Evidence Report/Technology Assessment: Number 106
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Introduction / Methods / Results / Discussion / Limitations of Research / Conclusions / Availability of Full Report / References
Heart failure is the fastest growing
cardiovascular diagnosis in North America, and it
carries a poor prognosis.1,2 To improve survival in
heart failure patients, therapies need to reduce
either sudden cardiac death (the most common
cause of death in patients with New York Heart
Association [NYHA] Class I or II symptoms) or
progressive heart failure (the predominant cause
of death in those with NYHA Class III or IV
Electrical conduction disturbances are common
in heart failure and are associated with increased
mortality risk.5-7 Atrial-synchronized biventricular
pacing (cardiac resynchronization therapy [CRT])
addresses many of the pathophysiological changes
seen in patients with wide QRS complexes in
whom delayed activation of the left free wall
results in mechanical dyssynchrony.
The University of Alberta Evidence-based
Practice Center conducted a systematic review to
examine the success rate and safety of
biventricular pacemaker implantation and the
efficacy of CRT in patients with heart failure.
Further, the researchers used these data in a
decision analysis to evaluate the incremental cost-effectiveness
of CRT versus medical therapy
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This report addresses the following questions:
- In adult patients with symptomatic heart failure, is CRT more effective than optimal medical care alone?
- Is the implantation of a CRT system safe for patients?
- What is the role of CRT in the treatment of heart failure?
- What is the cost-effectiveness of CRT in patients with congestive heart failure?
Detailed searches were conducted of the
Cochrane Heart Group Trial Registry, Cochrane
Library, EMBASE, International Pharmaceutical
Abstracts, MEDLINE®, Web of Science®, and
multiple trial registries. In addition, the
researchers contacted the primary authors of
included studies, sought U.S. Food and Drug
Administration reports, and reviewed the
reference lists of all included articles. Additional
unpublished data were sought from the
companies that produce CRT devices: Medtronic,
Inc., Guidant Corporation, and ELA Medical
The search was not limited
by language or publication status and is
considered up to date as of June 30, 2003.
Selection and Data Extraction
Two investigators independently screened all
titles and abstracts, and another two investigators
independently assessed the full text of potentially
relevant studies and extracted data.
Disagreements were resolved through third-party
adjudication or consensus.
Intention-to-treat analyses were done using the
same standardized endpoint definitions employed
in the primary studies. Stata 7.0 (Stata Corporation, version 7.0, 2003) was used to pool data and
calculate summary risk ratios for dichotomous results and
weighted mean differences for continuous variables. Because of
expected differences between studies (particularly in control
group therapies), the researchers decided a priori to combine
results primarily using a random effects model. Fixed effects
models were considered in sensitivity analyses. Statistical
heterogeneity was assessed by the chi-square test and was
quantified and appropriated using the I-squared statistic.8
Time-to-death data were summarized by the log hazards ratio;
Cox proportional hazards and/or Kaplan-Meier curves were
generated where appropriate.9,10
Simple pooling and exact 95-percent confidence intervals
(CIs) were used for the safety analyses. However, given the
possibility that reports may not always have reported zero for
adverse events that did not occur, the researchers performed
sensitivity analyses for safety outcomes in which they assumed
that, if a particular event (for example, peri-implantation death)
was not mentioned in a report, then it did not occur and
assigned a zero for that outcome in that study.
Decision Analysis Methods
A Markov decision model was constructed to compare the
lifetime effects and costs of CRT versus medical therapy for
patients with symptomatic heart failure. The analysis adopted
the U.S. health care perspective (including costs of
hospitalization, procedures, ambulatory visits, medications, and
laboratory tests), and costs are expressed in 2003 American
dollars. Input data were derived from multiple sources:
- Outcomes with CRT and risks of the procedure were derived from a systematic review with annualization using an exponential approximation.11,12 Transition probabilities incorporated into the Markov model were adjusted for the cycle length.
