Co-Morbidities and Cardiac Resynchronization Therapy: When
Should They Modify Patient Selection?
Martin H, Ruwald MD, PhD,
1Department of Cardiology, Gentofte Hospital, Denmark.2Department of Cardiology, Bispebjerg Hospital, Copenhagen, Denmark.
Cardiac resynchronization therapy (CRT) improves symptoms, reduces heart failure related hospitalizations and death in selected patients with heart failure. Based on thousands of patients enrolled in major clinical landmark trials, current guidelines describe in relatively precise terms which cardiac patients should receive a device. However, clinical trials often excluded sicker patients leaving clinicians with the dilemma of how to treat real-life patients with major co-morbidities, frailty, and increasing age, who are otherwise candidates for CRT implantation. This review investigates results from clinical trials and available observational data on the influence of co-morbidities on CRT benefit in order to provide better insight of when and why co-morbidities should modify patient selection for CRT.
Corresponding Address : Dr. Martin H. Ruwald, MD, PhD
Department of Cardiology
Bispebjerg Hospital, Bispebjerg Bakke 23
2400 Copenhagen N
Denmark.
Cardiac resynchronization therapy (CRT) has evolved vastly since its early stages as a treatment for patients with advanced heart failure (HF) and reduced systolic function. Mainly the improvement could transpire because of technical development and improved physician-related device skills. Furthermore, multiple randomized clinical trials have now shown a significant benefit in both morbidity and mortality associated with implantation of the device, and additionally identified patients who benefit most from this therapy.
International guidelines1-7 for CRT supports the use of CRT in patients with characteristics similar to those enrolled in the trials8-13 but with minor differences of opinion regarding left ventricular ejection fraction (LVEF) and QRS duration and morphology in current Canadian,7 US4 and European guidelines.2 A current, simple and practical synthesis is that CRT is a highly recommended and beneficial treatment in patients with sinus rhythm, left ventricular ejection fraction (LVEF) ≤35%, NYHA class II - IV and left bundle branch block (LBBB) QRS morphology with width ≥150 ms. However, the recent European CRT Survey14 found that CRT indications used in daily practice include patients with QRS less than 120 ms, patients with non-LBBB, asymptomatic patients in NYHA class I, and subjects with atrial fibrillation (AF) thus going far beyond guideline recommended indications, despite a well-known significant non-responder rate around 30%.15,16 Apart from these typical CRT indication criteria individual patient co-morbidities and co-morbidity burden may play an influential role in determining patients’ clinical response to CRT. Co-morbidities can be perceived as related to cardiac conditions such as AF and disease of the conduction system, and non-cardiac co-morbidities such as chronic obstructive pulmonary disease, chronic kidney disease, diabetes, cancers, and others. This review covers the importance of patient selection and the influence of cardiac and non-cardiac co-morbidities in relation to CRT efficacy and outcomes.
Analyses have consistently shown that patients with non-LBBB QRS morphology, patients with ischemic cardiomyopathy, those with higher scar burden, males and those with increased disease burden (larger atrial and ventricular volumes and lower baseline LVEF) derive a relatively reduced benefit of CRT implantation.15,17,18 A simple and better selection of patients may reduce this number of non-responders substantially. A suboptimal response to CRT is believed to be multifactorial and depends on patient selection and CRT delivery techniques (lead positions, AV-delay etc.). Mullens et al.19,20 further showed that a protocol-driven assessment of CRT non-responders improves reverse remodeling by 50%. Additionally, a retrospective analysis comparing a multidisciplinary care setting to “conventional” care found a significant improvement in patient care and reduction in clinical outcomes.21 In addition to the factors above, several cardiac and non-cardiac co-morbidities may influence the efficacy of the CRT device and the overall outcome as discussed below. Evaluation and management of non-responders is beyond the scope of this review but recent reviews cover this matter.22,23
Scar burden in Ischemic HF
Among patients with ischemic HF a large scar burden as well as a lead position on top of localized scar is associated with lack of
response.24-26
The myocardial scar burden determined by magnetic resonance,
speckle track echocardiography or single-photon emission computed
tomography (SPECT) myocardial perfusion imaging (MPI)may add
prognostic value,27-30 but so far no definitive comparative studies have
been able to select any one of these to be included in pre-selection
of CRT candidates. Adelstein et al.24 compared 190 CRT patients
with ischemic cardiomyopathy to 380 CRT patients with nonischemic
cardiomyopathy and 50 patients referred for CRT but with
unsuccessful LV implant. They showed that a large scar burden score
≥23 (defined as a score based on 17 segments each allocated 0-4
points, 0=normal, 4=absence of uptake) of the ischemic patients was
associated with significantly worse survival and less improvement
in LVEF. Further ischemic patients with a low score <23 exhibited
similar survival and LVEF improvement as the comparison group of
non-ischemic. Overall this study indicated that patients with large
scar burden may not benefit from CRT and this group of patients is
very likely to be CRT non-responders.
