Download Cardiac Resynchronization Therapy for Patients With Left

CLINICIAN’S CORNER
CLINICAL REVIEW
Cardiac Resynchronization Therapy
for Patients With Left Ventricular
Systolic Dysfunction
A Systematic Review
Finlay A. McAlister, MD, MSc
Justin Ezekowitz, MBBCh, MSc
Nicola Hooton, MPH
Ben Vandermeer, MSc
Carol Spooner, BScN, MSc
Donna M. Dryden, PhD
Richard L. Page, MD
Mark A. Hlatky, MD, MPH
Brian H. Rowe, MD, MSc
H
EART FAILURE IS THE FASTest growing cardiovascular
diagnosis in the United
States, with a community
prevalence of 2.5% in adults, and the
direct and indirect costs of heart failure exceed $33 billion per year.1 Despite many advances in diagnosis and
pharmacotherapy for heart failure during the past 2 decades, morbidity and
mortality remain high and quality of life
is poor for many patients. Thus, there
is increasing enthusiasm for the therapeutic potential of atrial-synchronized biventricular pacemakers (cardiac resynchronization therapy [CRT])
in patients with heart failure and left
ventricular (LV) systolic dysfunction.
CRT is designed to eliminate the delay
in activation of the LV free wall found
in many patients with LV systolic dysfunction and thereby improves me-
See also Patient Page.
CME available online at
www.jama.com
Context Left ventricular (LV) systolic dysfunction causes substantial morbidity and
mortality, even with optimal pharmacotherapy. Atrial-synchronized biventricular pacemakers (cardiac resynchronization therapy [CRT]) received US Food and Drug Administration (FDA) approval for use in selected patients with LV systolic dysfunction in
2001.
Objective To summarize the current evidence base for the efficacy, effectiveness,
and safety of CRT in patients with LV systolic dysfunction.
Evidence Acquisition A search of multiple electronic databases until November 2006
was supplemented by hand searches of reference lists of included studies and review
articles, proceedings booklets from meetings, FDA reports, and contact with primary
study authors and device manufacturers. A total of 14 randomized trials (4420 patients) were included for the CRT efficacy review, 106 studies (9209 patients) for the
CRT effectiveness review, and 89 studies (9677 patients) reported safety outcomes
with implantation of a CRT device.
Evidence Synthesis All patients in the CRT studies had LV systolic dysfunction (mean
LV ejection fraction [LVEF] range, 21%-30%), prolonged QRS duration (mean
range,155-209 milliseconds), and 91% had New York Heart Association (NYHA) class
3 or 4 heart failure symptoms despite optimal pharmacotherapy. CRT improved LVEF
(weighted mean difference, 3.0%; 95% confidence interval [CI], 0.9%-5.1%), quality of life (weighted mean reduction in Minnesota Living With Heart Failure Questionnaire, 8.0 points; 95% CI, 5.6-10.4 points), and functional status (improvements
of ⱖ1 NYHA class were observed in 59% of CRT recipients in the randomized trials).
CRT decreased hospitalizations by 37% (95% CI, 7%-57%), and all-cause mortality
decreased by 22% (95% CI, 9%-33%). Implant success rate was 93.0% (95% CI,
92.2%-93.7%) and 0.3% of patients died during implantation (95% CI, 0.1%0.6%). During a median 11-month follow-up, 6.6% (95% CI, 5.6%-7.4%) of CRT
devices exhibited lead problems and 5% (95% CI, 4%-7%) malfunctioned.
Conclusions CRT reduces morbidity and mortality in patients with LV systolic dysfunction, prolonged QRS duration, and NYHA class 3 or 4 symptoms when combined
with optimal pharmacotherapy. The incremental benefits of combined CRT plus implantable cardioverter-defibrillator devices vs CRT-alone devices in patients with LV
systolic dysfunction remain uncertain.
www.jama.com
JAMA. 2007;297:2502-2514
Author Affiliations: The University of Alberta Evidencebased Practice Center, Edmonton, Alberta (Drs McAlister,
Ezekowitz, Dryden, and Rowe, and Mr Vandermeer, and
Mss Hooton and Spooner); Division of General Internal
Medicine (Dr McAlister), Division of Cardiology (Dr
Ezekowitz), and Department of Emergency Medicine (Dr
Rowe), University of Alberta, Edmonton; Division of Cardiology, University of Washington School of Medicine,
Seattle (Dr Page); and Department of Health Research
2502 JAMA, June 13, 2007—Vol 297, No. 22 (Reprinted)
andPolicy,StanfordUniversity,Stanford,Calif(DrHlatky).
Corresponding Author: Finlay A. McAlister, MD, MSc,
2E3.24 WMC, University of Alberta Hospital,
8440 112th St, Edmonton, Alberta, Canada T6G 2R7
([email protected]).
Clinical Review Section Editor: Michael S. Lauer, MD.
We encourage authors to submit papers for consideration as a Clinical Review. Please contact Michael
S. Lauer, MD, at [email protected].
©2007 American Medical Association. All rights reserved.
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CARDIAC RESYNCHRONIZATION THERAPY AND LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
chanical synchrony, which in turn increases LV filling time, reduces mitral
regurgitation, and reduces septal dyskinesis.
Although previous systematic
reviews 2-4 have reported morbidity
and mortality benefits with CRT
therapy in randomized controlled
trials (RCTs), there were areas of
uncertainty. First, although these
earlier systematic reviews focused on
randomized efficacy trials, the generalizability of their results to clinical
practice were unknown (particularly
with respect to response rates, clinical effects, and safety when these
devices are used in routine practice
outside of clinical trial centers and in
less selected patients). Second, none
of the earlier reviews was able to
clarify the incremental benefits conferred by CRT devices with implantable cardioverter-defibrillator (ICD)
capability (combined CRT-ICD
devices) over CRT-alone devices, or
were these earlier reviews able to
define which patient groups would
benefit most from these devices.
Finally, a number of RCTs have been
published since the earlier systematic
reviews were performed and their
impact on the pooled evidence base
was unknown.
Our systematic review summarizes
the current evidence regarding the efficacy (outcomes in randomized trial
participants), effectiveness (outcomes
in clinical settings), safety (in both randomized trial participants and in clinical settings), and cost-effectiveness of
CRT with or without an ICD in patients with LV systolic dysfunction.
