Download Indications for Cardiac Resynchronization Therapy: 2011

Journal of Cardiac Failure Vol. 18 No. 2 2012
HFSA CRT Guideline Update
Indications for Cardiac Resynchronization Therapy: 2011 Update
From the Heart Failure Society of America Guideline Committee
WILLIAM G. STEVENSON, MD,1 ADRIAN F. HERNANDEZ, MD,2 PETER E. CARSON, MD,3 JAMES C. FANG, MD,4
STUART D. KATZ, MD,5 JOHN A. SPERTUS, MD, MPH,6 NANCY K. SWEITZER, MD, PhD,7 W.H. WILSON TANG, MD,8
NANCY M. ALBERT, RN, PhD, CNS,9 JAVED BUTLER, MD,10 CHERYL A. WESTLAKE CANARY, RN, PhD,11
SEAN P. COLLINS, MD, MSc,12 MONICA COLVIN-ADAMS, MD,13 JUSTIN A. EZEKOWITZ, MBBCh,14
MICHAEL M. GIVERTZ, MD,1 RAY E. HERSHBERGER, MD,15 JOSEPH G. ROGERS, MD,2 JOHN R. TEERLINK, MD,16
MARY N. WALSH, MD,17 WENDY GATTIS STOUGH, PharmD,18 AND RANDALL C. STARLING, MD, MPH8
Boston, Massachusetts; Durham and Buies Creek, North Carolina; Washington, DC; Cleveland, Ohio; New York, New York; Kansas City, Missouri; Madison,
Wisconsin; Atlanta, Georgia; Azusa and San Francisco, California; Nashville, Tennessee; Minneapolis, Minnesota; Edmonton, Canada; Miami, Florida; and
Indianapolis, Indiana
ABSTRACT
Cardiac resynchronization therapy (CRT) improves survival, symptoms, quality of life, exercise capacity,
and cardiac structure and function in patients with New York Heart Association (NYHA) functional class
II or ambulatory class IV heart failure (HF) with wide QRS complex. The totality of evidence supports
the use of CRT in patients with less severe HF symptoms. CRT is recommended for patients in sinus
rhythm with a widened QRS interval ($150 ms) not due to right bundle branch block (RBBB) who
have severe left ventricular (LV) systolic dysfunction and persistent NYHA functional class II-III symptoms despite optimal medical therapy (strength of evidence A). CRT may be considered for several other
patient groups for whom evidence of benefit is clinically significant but less substantial, including patients with a QRS interval of $120 to !150 ms and severe LV systolic dysfunction who have persistent
mild to severe HF despite optimal medical therapy (strength of evidence B), some patients with atrial
fibrillation, and some with ambulatory class IV HF. Several evidence gaps remain that need to be addressed, including the ideal threshold for QRS duration, QRS morphology, lead placement, degree of
myocardial scarring, and the modality for evaluating dyssynchrony. Recommendations will evolve
over time as additional data emerge from completed and ongoing clinical trials. (J Cardiac Fail
2012;18:94e106)
Key Words: Heart failure, cardiac resynchronization therapy, guidelines.
Minneapolis, Minnesota; 14Division of Cardiology, University of Alberta,
Edmonton, Alberta, Canada; 15Department of Medicine, Division of Cardiology, University of Miami, Miami, Florida; 16Department of Medicine,
University of California, San Francisco, California; 17The Care Group,
Indianapolis, Indiana and 18Department of Clinical Research, Campbell
University College of Pharmacy and Health Sciences, Buies Creek, North
Carolina.
Reprint requests: Randall C. Starling, MD, MPH, Vice Chairman, Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland,
OH 44195. Tel: 216-444-2268. E-mail: [email protected]
This paper was reviewed and approved on December 9, 2011 by the
Heart Failure Society of America Executive Council, whose members
are listed in the Acknowledgment.
See page 104 for disclosure information.
1071-9164/$ - see front matter
Ó 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.cardfail.2011.12.004
From the 1Department of Medicine, Division of Cardiology Brigham
and Women’s Hospital, Boston, Massachusetts; 2Department of Medicine,
Division of Cardiology, Duke University Medical Center, Durham, North
Carolina; 3Georgetown University and Washington DC Veterans Affairs
Medical Center, Washington, DC; 4Harrington-McLaughlin Heart and
Vascular Institute, University Hospitals Case Medical Center, Case
Western Reserve University School of Medicine, Cleveland, Ohio; 5Leon
H. Charney Division of Cardiology, New York University School of Medicine, New York, New York; 6Mid-America Heart Institute of St Luke’s Hospital and University of MissourieKansas City, Kansas City, Missouri;
7
Department of Medicine, University of Wisconsin, Madison, Wisconsin;
8
Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland,
Ohio; 9Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio;
10
Department of Medicine, Division of Cardiology, Emory University,
Atlanta, Georgia; 11School of Nursing, Azusa Pacific University, Azusa,
California; 12Department of Emergency Medicine, Vanderbilt University,
Nashville, Tennessee; 13Cardiovascular Division, University of Minnesota,
94
Current Indications for CRT in Heart Failure
Cardiac resynchronization therapy (CRT), achieved by
biventricular (left ventricular [LV] and right ventricular
[RV]) pacing has been shown to improve survival, morbidity, symptoms, quality of life, exercise capacity, and
cardiac structure and function in patients with New
York Heart Association (NYHA) functional class III or
ambulatory class IV heart failure with wide QRS
complex.1e6 CRT improves morbidity and mortality in
this population, both with and without an implantable cardioverter defibrillator (ICD).7,8 As a result of these data,
national and international guidelines, including those of
the Heart Failure Society of America (HFSA), uniformly
recommend CRT for patients with appropriate clinical
characteristics when on optimal pharmacologic heart failure therapy.9e12
Although a substantial body of evidence supports the use
of CRT in NYHA functional class III or ambulatory class
IV patients with heart failure, clinical trial data for CRT
in patients with mild (NYHA functional class I and II)
heart failure symptoms were only beginning to emerge at
the time the 2010 HFSA Guideline update was being
written. Data have now been published for NYHA functional class I or II patients13e15 that may be sufficient
to justify a modification of existing HFSA guideline
recommendations.
The purpose of this paper is to examine the recent
evidence for CRT in patients with mild heart failure
symptoms and reduced LV ejection fraction (LVEF), to
reevaluate the indications for CRT in this population,
and to provide guidance for clinicians on how to integrate
this evidence into their clinical practice. This manuscript
has been developed by the HFSA Guidelines Committee
and reviewed and approved by the Executive Council.