- The health-related quality of life of patients with heart failure was estimated by eliciting utilities. Since the purpose of the decision analytic model was to consider an intervention in the context of resource allocation among different types of interventions, a generic source of preferences was used.13 A convenience sample (n = 66) was recruited of members of the general public age 40 and over and without underlying cardiac disease. Consenting subjects estimated utilities for standardized health state descriptions (NYHA Class II, III, and IV) by using the standard gamble technique.14 Hypothetical scenarios describing what one would typically feel and experience if living with each of these health states were developed with input from an expert panel based on descriptors from the Health Utilities Index.15
- The cost of a device capable of CRT was depreciated over its anticipated lifespan. Physician costs related to CRT implantation were based on Current Procedural Terminology codes.16 The costs of a resynchronization device were based on a survey of manufacturers' list prices. The costs of hospitalizations associated with heart failure were based on estimates derived from a cohort study of health resource use by patients participating in a previous randomized trial of medical therapy for heart failure.17 All costs were adjusted for inflation by using the U.S. Consumer Price Index.18
Structure of Decision Model
The primary analysis considered patients with NYHA Class III symptoms. The analysis considered the lifetime horizon and employed a state-transition Markov model with a cycle length
of 1 month. During each cycle, patients who received medical
therapy could die of unrelated causes, die of cardiovascular
disease, be hospitalized for heart failure, or remain stable.
Patients who underwent insertion of a device capable of CRT
could die during the initial implantation of the device or
experience lead infection, lead failure, battery failure, or any of
the health states associated with medical therapy for heart
Decision analyses were performed with DATA Pro™
software (TreeAge Software, Inc., Williamstown, Massachusetts)
and Excel 2000 software (Microsoft Corporation, Redmond,
Assumptions in Decision Analysis
A number of assumptions were necessary because of the
paucity of several pieces of data. First, it was assumed that unit
costs of heart failure therapy were identical between medical
therapy and CRT. Second, it was assumed that the incidence
of complications associated with CRT was constant over time.
However, since the duration of followup in each trial was
relatively short and the incidence of adverse effects in these
trials was higher than generally accepted for ICD
implantation,19 the researchers considered lower incidences of
device or device-related adverse effects than observed in the
trials in the sensitivity analyses. Third, it was assumed that any
mechanical malfunction of the device required battery
replacement with consequent costs. Finally, age-specific
mortality due to unrelated causes was based on life tables.20
Uncertainty and Variability Analyses
The analysis distinguished between parameter uncertainty
(i.e., variation in costs and effects because of sampling and
measurement error) and variability (i.e., heterogeneity in costs
and effects between groups of patients with systematic
differences in cost or effects). Uncertainty was assessed by
using 10,000 probabilistic Monte Carlo simulations.21,22
Empirical cost variables were assigned log-normal distributions.
Empirical probability variables were assigned beta
distributions.21 Variables without a known distributional form
(i.e., those with assumed values or those with values based on a
range of published reports) were assigned triangular
Variability was assessed by substituting the value of each
variable in the decision model by its upper and lower limits
while holding all other values constant.24-26 For empirical
variables, these limits were the 95-percent confidence limits for
each variable. For assumed variables (e.g., cost of CRT device
insertion and discount rate), these limits were based on
reasonable possible limits (i.e., ±50 percent). Threshold
analyses identified the value of each variable across its range, if
any, at which one should be indifferent between medical
therapy alone or CRT (i.e., the incremental cost per quality-adjusted
life year was $100,000).26
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Nine trials reported on the efficacy of CRT; three included
implantable cardioverter-defibrillators (ICDs).27-34 Seventeen
studies (eight trials and nine prospective studies without control
arms) reported on the safety of CRT. Most of the trials were
associated with multiple publications that either expanded on
the main results or reported secondary outcomes not included
in the primary report. This summary includes the reference to
only the primary report for each trial. However, a full listing of
all publications is available in the full evidence report.