In addition to the total scar burden, localized scar tissue near the
LV lead site may directly prevent resynchronization with the septum
and further reduce the electrical propagation from the stimulation
site to the viable myocardium. Many LBBB patients experience
super response to CRT which is most likely due to the presence of
a large anatomic sweet spot of potential response, particularly for
non-ischemic patients. If lead placement was guided by imaging it
seems that particularly non-LBBB and non-responder subgroup
populations such as ischemic patients with large areas of scar burden
could have improved outcomes, but this remains to be shown in
prospective trials. Although quantification of scar by magnetic
resonance imaging seems particularly promising a SPECT/MPI
is mostly used in clinical practice and is safe in patients with
implanted devices. The quadripolar LV leads increases the number
of pacing vectors compared to bipolar leads allowing a more optimal
posterolateral lead placement and potentially avoiding areas of
scar. The clinical value of quadripolar lead has been evaluated in
non-randomized observational studies showing a decreased risk of
hospitalization, reduced cost31 and better survival.32
Atrial Fibrillation in HF
AF is the most common arrhythmia in patients with HF. The
EuroHeart Failure survey reported that up to 45% of patients with
HF also had intermittent or permanent AF.14 AF is a typical cause
of decompensated HF and complicates management significantly.
Despite the huge number of patients with both permanent AF
and HF, accounting for more than 20% of CRT recipients in
Europe,14 these patients were included in very small numbers in
the large randomized clinical trials. The studies published, in which
the efficacy of CRT in patients in sinus rhythm was compared to
those with AF, showed a lower clinical efficacy and a higher rate
of non-responders in the AF group, which can partly be explained
by the difficulty in achieving an acceptable biventricular pacing
percentage.33,34 However for paroxysmal or intermittent AF the case
is less clear; in a MADIT-CRT sub-analysis, the clinical benefit
of cardiac resynchronization therapy with implantable cardioverter
defibrillator (CRT-D) was not attenuated neither by a prior history
of intermittent atrial tachyarrhythmias nor by the development of
in-trial atrial tachyarrhythmias.35 In the RAFT trial patients were stratified by presence of permanent AF and then randomized to
CRT-D (N=114) or implantable cardioverter defibrillator (ICD)-
alone (N=115). The results showed no difference in the primary
outcome of death or HF hospitalization between those assigned
to CRT-D versus ICD (HR= 0.96; P=0.82).36 This indicated that
patients with permanent AF who are otherwise CRT candidates
appear to gain minimal benefit from CRT-D compared with a
standard ICD. AV node ablation for the management of AF in CRT
HF patients is a treatment that permits complete rhythm and heart
rate control resulting in constant biventricular pacing. In a systematic
review and meta-analysis Wilton et al.37 compared the outcomes
of patients (n=7,495) with and without AF receiving CRT and
evaluated the influence of AV node ablation in those with AF. AF
was prevalent in 26% and was associated with significantly increased
risk of non-response to CRT (35 % vs 27%) and all-cause mortality
(11% vs 7% per year). AV node ablation appeared favorable with a
lower risk of clinical non-response (RR= 0.40) and a reduced risk
of death. One year later, in 2012, Ganesan et al. published a similar
meta-analysis with fewer studies but focusing on the role of AV node
ablation in the patients with AF. Results were similar showing AV
node ablation was associated with a substantial reduction in all-cause
mortality (RR = 0.42) and cardiovascular mortality (RR= 0.44) and
with improvements in NYHA class compared with medical therapy
in CRT plus AF patients.38 Therefore overall the benefits of CRT
appear to be attenuated in patients with permanent AF, in particular
in those with low biventricular pacing rates, but AV node ablation
can improve CRT outcomes in patients with AF.
