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Chapter 20. Non-responders and patient selection from an echocardiographic perspective
252 CARDIAC RESYNCHRONIZATION THERAPY
patient’s criteria for implant. Re-evaluation of
selection criteria must include a search for
reversible causes of heart failure and LV dysfunction (i.e., valve disease, coronary artery disease,
pulmonary disease, and congenital heart disease),
as well as the degree of baseline LV dysfunction,
the presence and degree of intraventricular
mechanical delay, and QRS duration pre-implant.
Patients with borderline LVEF or borderline
QRS durations as well as a QRS morphology
other than left bundle branch block (LBBB)
(i.e., right bundle branch block (RBBB) or intraventricular conduction delay (IVCD)) may be
less likely to demonstrate a positive response as
compared with those with non-ischemic cardiomyopathies, LVEF <35% and a QRS >150 ms,
and LBBB. Precise knowledge of this information may be able to provide insights into why a
patient may have realized a suboptimal response.
Non-responders often present with either symptoms or persistent or worsening LV dysfunction,
or both. Classifying these cases as they present
may be helpful in determining an etiology and
generating a management strategy.
delay has been defined as that which enables
completion of atrial filling prior to ventricular
contraction, thereby allowing for an optimal
diastolic filling time.11 Evidence demonstrating a
clinical benefit or positive impact of AV delay
optimization on outcome, however, is lacking.
Despite this lack of definitive data supporting its
utility, several centers have advocated various
methods for evaluating AV delay and optimizing AV intervals in patients undergoing CRT.
These protocols range from routinely evaluating
hemodynamics with Doppler echocardiography
in all patients undergoing CRT and optimizing
as indicated, to only evaluating AV synchrony
and ultimately optimizing AV delay if the
patient is considered a non-responder. In our
center, we have found it both useful and practical to evaluate diastolic filling parameters
(mitral inflow) by Doppler echocardiography in
all patients undergoing CRT and to proceed
with an AV optimization procedure only if the
hemodynamics are suboptimal9 (Figure 20.1). If
E–A wave reversal is present, there is adequate
separation of the E and A waves, the A wave terminates at least 40 ms after the onset of the QRS
SYMPTOMS AND/OR LVEF WORSENED
It is typically very clear that these patients have
not experienced the desired effect of CRT, and
therefore investigation must proceed to determine whether a specific reason for this lack of
response can be uncovered and if so whether it
can be corrected. A systematic approach may be
useful in managing these cases – specifically, one
that addresses issues related to intraventricular,
interventricular, and AV synchrony.
Mitral inflow pattern following CRT procedure
Stage II or III
Mitral E–A reversal,
QA interval > 40 ms,
Pulmonary vein S>D
(Ritter or Iterative)
AV delay setting
Target stage I
Once appropriate patient selection has been
assured, and assuming that the optimal lead
position has been achieved, evaluation of AV
and interventricular (V–V) timing intervals is
recommended. In comparison with the importance and impact of correction of intraventricular dyssynchrony, AV and V–V timing are minor
contributors to the overall impact of CRT.8
However, data clearly demonstrate that, in
selected patients, optimizing the AV delay does
improve hemodynamics.8–10 The optimal AV
Figure 20.1 Recommended algorithm utilizing pulsed Doppler
of mitral inflow to assess diastolic function for approaching
CRT patients being considered for AV optimization. If the
patient presents with stage I diastolic dysfunction or delayed
relaxation abnormality, the QA interval is >40 ms, and the
pulmonary vein flow pattern is systolic > diastolic (S>D), then
the baseline AV delay settings are maintained. If, on the other
hand, pseudonormal (stage II) or restrictive (stage III) physiology is present, then AV optimization is performed.