Description of Included Studies
All nine of the trials enrolled only patients with prolonged
QRS duration: >120 millisecond (msec) in three trials,27-29 >130
msec in two trials,30,31 >140 msec in one trial,32 >150 msec in
one trial,33 >180 msec in one trial, and >200 msec in the
remaining trial.34 Left bundle branch block was present in 64
percent of patients, and 95 percent of patients were in sinus
rhythm. All trials also restricted enrollment to patients with
reduced ejection fractions (>35 percent in six trials, >25 percent
in one trial, and >40 percent in the other), and the mean
ejection fractions were similar in all trials (from 21 percent to 26 percent).
In total, 3,574 patients were enrolled and 3,216 were
randomized to receive CRT (n = 2,063) or control (most
commonly pacemaker turned off, n = 1,153) in the nine trials.
The mean age was 64 years, 74 percent were male, 75 percent
had NYHA Class III symptoms, and 10 percent had NYHA
Class IV symptoms. Two trials included some patients with
NYHA Class II symptoms.27,31 Most of the patients in these
trials had ischemic etiologies for their heart failure (mean 58
percent, range 29 percent to 69 percent).
Including the nine additional single-arm prospective cohort
studies, a total of 3,512 patients who had undergone CRT
implantation were included in the safety analyses.
Based on data pooled from the nine
randomized controlled trials, CRT significantly reduced all-cause
mortality (relative risk [RR], 0.75, 95-percent CI, 0.60 to
0.93). The results were identical when analyses were limited to
patients with NYHA Class III or IV symptoms (RR, 0.76, 95-percent CI, 0.60 to 0.95). There was no significant statistical
heterogeneity between trials (p = 0.88, I-squared = 0 percent).
The all-cause mortality rate in the control patients was 14.9
percent, and the number needed to treat (NNT) to prevent one
death in patients with symptomatic heart failure was 27. A
Cox proportional hazards model revealed that the mortality
hazard ratio with CRT was 0.59 (95-percent CI, 0.43 to 0.81)
after the first 3 months.
Seven trials reported progressive heart
failure mortality (n = 60 deaths in 1,647 patients); the relative
risk favored CRT (random effects RR, 0.60, 95-percent CI, 0.36
to 1.01; fixed effects RR, 0.59, 95-percent CI, 0.35 to 0.98).
Results were similar when analysis was restricted to patients
with NYHA Class III or IV symptoms (random effects RR,
0.58, 95-percent CI, 0.32 to 1.06). In contrast, CRT did not
significantly reduce overall cardiac deaths (n = 91 in 1,628
patients, RR, 0.84, 95-percent CI, 0.56 to 1.25) because of a
nonsignificant excess in sudden cardiac deaths (n = 28 in 1,691
patients, RR, 1.99, 95-percent CI, 0.95 to 4.16). Data on
causes of death for patients in the COMPANION trial28 were
not yet available.
Using data pooled from the six trials
that reported noncardiac death (RR, 0.90, 95-percent CI, 0.35
to 2.35), results for CRT and control therapy did not
Heart Failure Hospitalizations
The pooled data revealed
benefits with CRT (random effects RR, 0.68, 95-percent CI,
0.41 to 1.12; fixed effects RR, 0.80, 95-percent CI, 0.64 to 1.003). This result was heterogeneous (p = 0.01, I-squared =
65 percent). Restricting this analysis to patients with NYHA
Class III or IV symptoms revealed homogeneous (p = 0.31, Isquared
= 16 percent) and statistically significant reductions in
heart failure hospitalizations (RR, 0.65, 95-percent CI, 0.48 to
0.88; NNT = 12).
Six-minute Walk Test
CRT was associated with an
improved 6-minute walk test, with a weighted mean difference
(WMD) of 23 meters (95-percent CI, 9 m to 38 m). This
improvement was similar in patients with NYHA Class III or
IV symptoms (WMD 26 m, 95-percent CI, 11 m to 41 m).
Although the data from the RD-CHF Trial were not available
for pooling, the RD-CHF investigators reported statistically
significant improvements in 6-minute walk test distances.35
New York Heart Association Functional Class
Combining the data on change in NYHA class from the three
studies that reported this endpoint revealed that 57 percent of
CRT-treated patients, compared to 34 percent of controls,
improved by at least one NYHA class. Thus, CRT was
associated with an RR, for improving at least one NYHA class
of 1.6 (95-percent CI, 1.1 to 2.5). Although the data from
MIRACLE-ICD31 and RD-CHF were not reported in a way
that they could be pooled with the other trials, both reported
statistically significant improvements in NYHA class with CRT.
