis
of the committee’s interpretation of atrial and ventricular arrhythmias
and classified as appropriate or inappropriate ATP and appropriate or
inappropriate shock or a combination of those.
MADIT-RIT
End Points
The protocol and primary report of the MADIT-RIT study have been
published previously.5,6 The study included 1500 patients from 98 hospital centers with a primary prevention guideline indication to receive
an ICD or CRT-D (cardiac resynchronization therapy defibrillator)
device. The protocol was approved by the institutional review board
at each participating center, and participants gave informed consent.
Patients were excluded if they had experienced atrial fibrillation within
1 month before implantation; if they previously had been implanted
Syncopal events were a prespecified end point and were identified by
the physicians at the enrolling centers and adjudicated by a 3-member
independent morbidity and mortality committee using device interrogation and supporting source documents as provided by the enrolling centers. Syncope was defined as a total loss of consciousness with a rapid
and spontaneous recovery with or without device therapy. Syncope with
ventricular fibrillation (cardiac arrest) that was treated successfully with
ICD shock was included in this definition of syncope (6 patients).
Figure 1. Cumulative probability of first
occurrence of all-cause syncope according
to treatment arm. Kaplan–Meier estimates
of the cumulative probability of a first
occurrence of all-cause syncope are
shown for patients randomly assigned
to implantable cardioverter-defibrillator
(ICD) programming of either conventional
ICD therapy at a heart rate of ≥170 bpm,
high-rate cutoff ICD therapy at a heart
rate of ≥200 bpm and a monitoring zone
between 170 and 199 bpm, or delayed ICD
therapy with prolonged monitored zones
at a heart rate >170 bpm. Conv indicates
conventional.
Ruwald et al Syncope in ICD Patients With Heart Failure 547
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Arrhythmogenic syncope was defined as syncopal episodes with
a direct rhythm-symptom correlation at adjudication and comprised a group of supraventricular arrhythmias, ventricular tachyarrhythmias, asystole, other arrhythmias, or unspecified arrhythmias.
Nonarrhythmogenic syncope was classified as vasovagal, orthostatic,
metabolic, or neurological transient loss of consciousness, with a separate category for unknown origin. For classification as nonarrhythmogenic syncope, rhythm-symptom correlation had been ruled out by
interrogation of the devices at follow-up. The available information
on the event as sent by the enrolling center, such as notes from the
discharging physician, notes about symptoms, notes from emergency
departments, and tests performed during an admission, if any, were
taken into account in the adjudication of the event. Thus, the evaluation
of syncope was not uniform or determined by an algorithmic approach,
and no definitive tests were performed to allocate a patient into a category (eg, vasovagal or orthostatic hypotension syncope). MADIT-RIT
was not specifically designed to address the mechanism of syncope.
All patient devices were programmed with a DDD lower rate of 40
bpm. For adjudication of syncope events, technical issues such as loss
of ventricular capture or pacing inhibition caused by oversensing for
pacemaker-dependent patients were taken into account.
Death was a prespecified end point and was adjudicated by the
mortality committee by review of the documents and classification of
death by the enrolling centers. A modified Hinkle-Thaler definition
was used for the cause of cardiac death.7
Ventricular arrhythmias were a prespecified end point, and a
3-member independent electrogram and device-interrogation committee reviewed all interrogation events and adjudicated them into
appropriate therapy (for ventricular arrhythmias) by ATP or shock
and inappropriate therapy for all nonventricular arrhythmias based on
tachycardia onset, morphology, and rate stability from the recorded
electrogram. Furthermore, device interrogations were used to classify
monitored (nontreated) ventricular and supraventricular arrhythmias
based on rhythms with ≥30 beats.
Monitored events were gathered from the monitored ventricular
arrhythmias in VT zones where no therapy was given in all treatment arms as recorded by the devices and as described under device
programming.
Statistical Analysis
To evaluate the association of baseline characteristics with the incidence of syncope, univariable Cox proportional hazards regression
models were fit.8 The comparison of distribution of syncope according to groups of causes was accomplished by log-rank test. The
cumulative probability of syncope was displayed by the method of
Kaplan–Meier using the log-rank test to compare cumulative event
rates between treatment arms.