Pathophysiology of Dyssynchrony and
Mechanism of Cardiac Resynchronization Therapy
Conduction delays occur commonly in patients with
heart failure and lead to electrical and mechanical dyssynchrony. Electrical dyssynchrony is defined by a QRS duration of $120 ms. An estimated 20%e30% of patients with
heart failure meet this criterion.1,16e18
Inter- and intraventricular mechanical dyssynchrony lead
to less efficient LV contractile performance, increased LV
end-systolic volume (LVESV), increased left atrial pressure, and valvular dysfunction.1,6e8,19 By restoring synchrony, CRT reverses LV remodeling as evidenced by
increases in LV filling time and LVEF and decreases in
LV end-diastolic and end-systolic volumes, mitral regurgitation, and septal dyskinesis.1,15,19,20 There is no evidence
to date that CRT provides a benefit in terms of functional
status21 or mortality and morbidity in patients with narrow
QRS and mechanical dyssynchrony.22 Until such evidence
develops, CRT is not recommended for patients with a narrow QRS. Ongoing clinical trials are addressing this important question.23,24
Stevenson et al
95
Review of the Evidence for Cardiac
Resynchronization Therapy in Patients With Mild
Heart Failure Symptoms and Reduced Ejection
Fraction
CRT reduced mortality and morbidity among patients
with NYHA functional class III-IV heart failure and dyssynchrony in several randomized controlled clinical trials.7,8,25 These data, in conjunction with evidence of
reverse remodeling, led to the hypothesis that CRT may
be effective at delaying or reversing disease progression
in a heart failure population with mild symptoms through
LV reverse remodeling. Three large randomized controlled
trials of CRT in patients with mild heart failure symptoms
have been completed (Tables 1 and 2).
Resynchronization Reverses Remodeling in Systolic
Left Ventricular Dysfunction (REVERSE)
Patients were eligible to participate in REVERSE if they
had American College of Cardiology (ACC)/American
Heart Association (AHA) stage C heart failure with
NYHA functional class I (history of symptoms but currently asymptomatic) or class II symptoms for $3 months
before enrollment.13 Other eligibility criteria included
LVEF #40%, QRS duration $120 ms, and LV enddiastolic diameter (LVEDD) $55 mm. Patients were
excluded if they had NYHA functional class IIIeIV symptoms or a heart failure hospitalization #3 months before
enrollment. All patients underwent CRT implantation and
were subsequently randomized 2:1 to CRT-ON or CRTOFF for 12 months in the North American cohort and for
24 months in the European cohort. The primary end point
was a clinical composite score of worsened (death, hospitalization, treatment crossover or discontinuation attributed
to worsening heart failure, worsening NYHA functional
class, or worsening patient global assessment of symptoms), unchanged, or improved (no worsening, and improvement in NYHA functional class or patient global
assessment of symptoms) status. The secondary end point
was absolute change in LV end-systolic volume index
(LVESVI) from baseline to 12 months.
A total of 419 patients were randomized to CRT-ON and
191 to CRT-OFF. The proportion of patients who worsened
over the 12-month study period was 16% in the CRT-ON
group and 21% in the CRT-OFF group, a difference that
was not statistically significant (P 5 .1). The odds ratio
for worsening in the clinical composite score was 0.7
(95% confidence interval [CI] 0.45e1.07), and its direction
was consistent across multiple subgroups. The only statistically significant effect of CRT on the risk of worsening was
in the QRS duration $152 ms subgroup (odds ratio [OR]
0.42, 95% CI 0.22e0.81) and in the nonischemic subgroup
(OR 0.49, 95% CI 0.24e0.99). Appropriate caution must be
taken when evaluating positive subgroup findings in circumstances where the test of the primary hypothesis was
not significant. CRT delayed the time to first heart failure
hospitalization (hazard ratio [HR] 0.47; P 5 .03). No
Trial
n
Population
Trials in Patients with Mild Heart Failure Symptoms
n 5 191 CRT- ACC/AHA stage C; NYHA
REVERSE13
OFF;
I or II; sinus rhythm;
n 5 419 CRTQRS $120 ms; LVEF #40;
ON
LVEDD $55 mm
n 5 82 CRT- ACC/AHA stage C; NYHA I or II;
REVERSEOFF;
sinus rhythm; QRS $120 ms;
Europe20
n 5 180 CRTLVEF #40; LVEDD $55 mm
ON
Mean
QRS, ms
154 6 23
156 6 23.5
MADIT CRT15
n 5 731 ICD; NYHA I or II, sinus rhythm,
n 5 1,089
LVEF #30, QRS $130 ms
CRT-D
64.7% with
QRS $150
ms
RAFT14
n 5 904 ICD; NYHA II or III (revised to
n 5 894
include only II; 80% were II);
CRT-D
LVEF #30
QRS $120 (paced QRS $200 ms)
Sinus or perm AF
157.5 6 24
Trials in Patients with Moderate to Severe Heart Failure Symptoms
COMPANION n 5 308 OPT; NYHA III or IV, LVEF #35%,
159
n 5 617 CRT; QRS $120 ms, PR O150 ms
n 5 595 CRT-D
CARE-HF
n 5 404 Med; NYHA III or IV despite standard tx; Median 160
n 5 409
LVEF !35%, LVEDDI O30 mm,
(IQR 152e
CRT þ Med
QRS O120 ms (those with
180)
120e149 ms had to meet 2 of 3
other criteria for dyssynchrony)
Mean
LVEF
Background
Therapy
26.2 6 7.1 ACEI or ARB 96.5%;
BB 95%; CRT-D
83.5%
Baseline
6-Min
Walk
Distance,
m
393.5 6
128.5
Mean
Age (y)
Comorbidities
62.4 6 11.1 Ischemic 53.5%;
diabetes 23%
Control
Control
Group HF
Group
Hospitalization
Mortality
Rate
(Length of
(Length of
Follow-Up) Follow-Up)
1.6% (12 mo)
28 6 6.5
ACEI or ARB 99.5%; 436 6 103.5 61.1 6 10.6 Ischemic 42.5%;
8.6% (24 mo)
BB 92.5%; CRT-D
previous MI
69%
34%;
diabetes 15.5%;
HTN 35%; PVD
4/5%
24 6 5
ACEI 77%;
361 6 108 64.5 6 11 Ischemic (NYHA I) 7.3% (2.4 y)
ARB 20.5%;
14.8%;
BB 93%; Ald
ischemic (NYHA
ant 31.5%
II) 40.2%;
nonischemic
(NYHA II)
45.1%; NYHA
III/IV
O3 mos
before 10%;
HTN 63.5%;
AF 11.9%;
diabetes: 30.4%
22.6 6 5.3 ACEI or ARB 96.5%; 353 6 108 66.2 6 9.4 Ischemic 66.8%;
26.1% (40
BB 89.5%; spiron
nonischemic
mo)
42%
33.2%;
HTN 44.5%;
Diabetes: 33.7%;
PVD 10%; HF
hosp preceding 6
mo 25.7%
21%
ACEI or ARB 89.5%;
BB 67%; loop
95.5%; spiron 54%
Median 25% ACEI or ARB 95%;
(IQR 21e
BB 72%; spiron
29)
56.5%; high-dose
loop 43.5%;
digoxin 42.5%
259
67
No data
Median
66.5%
Ischemic 56.5%;
diabetes 42%
Ischemic 38%
14/191 (7%)
(12 mo)
14/82 (17.1%)
(24 mo)
22.8% (2.4 y)
26.1% (5 y)
19% (annual)
12.6%
(annual)
33% (29.4 mo)
96 Journal of Cardiac Failure Vol. 18 No. 2 February 2012
Table 1. CRT in Patients With Heart Failure: Study Populations
Current Indications for CRT in Heart Failure
difference in all-cause mortality was observed between
study groups.