Quality of Life
The minimal clinically important difference
for the Minnesota Living With Heart Failure® Questionnaire
has been established in placebo-controlled trials as being 5
points.36-38 Pooled results from the six trials that used the
Minnesota Living With Heart Failure Questionnaire showed a
statistically and clinically significant improvement with CRT
(WMD -5.5 points, 95-percent CI, -9 to -2 points). This result
was statistically heterogeneous (p = 0.008, I-squared = 68
percent); however, results were consistent in direction in all six
trials. Restricting the analysis to only patients with NYHA
Class III or IV symptoms increased the difference between the
CRT and control groups (WMD -6.4 points, 95-percent CI,
-9.4 to -3.4 points), and the results were less heterogeneous (p
= 0.07, I-squared = 50 percent). Further, although the use of a
different scale prevented pooling with the other trials, the RDCHF
investigators reported statistically significant
improvements in quality of life with CRT.35
CRT was associated with improvements
in peak oxygen consumption (WMD versus control of 0.7
ml/kg/min, 95-percent CI, 0.3 to 1.0 ml/kg/min), ejection
fraction (WMD 3.5 percent, 95-percent CI, 1.5 to 5.5 percent),
and QRS interval (WMD 28 msec, 95-percent CI, -47 to -9).
Ten studies reported data on
deaths while undergoing implantation of a biventricular
pacemaker. There were 13 deaths in 3,113 patients (pooled
risk 0.4 percent, 95-percent CI, 0.2 percent to 0.7 percent); a
sensitivity analysis, in which it was assumed any studies that did
not report mortality had zero occurrences, yielded the same
result. Device implantation was successful in 90 percent of
attempts (95-percent CI, 89 percent to 91 percent) in 3,475
patients (16 studies).
Over a median 6 months of
followup, mechanical malfunction of the cardiac
resynchronization device was noted with 7 percent of successful
implants (95-percent CI, 5 percent to 8 percent); on sensitivity
analysis, in which it was assumed any studies that did not
report this outcome had zero occurrences, this rate was 4
percent (95-percent CI, 4 percent to 5 percent). Lead
dislodgment occurred in 9 percent of patients (95-percent CI, 7
percent to 10 percent). There were no differences in lead
dislodgment in studies using specially designed left ventricular
leads; the estimate was reduced to 8 percent (7 percent to 10
percent) on sensitivity analysis. Post-implantation infection
(most commonly in the device pocket) occurred in 1.4 percent
of patients (95-percent CI, 0.8 percent to 2.3 percent); the
estimate was reduced to 0.9 percent (95-percent CI, 0.5 percent
to 1.4 percent) with sensitivity analysis. Two percent (95
percent CI, 1 percent to 3 percent) of patients had arrhythmias
Sensitivity Analyses for Systematic Review
Using meta-regression (a between-study non-randomized
comparison), the researchers explored the impact of CRT when
combined with ICDs. The benefits of CRT on all-cause
mortality and heart failure hospitalizations were not appreciably
different in patients with an ICD and patients without an
ICD. The data from COMPANION were not eligible for this
analysis since only one arm in COMPANION received both
CRT and an ICD.39 Indeed, the COMPANION trial data
permit the only direct comparison between CRT with/without
an ICD. While the chi-square test for all-cause mortality
approached significance (p = 0.07) in favor of cardiac
defibrillators with CRT, the reductions in heart failure
hospitalizations were similar in CRT-treated patients
with/without ICDs.28 However, until detailed data from the
COMPANION subanalyses are made available, the most
conservative conclusion to make is that the benefits of CRT are
similar with/without an ICD.
