Programmed Electrical Stimulation for Patients With Asymptomatic Brugada Syndrome?

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 65, NO. 9, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jacc.2015.01.001

EDITORIAL COMMENT

Programmed Electrical Stimulation for Patients With Asymptomatic Brugada Syndrome? The Shock-Filled Debate Continues* Michael J. Ackerman, MD, PHD,yzx Christopher V. DeSimone, MD, PHDy

P

atients with Brugada syndrome (BrS) have

Eight years after the second consensus document,

benefited greatly from the work of the Bru-

the 2013 international guidelines gave a class IIb

gada brothers, and guideline-based manage-

indication for ICD implantation in patients found to

ment was first generated at conferences in 2002 and

have sustained VA inducibility on EPS (3). These most

2005 to provide recommendations for best practices

recent guidelines provide a soft-hearted recommen-

(1,2). These documents include the basis for the

dation to “consider” ICD implantation in a patient

management of asymptomatic patients, especially

with inducibility of VA (3), but realistically, this might

with respect to risk stratification, recommendations

as well be equated with inducible VA on EPS ¼ ICD,

for electrophysiologic study (EPS) and ventricular

especially given that we are dealing with life-and-

arrhythmia (VA) provocation, and criteria for im-

death considerations. However, the report also pro-

plantable cardioverter-defibrillator (ICD) placement

vides a more stoic statement that ICD therapy does

(1,2). A consensus was reached that EPS should be

not have a role in asymptomatic patients, but it again

performed in asymptomatic patients with family his-

becomes gentler with respect to asymptomatic pa-

tories of Brugada-associated sudden cardiac death

tients by recommending that they should be risk

(SCD), but firm recommendations for asymptomatic

stratified; one of these factors is VA inducibility on

patients with negative family histories were lacking

EPS (3). At first pass, a clinician may wonder why

(1). ICD therapy was recommended for patients with

these guideline and consensus recommendations

asymptomatic BrS who satisfied the triad of: 1) a

have been issued with a lack of gusto.

spontaneous or drug-induced type 1 Brugada electrocardiographic (ECG) pattern; 2) a family history of SCD secondary to BrS; and 3) demonstrable inducibility of VA on EPS (2).

SEE PAGE 879

In this issue of the Journal, Conte et al. (4) from the Brugada group in Belgium report their 20-year, single-center experience of ICD use in patients with BrS. They describe findings from a cohort of 176 pa-

*Editorials published in the Journal of the American College of Cardiology

tients with both ICDs and ECG findings of either drug-

reflect the views of the authors and do not necessarily represent the

induced or spontaneous type 1 Brugada pattern. This

views of JACC or the American College of Cardiology.

is a male-predominant cohort (67%), with a mean age

From the yDepartment of Medicine, Division of Cardiovascular Diseases,

of 43 years (range: 2 to 77 years) and a mean follow-up

Mayo Clinic, Rochester, Minnesota; zDepartment of Pediatric and

period of almost 7 years. The importance of ICD

Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic Rochester, Minnesota; and the xDepartment of Molecular Pharmacology

therapy in this study is reflected by the number of

& Experimental Therapeutics, Windland Smith Rice Sudden Death Ge-

patients with VAs (17%), electrical storm (2.3%), or

nomics Laboratory, Mayo Clinic, Rochester, Minnesota. Dr. Ackerman is a

death (7.5%). Multivariate analysis showed that both

consultant for Boston Scientific, Gilead Sciences, Medtronic, and St. Jude

aborted cardiac arrest and VA inducibility on EPS

Medical. The Mayo Clinic and Dr. Ackerman receive royalties from Transgenomic for the FAMILION-LQTS and FAMILION-CPVT genetic

were independent predictors of appropriate ICD

tests. Dr. DeSimone has reported that he has no relationships relevant to

shock delivery. However, these findings must be

the contents of this paper to disclose.