EVIDENCE ACQUISITION
Search Strategy
We sought studies that (1) reported
mortality, hospitalization, changes in
functional outcomes (New York Heart
Association [NYHA] class, 6-minute
walk test, LV ejection fraction [LVEF],
and/or quality of life), or peri-implant/
postimplant safety with CRT in (2) patients with LV systolic dysfunction
(LVEF ⱕ35%, whether or not heart failure symptoms were present) that (3)
followed participants for at least 2
weeks, (4) had more than 25 participants, (5) reported original research,
and (6) represented the primary report from studies with multiple publications. We searched MEDLINE, Ovid
MEDLINE In-Process and other nonindexed citations, Cochrane CENTRAL
Register of Controlled Trials, Cochrane Database of Systematic Reviews,
Database of Abstracts of Reviews of Effects, Health Technology Assessment
Database, EMBASE, Science Citation Index Expanded (via Web of Science), International Pharmaceutical Abstracts,
PubMed, National Library of Medicine Gateway, OCLC (Online Computer Library Center) Proceedings First
and Papers First, CRISP (Computer Retrieval of Information on Scientific
Projects), various trial registries (including the National Research Register [UK], Australian Clinical Trials Registry, clinicaltrials.gov, and current
controlled trials), and US Food and
Drug Administration reports.
In addition, we reviewed all abstracts from the annual Heart Rhythm
Society meetings, the reference lists of
review articles and included studies,
and contacted authors of included studies for additional citations and information. Additional data were also
sought from device manufacturers, including Medtronic Inc (Minneapolis,
Minn), Boston Scientific (formerly
Guidant Corp, Indianapolis, Ind), and
St Jude Medical Inc (St Paul, Minn). The
search was not limited by language or
publication status.
The search terms included biventricular pacing, biventricular pacer, biventricular stimulation, BiV, artificial
cardiac pacing, chronic cardiac failure resynchronization therapy, single chamber pacing, dual chamber pacing, cardiac resynchronization, Medtronic,
InSync, ELA medical, Guidant, St Jude,
congestive heart failure, CHF, chronic
heart failure, and heart diseases.
Study Selection
To address the efficacy of CRT in
ideal patients and practice settings,
we analyzed RCTs that compared
©2007 American Medical Association. All rights reserved.
CRT or combined CRT-ICD devices
with either placebo pacing, right ventricular pacing, or drug therapy alone
(or ICD alone for RCTs testing combined CRT-ICD devices). To address
the effectiveness of CRT in usual
clinical practice, we analyzed observational studies with contemporaneous comparison groups (eg, cohort
studies). To address device safety, we
included data for CRT recipients
from RCTs and observational studies
(including those without contemporaneous control groups, such as case
series and clinical registry data).
Data Extraction and Analysis
Study selection, quality assessment
(using the Jadad scale5 and evaluation
of adequacy of allocation concealment
for RCTs, and using the Downs and
Black checklist6 for observational studies), and data extraction were completed in duplicate and independently.
For dichotomous results (congestive
heart failure hospitalizations), we calculated relative risks (RRs) and for continuous variables (eg, 6-minute walk
test), we calculated weighted mean differences for the pooled estimates. Random-effects models were used for analyses in Review Manager 4.2.5 (The
Cochrane Collaboration, Copenhagen,
Denmark). All results were reported with
95% confidence intervals (CIs). The I2
statistic was used to describe the percentage of total variation across studies
that is due to heterogeneity rather than
chance (a value of 0% indicates limited
heterogeneity, and larger values demonstrate increasing heterogeneity).7
Device efficacy in different patient subgroups was explored using metaregression analyses.
EVIDENCE SYNTHESIS
Literature Search
From 7110 citations, we identified 14
RCTs8-21 (4420 patients) for determining CRT efficacy, 106 studies (9209
patients from 2 controlled nonrandomized studies, 91 prospective observational studies, and 13 retrospective observational studies) evaluating CRT
effectiveness,22-127 and 89 studies (9677
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2503
CARDIAC RESYNCHRONIZATION THERAPY AND LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
Figure 1. Study Flow
7110 Independent References
Identified in All Databases
48 References Identified in
Reference Lists, Authors’ Lists,
and Conference Presentations
6628 Excluded Based on Screening of Titles and
Abstracts Using General Criteria
530 Citations With Potential
Relevance
402 Excluded Using Specific Criteria
139 Did Not Report Primary Data (Review,
Editorial, Protocol)
134 Did Not Report Outcomes of Interest
48 Not CRT Intervention
22 Study Participants Did Not Have Left
Ventricular Systolic Dysfunction
10 Studies Had <25 Patients
49 Miscellaneous (Study <2 wk,
Effectiveness Studies Without
Contemporaneous Controls, Case Reports)
128 Unique Articles Reporting
130 Studies That Met
Inclusion Criteria
14 Included in Efficacy Review
(4420 Patients)
14 Randomized Controlled Trials
106 Included in Effectiveness Review
(9209 Patients)
2 Controlled Clinical Trials
91 Prospective Cohort Studies
13 Retrospective Cohort Studies
89 Included in Safety Review
(9677 Patients)
14 Randomized Controlled Trials
2 Controlled Clinical Trials
63 Prospective Cohort Studies
9 Retrospective Cohort Studies
1 Registry Data
CRT indicates cardiac resynchronization therapy.
patients from 14 RCTs, 2 controlled nonrandomized studies, 63 prospective
observational studies, and 10 retrospective observational studies) reporting
success rates and safety outcomes
with implantation of a CRT device
(FIGURE 1).* A full list of search strategies, search results, and quality assessments for each included study are available at http://www.ahrq.gov/clinic/tp
/defibtp.htm.
Description of Included Patients
in the RCTs
All patients in the CRT RCTs had LV
systolic dysfunction (mean LVEF
range, 21%-30%), prolonged QRS
duration (mean QRS range, 155-209
milliseconds), and heart failure symptoms (91% were NYHA class 3 or 4 at
baseline and 9% were NYHA class 2).