The APAF39 study from 2011 and the PAVE40 study from 2005
were both conducted on patients with AF and AV node ablation
was performed. CRT, compared to RV pacing alone, decreased
both mortality and the number of hospitalizations due to HF. The
observational CERTIFY study41 (N=7,384) compared mortality
between CRT patients in sinus rhythm with AF patients who had
undergone either AV node ablation or medical treatment. The results
showed that cardiac as well as total mortality were higher in patients
with AF and medically treated; while there were no significant
differences between patients in sinus rhythm and those with AF
who underwent AV node ablation. The rationale and evidence for
optimal outcomes among CRT patients based on biventricular
pacing percentage refer to the hypotheses that effective delivery
of CRT may be hindered by the presence of native ventricular
conduction, by inappropriate long AV delay programming, by atrial
or ventricular tachycardia, AF or frequent premature atrial and
ventricular complexes.1,23,33 AF is considered a major determinant of
loss of biventricular pacing.42
The optimal biventricular pacing percentage has been evaluated in
four studies. Initially, in 2006 Gasparini et al. set an arbitrary cutoff
of 85% biventricular pacing to define CRT in AF patients as
successful. Koplan et al43 followed in 2009 and reported 92% while
Hayes et al. in 201144 found 98.5% to be the cut-off with the greatest
magnitude of separation for total mortality. In the MADIT-CRT
trial (sinus rhythm patients) a biventricular pacing percentage ≥90%
was needed to show CRT-D efficacy when compared to ICD-only45
and biventricular pacing ≥97% was associated with an even further
decrease in the risk of HF events, as well as a significantly reduced
risk of death. Of importance Hayes et al. found that patients with AF
had similar survival as sinus rhythm patients as long as they achieved
biventricular pacing percent of 98.5% or more. Biventricular pacing percentage is a practical evaluation and measurement of biventricular
pacing success, however Kamath et al.46 demonstrated in 2009 that
that the absolute percentage of biventricular pacing alone, as obtained
from the CRT device interrogation, was an unreliable marker of
effective pacing. Although the interrogation documented more than
90% pacing, a concomitant Holter monitor revealed that fusion and
pseudo-fusion beats constituted as much as 40% of the overall paced
beats. Therefore using data from CRT interrogation counters alone
to estimate percentage of biventricular pacing can be misleading and
results in overestimation.
Current European guidelines give a IIa recommendation with
level of evidence B for patients in permanent AF with LVEF≤35%,
NYHA class III, QRS≥120 ms provided that close to 100%
biventricular pacing can be achieved. Otherwise an AV node ablation
is recommended with same level of evidence.2
Atrio-Ventricular Block in HF
Smaller proof-of-concept studies proposed that patients with
traditional pacemaker indications and moderate to severely reduced
LV function could benefit from CRT instead of RV apical pacing
alone. The HOBIPACE47 (n=30) and COMBAT48 (N=60) showed
effect on both echocardiographic and patient symptom parameters.
The rationale was that early intervention with CRT could prevent
deterioration and progression of HF due to chronic RV pacing.
For patients with preserved LV function and pacemaker indication
however the PREVENT-HF trial49 (n=108) showed no benefit of
CRT in terms of LV remodeling as compared to RV pacing, while
the PACE study (n=177) found the reduction in LVEF and the
increase in LV end-systolic volume observed at 1 year with RV
apical pacing was prevented by CRT but without any significant
difference in clinical endpoints. The BLOCK-HF50 included 691
patients with AV conduction disorders of different severity with a
traditional pacemaker indication and LVEF ≤50%. Patients were
randomized to CRT or RV pacing (LV pacing off) (either with or
without ICD based on standard indications). Patients assigned to
RV pacing showed a significantly higher incidence of the combined endpoint of HF hospitalization or death or 15% increase in LV endsystolic
volume). The study suggests that CRT can be beneficial in
patients with a lower degree of systolic dysfunction and an indication
for pacemaker avoiding the deleterious effect of stimulation from
the right ventricle. Another large trial, the BioPace trial enrolled
1,810 patients and has not yet published the final results. Preliminary
results presented at the ESC 2014 were negative with only a trend
towards benefit for patients randomized to CRT versus RV (HR
=0.87, p=0.08) but final results are pending.51,52 The above evidence
suggests that patients with HF and reduced LVEF who require
frequent ventricular pacing should be considered for CRT despite
native QRS width. Further studies should evaluate the long-term
benefits of CRT for patients with normal LV function and frequent
ventricular pacing.
