Download QRS Duration Criteria to Select Patients for Cardiac

Controversies in
Arrhythmia and
Electrophysiology
QRS Duration Criteria to Select Patients
for Cardiac Resynchronization Therapy
Downloaded from http://circep.ahajournals.org/ by guest on May 2, 2017
Cardiac Resynchronization Therapy: 150 Is Not A
Magic Number!
Maya Guglin, MD, PhD; Anne B. Curtis, MD
Scope of the Problem
one of the abovementioned meta-analyses,6 definitely recommends CRT only for patients with QRS durations >150 ms
(and not because of right bundle-branch block), with severe
left ventricular (LV) systolic dysfunction and persistent New
York Heart Association (NYHA) functional class II-III symptoms, despite optimal medical therapy. According to the same
update, CRT may still be considered for patients with QRS
intervals between 120 and 150 ms and severe left ventricular
dysfunction who have persistent symptoms on medical treatment.5 However, the wording “may be considered” reflects the
lowest possible strength of recommendation. Despite the high
quality of both meta-analyses, as well as of the individual trials
included in them, we doubt that such a conclusion is justified.
CRT is a unique therapy for patients with HF and prolonged
QRS duration. Not only does it induce reverse LV remodeling,
it also improves functional status and increases longevity in
these patients.8,9 Unlike any other therapy with the exception
of ventricular assist devices, CRT interrupts the progression of
the disease and reverses the natural course of HF,9 even in minimally symptomatic or asymptomatic patients with complete
left bundle-branch block (LBBB) and systolic dysfunction.
In just 1 year of therapy, LV end-systolic and end-diastolic
volume decreases and ejection fraction increases in most
patients, especially those with nonischemic cardiomyopathy.
There is also a subset of super-responders in whom biventricular pacing leads to restoration of cardiac geometry and
Current American College of Cardiology/American Heart
Association/Heart Rhythm Society as well as European Society of Cardiology guidelines recommend the use of cardiac
resynchronization therapy (CRT) in patients with symptomatic heart failure (HF) and QRS durations >120 ms1,2
(Table 1). However, 2 recent meta-analyses by Sipahi et al6
and Stavrakis et al7 challenged these recommendations. Both
studies found that patients with QRS durations between 120
and 150 ms do not benefit from CRT.
Response by Sipahi and Fang on p 435
This is a very important conclusion, from both the clinical and
financial standpoints. If the conclusions of these meta-analyses
are correct, the guidelines should be revised, and the cutoff for
QRS duration indicating the need for CRT should be changed
from 120 to 150 ms. From the reimbursement standpoint, these
analyses would suggest that the cost of CRT devices implanted
in patients with QRS durations shorter than 150 ms should not
be covered by insurers. Indeed, the authors of the second metaanalysis state that “the decision to routinely recommend CRT
for patients with QRS <150 ms may not be justified.”7
Although not in such categorical terms, some societies are
already embracing this idea. In fact, in their recently published update, the Heart Failure Society of America, citing
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From the Department of Cardiovascular Sciences, University of South Florida, Tampa, FL (M.G.); and Department of Medicine, University at Buffalo,
Buffalo, NY (A.B.C.).
Correspondence to Anne B. Curtis, MD, Charles and Mary Bauer Professor and Chair, Department of Medicine, University at Buffalo, 100 High St,
D2-76, Buffalo, NY 14203. E-mail [email protected]
(Circ Arrhythm Electrophysiol. 2013;6:429-435.)
© 2013 American Heart Association, Inc.
Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org
429
DOI: 10.1161/CIRCEP.112.970939
430 Circ Arrhythm Electrophysiol April 2013
Table 1. Indications for Cardiac Resynchronization Therapy
Guidelines, Year
Indication
All
LVEF ≤35%
NYHA Class
Strength of Recommendation
QRS ≥120 ms
ACC/AHA/HRS 20081
III-IV
Indicated
ACC/AHA HF, 20093 (on optimal medical therapy)
III-IV
Indicated
HFSA, 20104 (on optimal medical therapy)
II-IV
May be considered
ESC2 (on optimal medical therapy)
III-IV
Indicated
ACC/AHA/HRS 20081: consider when internal defibrillator is implanted
Reduced LVEF
II
To be considered
ESC (on optimal medical therapy)
LVEF ≤35%
II
Indicated
CRT
QRS ≥150 ms
HFSA, 20125
LVEF ≤35%
II-III
Indicated
2
Downloaded from http://circep.ahajournals.org/ by guest on May 2, 2017
QRS ≥150 ms
ACC indicates American College of Cardiology; AHA, American Heart Association; ESC, European Society of Cardiology; HFSA, Heart Failure Society of
America; HRS, Heart Rhythm Society; LVEF, left ventricular ejection fraction; and NYHA, New York Heart Association.
function to a normal or nearly normal state. Although the proportion of super-responders is modest (10% to 22%),10–14 the
large total volume of CRT procedures means that a significant
number of patients receive this benefit of almost complete
recovery of ventricular function.
