Download The effect of left ventricular pacing site on cardiac resynchronization

CLINICAL RESEARCH
Europace (2010) 12, 1750–1756
doi:10.1093/europace/euq324
Pacing and CRT
The effect of left ventricular pacing site on
cardiac resynchronization therapy outcome and
mortality: the results of a PROSPECT substudy
Peter T. Mortensen 1*, John M. Herre 2,3, Eugene S. Chung 4, Jeroen J. Bax 5,
Bart Gerritse 6, Margriet Kruijshoop 6, and Jaime Murillo 2,3
1
Department of Cardiology B, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus N, Denmark; 2Sentara Heart Hospital and Sentara Cardiac Research Institute, 600
Gresham Drive, Norfolk, VA 23507, USA; 3Eastern Virginia Medical School, PO Box 1980, Norfolk, VA 23501-1980, USA; 4The Heart and Vascular Center at The Christ Hospital,
2139 Auburn Avenue, Cincinnati, OH 45219, USA; 5Leiden University Medical Center, Albinusdreef 2, 2333 ZC Leiden, The Netherlands; and 6Medtronic Bakken Research Center,
Endepolsdomein 5, 6229 GW Maastricht, The Netherlands
Received 26 August 2009; accepted after revision 9 August 2010; online publish-ahead-of-print 18 September 2010
Aims
Left ventricular pacing site (LV-PS) was prospectively collected to test the influence of the anatomical LV-PS on the
outcome of cardiac resynchronization therapy (CRT) and mortality.
.....................................................................................................................................................................................
Methods
Four hundred and twenty-six patients with standard indications for CRT underwent echocardiographic and clinical
and results
evaluation before and after CRT implantation. The LV-PS was determined from fluoroscopy using the clockwise principle (CP). The LV-PS was categorized into three prospectively defined groups: between 3 and 5 o’clock and longitudinal basal/mid-position (Group A, ‘optimal’); between 12 and 2 o’clock and longitudinal mid–apical anterior
position (Group B, ‘non-optimal’); and all other (Group C, ‘other’). Of 333 patients, followed for 0.9 years
(mean), adequate images were available to define the LV-PS. Left ventricular pacing site was Group A for 118 patients,
Group B for 56, and Group C for 159. The three groups were comparable regarding gender, aetiology, and NYHA
class; however, patients in Group A were younger. No relation was found between the LV-PS groups and CRT
outcome or all-cause mortality. However, further exploratory subanalyses suggest that LV-PS may impact outcomes
in non-ischaemic patients, those with left bundle branch block, and when LV-PS is apical in location.
.....................................................................................................................................................................................
Conclusion
Using the CP to define anatomical LV-PS, no relation was found between the LV-PS groups and CRT outcome and
mortality. Exploratory analyses warrant further studies.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Heart failure † Cardiac resynchronization therapy † Left ventricular pacing site † Mortality † Predictors
Introduction
In patients with moderate-to-severe heart failure (HF) symptoms,
reduced left ventricular (LV) ejection fraction, and evidence of ventricular dyssynchrony, cardiac resynchronization therapy (CRT)
improves clinical status, quality of life, and survival.1 – 3 However,
because a significant proportion of patients treated with CRT
does not manifest improvement by traditional measures,4 there
has been increased focus on optimizing dyssynchrony evaluation,5
LV pacing lead placement,6 – 10 and device programming.11 Previous
studies have shown a significant correlation between the LV pacing
site (LV-PS), response to CRT, and mortality.8 – 10 Optimizing this
variable therefore may represent an opportunity for improving
response rates to CRT. The Predictors of Response to CRT (PROSPECT) study evaluated the ability of different echocardiographic
techniques to predict CRT outcomes5 and represents a large database of CRT patients in whom the LV lead position was prospectively collected from fluoroscopic images and classified using the
clockwise principle (CP) method.12 The main finding of PROSPECT was that echocardiographic measures of dyssynchrony do
not appear to have enough sensitivity or specificity to affect
patient selection and that the QRS duration remains the main
determinant of dyssynchrony relevant to CRT. This report presents the findings of the PROSPECT substudy exploring the
* Corresponding author. Fax: +45 89496002, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: [email protected].
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Effect of LV-PS on CRT outcome and mortality
Table 1 Baseline demographics of the overall PROSPECT study patients vs. the current study group demonstrate no
significant differences
Characteristic
All patients
A (optimal)
C (other)
Total recruitment
Age (years)
426
68 + 11
118
65 + 11
159
69 + 11
B (non-optimal)
...............................................................................................................................................................................