NON-RESPONDERS AND PATIENT SELECTION FROM AN ECHO PERSPECTIVE 253
Pulmonary Vein Flow
Figure 20.2 Because the mitral inflow pattern (a) demonstrates E–A reversal, adequate E–A wave separation, and a QA interval
> 40 ms, and the pulmonary vein flow (b) reveals S>D, no further optimization is necessary, as further modifications are unlikely
to improve hemodynamics.
complex, and the systolic flow velocity is greater
than the diastolic flow velocity on pulmonary
vein flow assessment, then the baseline ‘outof-the-box’ setting is maintained (Figure 20.2).
Regardless of a given institution’s preference
in routinely evaluating AV delay settings, it is
clear that AV delay is worth interrogating in the
non-responder population. Several Doppler
methods for optimization have been described
in the literature, all of which utilize a Doppler
parameter of either systolic or diastolic function
to determine functional response to various AV
delay settings. The two most commonly reported
Doppler parameters are pulsed-wave Doppler
assessment of mitral inflow and continuouswave Doppler assessment of aortic outflow
(stroke volume estimate).12 Also reported to be
useful in this setting is the Tei index,10 which
evaluates both systolic and diastolic function.
The utility of mitral inflow assessment is based
upon the ability to time the termination of the
atrial contribution to filling with the onset of
ventricular contraction, in addition to its ability
to assess diastolic function. This was initially
proposed to be useful in this context by Ritter
et al.13 The Doppler assessment of aortic flow is
a systolic parameter and is an estimation of
stroke volume. In our experience, mitral inflow
assessment has been more robust in regard to
ease of acquisition, interpretation, and prognostic value relative to the aortic flow parameter.
Utilizing the Doppler mitral inflow method as
a parameter to assess myocardial function and
the relationship between the termination of the
atrial contribution to filling and the onset of
ventricular systole, the optimal AV delay can be
determined using either an iterative or a Ritter
method. The iterative method simply attempts
to target stage I diastolic filling or early relaxation, which is an optimal diastolic function
status in a heart failure population. The AV delay
is set to an abnormally prolonged setting while
maintaining BiV capture if conduction is presumed to be relatively normal at baseline, and the
mitral inflow is sampled. The AV delay intervals
are decreased in 20 ms increments, with the mitral
inflow being sampled at each stage. Optimal AV
delay is achieved when E–A reversal is present,
adequate separation of an A wave is appreciated, and the A wave terminates at least 40 ms
after the onset of the QRS complex, representing
minimum electrical–mechanical delay. If there is
evidence of intraatrial or AV conduction delay
at baseline, the AV delay can be adjusted in
increasing increments, again targeting delayed
relaxation abnormality, stage I diastolic dysfunction (Figure 20.3). The Ritter method achieves
this same endpoint by initially setting the AV
delay to an inappropriately short setting,
sampling mitral inflow, measuring the QA interval (QRS onset to A-wave termination) and comparing this measure with the QA interval at an
254 CARDIAC RESYNCHRONIZATION THERAPY
Figure 20.3 This patient was a 69-year-old male with ischemic cardiomyopathy and s/p aortic valve replacement, atrial fibrillation, ventricular tachycardia, and heart failure who had recently undergone implantation of a biventricular (BiV) pacemaker. At a
baseline setting of 110 ms, there was no discernible A wave (a). The AV delay was then extended to 280 ms while maintaining
BiV capture (c). At an AV delay of 280 ms, the termination of the A wave fell before QRS onset, resulting in suboptimal diastolic
filling and the potential for diastolic mitral regurgitation. The AV delay was then empirically decreased to 230 ms, where a more
physiologic relationship between the end of the A wave and QRS onset could be realized. The AV delay setting was therefore
maintained at 230 ms.
inappropriately long AV delay setting. The optimal AV delay is then calculated from the difference of the QA intervals at each setting plus the
short AV delay setting.
Data from our institution suggests that
most patients (60%) exhibit optimal diastolic
filling or delayed relaxation (stage I) at an outof-the-box setting of approximately 100–140 ms.