The RCTs attempted to ensure partici*References 8-21, 24, 26, 30, 31, 33-37, 39, 40, 43,
45, 46, 48-50, 53, 54, 56, 57, 59-62, 64, 67-74, 77,
80, 82, 84, 86, 87, 89-91, 93, 95-98, 101, 102, 104,
106-110, 112, 113, 115-117, 121, 122, 127-136.
pants were treated with optimal pharmacotherapy (angiotensin-converting
enzyme inhibitors or angiotensin II
receptor blockers, plus ␤-blockers,
and spironolactone in eligible
patients) at baseline, and all comparisons were thus of CRT plus pharmacotherapy vs pharmacotherapy alone.
The mean (SD) age of trial participants
was 65.4 (10.8) years; 72% were male
and 5% had atrial fibrillation (data
available upon request). Of the
patients in the intervention groups,
1310 (47%) received CRT alone and
1474 (53%) received a combined
CRT-ICD device. Eleven of the RCTs
(n = 2166) 8 - 1 4 , 1 6 - 1 8 , 2 1 randomized
patients after successful CRT implantation; 3 RCTs (n = 2439)15,19,20 randomized patients before attempted
CRT implantation. All but 2 of the
RCTs14,17 reported industry funding.
Observational Studies
All patients in the CRT observational
studies had LV systolic dysfunction
2504 JAMA, June 13, 2007—Vol 297, No. 22 (Reprinted)
(mean LVEF range, 17%-35%) and prolonged QRS duration (mean QRS range,
140-206 milliseconds). Patient demographics were similar to the participants in the CRT RCTs (mean [SD] age,
66 [10] years; 77% were male and virtually all had heart failure symptoms at
baseline [8% NYHA class 2 and 91%
NYHA class 3 or 4]).
Efficacy of CRT
In the RCTs, 59% of CRT recipients improved by at least 1 NYHA class between baseline and 6 months vs 37% of
controls (RR, 1.55; 95% CI, 1.25-1.92 for
improving at least 1 NYHA class with
CRT). Compared with controls, patients assigned to CRT demonstrated improvements in LVEF (weighted mean
difference, 3.0%; 95% CI, 0.9%-5.1%),
6-minute walk test distance (weighted
mean difference, 24 m; 95% CI, 13-35
m), and quality of life (weighted mean
difference in Minnesota Living With
Heart Failure Questionnaire, 8.0 points;
95% CI, 5.6-10.4 points).
The percentage of patients hospitalized for heart failure was 27% in controls and 19% in patients assigned to
CRT (RR, 0.63; 95% CI, 0.43-0.93)
(FIGURE 2), and all-cause mortality was
13.2% in patients assigned to CRT vs
15.5% in controls (RR, 0.78; 95% CI,
0.67-0.91) (FIGURE 3). The survival
benefit was driven largely by reductions in progressive heart failure deaths
(RR, 0.64; 95% CI, 0.49-0.84). Although the mortality reduction with
CRT was evident by 6 months in these
trials, the mortality reduction was larger
in those RCTs with the longest followup. For example, a long-term extension of the CARE-HF trial 137 confirmed that the relative survival benefits
of CRT were stable (constant hazard ratio), and as such the absolute magnitude of benefit increased substantially
over time. Consequently, although our
meta-analysis demonstrated a number
needed to treat to prevent 1 death of 29
patients at 6 months, the CARE-HF trial
follow-up data demonstrated the numbers needed to treat to prevent 1 death
of 13 patients at 2 years and 9 patients
at 3 years.137 The long-term impact of
©2007 American Medical Association. All rights reserved.
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CARDIAC RESYNCHRONIZATION THERAPY AND LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
Figure 2. Effect of CRT on Proportion of Patients Hospitalized for Heart Failure (Randomized Trial Data)
Hospitalization for Heart
Failure, No./Total
Source
CRT Alone vs Medical Therapy
MUSTIC-SR,9 2001
MIRACLE,8 2002
MUSTIC-AF,11 2002
RD-CHF,14 2003
CARE-HF,19 2005
CRT
3/29
18/228
1/25
1/22
72/409
Control
9/29
34/225
2/18
7/22
133/404
Relative Risk
(95% Confidence Interval)
0.33 (0.10-1.11)
0.52 (0.30-0.90)
0.36 (0.04-3.67)
0.14 (0.02-1.07)
0.53 (0.42-0.69)
95/713
185/698
0.51 (0.41-0.64)
32/245
85/187
39/245
78/182
0.82 (0.53-1.26)
1.06 (0.84-1.33)
Subtotal
Test for Heterogeneity: χ21 = 1.10; P = .29; I 2 = 8.8%
Test for Overall Effect: Z = 0.04; P = .97
117/432
117/427
1.00 (0.80-1.24)
Total
Test for Heterogeneity: χ26 = 23.08; P<.001; I 2 = 74.0%
Test for Overall Effect: Z = 2.34; P = .02
212/1145
302/1125
0.63 (0.43-0.93)
Subtotal
Test for Heterogeneity: χ24 = 2.27; P = .69; I 2 = 0%
Test for Overall Effect: Z = 5.88; P<.001
CRT + ICD vs ICD Alone
CONTAK-CD,13 2003
MIRACLE-ICD,10 2003
Favors
CRT
0.01
0.1
Favors
Control
1.0
10
100
Relative Risk (95% Confidence Interval)
CRT indicates cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator. Size of data markers indicates the weight of the study.