Male (%)
NYHA (class III) (%)
QRS duration (ms)
LVEF (%)
LVESV (mL)
LVEDV (mL)
71
96
163 + 22
63
97
164 + 22
56
69 + 10
69
96
161 + 20
73
96
163 + 21
24 + 7
23 + 7
23 + 7
23 + 7
168 + 89
230 + 99
177 + 89
237 + 99
165 + 88
226 + 97
161 + 93
222 + 104
Ischaemic (%)
54
48
56
57
Previous myocardial infarction (%)
LBBB (%)
48
77
46
74
47
82
45
73
6MHW (m)
274 + 122
287 + 113
279 + 135
264 + 116
Using diuretics (%)
Using b-blocker (%)
83
85
84
87
80
87
88
84
Using ACE-inhibitors (%)
92
94
91
95
NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVEDV, left ventricular end-diastolic volume; LBBB, left
bundle branch block; MWH, minute hall walk; ACE, angiotensin-converting enzyme.
effect of LV-PS on clinical composite score (CCS), LV volumes, and
all-cause mortality.
Methods
A detailed description of the rationale and methods, as well as the full
patient population and study protocol for the PROSPECT study, has
been published previously.5 Briefly, the patients included in this substudy are a subset of the PROSPECT main analysis cohort. After exclusion of 93 patients without adequate fluoroscopic images to define the
LV lead-tip position, 333 remaining patients formed the final study
group of the present report. Baseline characteristics for the patient
population in the LV-PS substudy are shown in Table 1. Marketreleased Medtronic CRT devices, any manufacturer’s market-released
right atrial lead with an IS-1 connector, any manufacturer’s marketreleased right ventricular (RV) lead with an IS-1 or DF-1 connector,
and market-released Medtronic LV pacing leads were used in the
study. After cannulation of the coronary sinus (CS), a venogram was
obtained. Target location for the LV lead tip was the posterolateral/
lateral basal segment, but if veins to this segment were unable to be
successfully accessed, other cardiac veins could be used. It was recommended to locate a pacing site that could be captured with a
pulse of 3.0 V and 0.5 ms. Fluoroscopic images of the final lead placements were obtained with 308 right anterior oblique (RAO)- and 608
left anterior oblique (LAO)-angulated views. Information on the RV
lead position was not collected but it was recommended to place
the RV lead in the RV apex.
Clockwise definition of the anatomical left
ventricular pacing site
The CP method12 was proposed and evaluated for a more precise anatomical definition of the LV-PS in CRT. The method expresses an
LV-PS position projected on the mitral annular plane as a clock time
in the LAO view, with 12:00 corresponding to the anterior aspect of
the heart. The longitudinal position of the LV-PS position is classified
from the RAO view as basal, mid, or apical by dividing the length of
the LV into three equal-sized bins (Figure 1).
It is reasonable to assume that some lead positions would be
superior to others and potentially yield different outcomes. Indeed,
an anterior LV-PS6 or anatomical proximity between the RV pacing
site at the septum or apex and the LV-PS13 has been associated with
a worse outcome after CRT. We therefore defined three groups prospectively: basal or mid-LV-PS between 3 and 5 o’clock (Group A, traditionally considered ‘optimal’), anterior mid- or apical LV-PS earlier
than 2 o’clock (Group B, traditionally considered ‘non-optimal’), and
all other positions (Group C, ‘other’) (Figure 1). Although some of
the patients with an apical LV-PS between 3 and 5 o’clock (15) may
improve, in order to maximize spatial separation between Groups A
and B, these patients were placed in Group C rather than Group
A. For further analysis of the effect of LV-PS Group B, traditionally considered ‘non-optimal’, Groups A and C were combined and compared
with Group B.
Definition of response to cardiac
resynchronization therapy
Response to CRT was evaluated through HF CCS and relative change
in LV end-systolic volume (LVESV) at 6 months.5 The CCS includes
both objective (death and HF hospitalizations) and subjective
(NYHA class and Patient Global Assessment) measures of clinical
status and classifies patients as worsened, improved, or unchanged.14
If CCS was ‘improved’, this was defined as a positive response to
CRT. A reduction in LVESV by 15% or more was used in this study
as an objective measure of cardiac structural improvement and
response to CRT and has been used in previous trials.15,16
Subanalyses
In addition to analysis of lead positions’ relationship to the two primary
outcomes of the trial, CCS and change in LVESV, further subanalyses
were performed to explore the relationship between LV-PS and
1752
333 (100.0)
3 (0.9)
11 (3.3)
30 (9.0)
Colour codes identify Group A (‘optimal’, green), Group B (‘non-optimal’, red), and Group C (‘other’, uncoloured). Values are expressed as n (%).