Non Cardiovascular Co-Morbidities
Among HF patients undergoing CRT implantation the burden
of non-cardiovascular co-morbidities is generally high. In general,
patients with significant co-morbidities were excluded in the major
trials8-13,53-55 and efficacy of CRT in these patients has not been tested
in randomized trials.
Patients enrolled in the major randomized controlled trials were
most often male (75%), had a mean age of 65 years, a prevalence
of diabetes of 30-40% but the prevalence of COPD, active or prior
cancer and chronic kidney disease was rarely reported if the patient
was not excluded by enrollment criteria, see Table 1. The MADITCRT
and MIRACLE both excluded patients with creatinine >3 mg/
dL and in the MADIT-CRT a total of 89 (5%) of the patients had
severe renal dysfunction defined as eGFR <30 mL/min/1.73m2.56
As an example from the MADIT-CRT protocol exclusion criteria
involved patients that had “presence of any disease, other than the
subject’s cardiac disease, associated with a reduced likelihood of
survival for the duration of the trial (average follow-up 40 months),
e.g., cancer, uremia, liver failure, etc.57” From HF registry data of reallife
CRT patients we know that the patients are approximately 5
years older, obesity in general affects 30%, diabetes 30%, COPD 30%, chronic kidney disease 30% and anemia 10%.58,59 Co-morbidities
additionally affect optimal medical treatment, i.e. insufficient use of
antithrombotic medications in anemic patients, reduced use of betablockers
for COPD and reduced use of angiotensin blockers and
spironolactone among patients with chronic kidney disease.
Table 1. Triggers and risk factors for developing LAF
Trial (year) | Patients | NYHA | LVEF Critera
Mean | QRS Critera
Mean | Primary end point | Secondary
End points | Non-ischemic | Diabetes | Renal dysfunction | COPD |
---|
PATH-CHF
(2002) | 41 | III, IV | NA
22% | ≥150
175 | 6-MWT, peak VO2 | NYHA, QoL, HF hosp. | 71% | NR | NR | NR |
MIRACLE
(2002) | 228/225 | III, IV | ≤35%
22% | ≥130
166 | NYHA
6-MWT QoL | Peak VO2, LVEDD, LVEF,
MR, CCR | 76% | NR | NR | NR |
MIRACLE –ICD
(2003) | 187/182 | III, IV | ≤35%
25% | ≥130
164 | NYHA
6-MWT QoL | Peak VO2, LVV, LVEF, MR,
CCR | 31% | NR | NR | NR |
CONTAK-CD
(2003) | 245/245 | II,III,IV | ≤35%
22% | ≥120
158 | NYHA
6-MWT QoL | LVV, LVEF, CCR | 31% | NR | NR | NR |
COMPANION
(2004) | 617/595/308 | III, IV | ≤35%
21% | ≥120
159 | All-cause mortality
or hosp. | Cardiac mortality | 44% | 41% | NR | NR |
MIRACLE –ICD II
(2004) | 85/101 | II | ≤35%
25% | ≥130
166 | Peak VO2 | NYHA
QoL, 6-MWT, LVV, LVEF, CCR | 43% | NR | NR | NR |
CARE-HF
(2005) | 409/404 | III,IV | ≤35%
25% | ≥120
160 | All-cause mortality or
cardiovascular hosp. | NYHA, QoL, LVEF, LVESV,
HF hosp. | 46% | 21% | 18% | 19% |
REVERSE
(2008) | 419/191 | I,II | ≤40%
28% | ≥130
153 | CCR | LVESVi | 45% | 22% | Mean eGFR 83
mL/min | NR |
MADIT-CRT
(2009) | 1089/731 | I,II | ≤30%
25% | ≥130
162 | All-cause mortality or
HF hosp. | LVESV, LVEDV, LVEF | 45% | 30% | 32% | NR |
RAFT
(2010) | 894/904 | II,III | ≤30%
24% | ≥120
158 | All-cause mortality or
HF hosp. | Cardiac death
Non-fatal HF Hosp. | 33% | 34% | 43% | NR |
CCR: Clinical composite response, 6-MWT: 6 minute walking test, Qol: quality of life, LVEDD: left ventricular end-diastolic diameter, LVESV: left ventricular end-systolic volume, LVESVi: : left ventricular end-systolic volume index; LVEDV: left ventricular end-diastolic volume, LVEF: left ventricular ejection fraction, eGFR: estimated glomerular filtration rate, COPD: chronic obstructive pulmonary disease, NR: not reported, NYHA : New York Heart Association, MR: mitral regurgitation
Everyday physicians encounter patients who have per guideline
indication for CRT but also often present with one or more of these
co-morbidities possible affecting expected cardiac prognosis and
CRT efficacy.