Figure 3. Effect of CRT on All-Cause Mortality (Randomized Trial Data)
All-Cause Mortality,
No./Total
Source
CRT Alone vs Medical Therapy
MUSTIC-SR,9 2001
MIRACLE,8 2002
MUSTIC-AF,11 2002
PATH-CHF,12 2002
PATH-CHF II,16 2003
RD-CHF,14 2003
COMPANION,15 2004
CARE-HF,19 2005
VECTOR,20 2005
HOBIPACE,17 2006
CRT
1/29
12/228
1/25
2/24
2/43
2/22
131/617
92/409
1/59
1/16
Control
0/29
16/225
0/18
0/17
3/43
4/22
77/308
129/404
1/47
1/16
Relative Risk
(95% Confidence Interval)
3.00 (0.13-70.74)
0.74 (0.36-1.53)
2.19 (0.09-50.93)
3.60 (0.18-70.54)
0.67 (0.12-3.79)
0.50 (0.10-2.45)
0.85 (0.66-1.09)
0.70 (0.56-0.89)
0.80 (0.05-12.40)
1.00 (0.07-14.64)
245/1472
231/1129
0.77 (0.66-0.91)
11/245
14/187
2/85
6/119
16/245
15/182
2/101
2/60
0.69 (0.33-1.45)
0.91 (0.45-1.83)
1.19 (0.17-8.26)
1.51 (0.31-7.27)
Subtotal
Test for Heterogeneity: χ23 = 0.97; P = .81; I 2 = 0%
Test for Overall Effect: Z = 0.60; P = .55
33/636
35/588
0.86 (0.54-1.39)
Total
Test for Heterogeneity: χ132 = 4.90; P = .98; I 2 = 0%
Test for Overall Effect: Z = 3.18; P = .001
278/2108
266/1717
0.78 (0.67-0.91)
Subtotal
Test for Heterogeneity: χ29 = 3.72; P = .93; I 2 = 0%
Test for Overall Effect: Z = 3.16; P = .002
CRT + ICD vs ICD Alone
CONTAK-CD,13 2003
MIRACLE-ICD,10 2003
MIRACLE ICD II,18 2004
RHYTHM-ICD,21 2005
Favors
CRT
0.01
0.1
Favors
Control
1.0
10
100
Relative Risk (95% Confidence Interval)
CRT indicates cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator. Size of data markers indicates the weight of the study.
©2007 American Medical Association. All rights reserved.
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2505
CARDIAC RESYNCHRONIZATION THERAPY AND LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
CRT on hospitalizations and functional outcomes is uncertain due to a
paucity of data at this time.
No definitive subgroup effects were
apparent in the CRT RCTs, although it
should be recognized that these RCTs
were not powered to detect subgroup
effects of small to moderate magnitude. For example, although the PATH
CHF II Investigators16 reported significantly greater improvements in exercise capacity in their 16 patients with
QRS duration of more than 150 milliseconds at baseline than in those with
shorter QRS width, the 5 other
RCTs8,10,13,15,19 that evaluated this subgroup did not find such a relationship. Furthermore, although a post hoc
analysis of the MIRACLE trial138 suggested that patients with an ischemic
etiology demonstrated less improvements in LVEF and LV volumes with
CRT than those patients with nonischemic disease, the effect of CRT on mortality did not differ between patients
with and without ischemia in the
CONTAK CD,13 COMPANION,15 or
CARE-HF19 studies (3 RCTs that specifically tested for this interaction in a
priori specified subgroup analyses).
Univariate meta-regressions found no
significant modification of the effect of
CRT on all-cause mortality by presence or absence of ICD, ischemic etiology, duration of follow-up, whether
randomization was predevice or postdevice implantation, whether the RCT
was industry funded, the Jadad score
for the RCT, or various patient characteristics (including NYHA class, age,
or LVEF, within the narrow range enrolled in these RCTs). However, these
meta-regression analyses were based on
aggregate data from a small number of
relatively homogenous trials and thus
were underpowered to detect subgroup effects. In contrast, several factors were found to be associated with
a reduced benefit from CRT on heart
failure hospitalizations (presence of an
ICD in both controls and patients assigned to CRT [P⬍.001], NYHA class
2 at baseline [P = .003], and higher
LVEF [P=.004]). Although CRT markedly reduced the proportion of pa-
tients hospitalized with heart failure
when compared with medical therapy
alone (RR, 0.51; 95% CI, 0.41-0.64; in
the 5 RCTs reporting this outcome [280
of 1411 patients hospitalized]), CRT
had no effect on heart failure hospitalizations in those trials in which combined CRT-ICD devices were compared with ICD-alone devices (RR, 1.00;
95% CI, 0.80-1.24; in 2 trials [234 of
859 patients hospitalized]).
The COMPANION trial 1 5 performed the only direct comparison between combined CRT-ICD devices and
medical therapy alone, and confirmed
that combined CRT-ICD devices reduced all-cause mortality (hazard ratio, 0.64; 95% CI, 0.48-0.86) and improved 6-minute walk test distance
(weighted mean difference, 45 m; 95%
CI, 27-63 m), NYHA class (RR, 1.49;
95% CI, 1.23-1.81; for improving at
least 1 NYHA class), and quality of life
(weighted mean difference in Minnesota Living With Heart Failure Questionnaire, 14 points; 95% CI, 10-18
points) compared with medical therapy
alone.
The COMPANION trial15 also permits a secondary comparison of combined CRT-ICD devices vs CRT-alone
devices within the same trial. Although this latter comparison is underpowered and was not prespecified
in the protocol, there was a statistically nonsignificant reduction in allcause mortality (P=.13) and in time to
death or heart failure hospitalization in
those patients receiving the combined
CRT-ICD device compared with those
receiving the CRT-alone device.15 This
is consistent with our meta-regression
of aggregate trial data, which suggested that combined CRT-ICD devices and CRT-alone devices demonstrated similar effects, but is also not
definitive.
Effectiveness of CRT
Survival over time in recipients of CRT
or combined CRT-ICD devices was
similar in the 95 observational studies
that reported this outcome as in the 14
RCTs. Only 1 observational study43
compared outcomes in patients with
2506 JAMA, June 13, 2007—Vol 297, No. 22 (Reprinted)
CRT with outcomes in contemporaneous controls without CRT; their findings of improved LVEF (weighted mean
difference, 4.6%; 95% CI, 2.9%-6.3%)
and lower mortality rates (RR, 0.64;
95% CI, 0.26-1.56) in the CRT group
were consistent in magnitude to the
findings from our meta-analysis of the
CRT trials.
The pooled effectiveness estimates
from the observational studies for functional outcomes were consistent with
those estimates from the efficacy RCTs.
For example, in the RCTs, 59% of patients implanted with a CRT device improved by at least 1 NYHA class, and
in the observational studies between
63% and 82% of patients improved by
at least 1 NYHA class (TABLE 1). Determining the true response rate with
CRT is hampered by the lack of a universally accepted definition for response139 and the fact that patients may
demonstrate a response clinically but
not echocardiographically or vice versa
(with only 76% agreement in the classification of responder/nonresponder
between definitions).140 No covariates
were consistently shown across studies to predict CRT response.