Univariable and multivariable Cox proportional hazards regression
models were used to estimate the risk of all-cause syncope, arrhythmogenic syncope, and nonarrhythmogenic syncope as defined previously. In the multivariable model, we included variables found by
stepwise selection from the pool of all baseline variables, setting the
limits for entry into the model at 0.05. Four baseline variables had a
significant association with the end point of all-cause syncope and
thus were included in the multivariable Cox model, whereas only 2
variables had a significant association with the end point of arrhythmogenic syncope. To those 2 models we then added variables of
­time-dependent ICD therapy to examine the association between incident ICD therapy and subsequent risk of syncope. Variables including time-dependent appropriate therapy, appropriate ATP, appropriate
shock, inappropriate therapy, inappropriate ATP, and inappropriate
shock were tested separately to estimate whether they were significantly associated with the syncopal end points. A second model
was constructed for the end point of all-cause mortality in a similar
fashion and was adjusted for baseline variables that had a significant
impact on the end point. To maintain a robust model, we chose only 1
variable per 10 events; thus, a maximum of 7 variables were considered for incorporation into the final model. To assess the association
between all-cause syncope, arrhythmogenic syncope, and nonarrhythmogenic syncope throughout the study and the risk of death,
a third model was created that used the time-dependent variables of
all-cause syncope, arrhythmogenic syncope, and nonarrhythmogenic
syncope, with separate evaluation of those in the multivariable model.
Interaction terms were used systematically to interact with and analyze the time-dependent variables with the baseline variables and the
randomization arms; no significant interactions were found, although
there was limited statistical power for such an analysis. The assumption of proportional hazards was checked graphically by use of standard log(−log) survival density function plots, as well as by testing
the interaction of covariates with follow-up time in the multivariable
models. All assumptions were found to be valid. A 2-tailed P<0.05
was considered significant. Analyses were performed with the SAS
statistical system version 9.3 (SAS Institute, Cary, NC).
Results
During a mean follow-up of 1.4±0.6 years, a total of 64
patients (4.3%) experienced at least 1 syncopal episode, with
Table 1. Baseline Characteristics of the MADIT-RIT
Population
Clinical Characteristics
Number of patients
MADIT-RIT Population
1500 (100)
Treatment A, conventional
514 (34)
Treatment B, high-rate cutoff
500 (33)
Treatment C, delayed therapy
486 (32)
CRT-D type of defibrillator
757 (51)
NYHA class III
780 (52)
Age, y
63±12
Female
436 (29)
QRS duration <150 ms
312 (44)
Ejection fraction ≤25%
726 (48)
Ischemic cardiomyopathy
791 (53)
Diabetes mellitus
Hypertension
Current smoking
Previous ventricular arrhythmias
485 (33)
1029 (69)
247 (17)
48 (3)
Atrial arrhythmias
203 (14)
Non-CABG revascularization
455 (31)
CABG surgery
368 (25)
Myocardial infarction
638 (44)
Systolic blood pressure, mm Hg
124±19
Diastolic blood pressure, mm Hg
73±12
Resting heart rate, bpm
72±13
Amiodarone
96 (6)
ACE or ARB
1312 (88)
β-Blockers
1404 (94)
Digitalis
193 (13)
Aldosterone
544 (36)
Diuretics
1008 (67)
Values are n (%) or mean±SD. There were no significant differences (P<0.05)
between treatment groups A, B, and C, as reported previously.5 Note that some
variables have missing values and do not add to 100%, for instance, QRS
duration <150 ms.
ACE/ARB indicates angiotensin-converting enzyme inhibitor/angiotensin
receptor blocker; CABG, coronary artery bypass grafting; CRT-D, cardiac
resynchronization therapy with defibrillator; MADIT-RIT, Multicenter Automatic
Defibrillator Implantation Trial–Reduce Inappropriate Therapy; and NYHA, New
York Heart Association.
548 Circulation February 4, 2014
Figure 2. Cumulative probability of first
occurrence of arrhythmogenic syncope
according to treatment arm. Kaplan–Meier
estimates of the cumulative probability
of a first occurrence of arrhythmogenic
syncope in patients randomly assigned to
implantable cardioverter-defibrillator (ICD)
programming of either conventional ICD
therapy at a heart rate of ≥170 bpm, ­highrate cutoff ICD therapy at a heart rate of
≥200 bpm and a monitoring zone between
170 and 199 bpm, or delayed ICD therapy
with prolonged monitored zones at a heart
rate >170 bpm.