61 (18.3)
36 (10.8)
57 (17.1)
36 (10.8)
36 (10.8)
30 (9.0)
19 (5.7)
6 (1.8)
8 (2.4)
93 (27.9)
107 (32.1)
133 (39.9)
0 (0.0)
1 (0.3)
2 (0.6)
3 (0.9)
8 (2.4)
0 (0.0)
6 (1.8)
8 (2.4)
16 (4.8)
19 (5.7)
27 (8.1)
15 (4.5)
17 (5.1)
8 (2.4)
11 (3.3)
12 (3.6)
15 (4.5)
30 (9.0)
22 (6.6)
4 (1.2)
10 (3.0)
8 (2.4)
2 (0.6)
26 (7.8)
10 (3.0)
16 (4.8)
4 (1.2)
8 (2.4)
6 (1.8)
1:00
12:30
5 (1.5)
Total
Figure 2 shows the effect of CRT on CCS and LVESV at 6 months,
stratified by the lead position. Improved CCS was found in 72% of
the patients with the LV lead position in Group A and 66% in
12:00
Cardiac resynchronization therapy
outcomes
Table 2 Frequency of LV lead locations
Baseline characteristics are shown in Table 1, for the overall PROSPECT population and those in this current analysis, showing no
significant differences. In general, most patients were males
(68%) and 53% had ischaemic origin of HF, which is comparable
with the main PROSPECT study. Table 2 shows the frequency of
final LV lead positions, colour coded by grouping A, B, and C
(‘optimal’, ‘non-optimal’, and ‘other’, respectively). The three
groups are statistically comparable regarding gender, HF aetiology,
and NYHA class. Overall, 35.4% (n ¼ 118) patients had the LV-PS
placed in the target position of posterolateral or lateral basal
segment, which is somewhat lower than the percentage reported
in a recently published study by D’Ivernois et al.17
1:30
Results
4 (1.2)
2 (0.6)
2:00
2:30
Percentages were calculated relative to all patients included in this substudy (n ¼ 333). Trend analyses were performed with the Cochran–
Mantel – Haenszel test for trend. Log-rank tests were performed to
evaluate differences between the groups in the Kaplan –Meier
patient survival curves. The relation between mortality and LV lead
location was investigated in addition to the pre-defined analysis at
study design. A P-value of ,0.05 was considered statistically significant.
2 (0.6)
Statistics
2 (0.6)
4 (1.2)
3:00
outcomes: (i) the presence of left bundle branch block (LBBB), (ii)
apical LV lead position, and (iii) HF aetiology.
0 (0.0)
3:30
4:00
mitral annular plane as a clock time in the LAO view, with 12:00
corresponding to the anterior aspect of the heart. The longitudinal position of the LV-PS position is classified from the RAO view
as basal, mid, or apical by dividing the length of the LV into three
equal-sized bins. Positions are classified as Groups A (optimal), B
(non-optimal), and C (other), based on the general clinical
practice.
Mid
Apical
Figure 1 Left ventricular pacing site position projected on the
Basal
4:30
5:00
5:30
Total
.............................................................................................................................................................................................................................................
P.T. Mortensen et al.
1753
Effect of LV-PS on CRT outcome and mortality
Figure 2 The effect of the LV lead position on the primary endpoints of the PROSPECT trial. Although there is a trend, no significant differences in outcomes are seen based on the lead position. Error bars correspond to one asymptotic standard error.
Group B (P ¼ 0.48). For LVESV, paired baseline and 6-month
measurements were available in 226 of the 333 (68%) patients.
Of 81 patients with paired LVESV data and the LV lead position
in Group A, 63% had an LVESV reduction of 15% or more. Of
40 patients with paired LVESV data and the LV lead position in
Group B, 50% had an LVESV reduction of 15% or more (P ¼ 0.18).
The effect of LV-PS on secondary endpoints assessed in PROSPECT is shown in Figure 3. Although there may be emerging
trends suggesting that position A patients tend to do better,
there is no clear pattern of benefit or harm based on the lead
position.
Discussion
Mortality subanalyses
Determination of left ventricular
pacing site
There were 26 deaths in the subanalysis cohort of 333 patients
(8%). The Kaplan– Meier estimate for patient survival is 96.9% at
6-month follow-up, 92.7% at 12 months, and 86.9% at 18
months. There is no difference in survival between the three
LV-PS groups (P ¼ 0.22). However, the comparison of the combination group A + C vs. Group B shows a significant reduction in
mortality at 1 year for the combination group A + C (P ¼ 0.008).