Safety of CRT
In 54 studies (6123 patients) of CRTalone devices, implant success rate was
93.0% (95% CI, 92.2%-93.7%), periimplantation mechanical complications
occurred in 4.3% (95% CI, 3.6%5.1%) of procedures, and periimplant deaths occurred in 0.3% of patients (95% CI, 0.1%-0.6%). During a
median 6-month follow-up, 5% (95%
CI, 4%-7%) of CRT devices malfunctioned and 1.8% (95% CI, 1.3%-2.5%)
of patients were hospitalized for infections in the implant site; and during a
median 11-month follow-up, lead problems occurred in 6.6% (95% CI, 5.6%7.4%) of CRT devices. Although earlier studies raised concerns about a
potentially higher risk of non–heart failure outcomes in patients with CRT
(particularly an excess of ventricular arrhythmias),141 pooling the data from all
of the RCTs did not reveal any excess
risk of sudden death (RR, 1.07; 95% CI,
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CARDIAC RESYNCHRONIZATION THERAPY AND LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
0.79-1.46) or noncardiac death (RR,
0.81; 95% CI, 0.43-1.52) in recipients
of a CRT device.
In 36 studies (5199 patients) of
combined CRT-ICD devices, safety
outcomes were similar to CRT-alone
devices (implant success rate was
93.7% [95% CI, 92.9%-94.4%]; periimplantation mechanical complica-
Table 1. Response Rates Reported in Observational Studies: CRT Alone or Combined CRT-ICD Devices
Follow-up, Sample
mo
Size
Source
Functional definition of response
CRT alone
Bleeker et al,34 2005
Definition of Responder
Proportion of
Responders, %
Independent
Predictors of
Positive Response
6
170
Improved ⱖ1 NYHA class
78
Chan et al,47 2003
Lecoq et al,72 2005
3
6
63
139
67
72
Lenom et al,73 2005
Molhoek et al,86 2005
Sawhney et al,109 2004
6
6
3
36
74
40
6-min walk test increased 10%
Alive, no CHF hospitalizations, improved
ⱖ1 NYHA class or ⬎10% increase V̇O2max
during 6-min walk test
Improved NYHA class
Improved ⱖ1 NYHA class
Improved ⱖ1 NYHA class
Ståhlberg et al,112 2005
6
35
Alive, no CHF hospitalizations, improved
ⱖ1 NYHA class and/or 10% increase
in 6-min walk test distance
66
Not performed
Analysis by etiology*
Acute response to CRT
by aortic Doppler VTI
Not performed
Combined CRT-ICD
Alonso et al,25 1999
6
26
73
Not performed
Bax et al,33 2004
6
85
Alive, improved ⱖ1 NYHA class, 10%
increase in peak V̇O2max
Improved ⱖ1 NYHA class, improved 6-min
walk test ⱖ25%
74
Díaz-Infante et al,53 2005
6
143
Hernández et al,63 2004
6
Kiès et al,65 2005
Baseline LV
dysynchrony of ⱖ65
milliseconds
Etiology, mitral
regurgitation,
LVEDD ⬍75 mm
BNP level, etiology,
baseline NYHA
Analysis by diabetes
mellitus vs no
diabetes mellitus*
Not performed
NYHA class 3 vs 4
Analysis by
baseline QRS*
Etiology, cardiac output
71
68
63
Alive, no heart transplant, 10% increase
in 6-min walk test
80
28
Improved 6-min walk test ⱖ10%
79
6
97
Improved ⱖ1 NYHA class
74
Molhoek et al,83 2004
Molhoek et al,84 2004
Molhoek et al,85 2004
6
6
6
60
117
61
Improved ⱖ1 NYHA class
Improved ⱖ1 NYHA class
Improved ⱖ1 NYHA class
72
78
74
Reuter et al,104 2002
12
102
Improved NYHA class associated with
improved quality of life score
82
6
6
25
49
Absolute increase in LVEF ⱖ5%
Relative increase in LVEF ⱖ25%
68
55
Yu et al,122 2002
Multiple definitions of response
CRT alone
Mascioli et al,80 2002
3-6
141
Reduction in LV end-systolic volume ⬎10%
62
6
68
69
Yu et al,124 2004
3
30
Improved ⱖ1 NYHA class, LVEF increased
by ⱖ10%
Reduction in LV end-systolic volume ⬎15%
3
49
Clinical: any 2 of (1) improved ⱖ1 NYHA class,
(2) ⬎50 m increase in 6-min walk test,
or (3) decrease in quality of life
score = 15 points
Echocardiographic: reduction in LV
end-systolic volume ⬎15%
75 (clinical)
Echocardiographic definition of response
CRT alone
Bax et al,32 2003
Penicka et al,97 2004
Combined CRT-ICD
Notabartolo et al,92 2004
57
59 (echo)
Analysis by age
⬍70 vs ⱖ70 years*
Not performed
⌬ QRS (step of 20
milliseconds)
Septal to lateral delay
Tissue doppler imaging
derived indices
of asynchrony
None
Analysis performed
but none found
Systolic dysynchrony by
tissue doppler
imaging
PVD predicted
echocardiographic
response; no
significant predictors
of clinical response
Abbreviations: BNP, brain natriuretic peptide; CHF, congestive heart failure; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator; LV, left ventricular; LVEDD,
LV end-diastolic diameter; LVEF, LV ejection fraction; NYHA, New York Heart Association class; PVD, pulmonary vein doppler; V̇O2max, maximum oxygen consumption; VTI, velocity
time integral.
*Not significant (P⬎.05).
©2007 American Medical Association. All rights reserved.
(Reprinted) JAMA, June 13, 2007—Vol 297, No. 22
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2507
CARDIAC RESYNCHRONIZATION THERAPY AND LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
tions occurred in 4.6% [95% CI, 3.7%5.6%] of procedures; peri-implant
deaths occurred in 0.5% [95% CI,
0.2%-0.8%] of patients; and during a
median 12-month follow-up, 5% [95%
CI, 4.0%-6.3%] of combined CRT-ICD
devices malfunctioned, 1.1% [95% CI,
0.7%-1.7%] of patients developed site
infection, and lead problems were
detected in 7.2% [95% CI, 6.3%-8.1%]
of patients). There were no appreciable differences between implant
success rates or frequency of adverse
events in the RCTs or the observational studies for CRT-alone or combined CRT-ICD devices.