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a mean time to event of 0.7±0.6 years. The overall 2.5-year
cumulative probability of all-cause syncope was 8%. Syncope
occurred evenly in all 3 treatment arms (in 21, 22, and 21
patients in arms A, B, and C, respectively; Figure 1). The clinical characteristics of the patients are shown in Table 1.
patients (3%) had syncope while driving (1 arrhythmogenic
and 1 nonarrhythmogenic).
Recurrent Syncope
Of the 64 patients with a first episode of syncope, 16 (25%) had
recurrent episodes, and a total of 85 syncopal events were registered during follow-up. The total number of recurrences was
found to be 10 events in arm A, 4 in arm B, and 7 in arm C. Five
of the recurrent syncopal episodes were caused by ventricular
tachyarrhythmias (2 in arm A and 3 in arm C), of which 1 was
a monitored VT episode with a heart rate >200 bpm and a duration of <12 seconds that terminated spontaneously, whereas the
others were treated appropriately by either ATP or shock.
Cause of Syncope According to Randomization Arm
After adjudication, 21 syncopal events (33%) were classified as caused by VT or ventricular fibrillation and 4 (6%) as
caused by other or unspecified arrhythmias, whereas a total
of 39 events (61%) were classified as nonarrhythmogenic.
In total, 11 of these nonarrhythmogenic events (17% of all
events [11/64]) were classified as being of unknown cause,
but only after an arrhythmogenic cause had been ruled out.
Syncope caused by ventricular tachyarrhythmias did not differ
between the 3 randomization arms, with 6 events in arm A, 6
in arm B, and 9 in arm C (log-rank test P=0.64; Figure 2). The
adjudicated cause for first syncope is shown in Table 2. Two
Frequency of Syncope According to First
Appropriate Shock for Ventricular Arrhythmias
A total of 74 patients experienced first appropriate shock
because of ventricular tachyarrhythmias. In 10 of these
Table 2. Distribution of Syncope According to Cause by ICD Programming/Treatment Arm
Arrhythmogenic
Supraventricular
Total
A: Conventional
B: High-Rate Cutoff
C: Delayed Therapy
25 (39%)
8
7
10
1
1
0
0
15
3
4
8
Ventricular fibrillation
6
3
2
1
Other
2
0
1
1
Ventricular tachycardia
Undetermined arrhythmia
Nonarrhythmogenic
Vasovagal
1
1
0
0
39 (61%)
13
15
11
11
2
7
2
Structural heart disease
1
1
0
0
Orthostatic hypotension
14
7
3
4
Neurological/epilepsy
1
0
1
0
Metabolic
1
0
1
0
Unknown cause (not
arrhythmic)
11
3
3
5
Total all-cause syncope
64
21
22
21
No significant difference was found for risk of all-cause, arrhythmogenic, or nonarrhythmogenic syncope when the 3
programming/treatment arms were compared. ICD indicates implantable cardioverter-defibrillator.
Ruwald et al Syncope in ICD Patients With Heart Failure 549
Figure 3. Distribution of first and recurrent
syncope attributable to ventricular
tachyarrhythmias according to rate and
duration of ventricular tachycardia (VT) or
ventricular fibrillation (VF) with or without
therapy. The distribution of rates according
to ventricular arrhythmias with syncope
includes recurrent syncope events (n=26;
21 first events and 5 recurrent).
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patients (14%), an appropriate ICD shock was preceded by
syncope, thus rendering the patient unconscious for the subsequent shock. Of these 10 patients, 2 were randomized to
arm A, 3 to arm B, and 5 to arm C. Among the remaining
64 patients who experienced first appropriate shock, 49 first
shocks (77%) were given during waking hours (7 am to 11 pm).
Therefore, when we eliminated the appropriate shocks given
during sleeping hours, ≈17% (10/59) of the patients were
unconscious when they received their first appropriate shock
for either VT or ventricular fibrillation.