Theuns et al.60 prospectively followed 463 patients who received a
CRT-D. They found that non-cardiac co-morbidities were common
in their population of HF patients with 81% of the patients having
at least three comorbid conditions. They reported that patients with
a high co-morbidity burden had an increased risk with a hazard
ratio of 3.7 for mortality as compared to those with a lower burden.
However, since there was no control group, the study could not assess
whether there were any relative benefit of CRT among the patients
with high co-morbidity burden. Bai et al.61 also demonstrated
that renal failure and diabetes were strong independent predictors
of mortality in patients treated with CRT. In this study patients
with one of three co-morbidities, chronic renal failure (OR = 4.9),
diabetes mellitus (OR = 4.1), and history of AF (OR = 1.5) had a
higher risk of death but again without a control group leaving the
question of CRT efficacy based on co-morbidity burden unanswered.
Dominguez-Rodrigues et al.62 recently reported that frailty defined
as a syndrome of wasting and malnutrition, weakness, slowness, and
inactivity, was a strong predictor of HF decompensation (HR = 4.6)
in patients with non-ischemic cardiomyopathy undergoing CRT-D.
Frailty and high co-morbidity burden, illustrated by Charlson Index
>4, has previously been associated with high risk of non-sudden
death in HF but non-CRT patients6. These observational data and
other reports58,59,63 suggest that patients with high burden of noncardiac
co-morbidity are at higher risk of death on both short and
long-term, but so far no reports have been able to set a cut-off of
where patients with high co-morbidity burden no longer benefit
from a CRT device. In particular frailty and cachexia might reduce
the overall benefit of CRT, but many of contributing factors in frailty
may be reversible through CRT effect. Consultation with geriatrician
could be helpful in these borderline cases. Recent detailed statistical
analysis64 of five landmark CRT trials (COMPANION, CARE-HF,
MADIT-CRT, RAFT and REVERSE) found that the lifespan gain
from biventricular pacing rises nonlinearly with time. They showed
that lower-risk patients seemed to gain less over the first 1 or 2 years,
but ultimately they could be the ones who gained the most from
implantation of the device.
Renal dysfunction is one of the most important co-morbidities
in HF and is associated with increased mortality and affects cardiac
function and renal function bidirectionally so that worsening HF or
acute decompensated HF can accelerate worsening of renal function-
-the so-called cardiorenal syndrome.65 Beneficial effects of CRT can
be related to improvement in renal function leading to the hypothesis
that CRT is a renal-protective strategy in HF. From the MIRACLE
study the patients were categorized according to their baseline
eGFR≥90, 60-89 and 30-59 mL/min per 1.73 m2. CRT improved
LV function in all three categories and when compared with controls,
CRT increased eGFR and reduced blood urea nitrogen in those with
worst renal function, whereas no differences were observed in the group of eGFR 60-89 and eGFR≥90.66 Goldenberg et al. showed in
the MADIT-CRT that pre-implantation patients with an elevated
ratio of blood urea nitrogen to creatinine experienced a significantly
greater reduction in the risk of HF or death with CRT-D therapy
as compared with patients with a low ratio.56 The cumulative 3-year
incidence of HF or death was 35% among ICD patients with high
BUN:crea level compared to 18% for those with low BUN:crea level.