Furthermore, approximately 10% of patients
with suboptimal diastolic filling hemodynamics (stage II or III) will exhibit improved diastolic filling with optimization of the AV delay
(Figure 20.4). The predictors of a longer than
normal (optimal) AV delay include a paced
rhythm, AV block, and an enlarged left atrium
(LA) (Figure 20.5), suggesting that intraatrial
conduction delay necessitates an abnormally
prolonged AV delay in order to optimize diastolic filling.9 Although there are no known
data supporting the utility or impact of AV optimization on outcome, data from several centers
experienced in performing these procedures
suggest that this intervention may positively
impact a segment (albeit small) of the nonresponder group.9,14 Because conduction times
may vary over time – likely related to reverse
remodeling – regular interrogation at 6- to
12-month intervals seems prudent.15
NON-RESPONDERS AND PATIENT SELECTION FROM AN ECHO PERSPECTIVE 255
Figure 20.4 Using an iterative method for AV delay optimization, the AV delay was extended in this 69-year-old male with known
underlying conduction disease. There is no effective late diastolic filling (no A wave) at the baseline AV delay setting of 100 ms (a),
which was set in the laboratory during the CRT procedure. At an AV delay of 150 ms (b), the Doppler mitral inflow pattern has
improved, as an A wave is unmasked, whereas optimal diastolic filling is realized only when the AV delay is prolonged to
250 ms. Notably, at this prolonged AV delay setting of 250 ms (c), the A-wave termination falls clearly after the QRS onset – hence,
a relatively physiologic electrical–mechanical delay can be assumed.
V–V timing is another parameter that can be
modified in patients undergoing BiV pacing,
especially in the non-responder group. As with
AV optimization, optimization of V–V timing
has little data to support its utility and impact on
outcome measures. Additionally, similar to AV
timing, V–V timing likely contributes relatively
little to the overall impact of CRT. However, in
selected cases, V–V timing may have a significant impact. Preliminary studies have demonstrated improvement in hemodynamics.16–18
It has been speculated that this may in part be
the result of compensation for suboptimal lead
position.19 Sogaard et al,20 for example, suggested that patients with ischemic cardiomyopathies benefit from a right ventricular (RV)
pre-offset, whereas patients with dilated cardiomyopathies benefit from an LV pre-offset.
Furthermore, Porciani et al10 demonstrated that
tailored BiV pacing was advantageous. Bordacher
et al17 demonstrated that V–V optimization
resulted in a significant reduction in mitral regurgitation, whereas Van Gelder et al18 reported that
256 CARDIAC RESYNCHRONIZATION THERAPY
Figure 20.5 This patient is a 76-year-old female with ischemic cardiomyopathy, ischemic mitral regurgitation, hypertension, and
paroxysmal atrial fibrillation who was s/p Carpentier–Edwards mitral valve replacement. She had recently undergone CRT and
now presented for an AV optimization procedure. The AV delay was set at 320 ms at the time of the BiV implant. Further investigation revealed that the interatrial conduction times had been measured at time of BiV implant in the endocardial prosthesis
laboratory and found to be very abnormally prolonged (350 ms) as the patient had biatrial enlargement with an LA diameter of
6 cm and an area of 34 cm2. It was decided to modify the AV delay to investigate whether changes in diastolic filling could be
elicited. Mitral inflow is shown at AV delays of 320 ms (a), 150 ms (b), and 250 ms (c). The optimal diastolic filling was confirmed to be at an AV delay of 320 ms.
most patients (83%) benefited from LV-first preactivation in a series of 53 patients. One of the
major challenges, however, is to agree or settle
on the best non-invasive parameter available in
our armamentarium that can be practically
employed to assist in detecting whether simultaneous versus LV pre-offset versus RV pre-offset
is best in a given patient.
Clearly, further investigation is needed to
guide appropriate adjustment of this capability.