Distribution of Syncope According to Rate
and Duration of VT and Incidence of Syncope
According to Monitored and Treated Ventricular
Tachyarrhythmias
Figure 3 shows the relationship between heart rate and duration of VT and syncope derived from the differences among
the 3 different ICD programming settings from arms A, B,
and C. Only 1 syncopal episode occurred because of VT with
a rate between 170 and 199 bpm, whereas the number of syncopal events was essentially equally distributed depending on
ventricular rate ≥200 bpm and ICD programming delays.
Among the treated or monitored first ventricular tachyarrhythmias in the heart rate range ≥200 bpm, 11 of 133 (8%)
resulted in syncope, whereas 92% did not (Table 3). In other
words, 10 patients (48%; 10/21) who experienced syncope
attributable to ventricular tachyarrhythmias had already experienced a ventricular tachyarrhythmic event during follow-up.
Factors Associated With All-Cause Syncope
Independent prognostic factors for all-cause syncope included
ischemic cardiomyopathy, previous ventricular arrhythmias,
left ventricular ejection fraction ≤25%, and younger age,
although the latter 2 were only borderline significant (Table 4).
With the exception of age, the baseline variables that were
associated with all-cause syncope were factors associated
with an increased cardiovascular risk profile. In multivariable
analysis, appropriate ICD therapy at any time before syncope
was also independently associated with increased risk of
subsequent all-cause syncope (hazard ratio [HR], 2.27; 95%
confidence interval [CI], 1.02–5.07; P=0.045). The increased
risk observed was primarily driven by appropriate shock (HR,
3.33; 95% CI, 1.28–8.68; P=0.014; data not shown in Tables).
Risk Factors Associated With Arrhythmogenic and
Nonarrhythmogenic Syncope
Baseline variables associated with arrhythmogenic syncope
were ischemic cardiomyopathy and previous ventricular
arrhythmias (Table 5). Appropriate ICD therapy was independently associated with later occurrence of arrhythmogenic
syncope (HR, 5.89; 95% CI, 2.06–16.82; P=0.001) driven by
appropriate shock (HR, 8.16; 95% CI, 2.57–25.93; P<0.001;
Table 3. Incidence of Syncope Caused by Ventricular Tachyarrhythmias According to Appropriately Treated or
Monitored First Ventricular Tachyarrhythmias (First Syncope and First Ventricular Tachyarrhythmia Only)
Syncope at Time of First VTA, n (%)
No Syncope at Time of VTA, n (%)
Total First VTA Events, n
Monitored VTA 170–199 bpm
1 (3)
33 (97)
34
Monitored VTA ≥200 bpm
2 (10)
18 (90)
20
Monitored or treated VTA 170–199 bpm
1 (1)
117 (99)
118
11 (8)
122 (92)
133
Monitored or treated VTA ≥ 200 bpm
VTA indicates ventricular tachyarrhythmia.
550 Circulation February 4, 2014
Table 4. Risk Factors Associated With All-Cause Syncope
Univariable
HR and 95% CI
P Value
Multivariable*
HR and 95% CI
P Value
Age per 10-y decrease
1.15 (0.94–1.41)
0.17
1.25 (1.00–1.52)
0.046
Ejection fraction ≤25%
1.30 (0.80–2.13)
0.29
1.65 (0.98–2.77)
0.059
Ischemic origin
2.03 (1.20–3.45)
0.009
2.48 (1.42–4.34)
0.002
Previous ventricular arrhythmias
2.57 (1.03–6.41)
0.043
2.99 (1.18–7.59)
0.021
Variables
From univariable and multivariable Cox regression analysis; n=64. CI indicates confidence interval; and HR, hazard ratio.
*Adjusted for the variables in Table 4.
data not shown in Tables). We were unable to establish any
factors associated with nonarrhythmogenic syncope from
baseline patient characteristics, medications, or ICD therapy
delivered throughout the study.
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Association With Mortality by All-Cause,
Arrhythmogenic Syncope, and Nonarrhythmogenic
Syncope
Table 6 shows the association between arrhythmogenic and
nonarrhythmogenic syncope, as well as all-cause syncope,
and the risk of death. All-cause syncope, arrhythmogenic syncope, and nonarrhythmogenic syncope were all significantly
associated with increased risk of death.