Cost-effectiveness of CRT
Five published decision analyses142-146
have explored the cost-effectiveness of
CRT therapy. Although 1 study142 estimated the median incremental cost of
CRT plus medical therapy over medical therapy alone to be as high as
$107 800 per quality-adjusted lifeyear, this was based on outcome data
from the early CRT RCTs (most of
which reported outcome data only
within the first 3 months after CRT
activation). Four subsequent costeffectiveness analyses, 143-146 which
incorporated more recently published
trials with substantially longer
follow-up durations, reported lower
incremental costs per quality-adjusted
life-year gained with CRT devices:
$19 600 in an analysis of the
COMPANION trial data,143 £19 319
(US $38 202) in an analysis of the
CARE-HF trial data, 144 €7538 (US
$10 192) in an analysis using data
from the COMPANION trial and longterm follow-up data from the
CARE-HF database, 145 and £16 598
(US $32 822) in an analysis based on
data from the 5 longest CRT RCTs.146
An analysis using long-term individual
patient data from the CARE-HF trial
confirmed that CRT alone was costeffective in all age groups (ranging
from €7139 [US $9653] per qualityadjusted life-year in 55-year-old
patients to €7982 [US $10 792] in
75-year-old patients).145 Combined
CRT-ICD devices were also found to
be cost-effective when compared
against medical therapy (€18 017 [US
$24 360] per quality-adjusted life-year
gained), but the cost-effectiveness
ratios were less favorable in older
patients (€15 805 [US $21 370] in
55-year-old patients vs €22 490 [US
$30 408] in 75-year-old patients).145
The incremental cost-effectiveness of
combined CRT-ICD devices vs CRTalone devices, however, was markedly
higher in all of these analyses
($171 538 per quality-adjusted lifeyear in the United States, £34 664 [US
$68 547] in the United Kingdom, and
€47 909 [US $64 777] in Europe).
Thus, although CRT-alone devices are
clearly cost-effective compared with
medical therapy alone in trial eligible
patients, the cost-effectiveness ratios
when these devices are used in clinical
practice are uncertain, as is the incremental cost-effectiveness of combined
CRT-ICD devices vs CRT-alone
devices remains uncertain pending
further research.
Proportion of Patients
With Heart Failure Likely
to Be Eligible for CRT
Approximately 1% to 3% of all
patients discharged alive after their
index hospitalization for heart failure
and 15% to 20% of patients observed
in specialized heart failure clinics met
CRT trial eligibility criteria (LVEF
ⱕ35%, QRS ⱖ120 milliseconds, sinus
rhythm, and NYHA class 3 or 4 symptoms despite optimal medical management).147 Of these patients, approximately 50% also met trial eligibility
criteria for an ICD.148
Controversies and Areas
for Future Research
Despite consistent evidence across published studies, a number of areas of uncertainty remain. Some of these gray
areas result from the underrepresentation of patients with particular characteristics, such as bradyarrhythmias,
atrial fibrillation, less severe heart failure symptoms, chronic kidney disease, or right-bundle branch blocks, in
the RCTs conducted thus far and should
2508 JAMA, June 13, 2007—Vol 297, No. 22 (Reprinted)
be resolved by ongoing trials (TABLE 2).
However, a number of other caveats
should be raised when considering the
CRT data presented herein.
First, an important question about
CRT, as with any new therapy, is
whether the efficacy demonstrated in
RCTs translates into effectiveness
when applied in clinical practice. This
is of particular concern for device
therapies such as CRT that have been
tested in a selected spectrum of
patients and depend on specialized
technical expertise. Thus, although
the trials proving the efficacy of CRT
enrolled relatively young patients and
a high proportion of men, populationbased cohort data147 demonstrate that
patients with heart failure in clinical
practice are almost a decade older than
trial participants and have a substantially greater burden of comorbid illnesses. Recent analyses of Medicare
ICD recipients confirmed that these
devices are being implanted in older
patients with more comorbidities152
than trial participants, and are being
implanted by less experienced health
care practitioners working in lower
volume hospitals153 than those health
care practitioners and hospitals that
participated in the RCTs. It seems
likely that such trends exist in CRT
implants as well.
Second, approximately half of the patients in our efficacy analysis were participants in RCTs that randomized patients only after successful device
implantation; as a result, patients who
could not tolerate the procedure or in
whom implantation was unsuccessful
were not included in the final trial data.
Although our meta-regression did not
demonstrate this factor to be statistically significantly related to magnitude of demonstrated benefits, this
analysis was underpowered due to the
small number of studies, and it is still
possible that these RCTs may overestimate the potential benefits from CRT
and underestimate the risks.
And third, our estimates of implant
success and peri-implant vs postimplant safety are based on only a few
thousand patients and thus should not
©2007 American Medical Association. All rights reserved.
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CARDIAC RESYNCHRONIZATION THERAPY AND LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
be considered definitive (particularly in
light of the recent experiences with ICD
device recalls).
These points serve to emphasize
the importance of establishing a prospective CRT registry—akin to the
Heart Rhythm Society and American
College of Cardiology National Cardiovascular Data Registry for ICD
devices—to provide real world estimates of benefits and risks with CRT
or combined CRT-ICD devices. Such
a registry would also provide much
needed data on the long-term func-
tional and morbidity outcomes with
CRT and combined CRT-ICD devices,
and would permit the tracking of
complication rates as device implanters, the tools for implantation, and the
sophistication of the devices change
over time.