Because of the uniqueness of this therapy, indications for
CRT should be worded very carefully, with full consideration
of the entire pool of data accumulated to date.
Evidence for the 150 ms Cutoff
A summary of the CRT clinical trials is presented in Table 2.
Almost all of them performed a subanalysis of clinical outcomes in patients with severely prolonged QRS (>150 ms,
with some interstudy variability) and moderately prolonged
QRS (<150 ms, also with some variability).
The Comparison of Medical Therapy, Pacing, and Defibril­
lation in Heart Failure (COMPANION) trial15 demonstrated
Table 2. Cardiac Resynchronization Therapy Trials
Trial
MUSTIC-SR18
MIRACLE
22
PATH CHF8
COMPANION
15
NYHA Class
LVEF, %
QRS Width, ms
Subanalysis by QRS Duration, ms
Benefit (− no; + yes)
Intermediate Value
Studies
III
≤35
>150
None
+
No
III, IV
≤35
≥130
Benefit is independent of QRS duration, which
was analyzed as a continuous variable
+
Yes
III, IV
≤35
≥120
None
III, IV
≤35
≥120
CARE HF16
III, IV
≤35
REVERSE9
I, II
≤40
≥120
No
≤147
−
148–168
+
>168
++
<160
−
≥160
+
≤140
−
141–160
+
>160
++
No
No
No
Effects on reverse remodeling
≤40
REVERSE20
(European cohort)
I, II
MADIT CRT21
I, II
≤30
RAFT19
II, III
≤30
<152
−
≥152
+
≥130
<150
−
≥150
+
≥120
<150
−
≥150
+
No
No
No
CARE-HF indicates The Cardiac Resynchronization -Heart Failure; COMPANION, The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure; LVEF,
left ventricular ejection fraction; MADIT-CRT, The Multicenter Automatic Defibrillator Implantation Trial—Cardiac Resynchronization Therapy; MIRACLE, the Multicenter
InSync Randomized Clinical Evaluation; MUSTIC, The MUltisite STimulation In Cardiomyopathy; NYHA, New York Heart Association; PATH-CHF, the Pacing Therapies
for Congestive Heart Failure; RAFT, The Resynchronization–Defibrillation for Ambulatory Heart Failure; and REVERSE, The REsynchronization reVErses Remodeling in
Systolic Left vEntricular Dysfunction.
Guglin and Curtis 150 Is Not a Magic Number 431
Downloaded from http://circep.ahajournals.org/ by guest on May 2, 2017
that CRT decreased the combined risk of death from any cause
or first hospitalization, but provided no benefit if the QRS
was <147 ms.
The Cardiac Resynchronization-Heart Failure (CARE-HF)
Study16 showed that biventricular pacing decreased morbidity and mortality, and improved LV ejection fraction as well
as symptoms and quality of life. Although patients with QRS
durations >120 ms qualified for the study, there were additional requirements of dyssynchrony by echocardiographic
criteria for QRS durations between 120 and 149 ms. Patients
were categorized into QRS durations above and below 160 ms,
and only the latter subgroup did better with CRT. However,
during a 3-year extended follow-up, there was benefit for both
subsets.17
The MUltisite STimulation In Cardiomyopathy (MUSTIC)
Study18 included only patients with QRS durations >150 ms.
The Resynchronization–Defibrillation for Ambulatory Heart
Failure (RAFT) trial19 demonstrated that the addition of CRT
to an implantable cardioverter defibrillator (ICD) reduced the
rates of death and hospitalization for symptomatic HF. CRT
was effective in patients with QRS durations >150 ms and
ineffective in patients with QRS durations <150 ms.