Discussion
Syncope caused by a higher threshold for ICD firing or by
delayed ICD firing was a concern when MADIT-RIT was
designed, and therefore, syncope was a prespecified safety
end point. The present study reveals 4 major findings.
First, hemodynamic instability and subsequent syncope
attributable to slow ventricular arrhythmias between 170 and
199 bpm were rare and only occurred in 1 patient during a
mean follow-up of 1.4 years.
Second, a high-rate cutoff and delayed activation of ICD
treatment resulted in very few syncopal events directly caused
by the setting of the ICD device. Only 2 patients experienced
syncope caused by fast untreated VT, monitored for 2.5 and
12 seconds, respectively. Thus, the 3 monitored ventricular
arrhythmias observed terminated spontaneously before any
ICD treatment was initiated.
Third, both arrhythmogenic and nonarrhythmogenic syncope were significantly associated with increased risk of death.
We could not establish any risk factors associated with the risk
of nonarrhythmogenic syncope, which suggests a multifactorial causality. Patients with nonarrhythmogenic syncope are
at high risk despite a “negative” ICD interrogation for ventricular tachyarrhythmias, which indicates that further evaluation and close follow-up of these patients is a necessity and
is recommended.
Fourth, the present study supports that syncope in heart failure
patients (with a defibrillator) is primarily vasovagal, orthostatic,
or otherwise nonarrhythmogenic in mechanism and underscores
the fact that the presence of heart disease (in this case, ischemic
or nonischemic heart failure) does not dictate that syncope has a
cardiac cause, as also demonstrated by Alboni et al.9
Mechanistically, these results further indicate that high-risk
heart failure patients with moderate to severe heart failure
symptoms and reduced ejection fraction are able to tolerate
rather long durations of fast VTs, whereas slow VTs for practical purposes do not result in a loss of consciousness. A small
retrospective study supports this and likewise found that no
patients with slow VT (<187 bpm) experienced syncope.10
Heart failure patients, who experience syncope, independent
of the mechanism, have an increased cardiovascular risk profile compared with those who do not experience syncope.
The association between nonarrhythmogenic syncope and
increased risk of death found in the present study supports
the mechanistic approach and conclusion previously formulated, that syncope in many heart failure patients represents
an inability to compensate for a hemodynamic collapse rather
than an arrhythmic event.1 For both arrhythmogenic and nonarrhythmogenic syncope, we found that the symptom “syncope”
was a reliable indicator of unstable hemodynamic response
and subsequently significantly predicted adverse prognosis.
A practical detail for clinicians derived from the present
study is the frequency of syncope when patients experience an
appropriate shock. Approximately 80% of the patients were
awake when they received the first appropriate shock. This
should be an important message for patients about to receive
an ICD device and needs to be discussed with patients more
prone to anxiety with ICD device therapies, which has been
shown to be a major concern.
We found that ≈8% of all sustained first ventricular tachyarrhythmias ≥200 bpm (treated or monitored) resulted in syncope, and nearly one third of the total syncopal events were
attributable to ventricular tachyarrhythmias. Demonstration of
the ability to produce ventricular tachyarrhythmias increases
the likelihood that the patient will also be subject to a later
Table 5. Risk Factors Associated With Arrhythmogenic Syncope
Univariable
HR and 95% CI
P Value
Multivariable*
HR and 95% CI
P Value
Ischemic origin
2.94 (1.17–7.36)
0.021
3.09 (1.23–7.76)
0.016
Previous ventricular arrhythmias
3.94 (1.18–13.19)
0.026
4.58 (1.33–15.05)
0.015
Variables
From univariable and multivariable Cox regression analysis; n=25. CI indicates confidence interval; and HR, hazard ratio.
*Adjusted for the variables in Table 5.
Ruwald et al Syncope in ICD Patients With Heart Failure 551
Table 6. Risk Factors Associated With All-Cause Death by Arrhythmogenic, Nonarrhythmogenic, and All-Cause
Syncope in Univariable and Multivariable Cox Regression Models
Variable
Univariable HR (95% CI)
P Value
Multivariable* HR (95% CI)
P Value
Events:
Death/Syncope, n (%)
Arrhythmogenic syncope
3.94 (1.23–12.61)
0.021
4.51 (1.39–14.64)
0.012
3/25 (12)
Nonarrhythmogenic syncope
3.26 (1.18–9.04
0.023
2.97 (1.07–8.28)
0.038
4/39 (10)
All-cause syncope
3.70 (1.67–8.18)
0.001
3.65 (1.64–8.12)
0.002
7/64 (11)
Total deaths, n=71.