Cost-Effectiveness of CRT
In patients with NYHA Class III heart failure, medical
therapy was associated with a median gain of 2.68 discounted
quality-adjusted life years (interquartile range [IQR] = 2.49 to 2.85) and median $34,700 lifetime costs (IQR = $31,100 to
$38,100). CRT was associated with a median gain of 3.03 discounted quality-adjusted life years (IQR = 2.82 to 3.27) and
median $67,600 lifetime costs (IQR = $62,000 to $73,800).
Thus, CRT was associated with an incremental cost of a
median $90,700 (IQR = $69,500 to $124,900) per additional
quality-adjusted life year. The cost-effectiveness acceptability
curve illustrates that the probability that resynchronization is
cost effective is less than 59 percent, given a maximum
willingness to pay for a quality-adjusted life year of $100,000.
The incremental cost-effectiveness of CRT was sensitive to
reasonable changes in the values of several variables, particularly
the incidence of device-related complications.
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In summary, when added to medical therapy in patients with
symptomatic heart failure who have prolonged QRS duration
and reduced left ventricular ejection fraction, CRT reduces all-cause
mortality by 25 percent and heart failure hospitalizations
by 32 percent. These benefits were particularly marked in heart
failure patients at higher risk (i.e., those with NYHA Class III
or IV symptoms). These benefits are similar to those reported
for ACE inhibitors, beta-blockers, and aldosterone antagonists
in recent trials.40-43 CRT also conferred statistically and
clinically significant benefits in a variety of surrogate outcomes.
Indeed, a pooled six-point improvement on the Minnesota
Living With Heart Failure® Questionnaire is greater than that
seen in recent heart failure trials testing pharmacologic
therapies.44,45 However, CRT for patients with heart failure is
associated with large uncertainty in the incremental costs per
quality-adjusted life year; in particular, the results are sensitive
to the incidence of device-related adverse effects.
The survival benefits with CRT appear to be attributable
largely to reductions in progressive heart failure deaths and
become apparent by 3 months after implantation. This is not
surprising, as the benefits of CRT are thought to be mediated
through morphometric remodeling of the left ventricle (leading
to increased left ventricular filling time, reduced mitral
regurgitation, and reduced septal dyskinesis) rather than acute
changes in the neurohormonal system.46
While the researchers found a nonsignificant trend toward
increased sudden cardiac death that was consistent across these
trials, it was based on a very small number of events (28 in
total). In particular, the lack of difference in the number of
ventricular arrhythmia episodes between patients with
compared to without CRT in the MIRACLE-ICD Trial (22
percent vs. 26 percent, p = 0.47) suggests that the trend toward
excess sudden cardiac deaths may well be due to small
numbers.31 Regardless, the benefits of CRT are similar in
patients with or without implantable cardioverter-defibrillators,
providing some reassurance that, in those patients who have
indications for both a defibrillator and CRT, the two may be
administered together. The indications for an ICD in heart
failure patients without an ischemic etiology remain uncertain
pending completion of the SCD-HeFT Trial.47
An important finding of this systematic review is the safety
of CRT and its tolerability in patients with advanced heart
failure. Peri-implantation mortality rates were less than 1
percent and post-implantation infection rates were also low.
Although there were few serious complications, implantation of
a biventricular pacemaker (in particular the left ventricular lead)
is technically challenging: the systematic review identified a 10-percent failure rate.
Furthermore, even if implantation is
successful, patients with these devices require close followup, as
7 percent of devices malfunctioned over a median followup of
6 months and 9 percent of left ventricular leads dislodged.
Because these complications necessitate another procedure, the
failure rates have to be incorporated into any policy decisions.
Although the systematic review results are promising, the
results of the decision analysis suggest caution given the
magnitude of the uncertainty in the long-term results. Indeed,
the researchers believe that there are insufficient long-term
effectiveness and cost data to warrant broad implementation of
CRT at this time.