The European cohort included 24-month follow-up on
blinded therapy in 262 patients (CRT-ON: n 5 180; CRTOFF: n 5 82).20 Compared with the overall cohort, the
European patients were younger, had a longer mean QRS duration, and were less likely to have ischemic or hypertensive
heart disease. At 24 months, the heart failure clinical composite score worsened in 19% of CRT-ON patients compared
with 34% of CRT-OFF patients (P 5 .01). The direction and
magnitude of benefit for CRT on the heart failure clinical
composite score was consistent across multiple subgroups.
In the NYHA functional class I subgroup, the point estimate
favored CRT-OFF, but the confidence interval was quite
large, reflecting the small number (n 5 44) of subjects in
this subgroup. Therefore, definitive conclusions cannot be
drawn from this observation. Although the effect size appeared to be larger in the QRS duration $152 ms subgroup,
no statistically significant heterogeneity was detected. CRT
was beneficial and significantly increased the time to first
heart failure hospitalization or death (P 5 .003) and time
to first hospitalization alone (P 5 .01).
Multicenter Automatic Defibrillator Implantation
Trial With Cardiac Resynchronization Therapy
(MADIT-CRT)
MADIT-CRT randomized 1,820 patients with NYHA
functional class I or II ischemic cardiomyopathy or
NYHA functional class II nonischemic cardiomyopathy,
LVEF #30%, and a QRS duration of $130 ms to CRT
with defibrillator (CRT-D) or ICD only.15 The primary
end point was all-cause mortality or nonfatal heart failure
events (signs and symptoms of heart failure responsive to
intravenous decongestive therapy on an outpatient basis
or augmented decongestive therapy during an inpatient
stay). Recurrent heart failure events were analyzed as secondary end points, and echocardiographic parameters of remodeling were evaluated as tertiary end points. The trial
was stopped early by the data safety monitoring board after
the prespecified efficacy boundary was crossed. Mean
follow-up was 2.4 years. Background medical therapy
was excellent, with the majority of patients on inhibitors
of the renin-angiotensin-aldosterone system and betablockers.
All-cause death or nonfatal heart failure events occurred
in 187 patients (17.2%) randomized to CRT-D and to 185
(25.3%) randomized to ICD only (HR 0.66, 95% CI
0.52e0.84; P 5 .001). The effect was driven by a reduction
in heart failure events (mortality 3.3% CRT-D vs 2.5% ICD
only; nonfatal heart failure 13.9% CRT-D vs 22.8% ICD
only). Results from a prespecified MADIT-CRT substudy
showed that CRT-D was associated with a significant reduction in the risk of a first heart failure event (as defined
above; HR 0.54, 95% CI 0.44e0.67; P ! .001) and subsequent heart failure events (HR 0.62, 95% CI 0.45e0.85;
P 5 .003).26
Stevenson et al
97
The MADIT-CRT results illustrate the importance of individually reporting the components of composite end
points so that the weight of evidence can be fully evaluated,
particularly when ‘‘softer’’ end points are used (eg, outpatient intravenous diuretics for worsening heart failure).
Such data underscore the importance of prespecified subgroup analyses that show the impact of the intervention
on hospitalizations and nonhospitalization ‘‘heart failure
events.’’
The hazard ratio for the primary end point was similar in
ischemic and nonischemic patients. The findings were consistent across most prespecified subgroups, although subgroup treatment interactions were observed by sex (the
effect size in women was larger than in men; P 5 .01)
and QRS duration, where a reduction in the primary end
point for CRT was observed only in the $150 ms subgroup
(P 5 .001).15
Resynchronization-Defibrillation for Ambulatory Heart
Failure Trial (RAFT)
The primary objective of RAFT was to determine if CRT
added to an ICD and optimal evidence-based pharmacologic therapy would decrease mortality and hospitalization
for heart failure compared with ICD and optimal pharmacologic therapy alone.14 Initially, patients with NYHA functional class II or III symptoms were eligible, but the
protocol was modified to include only class II patients after
a mortality benefit was demonstrated in other studies of
CRT for NYHA functional class III. Overall, 80% of patients were NYHA functional class II. Additional eligibility
requirements included LVEF #30% and intrinsic QRS duration $120 ms or paced QRS duration $200 ms. A total of
1,798 patients were enrolled; 904 were randomized to ICD
and 894 to CRT-D.
Death or hospitalization for heart failure occurred in
33.2% of patients in the CRT-D group and 40.3% of patients in the ICD group (HR 0.75, 95% CI 0.64e0.87;
P ! .001). All-cause mortality was 20.8% in the CRT-D
group compared with 26.1% in the ICD group (HR 0.75,
95% CI 0.62e0.91; P 5 .003). The individual secondary
end points of cardiovascular death and heart failure hospitalization were also significantly lower for patients randomized to the CRT-D group compared with ICD alone. Mean
follow-up was 40 6 20 months.
The findings of the primary analysis were consistent
across multiple prespecified subgroups. The direction and
magnitude of benefit was similar for patients with ischemic
or nonischemic etiology and among patients with NYHA
functional class II or III symptoms. A significant treatment
interaction was noted for QRS duration (P 5 .003), indicating that patients with QRS duration $150 ms received
greater benefit from CRT-D than the QRS !150 ms or
paced QRS $200 ms subgroups. A weak interaction between treatment and QRS morphology was also observed,
suggesting that CRT-D conferred a greater benefit in patients with left bundle-branch block (LBBB) than other
types of conduction delay.