CI indicates confidence interval; and HR, hazard ratio.
*Adjusted for treatment arm B, age, diastolic blood pressure, diabetes mellitus, treatment with implantable cardioverter-defibrillator or cardiac
resynchronization therapy defibrillator, New York Heart Association class II or III, and ejection fraction ≤25%.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
syncope caused by a ventricular tachyarrhythmia. Despite
our findings, the optimal ICD therapy cutoff, in terms of both
heart rate and duration, and the balance between patient safety
(syncope) and timely termination of sustained ventricular
arrhythmias remain to be established. Even with expert adjudication in a randomized trial and with syncope as a specific
safety end point, a large volume of syncopal events remained
of unknown origin. This difficult assessment is in agreement
with previous studies.11–13
A post hoc analysis of the Sudden Cardiac Death in Heart
Failure Trial (SCD-HeFT)2 indicated that heart failure patients
with syncope had a higher risk of death than those without
syncope, and these patients did not benefit from ICD (compared with amiodarone or placebo). In SCD-HeFT and in the
study by Middlekauff et al,1 the causal link between syncope
and death may be attributable to hemodynamic collapse and
terminal pump failure rather than an ICD-treatable ventricular arrhythmia. In SCD-HeFT, study data on syncope were not
collected systematically to define the temporal relationship
between syncope and ICD therapy, and events were not adjudicated by an independent committee. Predictors of (all-cause)
syncope in SCD-HeFT were New York Heart Association
class III, QRS duration ≥120 ms, and lack of β-blocker use.
The difference in predictors of all-cause syncope is not readily explained, but there were important differences in the
study characteristics and study interventions between these 2
studies; for instance, in SCD-HeFT, 30% of patients were in
New York Heart Association class III compared with 52% in
MADIT-RIT. Furthermore, all patients in MADIT-RIT were
implanted with an ICD or CRT-D with a backup pacing mode
versus only one third of the patients in SCD-HeFT. Because
39% of all syncopal events in MADIT-RIT were arrhythmogenic compared with ≈15% in SCD-HeFT, many factors associated with nonarrhythmogenic syncope may have confounded
the overall predictive model in SCD-HeFT. The incidence of
first-time all-cause syncope in MADIT-RIT was much lower
than in SCD-HeFT (4% versus 14%), but with follow-up of
1.4 years versus 3.8 years, respectively, with 2.5-year Kaplan–
Meier rates of 8% versus 18% to 22%. It is likely that with
a longer follow-up, a similar incidence of all-cause syncope
would be found in MADIT-RIT. However, because all patients
in MADIT-RIT and only one third of the patients in ­SCD-HeFT
received an ICD with backup pacing mode, some of the cases
classified as “unknown” or “other” in SCD-HeFT may have
been bradycardic events that were essentially avoided in
MADIT-RIT unless a marked vasodepressor component was
present. Furthermore, the incidence may have been slightly
overestimated in SCD-HeFT, because no formal adjudication
was performed and some of the syncopal events may have been
syncope-mimicking conditions. SCD-HeFT found that ICDs
did not protect patients against all-cause syncope and only
protected against the risk of sudden cardiac death. The present data support this statement when the patients from treatment arm A (conventional) are evaluated. In treatment arm A, 3
episodes of syncope attributable to ventricular fibrillation were
treated successfully as ventricular fibrillation with a shock.
The MADIT-RIT syncope data represent a large volume of
patients with heart failure, in which patients were randomized
according to ICD programming. The difference in ICD programming between the 3 randomization arms yields insight
into the mechanisms that link arrhythmogenic syncope to rate
and duration of ventricular tachyarrhythmias.