This is in contrast to 18% versus 22% for the patients treated with
CRT-D in the same categories, leaving a relative risk reduction
markedly higher for CRT-D patients with high BUN:crea levels of
0.46 compared to 0.85 for those with low BUN:crea levels. These
findings suggested important interaction between prerenal function
and response to CRT, but importantly these data were from less
symptomatic NYHA II and I patients. This was supported by smaller
studies where elderly patients who had a higher prevalence of renal
dysfunction still had positive response to CRT,67,68 while others
report that the effect of CRT was attenuated in patients with more
advanced chronic kidney disease (<30 mL/min/1.73m2). Adelstein
et al.69 reported no echocardiographic or survival improvement in 64
of 787 CRT patients with eGFR <30 mL/min/1.73m2 compared to
a control group of unsuccessful LV implant. Considering increased
procedural risk among patients with advanced chronic kidney
disease or on dialysis benefit/risk assessment needs to be cautiously
evaluated.70
Based on the available data, the possible attenuated benefits and the
increased risk should be taken into consideration when considering
the implantation of a CRT device in a dialysis patient. The role of
CRT in end-stage renal failure patients or on dialysis therapy has
therefore not been fully established.56,63,71-73 Recent appropriate use
criteria for ICD and CRT-D gives an M for “may be appropriate” for
the implantation of ICD/CRT-D in patients with advanced renal
dysfunction or in patients on dialysis.74
Diabetes and HF are associated and each condition is a risk factor
for the development of the other. Several analyses both from HF
populations and HF with CRT populations have found diabetes as
an independent predictor of morbidity and mortality,75-79 while some
studies disagree and find similar mortality with or without diabetes.80
The pathophysiology underlying HF in diabetic patients differs from
that of non-diabetic patients81 and therefore CRT might have reduced
efficacy however there is overwhelming evidence that CRT performs
equally well in both diabetic and non-diabetic patients.80,82-84
Clinical risk scores have been encouraged as a means of identifying
patients who are less likely to benefit from ICD therapy, notably the
very elderly, patients with very advanced symptoms of HF, and those
with chronic kidney disease but similar clinical risk scores have not
been developed in CRT patients.85-88 Furthermore, none of these
risk scores have been independently validated and there are no
randomized data to guide clinical decision-making.
Currently patient selection for CRT considering co-morbidities
relies on individual physician judgement.
Elderly patients differ substantially from younger patients and agerelated
changes in cardiac structure include increased left ventricular
mass, decreased myocyte function and increased apoptosis.89 As
mentioned above there is a natural age-dependent increase in
coexisting co-morbidities such as cerebral vascular disease, renal
dysfunction, anemia, hyponatremia, etc. in elderly patients leading
to higher rates of mortality and hospitalizations when compared with younger patients.90 It was hypothesized that the elderly would
not benefit as much from CRT as the young maybe because of high
incidence of non-cardiac death, on the other hand even a small
relative risk reduction with CRT can become evident when the
absolute risk for mortality is high.
In a MADIT-CRT sub-analysis91 a multivariate analysis
demonstrated that CRT-D therapy was associated with a significant
reduction in the risks of HF or death in patients aged 60-74, and ≥75
years (HR = 0.57 and HR = 0.59, respectively), while no significant
benefit in patients aged <60 years (HR = 0.81) was observed. Other
smaller observational studies have supported this finding.67,92
Recently it was however shown that among elderly patients (>75
years),(N=208) implanted with CRT the cause of death was mainly
non-cardiac (29% in the elderly versus 19% in non-elderly; P<0.001).
Diabetes, impaired renal function and reduced 6-minute walk
distance were independently associated with all-cause mortality in
the elderly patients.93 Competing risk of non-cardiac death could
indicate an overall reduced efficacy of a CRT device among the
elderly. Currently patient selection for CRT considering age relies
on individual physician judgement. Expected lifespan <1 year is
considered a contraindication for CRT-D or ICD. Current evidence
does not support that high age alone should be regarded as a limiting
factor or a contraindication for CRT implantation.
Physicians implanting CRT should take into account several
clinical factors when selecting patients for this therapy. Aside from
the guidelines recommended cardiac criteria of disease severity
(NYHA class), the magnitude of left ventricular dysfunction, QRS
width and morphology as well as rhythm and life-expectancy it is
important to evaluate important comorbid factors. Further data is
needed to help guide clinicians in future patient selection by setting
the right cut-off of risk/benefit and co-morbidity burden where we
cannot expect the device to have an overall positive effect.