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Limitations of Research
A substantial limitation of the trials included in this analysis
is that randomization occurred after implantation of the device
in all but one trial. This design, similar to the run-in period
used in some pharmaceutical trials, does not affect the internal
validity of the trials but does impact the generalizability of the
results, as patients who could not tolerate the procedure or in
whom implantation was unsuccessful were not included. As a
result, these trials likely overestimate the potential benefits from
Because very few patients in these trials had
brady arrhythmias or atrial fibrillation, the role of CRT in such
patients is unknown and is an important area for further study,
particularly since almost one-third of CHF patients have atrial
fibrillation or indications for conventional pacemakers.49
Finally, it should be emphasized that only selected cases and
experienced providers participated in these trials, so it is
plausible that the observed complication rates may not be
applicable to other settings and, in particular, clinicians less
experienced with device implantation. If so, this decision
analysis overestimates survival and underestimates the
incremental cost of CRT. Conversely, if adverse effects are less
frequent as providers gain experience, the analysis may
underestimate survival and overestimate the incremental cost of 6
CRT. This is particularly important, since the results of the
analysis were sensitive to the rate of complications associated
The decision analysis also has some limitations:
- Although cardiac resynchronization is more costly and more effective than medical therapy, the incremental cost-effectiveness ratio had a large range and there are insufficient data to determine whether to adopt resynchronization therapy for broad use.
- It is likely that the incidence of complications associated with CRT decreases over time, although for the purposes of our analysis it had to be assumed that they were constant. Thus, the model may underestimate survival and overestimate the incremental cost-effectiveness of CRT. Long-term followup of patients enrolled in the previously completed trials will determine whether the incidence of complications does indeed decline over time.
- It is unlikely that the relative benefits of CRT will be constant, as the severity of heart failure varies. Therefore, as results from other trials and registries become available, the analysis should be revised to reflect better estimates of the true effectiveness and costs of the program in patients with other classes of CHF.
- It was assumed that heart failure costs were constant even though CRT will decrease heart failure costs if ventricular remodeling decreases the frequency of use of outpatient pharmaceuticals or duration of hospitalization.
- The input data were derived from several sources and may be confounded by information that was not incorporated into the model. For example, the effectiveness of CRT was not adjusted for the patient's comorbid illnesses.
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CRT exerts a 24-percent relative reduction in all-cause
mortality (largely driven by a 42-percent reduction in
progressive heart failure deaths) and a 35-percent reduction in
heart failure hospitalizations in patients with reduced ejection
fractions, NYHA Class III or IV symptoms despite medical
management, and a prolonged QRS duration on
electrocardiogram. While preliminary data suggest similar
relative benefits in patients with NYHA Class II symptoms, this
is based on very few events. Further data are required before
extending the device indications beyond those currently
authorized by the U.S. Food and Drug Administration (i.e.,
patients with NYHA Class III or IV symptoms).
very few such patients were enrolled in the trials, the role of
CRT in patients with indications for conventional pacemakers
or with atrial fibrillation remains uncertain and requires further
study. Approximately 10 percent of heart failure patients have
NYHA Class III or IV symptoms, reduced ejection fraction,
and a prolonged QRS duration, and up to one-half of these patients may also have indications for an implantable
While CRT should join the list of proven efficacious
therapies for selected patients with heart failure, it is an
expensive therapy and cost-effectiveness analysis reveals
uncertainty in the incremental costs per quality-adjusted life
year. In particular, there are insufficient long-term effectiveness
and cost data to determine whether CRT is sufficient value for
money to warrant its broad implementation at this time. This
is in contradistinction to ACE inhibitors, beta-blockers, and
spironolactone for patients with advanced symptomatic heart
Return to Contents
Availability of Full Report
The full evidence report from which this summary was taken
was prepared for the Agency for Healthcare Research and
Quality (AHRQ) by the University of Alberta Evidence-based
Practice Center under Contract No. 290-02-0023. Printed copies may be obtained free of charge from the AHRQ
Publications Clearinghouse by calling 800-358-9295.
Requesters should ask for Evidence Report/Technology
Assessment No. 106, Cardiac Resynchronization Therapy for
Congestive Heart Failure.
The Evidence Report can be also downloaded as a PDF File (1.75 MB). Plugin Software Help.
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AHRQ Publication Number 05-E001-1
Current as of November 2004