Table 2. Summary of Evidence for CRT Alone or Combined CRT-ICD Devices in Patients With Left Ventricular Systolic Dysfunction
(LVEF ⱕ35%)*
Other Characteristics
Device
CRT alone
Symptom
Status
NYHA class
3 or 4
Electrocardiogram
Criteria
QRS ⬎120
millisecond and
sinus rhythm
NYHA class 2 QRS ⬎120
millisecond and
sinus rhythm
Magnitude of Effect
Conclusion
High (multiple RCTs with Reduced mortality: RR, 0.78;
homogeneous
95% CI, 0.67-0.91
results)
Reduced heart failure
hospitalizations: RR, 0.51;
95% CI, 0.41-0.64
5 RCTs, 344
patients
No significant effect on mortality
Moderate (1 small RCT
Inconclusive
(in 1 RCT: RR, 1.19; 95% CI,
plus post hoc
0.17-8.26); in meta-regression,
meta-regression of
patients with class 2 symptoms
aggregate trial data
not significantly associated with
from 14 RCTs, but
reduction in mortality (P = .76)
few patients had
Effect on hospitalization smaller in
NYHA class 2)
NYHA class 2 vs class 3 or 4
Ongoing RCTs:
heart failure; in meta-regression,
REVERSE,149 RAFT†
patients with class 2 symptoms
significantly associated with
reduction in hospitalization
(P = .003)
Definite benefit
QRS ⬎120
3 RCTs, 191
millisecond and
patients
bradyarrhythmia
or atrial fibrillation
Low (post hoc
meta-regression of
aggregate trial data
from 14 RCTs)
Ongoing RCTs‡: Trip
HF, RAFT,† APAF,
BLOCK HF
NYHA class
3 or 4
QRS ⬍120
millisecond
Any rhythm
5 nonrandomized
studies, 120
patients
Low (secondary analyses Improvements in symptoms and
of small
LV remodelling not significantly
observational
different between patients with
studies)
narrow QRS and patients with
wide QRS in any of the studies
Inconclusive
None
No published evidence
Ongoing RCT:
REVERSE149
Not applicable
Inconclusive
1 RCT, 903
patients in
relevant
comparison
groups
Moderate (1 large RCT)
Ongoing RCTs:
DECREASE-HF,150
RAFT†
Reduced mortality: HR, 0.64;
95% CI, 0.48-0.86
Reduced mortality or all-cause
hospitalization: HR, 0.80;
95% CI, 0.68-0.95
Definite benefit
None
No published evidence
Ongoing RCTs:
MADIT-CRT,151
RAFT†
Not applicable
Inconclusive
1 RCT, 1212
patients in
relevant
comparison
groups
Moderate (1 large RCT,
but comparison was
not a priori specified
or adequately
powered)
No significant effect on mortality
Inconclusive
(RR, 0.83; 95% CI, 0.66-1.05)
and no significant effect on time
to death in NYHA class 4
subgroup (HR, 1.27; 95% CI,
0.68-2.37)
None
No published evidence
Not applicable
NYHA class
3 or 4
QRS ⬎120
millisecond and
sinus rhythm
All other patient subgroups
Combined
CRT-ICD
device (vs
CRT alone)
Quality of Evidence
13 RCTs, 3481
patients
NYHA class
3 or 4
NYHA class 1 Any QRS duration
Any rhythm
Combined
CRT-ICD
device (vs
no device)
Quantity of
Evidence for
Patient
Subgroup
NYHA class
3 or 4
QRS ⬎120
millisecond and
sinus rhythm
All other patient subgroups
No significant association in
meta-regression between
patients with atrial fibrillation
and reduction in mortality or
hospitalizations (P = .73 and
P = .58, respectively)
Inconclusive
Inconclusive
Abbreviations: CI, confidence interval; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator; HR, hazard ratio; LV, left ventricular; LVEF, LV ejection fraction;
NYHA, New York Heart Association class; RCT, randomized controlled trial; RR, risk ratio.
*Note that other considerations may outweigh the trial evidence in some situations (for example, the patient who wishes to be “do not resuscitate”), and there is no data on the effects of
either CRT or ICD in patients with advanced age or severe comorbidities, such as end-stage renal disease.
†Resynchronization/Defibrillation for Advanced Heart Failure Trial (http://www.clinicaltrials.gov: NCT00251251).
‡Protocols can be found at http://www.clinicaltrials.gov (Trip HF: NCT00187265; APAF: NCT00111527; BLOCK HF: NCT00267098).
©2007 American Medical Association. All rights reserved.
(Reprinted) JAMA, June 13, 2007—Vol 297, No. 22
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2509
CARDIAC RESYNCHRONIZATION THERAPY AND LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
Second, although we were unable to
detect any differential subgroup effects in the efficacy of CRT, the RCT
subgroup analyses and our metaregressions were post hoc and underpowered. Individual patient data from
the RCTs conducted thus far would be
needed to appropriately examine this
issue, and we believe the compilation
and analysis of this data should be an
urgent research priority in this field. Indeed, relying on RCT eligibility criteria to define those patients most likely
to benefit is imperfect, particularly since
more than one third of CRT recipients
do not exhibit any functional or echocardiographic improvements after activation of their CRT.
In particular, QRS duration has been
used to select patients for CRT in the
RCTs conducted thus far and it is uncertain whether, and to what extent, the
use of newer techniques to detect electromechanical dyssynchrony, such as
tissue doppler imaging, or to detect
those patients at increased risk for ventricular arrhythmias, such as the microvolt T-wave alternans test, will impact the effectiveness and safety of these
devices.154
Although the incremental benefit of
combined CRT-ICD devices vs ICD
alone is uncertain, this issue should
be resolved after the ongoing RAFT
(Resynchronization/Defibrillation for
Advanced Heart Failure Trial; http:
//www.clinicaltrial.gov: NCT00251251)
and DECREASE-HF150 trials are completed. However, we are not aware of any
ongoing randomized trials exploring the
incremental benefit of combined CRTICD devices vs CRT alone, which we believe is a key area of residual uncertainty for patients with LV systolic
dysfunction. Because CRT alone appears to reduce the frequency of ventricular arrhythmias155 and the longterm risk of sudden death, 1 3 7 the
incremental benefits of a combined CRTICD device in patients who are CRT eligible may be less than anticipated by
those clinicians extrapolating from RCTs
comparing ICD with drug therapy. Although we believe that combined CRTICD devices should be considered in pa-
tients who are CRT eligible who would
otherwise be candidates for ICD (those
patients with a history of, or at increased risk for, sudden cardiac death
who do not have significant comorbidities), this should not be extrapolated to
endorse the implantation of combined
CRT-ICD devices in all patients who are
CRT eligible or all patients who are ICD
eligible. We believe there is a need for
device manufacturers and trialists to design studies that compare the effect of
combined CRT-ICD devices with CRTalone devices.