Further subgroup analyses are shown in Table 3, exploring the
interplay of the lead position and the presence of LBBB, apical
LV-PS, and HF aetiology. In this comparison, LBBB patients’ survival
was significantly improved with the LV lead position in the A + C
location compared with location B, whereas in those without an
LBBB, there was a trend but no significant difference in survival.
When apical LV-PS patients were subdivided into A + C vs. B, survival for those with leads in location B was significantly reduced. In
the non-ischaemic group, survival was improved in those with lead
location in the A + C group compared with B, whereas the ischaemic group’s survival was not affected by lead location.
After categorizing the LV lead-tip position into three prospectively
defined groups by the CP method, the assessment of clinical or
structural outcomes as response to CRT does not demonstrate
significant differences between the three lead locations, in the
overall PROSPECT population. However, when the effect of a
‘suboptimal’ location (Group B) was analysed by comparing to all
others (A + C), the lead location did appear to have a significant
impact in certain subgroups, such as those with LBBB, nonischaemic aetiology, and apical LV lead location.
In CRT, the LV-PS has been defined generally by the CS tributary in
which the tip of the lead has been placed, further specified as basal,
mid, or apical. Owing to a number of factors, including the influence of personal interpretation and the pronounced variation in
CS anatomy, a consistent methodology for describing LV-PS has
been lacking. To ensure the highest possible precision in defining
the location of LV-PS, only patients where adequate images were
available to define the LV-PS using the CP were included in the
present study. Analysis of the images was done by a single
reader, an experienced electrophysiologist. Although this approach
ensures consistency, lack of peer review of the readings is
recognized.
Three different position groups were defined prospectively.
A lateral or posterior –lateral LV-PS is expected to be close to
the area of late activation and contraction during sinus rhythm18
and is therefore considered to have a beneficial effect for most
CRT patients; thus, in this study, a basal or mid-LV-PS between
1754
P.T. Mortensen et al.
Figure 3 The effect of the LV lead position on the secondary endpoints measured in PROSPECT. There are no significant differences in any of
the measures.
Table 3 Improved survival in combined group A 1 C
vs. Group B
Left bundle
branch block
Apical left
ventricular pacing
site
Non-ischaemic
aetiology
................................................................................
Yes
P ¼ 0.016
P ¼ 0.002
P ¼ 0.011
No
P ¼ NS
P ¼ NS
P ¼ NS
When combined group A + C was compared with Group B, the combined
group’s survival was significantly better than Group B, the ‘non-optimal’ group in
certain subgroups.
3 and 5 o’clock was defined as a separate group (Group A,
‘optimal’). A mid- or apical LV-PS between 12 and 2 o’clock was
in this study defined as a separate group as it will be situated in
close anatomical proximity with the RV lead with presumed little
or even negative influence on LV resynchronization (Group B,
‘non-optimal’). All other lead positions comprised Group C
(‘other’). Although the effects of these different groups on outcomes are not well established, and they cannot be definitively
labelled as ‘optimal’, ‘sub-optimal’, and ‘other’, it is true that
most implanting physicians locate the LV lead guided by a rough
understanding that some positions are more desirable than others.
Physiology impact of lead location
On the basis of data from Butter et al.,6 a lateral or posterior–
lateral LV-PS has been considered optimal for the majority of
patients. However, a number of recent studies indicate that a standard optimal LV-PS covering all patients cannot be pre-defined but
needs to be tailored to the individual patient.10,18 The LV
dyssynchrony seen in patients with non-ischaemic, dilated cardiomyopathy is generally more uniform in comparison to the more
complex ischaemic heart disease patients with single or multiple
infarct areas separated by segments with normal or near-normal
function.19 It is therefore not surprising that some patients are
not resynchronized at a standard optimal LV-PS, whereas other
patients are well resynchronized, despite a presumed non-optimal
LV-PS. This is supported by Ypenburg et al.10 who showed a
potential optimal LV-PS outside the lateral and posterior LV
region in 31% of CRT candidates. Animal studies have shown
rather extended LV-PS functional iso-regions for CRT response,12
indicating that the effect of LV-PS is not an all-or-none phenomenon but a spectrum, dependent on multiple factors, including
the proximity of LV-PS to the optimal target site. Besides LV-PS,
the overall clinical effect of CRT is governed by a number of
other factors including device programming, which was not collected in this study, that could also influence LV resynchronization
and clinical outcomes.11
Effect of left ventricular pacing site
on outcomes
Despite several small studies on the topic, the role of LV-PS on LV
resynchronization and outcomes remains inconclusive. In the
CARE-HF study,1 the importance of LV-PS on clinical outcome
or mortality was not evaluated. In the present PROSPECT substudy, we did not find a significant relation between LV-PS classified by CP and the clinical endpoints of the main study, i.e.