examined in the context of delivery of inappropriate

890

Ackerman and DeSimone

JACC VOL. 65, NO. 9, 2015 MARCH 10, 2015:889–91

The Shock-Filled Debate Continues

(18.7%) and appropriate (15.9%) shocks, as well as the

(Programmed Electrical Stimulation Predictive Value)

large number of device-related complications (15.9%).

study, which provided the strongest evidence against

The investigators conclude that ICD therapy can be

the use of EPS in asymptomatic patients. In that

associated with a sizable amount of appropriate shock

study, even though inducibility of 40% was found on

therapy in patients with BrS, and EPS may be useful

EPS, 9 events still occurred among the total 14 pa-

to identify patients with asymptomatic BrS who may

tients who were “noninducible.” A few elegant as-

benefit from ICD placement.

pects of the study further denounced the utility of

Does this study provide the information needed for

EPS: 1) 2 sites were used for stimulation, the right

the proverbial “slam-dunk” recommendation when

ventricular apex and outflow tract; 2) stricter pro-

facing a patient with asymptomatic BrS? Namely, EPS

tocols were used, with only single or double stimula-

should be performed, and if VA is induced, an ICD

tions, but still showing a poorer correlation of

should be implanted. It seems as though the “World

outcomes and inducibility; and 3) poor reliability and

Cup of Electrophysiology” has been going on much

reproducibility of EPS were demonstrated (only 34%

longer then the recent tournament in Brazil, as

of studies were reproducible) (10).

“match play” for this discussion first began in 2002

Not only has EPS been shown to be unreliable in

with conflicting reports (5,6). The Brugada group re-

some cohorts, but how can we explain the issue of the

ported that 33% of patients who were asymptomatic

large number of false positives and false negatives to

(with a spontaneous or drug-induced type 1 Brugada

justify ICD placement to our patients? If these are the

ECG pattern) had an 8% incidence of ventricular

guidelines, then we must be prepared to accept the

fibrillation or SCD at a mean follow-up of 2 years (5).

fact of inappropriate shocks and device complica-

Notably, they used only 1 site of ventricular stimula-

tions. The investigators of the present study rightly

tion (the right ventricular apex) and used 3 extra-

discuss

stimulations down to a cycle length of 200 ms (5). In

compared with patients without BrS receiving ICD

the same year, the Priori group (6) reported con-

therapy for structural heart disease: patients with BrS

trasting findings regarding the natural history of

live longer post device placement, and because of

patients with BrS, finding poor sensitivity and speci-

younger age and more activity, they have a greater

ficity in predicting ventricular fibrillation from EPS

propensity

inducibility.

generator exchanges over a lifetime, and experience

In 2003, the Brugada group published another

the

issues

for

lead

of

ICDs in

fractures,

this

population

require

multiple

quality-of-life issues from inappropriate shocks (4).

study supporting the utility of EPS in risk stratifica-

In the follow-up period, 16% of patients had device-

tion, reporting a 6-fold increased risk for those with

related complications, and almost three-quarters of

inducible VAs, as well as better prediction perfor-

these patients were younger than 40 years (4). We

mance of the test in the asymptomatic population (7).

must therefore take into account the additional risk

In 2005, Eckardt et al. (8) reported on a cohort in

we are putting patients at over a longer follow-up

which 59% of patients had spontaneous type 1 Bru-

period; this can be on the order of decades. Further

gada ECG pattern, and only 1 of these asymptomatic

appreciation can be deduced from the shock rate per

patients had an event (in the setting of an additional

year (4). A simple extrapolation from the group with

year of follow-up when compared with the Brugada

syncope calculates a mean of 3 inappropriate shocks

cohort). Even more disconcerting was that in the 9

every 5 years. In contrast, patients with aborted car-

patients who went on to have events, 4 did not have

diac arrest and asymptomatic patients would have

inducible VAs; this was despite the use of 2 sites for

about 1 inappropriate shock every 5 years. In the

stimulation and 3 premature beats. The investigators

setting of a 40-year-old patient with BrS who lived

proposed that the Brugada cohort was composed of

to the age of 80 years, ICD implantation would

patients with a much higher risk “substrate,” because

confer a mean of 8 inappropriate shocks over the rest

the Eckardt and Priori cohorts had a much lower rate

of that patient’s lifetime. This may be quite a telling

of family history of SCD (8).

number and situation to ponder when discussing ICD

It was just past “halftime” in 2010, when the

implantation.