The REsynchronization reVErses Remodeling in Systolic
Left vEntricular Dysfunction (REVERSE) trial9 demonstrated
that CRT in asymptomatic LV dysfunction and in minimally
symptomatic HF resulted in major structural and functional
reverse remodeling, especially in nonischemic cardiomyopathy. There was no benefit in patients with QRS durations
<140 ms, significant benefit in patients with QRS durations
from 140 to 160 ms, and even greater benefit in patients with
QRS >160 ms. In the European cohort of the REVERSE trial,
no benefit was demonstrated in patients with QRS durations
<152 ms as opposed to those with wider QRS.20
The Multicenter Automatic Defibrillator Implantation
Trial—Cardiac Resynchronization Therapy (MADIT-CRT)
trial showed that CRT combined with ICD therapy decreased
the risk of HF events in relatively asymptomatic patients. In
a prespecified subgroup analysis, there was benefit in patients
with QRS >150 ms, whereas no benefit was derived in the
subset with QRS between 120 and 149 ms.21
In summary, almost all of the CRT trials reported no effect
in patients with moderately prolonged QRS durations. Indeed,
every 1 of the 5 trials included in both of the aforementioned
meta-analyses (COMPANION, CARE-HF, MADIT-CRT,
REVERSE, and RAFT) demonstrated a beneficial effect of
CRT in severely prolonged QRS and no effect in moderately prolonged QRS. Examining this point in greater detail,
in both the REVERSE (European cohort)20 and the RAFT19
studies, the investigators stated that their cohorts with longer
QRS durations derived more benefit than those with shorter
QRS durations, implying that patients with shorter QRS durations also benefit, at least somewhat, from CRT. However, the
odds ratios with corresponding confidence intervals overlapping one indicate that, in terms of clinical outcomes, CRT,
in fact, made no difference in patients with shorter QRS
durations.19,20
Flaws in the Evidence for the 150 ms Cutoff
Indeed, there is no need to do a meta-analysis to demonstrate
that there is no benefit from CRT in patients with moderately
prolonged QRS if each of the included trials already reached
the same conclusion individually. However, there is an important problem with this seemingly obvious conclusion. All the
above studies share the same feature: the duration of the QRS
interval was categorized.
In clinical trials, many continuous variables are categorized
for analysis purposes. For instance, LV ejection fraction is a
continuous variable. It can theoretically be anywhere between
0% and 100%. But, for the purpose of this analysis, let us say
that it is either normal, above 50%, or reduced, below 50%.
Now, instead of a continuous set of values, we have 2 categories: normal and reduced. If we use these categories for analysis, all ejection fractions below 50%, whether, for example,
10% or 45%, will be analyzed together, as if there is no difference between them.
Likewise, QRS duration is a continuous variable. But, for
the subgroup analyses, the investigators categorized QRS
durations into those above 150 ms and below 150 ms (120–
150), and thus they obscured all the differences that can exist
between 121 and 149 ms. The authors of both meta-analyses
reproduced the same strategy. Lo and behold! They found
exactly what each of the trials already proved individually.
In other words, outcomes in patients with QRS durations
120 to 149 ms were analyzed as a single group. Meanwhile,
better outcomes in patients with QRS durations >160 ms compared with <160 ms,16 and in QRS durations exceeding 168 ms
in comparison with 148 to 168 ms,15 prompt the extrapolation
that longer QRS predicts better response to CRT. It means that
QRS durations within the group from 120 to 149 ms must be
analyzed as a continuous variable and not as a single category.
Only a couple of trials, not included in either meta-analysis,
looked at different groups of patients within the range of 120
to 150 ms for QRS duration and did not treat them as a single
group. Data from the Pacing Therapies for Congestive Heart
Failure (PATH-CHF) I demonstrated that CRT produces symptomatic improvement in patients with HF.8 Although those
with a baseline QRS >150 ms virtually always experienced
acute hemodynamic improvement, some patients with QRS
durations between 120 and 150 ms also showed improvement.
In the Multicenter InSync Randomized Clinical Evaluation
(MIRACLE) trial, the only study in which QRS duration was
analyzed as a continuous variable, the magnitude of favorable
effects was not influenced by baseline QRS duration.22
QRS Duration and Dyssynchrony
These results are not surprising, because there is plenty of evidence that the severity and prognosis of HF is dependent on
QRS duration.23 Intraventricular conduction delay resulting
in electric and mechanical dyssynchrony occurs commonly
in HF. According to different sources, the prevalence of prolonged intraventricular conduction ranges from 20% to 30%
in HF with systolic dysfunction.22,24,25 It is well established
that a QRS duration above 120 ms is a significant predictor
432 Circ Arrhythm Electrophysiol April 2013
Downloaded from http://circep.ahajournals.org/ by guest on May 2, 2017
of LV systolic dysfunction, and moreover, prolonged QRS
is associated with a poor prognosis.2,3,15 For the purpose of
this discussion, studies examining outcomes in HF based on
graded duration of QRS are of particular interest. It is important to realize that patients with QRS durations exceeding 120
ms are almost equally distributed between moderately and
severely prolonged QRS.26 This means that if the cutoff 150
ms is accepted, about half of all patients who currently qualify
for CRT would be found ineligible for this therapy.