Trial
n
Primary End
Point Definition
Mean
Length
of FollowUp
REVERSE13
n 5 191 CRT-OFF; HF clinical composite response at
n 5 419 CRT12 mo (worsened, unchanged,
ON
improved)
12 mo
REVERSE
Europe20
n 5 82 CRT-OFF; HF clinical composite response
n 5 180 CRTat 12 mo (worsened,
ON
unchanged, improved)
24 mo
MADIT
CRT15
n 5 731 ICD;
Death from any cause or
n 5 1,089 CRTnonfatal HF events (signs/sx
D
of CHF responsive to IV outpt
decongestive tx or augmented
decongestive tx during inpt
stay)
n 5 904 ICD;
Death from any cause or
n 5 894 CRT-D
HF leading to hosp
2.4 y
RAFT14
Primary End
Point
Worsened: 21% CRT OFF vs 16%
CRT-ON (P 5 .1);
Improved/unchanged: 79%
CRT-OFF vs 84% CRT-ON
Mortality: 2.2% CRT-ON vs
1.6% CRT-OFF; P 5 .63
HF hosp: 17/419 CRT-ON vs 15/191
CRT-OFF
HR for time to first
HF hosp for CRT-ON vs
CRT-OFF 5 0.47; P 5 .03
Worsened: 34% CRT OFF vs 19% Mortality (24 mo): 5.7%
CRT-ON (P 5 .01);
CRT-ON vs 8.6%
Improved: 29% CRT-OFF vs 54%
CRT-OFF (HR 0.4; P 5 .09)
CRT-ON;
HR for time to first
Unchanged: 37%
HF hosp for CRT-ON vs
CRT-OFF vs 27% CRT-ON
CRT-OFF 5 0.39; P 5 .01
187 (17.2%) CRT-D vs 185 (25.3%) All-cause mortality: 74 (6.8%)
ICD; HR 0.66 (0.52e0.84),
CRT-D vs 53 (7.3%)
P 5 .001
ICD; HR 1.00, 95%
CI 0.69e1.44; P 5 .99
40 6 20 364 (40.3%) ICD; 297 (33.2%)
mo
CRT-D; HR 0.75, 95%
CI 0.64e0.87; P ! .001
COMPANION n 5 308 OPT;
All-cause death or all-cause hosp 11.9e16.2 68% OPT; 56% CRT (HR 0.81,
n 5 617 CRT;
mo
95% CI 0.69e0.96;
n 5 595 CRT-D
P 5 .014); 56% CRT-D
(HR 0.80, 95%
CI 0.68e0.95; P 5 .01)
CARE-HF
n 5 404 Med;
All-cause death or unplanned
n 5 409 CRT þ
hosp for CV event
Med
Additional
Clinical Outcomes
29.4 (range 39% CRT vs 55% Med;
18e
HR 0.63, 95% CI 0.51e0.77;
44.7) mo P ! .001
Subgroup
Findings
Consistent across subgroups; more
benefit for QRS $152 ms vs !152 ms
but interaction not significant
Consistent across subgroups; more benefit for
QRS $152 ms vs !152 ms but interaction
not significant
Subgroup treatment interactions:
CRT-D benefit in men and women,
but greater in women (P 5 .01);
CRT-D better in QRS $150 ms; significant
benefit not detected for QRS !150 ms
(P 5 .001)
Interaction for QRS !150 ms vs QRS $150 ms:
P 5 .003;
All-cause mortality: 236 (26.1%)
ICD, 186 (20.8%)
CRT-D; HR 0.75, 95%
CI 0.62e0.91; P 5 .003
All-cause mortality (12 mo): 19% Consistent across subgroups, but progressive
OPT, 15% CRT, 12% CRT-D;
lowering of HR with increasing QRS
CRT vs OPT: HR 0.76, 95%
CI 0.58e1.01; P 5 .059
CRT-D vs OPT: HR 0.64, 95%
CI 0.48e0.86, P 5 .003)
All-cause mortality: 20% CRT, 30% Consistent across subgroups
Med; HR 0.64, 95% CI 0.48e
0.85; P ! .002
98 Journal of Cardiac Failure Vol. 18 No. 2 February 2012
Table 2. CRT in Patients With Heart Failure: Clinical Outcomes
Current Indications for CRT in Heart Failure
Meta-Analyses
A recent meta-analysis sought to evaluate the effect of
CRT on all-cause mortality and included all CRT trials regardless of heart failure symptom severity.27 The overall
analysis included 7,538 patients enrolled in 12 trials. A total of 4,054 patients were enrolled in 4 trials that included
NYHA functional class I and II patients. Among patients
with mild heart failure symptoms, 195/2,301 receiving
CRT-D died compared with 212/1,753 patients receiving
an ICD alone (risk ratio [RR] 0.80, 95% CI 0.67e0.96).
This finding was similar to the effect in the total population
(RR 0.83, 95% CI 0.72e0.96).27
Al-Majed et al evaluated the effect of CRT on morbidity
and mortality in a meta-analysis of 25 trials including 9,082
patients.28 Among the 6 trials enrolling predominantly
NYHA functional class I and II patients (n 5 4,572),
CRT reduced all-cause mortality by 17% (RR 0.83, 95%
CI 0.72e0.96; P 5 .01). Virtually all of the effect was
due to RAFT. This effect was consistent with the risk reduction observed in the 19 trials enrolling predominantly
NYHA functional class III and IV patients (n 5 4,510)
(RR 0.78, 95% CI 0.67e0.91; P 5 .001). CRT was also
associated with a decreased risk of heart failure hospitalization in NYHA functional class I and II patients (RR 0.71,
95% CI 0.57e0.87; P 5 .001) and in the NYHA functional
class III and IV patients (RR 0.65, 95% CI 0.50e0.86;
P 5 .002).28
The importance of QRS duration was recently explored
in a meta-analysis by Sipahi et al.29 They hypothesized
that patients with significantly prolonged QRS duration
($150 ms) derived greater benefit from CRT than those
with shorter QRS duration (120e150 ms). The authors examined 5 prospective randomized CRT trials including 581
patients (in all NYHA functional classes) that reported
clinical outcomes according to QRS duration. A reduction
in death and hospitalizations with CRT was observed in patients with QRS duration $150 ms (RR 0.60, 95% CI
0.53e0.67; P ! .001). In contrast, no benefit of CRT
was detected in patients with QRS !150 ms (RR 0.95,
95% CI 0.82e1.10; P 5 .49). There was a significant relationship between baseline QRS duration and risk ratio
(P ! .001), with benefit of CRT appearing at a QRS $
150 ms. The differential response of the 2 QRS groups
was evident for all NYHA functional classes. This analysis
supports the HFSA Guideline Committee’s approach to incorporate the magnitude of QRS prolongation into clinical
decisions about appropriateness of CRT in chronic heart
failure.
Impact of New Evidence on Guideline
Recommendations and Clinical Practice
Guideline recommendations are based on the strength of
evidence, which determines the strength of the recommendation.12 The HFSA uses 4 levels of strength in its guideline recommendations. These include ‘‘is recommended,’’
Stevenson et al
99
indicating that the therapy should be part of routine care
and exceptions minimized; ‘‘should be considered,’’ indicating that the majority of patients should receive the intervention; ‘‘may be considered,’’ indicating that patient
individualization is needed in the application of therapy;
and ‘‘is not recommended,’’ indicating that the therapy
should not be used.12 The 2010 HFSA Guideline contains
the following recommendation regarding CRT in patients
with mild heart failure symptoms: ‘‘9.10 Biventricular pacing therapy may be considered in patients with reduced
LVEF and QRS duration $150 ms who have NYHA functional class I or II heart failure symptoms; strength of evidence 5 B.’’12 This recommendation reflects the lowest
recommendation strength (‘‘may be considered’’) and
a moderate strength of evidence (B). This recommendation
was based on evidence from REVERSE and MADIT-CRT,
studies that were available at the time of the last guideline
update. The RAFT study contributes importantly to the totality of evidence and provides justification for a reexamination of the role of CRT in patients with heart failure and
self-reported mild symptoms. Likewise, systematic reviews
indicate that CRT is beneficial for patients with reduced
LVEF, symptoms of heart failure, and prolonged QRS, regardless of NYHA functional class.27 Clearly, CRT trials
are limited by the difficulty of correctly classifying the patient’s NYHA functional class, both as an entry criterion
and as an assessment of efficacy. Therefore, it should be acknowledged that clinical benefit based on NYHA functional
classification should be interpreted with caution.