improved CCS or LVESV reduction. This is in line with the
earlier published COMPANION study which showed that LV
lead location was not a major determinant of multiple measures
of response to CRT over time, including 6 min walk distance,
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Effect of LV-PS on CRT outcome and mortality
quality of life, and NYHA class.20 It is probable that in large databases of relatively heterogeneous patients and centre participants,
‘optimal’ lead locations are quite variable and that one definition
will not fit the entire study group. Accordingly, in a smaller
more controlled population, CRT with an ‘optimal’ LV-PS was correlated with reverse remodelling and improved survival, as well as
reduced HF hospitalizations and heart transplantation, compared
with a non-optimal LV-PS.10 In the current study, although all-cause
mortality is not significantly different between the three groups
stratified by LV-PS, further analysis of mortality comparing the
effect of a combined group (A and C) vs. Group B (anterior
mid- or apical LV-PS earlier than 2 o’clock, or ‘non-optimal’)
showed that all-cause mortality at 1-year follow-up was significantly increased in Group B. This finding is largely driven by
increased mortality in the non-ischaemic subgroup with LV-PS in
position B. This finding may reflect the likelihood that an
‘optimal’ LV-PS is more consistent and better defined in nonischaemic patients, whereas ischaemic patients have more
complex LV dyssynchrony. In such patients, an ‘optimal’ LV-PS
cannot be pre-defined and need to be tailored to the individual
patient.
Exploratory subanalyses
To further explore the relationship between LV-PS and outcomes
with CRT, Group B (anterior, mid –apical location, ‘non-optimal’),
which represents nearly one in five patients, was compared with
the clinically more favoured combined groups A + C. Subgroups
studied of interest included HF aetiology, in which non-ischaemic
patients were more dependent on lead location, as described
above. Recent presentation of results from Multicenter Automatic
Defibrillator Implantation Trial with Cardiac Resynchronization
Therapy demonstrated that patients with the LV lead in an apical
position manifested a much higher mortality rate.21 In contrast,
the current study found that those with apical lead location
tended to do as well as others. However, when these patients
were examined stratified into Group A + C or B, Group B patients
did significantly worse, perhaps leading to the hypothesis that
when the two leads are close together, even a nominal increase
in distance can make a difference. The patients with LBBB also
appeared to show worse survival in Group B compared with
Group A + C. In the non-LBBB group, this relationship does not
exist. We hypothesize that in LBBB patients, the late-activating
zone is classically the lateral–posterior segments, and LV-PS in
that location would more clearly have a salutary impact on outcomes. Also notable is that the subgroup of non-ischaemic patients
with LBBB was the most clearly impacted by lead location. Conceptually, this last group may have the ‘cleanest’ profile of LV dyssynchrony and late-activating region, amenable to traditional CRT.
Limitations
The non-randomized nature of this substudy does not allow definitive conclusions regarding the effect of lead placement on outcomes. Additionally, although lead-tip location images were
collected prospectively, variations in fluoroscopic and X-ray techniques may reduce the accuracy of these analyses. However, to
minimize variation, analysis of the images was performed by a
single reader. Furthermore, there was no attempt to relate the
area of latest mechanical activation and the LV lead position, as
was performed in the study by Ypenburg et al.10 because this information was not systematically available in this substudy. This may
explain the different findings between the two studies.
Conclusions
Using the CP to define anatomical LV-PS, no relationship was
found between the three prospectively defined LV-PS groups
and CRT outcomes. However, exploratory analysis showed that
mid- or apical anterior LV-PS between 12 and 2 o’clock as
defined by the CP is associated with an increased 1-year total mortality. The apparent differential effect of LV-PS on mortality in
patients with non-ischaemic vs. ischaemic aetiology, LBBB vs.
non-LBBB QRS, and apical LV lead location warrants a prospective
study to clarify implant techniques tailored to patient
characteristics.
Conflict of interest: J.M.H., receives research support and consulting fees from Medtronic, St Jude Medical, and Boston Scientific;
E.S.C., conducting research sponsored by Medtronic and a
member of the speaker’s bureau for Medtronic; J.J.B., research
grant support from Edwards Lifesciences, Biotronik, GE Healthcare, BMS Medical Imaging, St Jude Medical, and Medtronic; B.G.,
employee of Medtronic and owns shares; M.K., employee of
Medtronic.
Funding
This work was supported by Medtronic Inc., Minneapolis, MN, USA.
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