In a study of nearly 3500 patients with HF, Shenkman et
al24 found a stepwise increase in the prevalence of systolic LV
dysfunction as QRS duration increased progressively above
120 ms. Reduced LV ejection fraction was present in 42.5% of
patients with a QRS duration <120 ms, 60% of patients with
a QRS duration 120 to 129 ms, 61.6% of patients with a QRS
duration 130 to 139 ms, 67.3% of patients with a QRS duration
140 to 149 ms, and in 75.7% of patients with a QRS duration
>150 ms (P=0.01). Sandhu and Bahler26 reported a progressive
decrease in LV ejection fraction and an increase in LV diameter and the severity of mitral regurgitation with incremental
prolongation of the QRS from <100 ms to 100 to 119 ms, 120
to 149 ms, and >150 ms (Figure 1). In other words, a moderate
degree of QRS prolongation, which, according to the new proposals, should not be corrected with CRT, was associated with
significant deterioration of LV systolic dysfunction.
In terms of prognosis, a prolonged QRS duration of 120
to 149 ms was associated with an increased mortality at 60
months (P=0.001), even after adjustment for age, sex, and
race (P=0.001).24 In another study, the 3-year mortality rate
was 20% for an intraventricular conduction delay of <120 ms,
36% for a QRS duration 120 to 160 ms, and 58.3% for QRS
duration >160 ms27 (Figure 2).
Stratifying patients according to 2-year event free survival,
Kalra et al28 found that the optimal QRS duration providing the
best demarcation between benign and poor prognosis was 120
ms. Moderate prolongation of QRS duration (120–149 ms)
was associated with worse NYHA class, lower peak oxygen
consumption, and poorer LV ejection fraction compared with
patients with normal QRS durations (all P<0.05). Moreover,
patients with moderate prolongation of the QRS had similar
impairment of NYHA class and peak oxygen consumption
compared with patients with QRS >150 ms.
Figure 2. Graded increase in mortality with increasing intraventricular conduction delay (IVCD).27
Studying the predictors of response to CRT in patients with
non-LBBB morphology, Rickard et al29 found that QRS duration
(>120 ms) was the only variable significantly associated with
response (odds ratio per each 10 ms increase in QRS, 1.23; 95%
confidence interval, 1.01–1.52; P=0.048). During follow-up,
QRS duration was inversely related to poor long-term outcomes
(hazard ratio per 10 ms increase in QRS duration, 0.79; 95%
confidence interval, 0.66–0.94; P=0.005). When the authors categorized QRS duration into <130 ms, 130 to 150 ms, and >150
ms, there was a clear-cut survival benefit in patients with QRS
130 to 150 ms in comparison with those with narrower QRS.
When patients with symptomatic end-stage HF were grouped
according to QRS duration (QRS <120 ms, QRS ≥120 ms but
<150 ms, and QRS ≥150 ms), conventional (posterolateral LV
and right ventricular apex) CRT did not lead to improvement
in stroke work and contractility in the narrow QRS group, but
there was a significant increase in the intermediate (+27%,
P=0.020; and +5%, P=0.044) and wide (+48%, P=0.002;
and +18%, P<0.001) QRS groups. In contrast, 15% of patients
had deterioration by conventional CRT in the intermediate
and wide QRS groups. Apparently, some patients could be
improved by lead placement in the anterolateral rather than the
posterolateral region, which may be of particular importance
with patients with moderately prolonged QRS.30
Thus, it is clear that many patients with QRS durations <150
ms do respond to CRT, but it may be even more important
in these patients compared with those with severe QRS prolongation to select the location of the LV lead carefully, and
to program the device optimally. In other words, almost any
posterolateral or lateral lead location could potentially lead
to at least some improvement in LV structure and functional
status in patients with marked QRS prolongation, provided
that the lead is not placed in a location of scar. In contrast, in
patients with milder degrees of QRS prolongation, improvement over native conduction may require more targeted lead
placement and more careful selection of atrioventricular (AV)
and v­ entricular-ventricular (VV) timing.