Is the Evidence Adequate to Justify an Increase in
Recommendation and/or Evidence Strength?
After evaluating the totality of evidence and based on the
general consistency across clinical trials, the HFSA Guideline Committee determined that CRT is recommended for
patients in sinus rhythm with a widened QRS interval
($150 ms) that is not due to right bundle branch block
who have severe LV systolic dysfunction (LVEF #35%)
and persistent mild-to-moderate heart failure (NYHA functional class IIeIII) despite optimal medical therapy
(strength of evidence A). CRT may be considered for ambulatory NYHA functional class IV patients with QRS interval $150 ms and severe LV systolic dysfunction (LVEF
#35%) (strength of evidence B). CRT may be considered
for patients with a QRS interval of $120 to !150 ms
and severe LV systolic dysfunction (LVEF #35%) who
have persistent mild to severe heart failure (NYHA functional class II to ambulatory class IV) despite optimal medical therapy (strength of evidence B; Table 3).
The evidence supporting the QRS thresholds in these
recommendations is based primarily on findings from subgroup analyses (usually prespecified) and systematic reviews rather than on the boundaries of eligibility criteria
used in the trials. It is acknowledged that subgroup analyses
are generally limited by the potential for chance findings.
However, the observation that the majority of benefit exists
in the QRS duration $150 ms subgroup has been
100 Journal of Cardiac Failure Vol. 18 No. 2 February 2012
Table 3. Current HFSA Guideline Recommendations12
Existing Recommendation
(2010 Guideline)
9.7 Biventricular pacing therapy is
recommended for patients in sinus rhythm
with a widened QRS interval ($120 ms) and
severe LV systolic dysfunction LVEF (#35%)
who have persistent moderate to severe HF
(NYHA III) despite optimal medical therapy
(strength of evidence A)
9.9 Selected ambulatory NYHA IV patients
in sinus rhythm with QRS $120 ms and
LV systolic dysfunction may be considered
for biventricular pacing therapy
(strength of evidence B)
Add new recommendation
9.8 Biventricular pacing therapy may be
considered for patients with atrial fibrillation
with a widened QRS interval ($120 ms) and
severe LV systolic dysfunction LVEF (#35%)
who have persistent moderate to severe HF
(NYHA III) despite optimal medical therapy
(strength of evidence B).
9.10 Biventricular pacing therapy may be
considered in patients with reduced LVEF and
QRS $150 ms who have NYHA I or II HF
symptoms (strength of evidence B)
9.11 In patients with reduced LVEF who
require chronic pacing and in whom
frequent ventricular pacing is expected,
biventricular pacing may be considered
(strength of evidence C)
Summary of Change
Potential Change in Recommendation
and/or Strength of Evidence
Change biventricular pacing to CRT throughout all recommendations
Change QRS to $150, add not due to right
9.7 CRT is recommended for patients in sinus
bundle branch block, add NYHA II
rhythm with a widened QRS interval
($150 ms) that is not due to right bundle
branch block who have severe LV systolic
dysfunction LVEF (#35%) and persistent
mild to moderate HF (NYHA functional class
IIeIII) despite optimal medical therapy
(strength of evidence A)
Becomes 9.8; Change QRS to $150 ms
9.8 CRT may be considered for ambulatory
NYHA functional class IV patients with
QRS $150 ms and LV systolic dysfunction
(LVEF #35%) despite optimal medical
therapy (strength of evidence B)
Becomes 9.9
9.9 CRT may be considered for patients with a
QRS interval of $120 to !150 ms and severe
LV systolic dysfunction (LVEF #35%) who
have persistent mild to severe HF (NYHA
functional class II to ambulatory class IV)
despite optimal medical therapy
(strength of evidence B)
Becomes 9.10; Expand to include NYHA II
9.10 CRT may be considered for patients with
atrial fibrillation with a widened QRS interval
($120 ms) and severe LV systolic
dysfunction LVEF (#35%) who have
persistent mild to moderate HF
(NYHA functional class IIeIII)
despite optimal medical therapy
(strength of evidence B).
Delete, covered under 9.7
Deleted
No change
a consistent finding across multiple clinical trials, and it has
been confirmed in meta-analyses.29,30 Therefore, the guideline committee thought that the totality of evidence supported the QRS duration thresholds discussed above and
in Table 3. The HFSA Guideline Committee also considers
it their charge to place recommendations in the context of
safety, efficacy, appropriateness, and cost-effectiveness.
Patient Selection and Optimizing Response
CRT is associated with a nonresponse rate of w30%.8
The ability to predict response or nonresponse is increasingly important for interventions that are costly, invasive,
or associated with unique risks. There is considerable debate as to what clinical, echocardiographic, biochemical,
or electrical outcome should be used, and at what time
point, to assess response. Therefore, caution should be
used when interpreting a single variable or study to identify
a patient group that may respond more or less often to CRT.
Although the totality of evidence supporting CRT in patients with mild heart failure symptoms is compelling, it
is the HFSA’s view that consideration should be given to
9.11 In patients with reduced LVEF who require
chronic pacing and in whom frequent
ventricular pacing is expected, CRT may be
considered (strength of evidence C)
factors that influence responsiveness in an effort to ensure
the optimal benefit and application of these data.31,32
Defining Mild Heart Failure. Categorizing patients
into NYHA functional classifications IeIV is a subjective
process. Therefore, it is helpful to quantitatively evaluate
the severity of illness of patients enrolled in clinical trials
so that the study results can be accurately applied to
patient-level care.33
Control group mortality rates are useful indicators of
illness severity. In the trials of CRT in patients with mild
heart failure symptoms, control group mortality was 1.6%
(12-month follow-up, REVERSE),13 8.6% (24-month
follow-up, REVERSE-Europe),20 7.3% (2.4-year followup, MADIT-CRT),15 and 26.1% (40-month follow-up,
RAFT).14 The use of background evidence-based therapies
was similar across studies (Table 1). In comparison, the annual control group mortality in COMPANION (Comparison
of Medical Therapy, Pacing, and Defibrillation in Heart Failure) was 19%8 and in CARE-HF (Cardiac Resynchronization
Heart Failure Study) 12.6%,7 but these studies included
NYHA functional class IV patients, who did not receive
ICD, so they are not directly comparable with REVERSE,
MADIT-CRT, and RAFT. The 1-year mortality rate in the
Current Indications for CRT in Heart Failure
CRTarm of CARE-HF was 9%, whereas it was w7.8% in the
CRT-D arm of RAFT. These mortality rates suggest that the
patient groups in REVERSE, MADIT-CRT, and RAFT were
indeed less severely ill compared with earlier studies, with
RAFT patients perhaps approaching a moderate severity of
illness.