However, in the absence of definitive guidelines,
and particularly in patients with a suboptimal
response to CRT, it is certainly reasonable to
optimize hemodynamics utilizing one or more
parameters of cardiac function. The protocol utilized in our laboratory is to measure aortic outflow (stroke volume estimate) and the Tei index
(aortic outflow and mitral inflow by pulsed
Doppler) with simultaneous pacing, and four
LV and four RV pre-offsets at 20 ms intervals.
Simultaneous pacing is maintained in most
cases, and only if both parameters exhibit a consistent positive improvement in function at a
given setting will we recommend modification
of the V–V timing. The evaluation will then be
repeated in 6 months to reassess the patients’
clinical status, as well as the associated hemodynamic parameters.
RE-EVALUATION OF INTRAVENTRICULAR
Once AV and V–V timing has been optimized,
and if no improvement in symptoms or ventricular function has been realized, then a reassessment of intraventricular dyssynchrony using
Doppler tissue imaging could be informative.
Importantly, comparison with baseline or preimplant dyssynchrony information, as well as
precise knowledge of the coronary sinus lead
location, are necessary in order to provide the
greatest possible insight into the impact of BiV
stimulation on ventricular mechanical function.
Evaluating intraventricular dyssynchrony post
implant without pre-implant baseline dyssynchrony data and without precise information on
lead location can be problematic, as residual
dyssynchrony will likely be present (Figure 20.6) –
and, without baseline data, much less meaningful.
Improvement in intraventricular dyssynchrony
may be useful to document but is not necessary
for success of therapy (Figure 6 and 7).
If LV function is poor (ഛ 35%), unchanged
from baseline, or worse as compared with baseline, and significant intraventricular dyssynchrony persists, particularly if the segment of
most significant delay does not correspond to
NON-RESPONDERS AND PATIENT SELECTION FROM AN ECHO PERSPECTIVE 257
Figure 20.6 Basal and mid myocardial velocity data pre and post CRT obtained using Doppler Tissue Imaging from a 49 y/o
female with a dilated cardiomyopathy and LBBB who responded favorably with improvement in symptoms and EF from 20% to
30%. The left panel is pre implant and demonstrates significant intraventricular dyssynchrony (opposing wall time to peak velocity difference of 112ms from the apical 4 chamber view). The right panel is post implant and reveals persistent residual intraventricular dyssynchrony (opposing wall time to peak velocity difference of 120ms) despite satisfactory lead placement and a
favorable clinical response to CRT.
the site of the coronary sinus lead placement, then
it would seem reasonable to consider revising
lead placement either transvenously or surgically
with an epicardial lead. The recognition of an
anterior lead location combined with a nonresponder status would also favor proceeding
with lead repositioning (Figure 20.8). When a
clear discordance between lead position and
dyssynchrony data cannot be determined with a
high degree of confidence, attempting an
empiric lead revision should be avoided.
Finally, if no clear explanation of the patient’s
failure to respond can be confidently diagnosed, a
trial of allowing intrinsic conduction by discontinuing pacing therapy should be attempted. Global
ventricular function as well as re-acquisition of
dyssynchrony parameters can be re-evaluated
during intrinsic conduction, along with a clinical
Figure 20.7 Base and mid myocardial velocity data pre and post CRT within 3 days of implant of a CRT device obtained using
Doppler Tissue Imaging. The left panel is pre implant and demonstrates significant intraventricular dyssynchrony (opposing wall
time to peak velocity difference of 100 ms from the apical 4 chamber view at the base) with improvement in dyssynchrony (right
panel) as the systolic peaks align nearly perfectly. The patient responded favorably with an improvement in symptoms and
258 CARDIAC RESYNCHRONIZATION THERAPY
Figure 20.8 Multislice computed tomographic (MSCT) scan of
the heart, and more specifically of the coronary veins. This is
a 65-year-old male who underwent CRT and was designated a
non-responder, as after 3 months and then 6 months, his
LVEF was unchanged and his symptomatology was not
improved. Further diagnostics were performed, including a
MSCT scan to assess precise lead placement. The coronary
sinus lead here is seen traversing the great cardiac vein on
the anterior aspect of the heart, and could well explain the
suboptimal response described clinically.