LBBB and HF
Figure 1. Prevalence of left ventricular systolic dysfunction (ejection fraction <45%) in relation to QRS duration.26
In particular, LBBB has been found to have a detrimental
effect in HF. In 1 study, mean ejection fraction in patients with
Guglin and Curtis 150 Is Not a Magic Number 433
Downloaded from http://circep.ahajournals.org/ by guest on May 2, 2017
HF was 40% in those with normal QRS (<120 ms), 36.3%
in those with right bundle-branch block, and 29.6% in those
with LBBB. Short-term mortality rates were 46.1%, 56.8%,
and 57.7%, respectively (P<0.0001).31
The normal sequence of electric activation is reversed in
LBBB, with the direction of septal depolarization proceeding
from right to left and the impulse spreading first to the right
ventricle and then to the LV. The resulting delay in the inward
motion of the lateral wall of the LV depends on the duration
of the QRS, with greater duration of the QRS producing more
dyssynchronous contraction.32 When patients with LBBB
have been compared with control subjects, striking delays
were observed in both LV systolic and diastolic events in the
LBBB group. The delay was associated with shortening of LV
diastole with a resultant increase in the ratio of right to LV diastolic time. Also, the abnormal interventricular septal motion
in LBBB corresponded to periods of asynchrony in contraction, ejection, end systole, and end diastole between the right
and left ventricles. This loss of septal contribution resulted
in a reduction in global ejection fraction in LBBB compared
with normals (54+7% compared with 62+5%; P<0.005).33
In the Framingham study, QRS duration was modeled as a
continuous and as a categorical variable (<100, 100–119, and
≥120 ms). QRS duration was positively related to LV dimensions but inversely related to fractional shortening (a surrogate
of ejection fraction). Importantly, LBBB was associated with
greater LV mass and dimensions, and with lower fractional
shortening than other types of QRS prolongation.34 In another
study, LBBB was an independent predictor of long-term mortality in patients with acute HF.35
In the MADIT-CRT trial, patients with LBBB treated
with CRT experienced a 53% reduction (hazard ratio, 0.47;
P<0.001) in the risk of a HF event or death compared with
patients with LBBB treated with an implantable defibrillator
only. This effect was consistent across the whole spectrum of
QRS durations, especially for women, indicating that LBBB,
per se, with its abnormal activation was responsible for the
dyssynchrony to a greater extent than QRS duration alone.36
Therefore, the presence of LBBB by itself, in patients with
systolic dysfunction and symptomatic HF, should justify CRT,
regardless of the extent of QRS prolongation beyond 120 ms.
Reverse LV Remodeling and QRS Duration
Although all sets of guidelines consistently put NYHA functional class among other criteria for CRT, there is hardly any
evidence that the severity of symptoms in HF before biventricular stimulation determines the success of CRT.37 The
essence of this treatment is reverse remodeling of the LV
with secondary improvement in symptoms.38 Meanwhile, LV
systolic dysfunction, per se, is a poor prognostic sign even
if completely asymptomatic, and reversal of LV remodeling
results in survival benefit. Comparison of reverse LV remodeling with 3 months of biventricular pacing in patients with
baseline QRS duration of 120 to 150 ms and above 150 ms
showed benefit in both groups, although it was greater in those
with longer QRS. Significant reverse remodeling, defined as a
reduction of LV end-systolic volume by >15%, was evident
in 46% of the moderately prolonged QRS group and in 68%
of those with severely prolonged QRS. Similarly, improvement in LV systolic function and in functional status (NYHA
class) occurred in all patients with QRS >120 ms. Specifically, LV ejection fraction increased from a baseline value of
28.4±7.3% to 33.9±9.7% (P<0.001) in 3 months in patients
with QRS between 120 and 150 ms, and from 26.0±12.9% to
37.0±12.5% (P<0.001) in those with QRS >150 ms, creating a
gain of 5.5±7.3% versus 11.0±12.1% (P=0.04), respectively.39
The origin of the currently recommended cutoff for CRT of
120 ms is clear. It is an upper range for normal intraventricular
conduction. Beyond that, longer QRS durations mean a higher
degree of dyssynchrony (because of greater delay between the
arrival of the electric signal at the ventricular septum and the
LV free wall), which translates into poorer clinical outcomes.
Therefore, the response to CRT will be better in patients with
longer QRS durations. However, there is no reason to limit
CRT only to patients with QRS durations above 150 ms. There
is nothing magical about this number! It is simply an arbitrary
cutoff chosen by clinical trial investigators for categorization
of QRS into moderately and severely prolonged.
If we really want to know the appropriate cutoff for QRS
duration below which the risks of CRT implantation outweigh
the benefits, we would need to reanalyze existing data sets
from the clinical trials studying QRS as a continuous variable
or subdivide QRS durations between 120 and 150 ms into
smaller increments. This should be a topic of a separate metaanalysis. But eliminating all the gradations between 120 and
150 ms, and only recommending CRT for patients with very
prolonged QRS (>150 ms) will deny a very effective treatment
to a substantial number of patients with HF.
Disclosures
Dr Curtis is a consultant with Medtronic, Inc. and has received honoraria and research grants, and is a member of the advisory board of
St. Jude Medical and has received honoraria from the same. The other
author has no conflicts to report.