It should be noted that !20% of patients enrolled in REVERSE (107 [17.5%]) and MADIT-CRT (265 [14.5%]),
and no patients enrolled in RAFT, were NYHA functional
class I. In REVERSE, it was stipulated that NYHA I patients had been symptomatic NYHA II before enrollment.
In REVERSE-Europe, the point estimate for the effect of
CRT on the composite clinical score in NYHA I favored
CRT-OFF, but with an extremely wide confidence interval.20 In MADIT-CRT, the subgroup analysis of ischemic
NYHA I also revealed an inconclusive finding for the effect
of CRT on the end point of death or heart failure.15 Definitive conclusions cannot be drawn from these subgroup
analyses. However, the findings, in conjunction with the
small numbers of NYHA I patients enrolled, indicate that
data are insufficient to support the broad application of
CRT therapy in NYHA I patients at this time. In the mildly
symptomatic heart failure population, objective evaluation
of symptoms and functional capacity is critical, as is an assessment of optimal medical therapy before the implementation of CRT. Trials seeking to assess symptoms should
use validated heart failureespecific tools and submaximal
exercise testing.34e36
QRS Duration. As described above, a significant
treatment interaction with QRS duration was observed in
MADIT-CRT and RAFT, and a trend toward an interaction
was observed in REVERSE (Table 1). QRS subgroup findings, along with results from meta-analyses, suggest that
the effect of CRT on the study primary end point was limited to those patients with a QRS duration $150 ms.29
Based on the totality of evidence, the recommendation
has been revised based on QRS duration and NYHA functional class, as presented in Table 3.
In addition to the optimal QRS duration threshold, the
optimal measurement technique for dyssynchrony or if it
is even necessary is debated.37,38 Because CRT aims to correct mechanical dyssynchrony, the utility of QRS duration
to predict response to CRT may be imperfect. Echocardiographic measures of dyssynchrony have been proposed as
alternatives to QRS duration, but the reliability of current
approaches have not been confirmed in clinical trials.21,39
Minimal research in this area has been done specifically
in the mildly symptomatic heart failure population. Currently, mechanical dyssynchrony is not recommended as
a means to identify patients who should receive CRT.
QRS Morphology. Subgroup analyses from MADITCRT demonstrated that patients with LBBB benefit from
CRT, whereas the effect of CRT was neutral among patients
with other types of conduction delay.40 The LBBB subgroup was not prespecified, but the data were considered
to be sufficient by the US Food and Drug Administration
to justify adding LBBB to the indication labeling for
Stevenson et al
101
CRT-D in NYHA functional class II or ischemic class I
heart failure. In RAFT, patients with LBBB who were randomized to CRT-D had a lower risk of death or hospitalization for heart failure, whereas no benefit was observed in
the right bundle branch block, nonspecific intraventricular
conduction delay, or paced subgroups, with an interaction
P value of .046.14 Although not definitive, patients with
LBBB appear to derive the most benefit from CRT, and it
may be a useful marker to guide patient selection. It should
be noted that patients with RBBB appear to derive minimal
to no benefit from CRT, regardless of QRS duration.
Sex. Although both men and women benefit from
CRT, some data suggest that women may benefit to a greater
degree than men. In MADIT-CRT, the point estimate for
benefit in women was larger than that for men, with a treatment interaction of P 5 .01.15 On further analysis, women
had significantly greater reductions in death or heart failure,
heart failure alone, and all-cause mortality compared with
men.41 Additionally, women experienced greater improvements in echocardiographic measures of reverse remodeling.41 Current evidence does not support differences in
practice or delivery of care for men and women. More research is needed to further evaluate potential gender differences in response to CRT.
Lead Placement. The position of the LV pacing lead
influences patient responsiveness to CRT.42 The impact of
LV lead placement on clinical outcomes was analyzed in
799 patients enrolled in the MADIT-CRT study.43 Lead
placement was characterized as anterior, lateral, or posterior position for the short axis and basal, midventricular,
or apical for the long axis. No difference in the primary
end point (all-cause mortality or nonfatal heart failure)
was observed between leads placed in the posterior, anterior, or lateral regions (unadjusted P 5 .652). LV leads
positioned in the apical region were associated with a higher
risk of death or nonfatal heart failure events after adjustment for covariates (HR 1.72, 95% CI 1.09e2.71;
P 5 .019) and a higher risk of mortality alone (HR 2.91,
95% CI 1.42e5.97; P 5 .004). Based on present data,
physicians should avoid implanting a CRT lead in the
apical region of the LV.43
When transvenous placement of an LV lead is not possible, surgical epicardial placement may be feasible. The
accompanying surgical risks warrant careful individualized
consideration.44
Atrial Fibrillation. More evidence is needed to guide
the appropriate use of CRT in patients with atrial fibrillation. In patients with a CRT device and atrial fibrillation,
atrioventricular (AV) node ablation should be considered
when rapid AV conduction in atrial fibrillation prevents
consistent CRT pacing despite attempted pharmacologic
rate control.45
Other Patient Selection Criteria. Other factors may
also influence response to CRT.46 The extent of myocardial
scarring may play a role and may be associated with reduced CRT responsiveness. Data are insufficient to support
a specific recommendation, but clinicians should weigh the
102 Journal of Cardiac Failure Vol. 18 No. 2 February 2012
risks and potential benefits of CRT implantation in patients
with extensive myocardial scar, particularly in the location
of the LV lead placement.
Optimization Techniques and Follow-Up Management. CRT responsiveness may be influenced also by
LV lead location and the specific programmed settings for
pacing. The programmed AV delay is an important factor
in determining whether LV capture occurs sufficiently early
to promote synchrony, and it also influences ventricular filling. However, in a randomized trial of 1,014 patients, routine use of echocardiographic optimization of CRT pacing
parameters at rest did not improve ventricular volume,
6-minute walk, or NYHA functional class compared with
a fixed empirical AV delay or an electrocardiogram-based
algorithm for assigning AV delay.47 Anecdotal and nonrandomized data suggest that some patients who fail to improve with CRT may benefit from reprogramming the
device to ensure LV capture and improve AV timing.48
Thus, there is insufficient evidence to support any specific
protocols or routine implementation of optimization techniques at this time beyond comprehensive heart failure disease management.12 After implantation of CRT, it is
essential to assure utilization and monitoring of heart failure core therapies at recommended dosages, based on
evidence-based guidelines.49 Furthermore, patients must
understand that CRT implantation is not a substitute for adhering to self-care behaviors. Patients should continue to
follow their pre-CRT plan of care for monitoring worsening
signs and symptoms of heart failure and self-management
behaviors.