evaluation for a trial period. Clearly, pacing can
be detrimental to LV function – even BiV pacing
with the RV lead positioned in the RV apex.21
SYMPTOMATIC IMPROVEMENT, LVEF
This group of patients may or may not be
categorized as non-responders, depending on
whether or not reverse remodeling is considered
necessary to define success. The placebo effect
may be implicated as an explanation for improvement in this subgroup, and therefore a neutral
effect on ventricular function could be consistent
with this outcome. Yet another possibility, however, is that functional status is in fact truly
improved yet traditional methods of evaluating ventricular function are suboptimal for
measuring a real increase in ventricular contractility. In these cases, demonstrating improved
intraventricular synchrony as described above
by comparing pre- and post-implant dyssynchrony measures may be clinically useful.22
Even though no objective improvement in
ventricular function may be realized when using
standard measures of function such as LVEF, an
assessment of intraventricular dyssynchrony
may be worth documenting. This scenario
would contrast with that of a patient whose ventricular function has clearly improved by twodimensional echocardiographic assessment of
LVEF by volumes and in whom an assessment
of intraventricular dyssynchrony could therefore be considered irrelevant and potentially
even misleading to the uninformed.
The time to peak velocity measurements as
determined by color Doppler tissue imaging
utilizing the opposing-wall method (a standard
measure of intraventricular mechanical dyssynchrony) is recommended as a parameter
that could be collected pre and post implant
for comparison.5,23 It is important to note that
opposing-wall time to peak velocity measurements made in isolation post-implant will have
little meaning unless pre-implant data are readily available for comparison.22,24 As reported by
Yu et al,23 segmental opposing-wall times to peak
velocity (Ts) post BiV implant remain abnormally prolonged (anteroseptum 191 ± 32 ms and
lateral wall 213 ± 44 ms); however, the coefficient
of regional variation relative to pre-implant is
improved as a result of a more synchronized
segmental delay among regions of the LV.
SYMPTOMS AND LVEF UNCHANGED
If at 1–3 months post-implant a patient exhibits no
objective improvement in either symptoms or ventricular function, most clinicians would consider
this to be in the non-responder category. In these
cases, a systematic investigation of possible explanations for the lack of response should be initiated.
After reviewing the baseline data, including the
patient selection criteria to assure appropriate candidacy and to rule out other potential reversible
causes of ventricular dysfunction, procedural
issues (operative notes) should be reviewed and
pacing setting optimization should be considered.
Lead position should be reviewed and confirmed with a postero-anterior and lateral
NON-RESPONDERS AND PATIENT SELECTION FROM AN ECHO PERSPECTIVE 259
chest X-ray. If the lead position is in a location
typically considered suboptimal (i.e., anterior), if
the RV/cardiac sinus lead distance is not maximized, or if intraventricular dyssynchrony can
be confidently determined to be increased or
even unchanged as compared with the preimplant evaluation, then serious consideration
should be given to repositioning the LV lead.
Finally, useful information may be obtained by
re-examining intraventricular mechanical dyssynchrony by color TDI with the pacemaker in
both the off and the on mode and comparing
more acutely the real-time impact of the BiV
pacing therapy on ventricular synchrony and
function. On occasion, it can be determined that
ventricular function and/or intraventricular
dyssynchrony are worsened with BiV pacing.
Improving our understanding of the mechanisms underlying CRT, (which will lead to
improved selection criteria and implantation
technique), will be the basis for minimizing the
non-responder population. However, until this
progress can be realized, evaluation and management of the non-responder population must
be thoughtful, careful, and thorough.