References
1. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA III, Freedman RA,
Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky
MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW,
Sweeney MO, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Buller
CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF, Hunt
SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato JP,
Page RL, Riegel B, Tarkington LG, Yancy CW; American College of Cardiology/American Heart Association Task Force on Practice Guidelines
(Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline
Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices); American Association for Thoracic Surgery; Society of Thoracic
Surgeons. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy
of Cardiac Rhythm Abnormalities: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia
Devices): developed in collaboration with the American Association
for Thoracic Surgery and Society of Thoracic Surgeons. Circulation.
2008;117:e350–e408.
434 Circ Arrhythm Electrophysiol April 2013
Downloaded from http://circep.ahajournals.org/ by guest on May 2, 2017
2. Dickstein K, Vardas PE, Auricchio A, Daubert JC, Linde C, McMurray
J, Ponikowski P, Priori SG, Sutton R, van Veldhuisen DJ; ESC Committee for Practice Guidelines. 2010 Focused Update of ESC Guidelines on
device therapy in heart failure: an update of the 2008 ESC Guidelines
for the diagnosis and treatment of acute and chronic heart failure and the
2007 ESC Guidelines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Association and the
European Heart Rhythm Association. Europace. 2010;12:1526–1536.
3. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats
TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS,
Silver MA, Stevenson LW, Yancy CW; American College of Cardiology
Foundation; American Heart Association. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of
Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society
for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1–e90.
4.Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA,
Givertz MM, Katz SD, Klapholz M, Moser DK, Rogers JG, Starling RC,
Stevenson WG, Tang WH, Teerlink JR, Walsh MN. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010;16:e1–194.
5. Stevenson WG, Hernandez AF, Carson PE, Fang JC, Katz SD, Spertus
JA, Sweitzer NK, Tang WH, Albert NM, Butler J, Westlake Canary CA,
Collins SP, Colvin-Adams M, Ezekowitz JA, Givertz MM, Hershberger
RE, Rogers JG, Teerlink JR, Walsh MN, Stough WG, Starling RC; Heart
Failure Society of America Guideline Committee. Indications for cardiac
resynchronization therapy: 2011 update from the Heart Failure Society of
America Guideline Committee. J Card Fail. 2012;18:94–106.
6. Sipahi I, Carrigan TP, Rowland DY, Stambler BS, Fang JC. Impact of
QRS duration on clinical event reduction with cardiac resynchronization
therapy: meta-analysis of randomized controlled trials. Arch Intern Med.
2011;171:1454–1462.
7. Stavrakis S, Lazzara R, Thadani U. The benefit of cardiac resynchronization therapy and QRS duration: a meta-analysis. J Cardiovasc Electrophysiol. 2012;23:163–168.
8. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, Huth C,
Schöndube F, Wolfhard U, Böcker D, Krahnefeld O, Kirkels H; Pacing
Therapies in Congestive Heart Failure (PATH-CHF) Study Group. Longterm clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay.
J Am Coll Cardiol. 2002;39:2026–2033.
9. St John Sutton M, Ghio S, Plappert T, Tavazzi L, Scelsi L, Daubert C,
Abraham WT, Gold MR, Hassager C, Herre JM, Linde C; REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) Study Group. Cardiac resynchronization induces major structural
and functional reverse remodeling in patients with New York Heart Association class I/II heart failure. Circulation. 2009;120:1858–1865.
10. António N, Teixeira R, Coelho L, Lourenço C, Monteiro P, Ventura M,
Cristóvão J, Elvas L, Gonçalves L, Providência LA. Identification of
‘super-responders’ to cardiac resynchronization therapy: the importance of symptom duration and left ventricular geometry. Europace.
2009;11:343–349.
11. Reant P, Zaroui A, Donal E, Mignot A, Bordachar P, Deplagne A, Solnon
A, Ritter P, Daubert JC, Clementy J, Leclercq C, Roudaut R, Habib G,
Lafitte S. Identification and characterization of super-responders after cardiac resynchronization therapy. Am J Cardiol. 2010;105:1327–1335.
12. Rickard J, Kumbhani DJ, Popovic Z, Verhaert D, Manne M, Sraow D,
Baranowski B, Martin DO, Lindsay BD, Grimm RA, Wilkoff BL, Tchou
P. Characterization of super-response to cardiac resynchronization therapy. Heart Rhythm. 2010;7:885–889.
13.Serdoz LV, Daleffe E, Merlo M, Zecchin M, Barbati G, Pecora D,
Pinamonti B, Fantoni C, Lupo P, Di Lenarda A, Sinagra G, Cappato R.
Predictors for restoration of normal left ventricular function in response to
cardiac resynchronization therapy measured at time of implantation. Am J
Cardiol. 2011;108:75–80.