CONCLUSIONS
CRT is an efficacious and costeffective therapy for patients with
NYHA class 3 or 4 heart failure despite optimal medical management, an
LVEF of 35% or less, sinus rhythm, and
ventricular dyssynchrony (currently
identified by prolonged QRS duration). CRT improves ventricular function and remodelling, symptoms, and
exercise capacity, while also reducing
frequency of heart failure hospitalizations by 37% and death by 22%. The
magnitude of these benefits are similar to those reported for angiotensinconverting enzyme inhibitors or
␤-blockers and are additive to the benefit of such medical therapy. Although the periprocedural risks of CRT
appear modest and are similar to the frequency reported for patients undergoing implantation of conventional dualchamber pacemakers,156 there is a 5%
risk of device or lead failure and a 2%
risk of infection in the first 6 months
after CRT implantation, and these risks
should be factored into clinical decisions about whether to refer a patient
for device implantation.
However, implantation of a CRT
pacemaker (in particular the LV lead)
can be technically challenging, and
device malfunctions or lead problems
(most frequently with the LV lead) are
not infrequent. Even when lead placement is thought to be successful, CRT
does not always restore mechanical
synchrony. Studies to define which
patients are most likely to benefit from
CRT, such as the ongoing Predictors
2510 JAMA, June 13, 2007—Vol 297, No. 22 (Reprinted)
of Response to Cardiac Resynchronization Therapy Study,157 and which
positions in the ventricular wall are
most appropriate for implantation of
the pacing leads are clear research priorities,154 as are studies to better define
which patients who are CRT eligible
are at highest risk for ventricular
arrhythmias and thus most likely to
benefit from a combined CRT-ICD
device.
Author Contributions: Dr McAlister had full access to
all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analysis.
Study concept and design: McAlister, Ezekowitz, Page,
Rowe.
Acquisition of data: McAlister, Ezekowitz, Hooton,
Spooner, Dryden.
Analysis and interpretation of data: McAlister,
Ezekowitz, Vandermeer, Page, Hltaky, Rowe.
Drafting of the manuscript: McAlister, Ezekowitz,
Vandermeer.
Critical revision of the manuscript for important intellectual content: McAlister, Ezekowitz, Hooton,
Vandermeer, Spooner, Dryden, Page, Hltaky, Rowe.
Statistical analysis: Vandermeer.
Obtained funding: Rowe.
Administrative, technical, or material support: Hooton,
Spooner, Dryden.
Study supervision: McAlister, Ezekowitz, Hooton,
Dryden.
Financial Disclosures: Dr Page is an officer of the Heart
Rhythm Society and a member of the Circulatory System Device Panel of the Medical Devices Advisory
Committee, Center for Devices and Radiological Health,
Food and Drug Administration. He reports serving
within the past 5 years as a consultant for Procter &
Gamble Pharmaceuticals, GlaxoSmithKline, AstraZeneca, Forrest Research, Cardiome, Pharma Corp, Alza
Corp, Berlex Labs, Hewlett Packard Co, Reliant Pharmaceuticals Inc, Sanofi-Aventis, and Pfizer Inc. No other
authors reported financial disclosures.
Funding/Support: This work was based on an evidence report produced by the University of Alberta
Evidence-based Practice Center under contract 29002-0023 from the Agency for Healthcare Research and
Quality (AHRQ), US Department of Health and Human Services, Rockville, Md. The authors of this article are responsible for its content. Dr McAlister is a
Population Health Scholar supported by the Alberta
Heritage Foundation for Medical Research, a New Investigator of the Canadian Institutes of Health Research (CIHR), and holds the Merck Frosst/Aventis
Chair in Patient Health Management at the University of Alberta, Edmonton. Dr Ezekowitz is supported
by CIHR. Dr Rowe is supported by the 21st Century
Canada Research Chairs program through the Government of Canada. He is also supported by the Faculty of Medicine and Dentistry, University of Alberta,
Edmonton, and the Capital Health Authority,
Edmonton.
Role of the Sponsor: The funding source had no role
in the collection, analysis, or interpretation of the data,
or in the preparation of the manuscript, or in the decision to submit the paper for publication.
Disclaimer: Statements in this article should not be construed as endorsement by the AHRQ or the US Department of Health and Human Services.
Acknowledgment: We thank the members of the technical expert panel for this AHRQ article: Gillian D. Sanders, PhD, Department of Medicine, Duke University
Medical Center, Durham, NC, William T. Abraham,
©2007 American Medical Association. All rights reserved.
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CARDIAC RESYNCHRONIZATION THERAPY AND LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
MD, Division of Cardiovascular Medicine, The Ohio
State University, Columbus, and Mary Nix, MS, MT
(ASCP), AHRQ, who provided direction for the scope
and content of the review. We also thank our librarians, Carol Friesen, MA, MLIS, and Tamara Durec, BSc,
MLIS, University of Alberta Evidence-based Practice
Center, Edmonton, Alberta, and the external reviewers who submitted written comments on earlier drafts
of the manuscript: David Atkins, MD, MPH, AHRQ,
Eric Fain, MD, St Jude Medical, Sunnyvale, Calif, Martin Fromer, MD, Centre Hospitalier Universtaire Vaudois, Lausanne, Switzerland, Gordon Moe, MS, MD,
FRCPC, Heart Failure Program and Biomarker Laboratory, St Michael’s Hospital, University of Toronto,
Toronto, Ontario, Robert F. Rea, MD, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minn, John Spertus, MD, MPH, Cardiovascular Education and Outcomes Research,
University of Missouri, Kansas City, Mo, Bob Thompson, MS, MA, Medtronic Inc, Minneapolis, Minn, and
Clyde W. Yancy, MD, Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Tex.
No persons mentioned received any financial compensation outside of the baseline salary paid to employees of the University of Alberta Evidence-based
Practice Center, which is supported by the AHRQ. Finally, we also thank William T. Abraham, MD, C.
Leclerq, MD, and S. Cazeau, MD, for providing further information about their studies.
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Let me advise you not to aim too high. The big prizes
in our profession are only for the few, and they do not
always bring much happiness when gained. “Seekest
thou great things? Seek them not,” as the wise man
said. If you have earned enough for your needs and
been able to put a little aside for your old age, and if,
at the same time, you have won the esteem of your
colleagues and the affection of your patients, you have
done well enough, and that measure of success should
be within the reach of most of you.
—Sir Robert Hutchison (1871-1960)
2514 JAMA, June 13, 2007—Vol 297, No. 22 (Reprinted)
©2007 American Medical Association. All rights reserved.
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