Because of the many limitations and uncertainties clinicians have before them in trying to
identify and problem-solve this population of
patients, it is imperative that they accurately
define the problem with objective data, review
expectations with their patients, and pursue a
redirection of therapy only once definitive diagnosis can be delineated. Additionally, appreciating the utility as well as the limitations of
echocardiography can be extremely valuable in
arriving at a correct diagnosis and ultimately
applying the appropriate corrective therapy –
which may well include no therapy.
Cazeau S, Leclercq C, Lavergne T, et al. ftMSiCS
Investigators. Effects of multisite bi-ventricular pacing in
patients with heart failure and intra-ventricular
conduction delay. N Engl J Med 2001;344:873–80.
Bristow M, Saxon L, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable
defibrillator in advanced chronic heart failure. COMPANION Investigators. N Engl J Med 2004;350:2140–50.
Cleland J, Daubert J, Erdmann E, et al. CARE-HF Study
Investigators. The effect of cardiac resynchronization
on morbidity and mortality in heart failure. N Engl J
Bax JJ, Abraham T, Barold SS, et al. Cardiac resynchronization therapy: Part I: Issues before device implantation. J Am Coll Cardiol 2005;46:2153–67.
Yu CM, Bleeker GB, Fung JW, et al. Left ventricular
reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization
therapy. Circulation 2005;112:1580–6.
Young JB, Abraham WT, Smith AL. Multicenter Insync
ICD Randomized Clinical Evaluation (MIRACLE ICD)
Trial Investigators. Combined cardiac resynchronization and Implantable cardioversion defibrillation in
advanced chronic heart failure: the MIRACLE ICD trial.
St John Sutton MG, Plappert T, Abraham WT, et al.
Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure.
Auricchio A, Stellbrink C, Block M, et al. Effect of
pacing chamber and atrioventricular delay on acute
systolic function of paced patients with congestive
heart failure: the Pacing Therapies for Congestive Heart
Failure Study Group: the Guidant Congestive Heart
Failure Research Group. Circulation 1999;99:2993–3001.
Kedia N, Ng K, Apperson-Hansen C, et al. Usefulness
of atrioventricular delay optimization using Doppler
assessment of mitral inflow in patients undergoing
cardiac resynchronization therapy. Am J Cardiol 2006;
Porciani MC, Dondina C, Macioce R, et al.
Echocardiographic examination of atrioventricular and
interventricular delay optimization in cardiac resynchronization therapy. Am J Cardiol 2005;95:1108–10.
Ronaszeki A. Hemodynamic consequences of the
timing of atrial contraction during complete AV block.
Acta Biomed Lovaniensia 1989;15.
Faddis MN, Waggoner AD, Sawhney N. AV delay optimization by aortic VTI is superior to the pulsed
Doppler mitral inflow method for cardiac resynchronization therapy. Pacing Clin Electrophysiol 2003;
Ritter P, Padeletti L, Gillio-Meina L, et al. Determination
of the optimal atrioventricular delay in DDD pacing:
comparison between echo and peak endocardial acceleration measurements. Europace 1999; 1:126–30.
Sawhney NS, Waggoner AD, Garhwal S, et al.
Randomized prospective trial of AV delay programming for cardiac resynchronization therapy. Heart
260 CARDIAC RESYNCHRONIZATION THERAPY
15. O’Donnell D, Nadurata V, Hamer A, Kertes S,
Mohammed W. Long term variations in optimal programming of CRT devices. Pacing Clin Electrophysiol
16. Mortensen PT, Sogaard P, Mansour H, et al. Sequential
biventricular pacing: evaluation of safety and efficacy.
Pacing Clin Electrophysiol 2004;27:339–45.
17. Bordachar P, Lafitte S, Reuter S, et al. Echocardiographic
parameters of ventricular dyssynchrony validation
in patients with heart failure using sequential biventricular pacing. J Am Coll Cardiol 2004;44:2154–65.