14.Ypenburg C, van Bommel RJ, Borleffs CJ, Bleeker GB, Boersma E,
Schalij MJ, Bax JJ. Long-term prognosis after cardiac resynchronization
therapy is related to the extent of left ventricular reverse remodeling at
midterm follow-up. J Am Coll Cardiol. 2009;53:483–490.
15.Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco
T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman
AM; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart
Failure (COMPANION) Investigators. Cardiac-resynchronization therapy
with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140–2150.
16. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, ­Kappenberger
L, Tavazzi L; Cardiac Resynchronization-Heart Failure (CARE-HF)
Study Investigators. The effect of cardiac resynchronization on morbidity
and mortality in heart failure. N Engl J Med. 2005;352:1539–1549.
17. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, ­Kappenberger
L, Tavazzi L. Longer-term effects of cardiac resynchronization therapy on
mortality in heart failure [the CArdiac REsynchronization-Heart Failure
(CARE-HF) trial extension phase]. Eur Heart J. 2006;27:1928–1932.
18. Linde C, Leclercq C, Rex S, Garrigue S, Lavergne T, Cazeau S, ­McKenna
W, Fitzgerald M, Deharo JC, Alonso C, Walker S, Braunschweig F,
Bailleul C, Daubert JC. Long-term benefits of biventricular pacing in
congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol. 2002;40:111–118.
19.Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S,
Hohnloser SH, Nichol G, Birnie DH, Sapp JL, Yee R, Healey JS, Rouleau
JL; Resynchronization-Defibrillation for Ambulatory Heart Failure Trial
Investigators. Cardiac-resynchronization therapy for mild-to-moderate
heart failure. N Engl J Med. 2010;363:2385–2395.
20.Daubert C, Gold MR, Abraham WT, Ghio S, Hassager C, Goode G,
­Szili-Török T, Linde C; REVERSE Study Group. Prevention of disease
progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from
the European cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial. J Am Coll Cardiol. 2009;54:1837–1846.
21. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes
NA 3rd, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD,
Wilber D, Zareba W; MADIT-CRT Trial Investigators. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med.
2009;361:1329–1338.
22. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E,
Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ,
Underwood J, Pickering F, Truex C, McAtee P, Messenger J; MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med.
2002;346:1845–1853.
23. Kashani A, Barold SS. Significance of QRS complex duration in patients
with heart failure. J Am Coll Cardiol. 2005;46:2183–2192.
24. Shenkman HJ, Pampati V, Khandelwal AK, McKinnon J, Nori D, Kaatz
S, Sandberg KR, McCullough PA. Congestive heart failure and QRS duration: establishing prognosis study. Chest. 2002;122:528–534.
25. Iuliano S, Fisher SG, Karasik PE, Fletcher RD, Singh SN; Department
of Veterans Affairs Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. QRS duration and mortality in patients with congestive
heart failure. Am Heart J. 2002;143:1085–1091.
26. Sandhu R, Bahler RC. Prevalence of QRS prolongation in a community
hospital cohort of patients with heart failure and its relation to left ventricular systolic dysfunction. Am J Cardiol. 2004;93:244–246.
27. Shamim W, Francis DP, Yousufuddin M, Varney S, Pieopli MF, Anker
SD, Coats AJ. Intraventricular conduction delay: a prognostic marker in
chronic heart failure. Int J Cardiol. 1999;70:171–178.
28.Kalra PR, Sharma R, Shamim W, Doehner W, Wensel R, Bolger AP,
Genth-Zotz S, Cicoira M, Coats AJ, Anker SD. Clinical characteristics
and survival of patients with chronic heart failure and prolonged QRS duration. Int J Cardiol. 2002;86:225–231.
29. Rickard J, Bassiouny M, Cronin EM, Martin DO, Varma N, Niebauer MJ,
Tchou PJ, Tang WH, Wilkoff BL. Predictors of response to cardiac resynchronization therapy in patients with a non-left bundle branch block
morphology. Am J Cardiol. 2011;108:1576–1580.
30. de Roest GJ, Allaart CP, de Haan S, Hendriks ML, Bronzwaer JG, van
Rossum AC, de Cock CC. Effects of QRS duration and pacing location on
pressure-volume loop evaluation of cardiac resynchronization therapy in
end-stage heart failure. Am J Cardiol. 2011;108:1581–1588.
31.McCullough PA, Hassan SA, Pallekonda V, Sandberg KR, Nori DB,
­Soman SS, Bhatt S, Hudson MP, Weaver WD. Bundle branch block patterns, age, renal dysfunction, and heart failure mortality. Int J Cardiol.
2005;102:303–308.