Study Limitations
The small number of all-cause syncope and arrhythmogenic
syncope events, as well as deaths, and the relatively short
­follow-up result in limited power for statistical analysis. When
analyzing the risk of death, we used multivariable Cox regression models that took many confounding factors into account,
but unmeasured confounding associated with patients who experienced syncope may have biased the results. For the evaluation
on risk of syncope, patients were randomized at baseline to the 3
treatment arms. Despite adjudication and device interrogations,
many syncopal events remained of unknown origin, and this is
a limitation of the present study and other studies reported in
the literature. Ventricular arrhythmias below the defined detection zones of duration and rate of the devices and adjudicated as
nonarrhythmogenic syncope may have contributed to an underestimation of the frequency of arrhythmogenic syncope.
Conclusions
Syncope attributable to slow ventricular arrhythmias is a rare
event, and innovative ICD programming with either highrate cutoff or delayed therapy does not increase the risk of
arrhythmogenic or nonarrhythmogenic syncope. Syncope in
heart failure patients is related to an increased cardiovascular
risk profile and is associated with an increased risk of death
regardless of its cause.
Acknowledgments
We thank all patients who participated in MADIT-RIT and each of
the study coordinators and principal investigators of the enrolling
552 Circulation February 4, 2014
centers. We also acknowledge the great work of Bronislava Polonsky;
her skills in statistical programming and data management are an
invaluable asset to the University of Rochester’s Heart Research
Follow-up Program.
Sources of Funding
MADIT-RIT was supported by a research grant from Boston Scientific
to the University of Rochester, with funds distributed to the coordination and data center, enrolling centers, core laboratories, committees,
and boards under subcontract from the University of Rochester.
Disclosures
Dr Martin Ruwald has received unrestricted funding grants from the
Danish Heart Association, The Lundbeck Foundation, HelseFonden,
Arvid Nilssons Fond, and Knud Hoejgaard Fonden. Dr ­Anne-Christine
Ruwald is a Mirowski-Moss Awardee and has received unrestricted
grants from Falck Denmark and the Lundbeck Foundation. Dr
Zareba has received lecture fees from Boston Scientific. Dr Moss
has received grant support from Boston Scientific. The other authors
report no conflicts.
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Clinical Perspective
Syncope is a frequent event in heart failure patients with implantable cardioverter defibrillators (ICDs). Recently it was
shown that ICD programming to high-rate cutoff or prolonged monitoring did not increase the likelihood of syncope compared with conventional programming. In the present report, we further explore the specific cause and mechanism of syncope
in relation to ICD programming and the impact of both arrhythmogenic syncope and nonarrhythmogenic syncope on death.
Syncope caused by arrhythmias is responsible for 40%, whereas 60% of all syncopal events are caused by nonarrhythmic
events, such as orthostatic hypotension syncope or vasodepressor reflex syncope. ICD programming to high-rate cutoff or
prolonged monitoring algorithms did not increase the risk of syncope caused by ventricular tachyarrhythmias, and particularly slow ventricular tachyarrhythmias (in the range of 170–199 bpm) are rare causes of arrhythmogenic syncope. These
results indicate that high-risk heart failure patients with moderate to severe heart failure symptoms and reduced ejection
fraction are able to tolerate rather long durations of fast ventricular tachycardias, whereas slow ventricular tachycardias,
for practical purposes, do not result in a loss of consciousness. In the Multicenter Automatic Defibrillator Implantation
Trial–Reduce Inappropriate Therapy (MADIT-RIT), both arrhythmogenic and nonarrythmogenic syncope were significantly
associated with increased risk of death. These findings suggest that syncope in heart failure patients with ICDs is a significant
marker of high risk, despite the cause of the syncopal event.
Go to http://cme.ahajournals.org to take the CME quiz for this article.
Syncope in High-Risk Cardiomyopathy Patients With Implantable Defibrillators:
Frequency, Risk Factors, Mechanisms, and Association With Mortality: Results From the
Multicenter Automatic Defibrillator Implantation Trial−Reduce Inappropriate Therapy
(MADIT-RIT) Study
Martin H. Ruwald, Ken Okumura, Takeshi Kimura, Kazutaka Aonuma, Morio Shoda, Valentina
Kutyifa, Anne-Christine H. Ruwald, Scott McNitt, Wojciech Zareba and Arthur J. Moss
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Circulation. 2014;129:545-552; originally published online November 7, 2013;
doi: 10.1161/CIRCULATIONAHA.113.004196
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
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