Safety
Implementation of CRT requires an invasive procedure
that carries risks. Upgrading an existing ICD or pacing system requires the addition of a new lead, which increases
procedure risk. Replacing an existing ICD or pacemaker
has also been associated with greater risk of infection.
Lead dislodgment is generally the most commonly reported
adverse event, and it occurred in 7% of RAFT patients, 4%
of MADIT-CRT patients, and 10% of REVERSE patients
(Table 4).13e15,20 Reoperation for repositioning is often required and may lead to significant morbidity. Among ICD
patients in the National Cardiovascular Data Registry,
lead dislodgements were associated with a significantly increased risk of cardiac arrest, cardiac tamponade, device infection, pneumothorax, and in-hospital mortality.50 Risk
scores may be helpful to identify patients who are at
high-risk of postprocedural complications.51
The long-term safety risks associated with CRT in patients with heart failure and mild symptoms have not
been fully quantified. Patients with mild heart failure
symptoms will likely survive with the CRT device for a longer period of time than patients in NYHA class III/IV, creating a greater opportunity for adverse events to occur.
Complications due to pulse generator or lead failure requiring surgery are likely to be a greater concern for patients in
NYHA functional class I or II compared with class III or
IV, because the expected duration of therapy is longer in
patients with fewer symptoms. Although generator replacement is generally benign, lead extraction or revision
may be associated with greater risk. In the REPLACE
(Implantable Cardiac Pulse Generator Replacement Registry), the major complication rate among patients in whom
the addition of a lead was planned was 15.3% (95% CI
12.7e18.1%); the rate was 2.4% during the periprocedural
period (cardiac perforation, pneumothorax, hemothorax,
hemodynamic instability, cardiac arrest, respiratory arrest,
coronary sinus dissection) and 14% out to 6 months.52 The
major complication rate was 18.7% (95% CI 15.1e22.6%)
among patients who underwent an upgrade to or revision of
a CRT device, and this event rate differed significantly
from the major complication rate among patients undergoing an upgrade or revision of a single-chamber pacemaker or ICD to a dual-chamber pacemaker (11.1%) or
among those who did not ultimately receive a new lead
(4.4%).41 The available follow-up data from clinical trials
of CRT in patients with mild heart failure symptoms are
too short to accurately characterize the long-term risk profile of the devices.
Given the limited data currently available to describe
long-term safety, the potential risks and potential benefits
must be carefully evaluated for each patient. Patients and
caregivers should be engaged in this process and informed
about what is known and unknown regarding the benefits
and risks of CRT in the setting of heart failure and mild
symptoms to facilitate shared decision making among patients and their physicians. The potential for nonresponse
should also be addressed.
Cost Effectiveness of CRT in Patients With Mild
Heart Failure Symptoms
Among trials of CRT in patients with mild heart failure
symptoms, the only cost-effectiveness analysis that has
been published is from the REVERSE study.53 In that
analysis, CRT was associated with a difference of 0.8
quality-adjusted life-years (QALY) over 10 years, corresponding to an incremental cost-effectiveness ratio of
V14,278 per QALY gained (w$19,529). The number
needed to treat to prevent 1 death was 4.9 at 10 years,
and CRT became cost-effective after 4.5 years. These
data are consistent with cost-effectiveness analyses of
CRT in NYHA functional class IIIeIV patients. The incremental cost-effectiveness ratio was V18,017 (w$24,643) in
CARE-HF, $43,000 in COMPANION, and $32,822 in an
analysis of 5 CRT trials.19,53e56 Authors from REVERSE
estimated that a relative mortality hazard ratio of 0.82
should enable CRT to be considered as cost-effective in patients with mild heart failure symptoms.53 The hazard ratio
for mortality in RAFT was 0.75.14 It is important to recognize that because cost-effectiveness analyses consider both
the incremental improvement in survival and the quality of
that survival, the cost-benefit for patients with mild
Current Indications for CRT in Heart Failure
Stevenson et al
103
Table 4. Adverse Events Reported in Clinical Trials
MADIT-CRT
Pneumothorax (%)
Infection (%)
Pocket hematoma (%)
Coronary venous dissection with pericardial effusion, n (%)
LV coronary vein lead repositioned, n (%)
Serious device-related adverse events
RAFT
Device- or implantation-related complications, n (%)
Hemothorax or pneumothorax, n (%)
Device pocket hematoma, n (%)
Device pocket infection, n (%)
Lead dislodgement, n (%)
Device pocket problems, n (%)
Coronary sinus dissection, n (%)
REVERSE
Pre/periprocedural complications
Adverse drug reaction, n
Pneumothorax, n
Atrial fibrillation/flutter, n
Coronary sinus dissection, n
Pulmonary edema, n
Ventricular fibrillation, n
Complete heart block, n
Cardiac tamponade, n
Pericardial effusion, n
Electromechanical dissociation, n
Hypotension, n
Increased defibrillation threshold, n
Postimplantation complications
LV lead dislodgement, n
RV lead dislodgement, n
Right atrial lead dislodgement, n
Inappropriate device irritation of tissue, n
Atrial fibrillation/flutter, n
Implant site hematoma, n
Hypotension, n
Pericardial effusion, n
COMPANION
Moderate or severe AE from any cause, %
AE related to implantation procedure, %
Coronary venous dissection, %
Coronary venous perforation, %
Coronary venous tamponade, %
CARE-HF
Death from HF aggravated by lead displacement, n
Death, septicemia, n
Lead displacement, n
Coronary sinus dissection, n
Pocket erosion, n
Pneumothorax, n
Device-related infection, n
Worsening HF, n
Atrial arrhythmias or ectopy, n
CRT-D
ICD
1.7
1.1
3.3
5 (0.5)
44 (4)
4.5 per 100 device-months
0.8
0.7
2.5
118/888 (13.3%)
11 (1.2)
14 (1.6)
21 (2.4)
61 (6.9)
4 (0.5)
11 (1.2)
5.2 per 100 device-months
61/899 (6.8%)
8 (0.9)
11 (1.2)
16 (1.8)
20 (2.2)
1 (0.1)
26 procedure-/system-related complications in 642 patients (4%)
4
4
4
3
2
2
2
1
1
1
1
1
101/621 patients experienced 138 procedure-/system-related complications (16%)
41
15
10
14
8
5
4
4
69 (P 5 .03 vs OPT)
8
0.5
0.8
0.3
OPT: 61; CRT: 66 (P 5 .15 vs OPT)
10
0.3
1.1
0.5
1 (CRT)
1 (OPT after receiving a device)
24
10
8
6
3
OPT: 263; CRT: 191 (P ! .001)
OPT: 41; CRT: 64 (P 5 .02)
OPT, optimal pharmacologic therapy.
symptoms may be realized by a reduction in future events
through prevention of disease progression or an improvement in current symptoms.