Guglin and Curtis 150 Is Not a Magic Number 435
32. Auricchio A, Fantoni C, Regoli F, Carbucicchio C, Goette A, Geller C,
Kloss M, Klein H. Characterization of left ventricular activation in patients with heart failure and left bundle-branch block. Circulation.
2004;109:1133–1139.
33. Grines CL, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF.
Functional abnormalities in isolated left bundle branch block. The effect
of interventricular asynchrony. Circulation. 1989;79:845–853.
34. Dhingra R, Ho Nam B, Benjamin EJ, Wang TJ, Larson MG, D’Agostino
RB Sr, Levy D, Vasan RS. Cross-sectional relations of electrocardiographic QRS duration to left ventricular dimensions: the Framingham Heart
Study. J Am Coll Cardiol. 2005;45:685–689.
35. Huvelle E, Fay R, Alla F, Cohen Solal A, Mebazaa A, Zannad F. Left bundle
branch block and mortality in patients with acute heart failure syndrome:
a substudy of the EFICA cohort. Eur J Heart Fail. 2010;12:156–163.
36.Zareba W, Klein H, Cygankiewicz I, Hall WJ, McNitt S, Brown M,
Cannom D, Daubert JP, Eldar M, Gold MR, Goldberger JJ, Goldenberg
I, Lichstein E, Pitschner H, Rashtian M, Solomon S, Viskin S, Wang P,
Moss AJ; MADIT-CRT Investigators. Effectiveness of Cardiac Resynchronization Therapy by QRS Morphology in the Multicenter Automatic
Defibrillator Implantation Trial-Cardiac Resynchronization Therapy
(MADIT-CRT). Circulation. 2011;123:1061–1072.
37. Cleland JG, Freemantle N, Daubert JC, Toff WD, Leisch F, Tavazzi L.
Long-term effect of cardiac resynchronisation in patients reporting mild
symptoms of heart failure: a report from the CARE-HF study. Heart.
2008;94:278–283.
38. Guglin M, Barold SS. Electrical devices for left ventricular dysfunction
and heart failure: do we need revised guidelines? J Interv Card Electrophysiol. 2012;34:197–204.
39. Yu CM, Bleeker GB, Fung JW, Schalij MJ, Zhang Q, van der Wall EE,
Chan YS, Kong SL, Bax JJ. Left ventricular reverse remodeling but not
clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation. 2005;112:1580–1586.
Key Words: cardiac resynchronization therapy ◼ heart failure
Downloaded from http://circep.ahajournals.org/ by guest on May 2, 2017
Response to Maya Guglin, MD, PhD, and Anne B. Curtis, MD
Ilke Sipahi, MD, FACC; James C. Fang, MD, FACC
Transformation of continuous variables into categorical ones using cutoff values is inherently problematic and weakens the
strength of information provided by the variable. Nevertheless, dichotomization of continuous variables is a necessity while
practicing medicine. These cutoffs are used universally in every patient encounter, regardless of the medical specialty. The
QRS cutoff of 120 ms for cardiac resynchronization therapy used to be one such cutoff. We demonstrated that 120 ms is not
a good cutoff value, and that 150 ms is a better one, but inevitably an imperfect one, like all other cutoff values. Accordingly,
in their recently revised guidelines, the American College of Cardiology, the American Heart Association, the Heart Rhythm
Society, the American Association for Thoracic Surgery, the Heart Failure Society of America, and the Society of Thoracic
Surgeons agree with our observations and now recommend cardiac resynchronization therapy as a class I indication only for
patients with a QRS duration >150 ms with left bundle-branch block. Nevertheless, no number is a magic number in medicine, regardless of whether you put an exclamation mark after it.
QRS Duration Criteria to Select Patients for Cardiac Resynchronization Therapy:
Cardiac Resynchronization Therapy: 150 Is Not A Magic Number!
Maya Guglin and Anne B. Curtis
Downloaded from http://circep.ahajournals.org/ by guest on May 2, 2017
Circ Arrhythm Electrophysiol. 2013;6:429-435
doi: 10.1161/CIRCEP.112.970939
Circulation: Arrhythmia and Electrophysiology is published by the American Heart Association, 7272 Greenville
Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 1941-3149. Online ISSN: 1941-3084
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circep.ahajournals.org/content/6/2/429
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation: Arrhythmia and Electrophysiology can be obtained via RightsLink, a service of the Copyright
Clearance Center, not the Editorial Office. Once the online version of the published article for which
permission is being requested is located, click Request Permissions in the middle column of the Web page
under Services. Further information about this process is available in the Permissions and Rights Question and
Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation: Arrhythmia and Electrophysiology is online at:
http://circep.ahajournals.org//subscriptions/