18. Van Gelder BM, Bracke FA, Meijer A, Lakerveld LJ,
Pijls NH. Effect of optimizing the VV interval on left
ventricular contractility in cardiac resynchronization
therapy. Am J Cardiol 2004;93:1500–3.
19. Greenberg J, Delurgio DBM, Mera F. Left ventricular
lead location in biventricular pacing with variable
RV–LV timing does not affect optimal stroke volume.
In: North American Society for Pacing and
Electrophysiology (NASPE), 2002:151.
20. Sogaard P, Egeblad H, Pedersen AK, et al. Sequential
versus simultaneous biventricular resynchronization
for severe heart failure: evaluation by tissue Doppler
imaging. Circulation 2002;106:2078–84.
Willkoff BL, Cook JR, Epstein AE, et al. Dual-chamber
pacing or ventricular back-up pacing in patients with
an implantable defibrillator; the Dual chamber And
VVI Implantable Defibrillator (DAVID) trial. JAMA
Gorcsan J, Kanzaki H, Bazaz R, Dohi K, Schwartzman
D. Usefulness of echocardiographic tissue synchronization imaging to predict acute response to cardiac
resynchronization therapy. Am J Cardiol 2004;93:
Yu CM, Chau E, Sanderson JE, et al. Tissue Doppler
echocardiographic evidence of reverse remodeling and
improved synchronicity by simultaneously delaying
regional contraction after biventricular pacing therapy
in heart failure. Circulation 2002;105:438–45.
Yu CM, Lin H, Fung WH, et al. Comparison of acute
changes in left ventricular volume, systolic and diastolic functions, and intraventricular synchronicity after
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Use of devices with both cardiac
Arthur M Feldman, Reginald T Ho, and Behzad Pavri
Introduction • Clinical studies • Cost of CRT-D devices • Caveats regarding CRT-D therapy
As detailed in other chapters of this textbook, two
unique and distinct devices have been evaluated
for the treatment of patients with congestive heart
failure: implantable cardioverter–defibrillators
(ICD) and cardiac resynchronization devices
(CRT). The development of each of these devices
was based on a unique hypothesis. In the case of
the ICD, investigators hypothesized that because
a large number of heart failure patients died suddenly,1 presumably secondary to a lethal tachyor bradyarrhythmia, the ability of an implanted
device to sense and defibrillate a tachyarrhythmia
or to sense and pace a bradyarrhythmia would be
beneficial. Alternatively, the observation that
nearly 30% of patients with heart failure had
dyssynchronous left ventricular (LV) contraction
and that cardiac dyssynchrony was associated
with worsened ventricular function, increased
myocardial oxygen demand, maladaptive ventricular remodeling, and increased mortality2–5
led investigators to assume that resynchronizing
the pattern of ventricular contraction would have
salutary benefits. Indeed, these assumptions
proved true, as both individual trials6,7 and metaanalysis have demonstrated salutary benefits of
both ICD therapy8 and CRT9 in patients with
Interestingly, the development of both the
ICD and CRT devices was facilitated by similar
advances in engineering that provided miniaturization of the required electronics as well as the
capacity to both detect and transmit electrical
signals across wires that could readily be placed
in contact with the ventricular myocardium.
Furthermore, the utility of the CRT device was
enhanced by the development of techniques and
equipment for reaching the LV myocardium via
a percutaneous approach through the coronary
sinus. Engineers were also able to combine both
the technology for biventricular pacing and
requisite technology for defibrillation into the
same relatively small device, thereby overcoming the problems associated with the device–
device interactions that had plagued separately
implanted pacemakers and defibrillators.