Reimbursement for device therapy often lags behind the evidence and/or guideline recommendations. Clinicians should
be aware of reimbursement policies for CRT, and they should
discuss this issue with patients as individually relevant. The
potential for unreimbursed costs should be recognized and
communicated to patients before CRT implantation.
Remaining Evidence Gaps and Future
Research Needs
Further research is needed to clarify optimal strategies
for selection and implementation of CRT in heart failure
patients, because of the potential for heterogeneity in risks
and benefits.57 Optimal patient selection is an area of key
interest. Current patient selection is based on clinical trial
eligibility criteria and findings from subgroup analyses,
104 Journal of Cardiac Failure Vol. 18 No. 2 February 2012
but identification of patients who will and will not respond
to CRT needs to be further refined by rigorous scientific
data.57 The evidence for CRT in NYHA functional class I
patients is inconclusive, because these patients were underrepresented in the populations studied. However, in clinical
practice, LV leads may be placed in patients who are likely
to require frequent ventricular pacing, even if they have
NYHA I symptoms. Although this practice occurs clinically, it is not data driven, and additional research in this
area would be valuable. Identifying the most appropriate
methodology for measuring dyssynchrony, defining optimal
dyssynchrony thresholds, determining if CRT effects are
consistent across all types of conduction delay, evaluating
CRT effectiveness (responders vs nonresponders), and evaluating CRT in patients with atrial fibrillation are just some
of the important patient selection questions that need to be
addressed.
Based on data currently available, patients with a narrow
QRS complex derive no benefit from CRT. Whether there
are patients with narrow QRS but mechanical ventricular
dyssynchrony that would benefit from CRT is still under investigation, but CRT cannot be recommended at this time
for that population.23 At present, QRS duration remains
the best predictor of a favorable response to CRT.29 Furthermore, the clinical benefits of CRT for QRS durations
between 120 and 150 ms remain unclear and can only be
definitively addressed by prospective clinical trials. More
research is needed to determine the future utility of measuring mechanical dyssynchrony in this setting, and adequate
numbers of patients with mild symptoms (NYHA functional class II) should be studied to evaluate relevant differences across the spectrum of heart failure severity.
The existing evidence to date involves de novo devices.
Some patients who already have 1- or 2-lead ICDs experience changes in cardiac structure or function without an associated increase in symptoms. Whether or not these
patients may benefit from an upgrade to CRT because of
disease progression or chronic RV apical pacing is not
well defined or understood, and further investigation of
this issue is needed. Recent data have suggested that device
upgrades may be associated with more risk than new
implants.52,58e60
As CRT research moves into the mildly symptomatic
heart failure population, where prevention of disease
progression is a major concern, innovative research methodologies are needed. First, there needs to be an increased
use of standardized assessments of patients’ symptoms,
function, and quality of life, so that the results from clinical
trials can be more readily translated to clinical care without
the variability of interoperator reporting of NYHA functional class.61,62 Second, the use of functional status measures as outcomes that are clinically important to patients
will improve the power of studies to define treatment benefit, given that event rates in these populations are lower
than in the NYHA IIIeIV population. Third, functional status changes may trigger an order for an echocardiogram to
assess LVEF, creating greater standardization in early
identification of worsening LV systolic dysfunction that
may meet criteria for CRT placement. The use of other surrogate end points, such as LVESV, LV end-diastolic volume, or dyssynchrony will be debated among scientist
investigators and regulators.
Conclusion
The totality of evidence supports the use of CRT in heart
failure patients with reduced LVEF across the spectrum of
mild to severe symptoms. The evidence is most compelling
among patients with QRS duration $150 ms and without
RBBB. The guidance for clinicians offered in this document
is based on an analysis of available evidence. However,
many gaps exist in the data. Because these gaps are filled
by the completion of ongoing and future studies, it is anticipated that recommendations will evolve to focus on optimizing patient selection and identifying factors that
reliably predict a favorable response to CRT, ideally based
on criteria that are clinically important to our patients.
Acknowledgments
The HFSA Guideline Committee acknowledges the administrative support of Cheryl Yano, Executive Director,
HFSA, and Bart Galle, PhD. They also acknowledge the
HFSA Executive Council for their careful review of this
manuscript and their contributions to the document: Barry
M. Massie, MD, Thomas Force, MD, Hani N. Sabbah,
PhD, Mandeep R. Mehra, MD, Douglas L. Mann, MD, Inder
S. Anand, MD, PhD, John C. Burnett, Jr, MD, John Chin,
MD, Steven R. Houser, PhD, Sharon A. Hunt, MD, Mariell
L. Jessup, MD, JoAnn Lindenfeld, MD, Sara C. Paul, RN,
MSN, DNP, Mariann Piano, RN, PhD, Heather J. Ross,
MD, James E. Udelson, MD, and Michael R. Zile, MD.
Disclosures
Randall C. Starling, MD, MPH, has received consulting
fees/honoraria from Biocontrol, Medtronic, Novartis, Novella, and Thoratec and research grants from Biotronik
(paid to the Cleveland Clinic); has equity interests/stock/
stock options with CardioMEMS; and is a board member
of the United Network for Organ Sharing. James C. Fang,
MD, has received consulting fees/honoraria from Boston
Scientific and Medtronic and research grants from Medtronic (fellowship). Stuart D. Katz, MD, has received consulting fees/honoraria from Amgen, Bristol-Myers Squibb,
and Terumo and is with the speaker’s bureau of Otsuka
Pharmaceuticals. John A. Spertus, MD, MPH, receives
a salary from Kansas City Cardiomyopathy Questionnaire.
Nancy K. Sweitzer, MD, PhD, has received research grants
from Medtronic as a site investigator. W. H. Wilson Tang,
MD, has received consulting fees/honoraria from Medtronic and St Jude’s Medical and research grants from Abbott Laboratories. Javed Butler, MD, has received research
grants from Medtronic, St Jude, and Boston Scientific as
Current Indications for CRT in Heart Failure
a site investigator. Sean P. Collins, MD, MSc, has received
consulting fees/honoraria from Abbot Point-of-Care, PDL
Biopharma, Astellas, Otsuka Pharmaceuticals, Bayer, Trevena, Novartis, The Medicine Company, and Corthera and
research grants from Biosignetics, Inovise Medical, Abbott
Point-of-Care, National Institutes of Health/National Heart,
Lung, and Blood Institute, Corthera, and BRAHMS. Joseph
G. Rogers, MD, has received consulting fees/honoraria
from Thoratec. John R. Teerlink, MD, has received consulting fees/honoraria and research grants from Amgen, CardioMEMS, Corthera, Cytokinetics, Geron, Momentum
Research, Novartis, Scios/Johnson & Johnson, and St
Jude and research grants from the National Institutes of
Health. Mary N. Walsh, MD, has received consulting
fees/honoraria from Medtronic and United Health Care.
All of the other authors report no potential conflicts of
interest.
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