FINGER (France, Italy, the Netherlands, and Germany)

In light of such controversy and the lack of clarity,

Brugada Syndrome Registry was reported (9). Al-

there is a strain on the general acceptance of induc-

though a statistically significant percent of symp-

ibility of VA on EPS as the “make-or-break” step for

tomatic (46%) compared with asymptomatic patients

ICD implantation. The present study is unlikely to put

(37%) were inducible on EPS, SCD occurred in only

this controversy to rest but will likely lead to an

0.4% of patients without ICD implantation (9). In

“overtime period” in this ongoing debate. At one end

2012, the Priori group (10) published the PRELUDE

of the field, the last stand for EPS may be a study that

Ackerman and DeSimone

JACC VOL. 65, NO. 9, 2015 MARCH 10, 2015:889–91

The Shock-Filled Debate Continues

involves a standardized medication regimen, sched-

to all cohorts, discussion should continue, wherein

uling patients for EPS as the first case of the day to

both the clinician and the patient are paired up as

minimize variation in timing, and an agreement on

decision makers. Protecting the goal of prevention

protocol delivery. At the other end of the field lies the

from ventricular fibrillation, as well as quality-of-life

charge toward other prognostic factors, such as ven-

issues, should be jointly discussed, along with the

tricular effective refractory period and QRS frag-

risks and benefits of ICD implantation, such that we

mentation (10).

present a fair and balanced view of the information as

Ultimately, it may be that the recommendations

it currently exists.

cannot be completely generalizable and that the Brugada cohort has an inherently different substrate

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

of BrS that we are unable to detect, or, to date, we are

Michael J. Ackerman, Mayo Clinic, Windland Smith

simply unaware of the cellular and genetic milieu that

Rice Sudden Death Genomics Laboratory, Guggenheim

places these patients at higher risk. Until the best

501, 200 First Street, SW, Rochester, Minnesota 55905.

strategy is developed and shown to be generalizable

E-mail: [email protected].

REFERENCES 1. Wilde AAM, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation 2002;106:2514–9.

syndrome: a 20-year single-center experience. J Am Coll Cardiol 2015;65:879–88.

2. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111:659–70.

5. Brugada J, Brugada R, Antzelevitch C, Towbin J, Nademanee K, Brugada P. Long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3. Circulation 2002;105:73–8.

3. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/

6. Priori SG, Napolitano C, Gasparini M, et al.

APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932–63.

Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 2002;105:1342–7.

4. Conte G, Sieira J, Ciconte G, et al. Implantable cardioverter-defibrillator therapy in Brugada

and no previous cardiac arrest. Circulation 2003; 108:3092–6.

7. Brugada J, Brugada R, Brugada P. Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome

8. Eckardt L, Probst V, Smits JPP, et al. Long-term prognosis of individuals with right precordial STsegment–elevation Brugada syndrome. Circulation 2005;111:257–63. 9. Probst V, Veltmann C, Eckardt L, et al. Longterm prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry. Circulation 2010;121:635–43. 10. Priori SG, Gasparini M, Napolitano C, et al. Risk stratification in Brugada syndrome: results of the PRELUDE (Programmed Electrical Stimulation Predictive Value) registry. J Am Coll Cardiol 2012; 59:37–45.

KEY WORDS Brugada syndrome, implantable-cardioverter defibrillator, sudden cardiac death, syncope, ventricular arrhythmia

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