Intuitively, the combination of an ICD and a
CRT device seemed logical because each would
be expected to interact with different physiologic pathways in the ventricular myocardium
and thus provide salutary benefits through
different mechanisms. However, the combined
use of an ICD and a CRT device has not been
without controversy. Indeed, the recent
American College of Cardiology/American
Heart Association (ACC/AHA) Guidelines note
that the balance of risks and benefits of ICD
implantation in an individual patient is complex,
particularly in patients with advanced heart failure or other comorbidities, in whom the survival
benefit obtained with an ICD implantation
262 CARDIAC RESYNCHRONIZATION THERAPY
The first prospective multicenter study to evaluate an implantable CRT device was reported in
2002.13 The InSync study enrolled patients who
met indications for implantation of an ICD
because of symptomatic sustained ventricular
tachycardia (VT) and/or survival of a cardiac
arrest. Patients were required to have an LV ejection fraction (LVEF) <35%, an LV end-diastolic
diameter >55 mm, and a QRS duration >130 ms.
In comparison with baseline measures, the
81 patients in whom the LV lead was successfully
implanted demonstrated an improvement in
6-minute walk time, classification of New York
Heart Association (NYHA) symptoms, and LV
fractional shortening, as well as decreases in
both end-systolic and end-diastolic dimensions.
Of 81 patients, 26 experienced a total of 472
episodes of spontaneous sustained VT, with all
episodes being successfully terminated (with the
exception of 16 episodes in a single patient who
had incessant VT). Although interpretation of
the study was limited because of the lack of a
control arm, it was the first to demonstrate in a
modest-sized population of heart failure
patients that an ICD and a CRT could be used
together with favorable clinical outcomes.
QRS interval ജ120 ms. Because the patients
enrolled in the study had an immediate need for
an ICD, the total system was implanted but the
patient was not randomized to CRT or no CRT
until after a period of at least 30 days. The study
began as a crossover study after a period of
3 months, but was then changed to a parallel
design because of regulatory concerns. A total of
501 patients were implanted with the device
system, although 11% of patients received the
device via a transthoracic intervention. Patients
were then randomized to either CRT or control
for up to 6 months, with the primary endpoint
being heart failure progression as defined by
the combination of all-cause mortality, hospitalization for heart failure, and VT/ventricular
fibrillation (VF) requiring device intervention.
Randomization to the active treatment group
was associated with a trend towards an
improvement in heart failure progression, but,
this trend was not statistically significant.
However, patients randomized to CRT demonstrated an improvement in functional capacity, a
reduction in ventricular size, and an improvement in LV function – but not a change in NYHA
symptoms. Patients with NYHA class III and IV
symptoms appeared to have the most robust
response to CRT. Importantly, there were no
differences in the incidence or frequency of
ventricular tachyarrhythmias in the two treatment groups, and patients who experienced
spontaneous monomorphic VT were successfully treated in 88% of the episodes. Because of
the relatively short follow-up period of the trial,
investigators could not assess the effect of longterm therapy with CRT-D in this patient population. Nonetheless, it confirmed early studies
demonstrating improvements in functional
capacity in patients with heart failure, as well as
further documenting the safety of combining an
ICD with a CRT.
The CONTAK-CD study was a double-blind,
randomized, controlled study in patients with
symptomatic heart failure who also had indications for placement of an ICD.14 All patients had
typical enrollment criteria, including NYHA
class II–IV symptoms, an LVEF ഛ35%, and a
Similar to CONTAK-CD, the MIRACLE
(Multicenter Insync Randomized Clinical
Evaluation) ICD trial enrolled patients with
LVEF ഛ35%, QRS duration ജ130 ms, and a high
risk of life-threatening ventricular arrhythmias
but who had NYHA class III or IV symptoms.15
might not be evident for several years10–12 or
may be overshadowed by competing causes of
mortality. Therefore, in this chapter, we will
review the available data on the combined use of
an ICD and a resynchronization device (CRT-D),
address some of the ongoing controversies,
including the combined cost of both devices
versus the cost of either device alone, and provide some pragmatic recommendations for the
use of CRT-D.