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Journal review
Trials on cardiac resynchronization
therapy
• Early trials
• Randomised controlled trials
• Specific issues
– NYHA I/II
– AF
– Narrow QRS
– Upgradation of pacemaker
– Echo assessment of dyssynchrony
– Role of CMR
• Cazeau et al ,1994
– 54yr,NYHA IV,LBBB,QRS dur200 ms
– Temp. 4 chamber pacing-improved hemodynamics
– Permanent 4 chamber pacing-6 wks-marked
clinical imprvt
• Observational studies
• Epicardial leads to transvenous leads
• Various pacing sites
PATH-CHF
• First randomised controlled trial,2001
• 42 pts,NYHA III/IV,ischemic or non ischemic,SR,QRS
120ms,PR 150ms
• Univentricular Vs biventricular pacing
• Primary endpoints-Oxygen consumption at peak
exercise and at anerobic threshold,6-minute walk
distance
• Secondary endpoints-changes in New York Heart
Association functional class, hospitalization frequency
and quality of life
• Trend towards improvement in all primary &sec endpts
with biventricular pacing
MUSTIC-SR
• Single blind,randomised,crossover study
• NYHAIII,SR,EF<35%,LVEDD>60,QRS>150ms,6min
walk<450m
• 47pts completed
• Randomised to resynchronization or to no pacing for 3
mth,crossed over to alternative group for 3
mths,followed up for 12 mths
• Primary endpt-6-min walked distance
• Sec-peak Vo2, quality of life, NYHA class,worsening
HF,total mortality
• Significant improvement
MUSTIC-SR results
MUSTIC-AF
• Same study design,41 pts
• Significant imprvt,magnitude less than SR grp
MUSTIC-AF results
MIRACLE
• first prospective, randomized,double
blind,parallel-controlled clinical trial
• Idiopathic or ischemic dilated cardiomyopathy,
NYHA class III/IV , LVEF<35 %,LVEDD> 55
mm,QRS>130 ms,6min.walk<450 m
• CRT(n=228) Vs control(n=225) for 6 mths
MIRACLE ICD
• Trial design similar to MIRACLE
• CRT+ICD Vs CRT
• Included NYHA II also,all pts had class I
indication for ICD
NYHA II subgroup(MIRACLE-ICD)
CONTAK-CD
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•
•
•
randomized controlled, double-blind study
6-month parallel control study design
NYHA II–IV ,LVEF< 35%, QRS>120 ms,indication for an ICD.
581 patients were randomized, 248 into 3 mth crossover
study and 333 into the 6-month parallel controlled trial.
• Primary endpnt was a composite of mortality,
hospitalizations for HF &VT/VF-insignificant trend favoring
CRT grp
• Sec endpts-peak Vo2, 6-min.walk distance, quality of life,
and NYHA class-significant imprvnt in CRT grp
• Imprvmnt NYHA class III–IV subgroup
COMPANION
• 1520 patients,NYHA III or IV ,ischemic or nonischemic
cardiomyopathy,LVEF<35%, QRS ≥120 msec,PR int>150
ms, sinus rhythm, no clinical indication for pacemaker
or ICD
• Randomly assigned in a 1:2:2 ratio to receive
OMT,OMT+CRT,OMT+CRT-D
• Primary composite endpt-death from or hospitalization
for any cause
• Sec endpt-death from any cause
• Death from or hospitalization for cardiovascular causes
and death from or hospitalization for heart failure also
noted
• Implantation successful in 87% in CRT,91% in
CRT-D
• Follow-up 11.9 months OMT,16.2 months in
CRT,15.7 months in CRT-D
• CRT&CRT-D reduced the risk of the primary
end point by 20 %
• Death from or hospitalization for heart failure
– reduced by 34 percent in the pacemaker
group(P<0.002)
– 40 percent in the pacemaker–defibrillator group
(P<0.001)
• Death from any cause reduced by
– 24 percent (P=0.059) in CRT
– 36 percent (P=0.003) in CRT-D
CARE-HF
• Mortality benefit with CRT alone not significant in
COMPANION
• NYHA class III or IV,LVEF<35%,LVEDD>30 mm (indexed to
height),QRS≥150 ms/>120 ms +echo evidence of
dyssynchrony,SR,no indication for pacing
• Primary end point-composite of death from any cause or an
unplanned hospitalization for a major cardiovascular event
• Secondary outcome-death from any cause,composite of
death from any cause and hospitalization with heart
failure,NYHA class and quality of life
• OMT-404 patients Vs OMT+CRT-409,mean follow-up 29.4
mths
• McAlister et al,2004-meta-analysis of several
CRT trials- HF hospitalizations were reduced
by 32% and all-cause mortality by 25%
AHAscience advisory-2005,guidelines
2008,update 2009
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Sinus rhythm
LVEF <35%
Ischemic or nonischemic cardiomyopathy
QRS complex duration 120 ms
NYHA functional class III or IV
Maximal pharmacological therapy for heart
failure
ESC guidelines
CRT in NYHA I/II
• MIRACLE ICD,CONTAK CD-earlier trials
• MADIT CRT,REVERSE-reduced morbidity
• MADIT CRT
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–
–
–
–
1820 patients
Ischemic I/II or nonischemic cardiomyopathy II
EF 30% or less
QRS duration of ≥130msec
NYHA I/II
• 3:2 ratio,CRT+ICD(n=1089) Vs ICD alone (n=731)
• Follow-up of 2.4 years
• Primary end point:death or heart failure
– CRT–ICD group (17.2%)Vs ICD-only group (25.3%)
(hazard ratio=0.66; P = 0.001)
• 34% reduction in the risk of death or heart
failure
• Superiority of CRT was driven by a 41%
reduction in the risk of heart-failure
events,primarily in subgroup with a QRS >150
ms
REVERSE
• NYHA Class II or I (previously
symptomatic),QRS  120 ms; LVEF 
40%; LVEDD  55 mm ,SR,Optimal
medical therapy (OMT)
• 610 pts,12 mth follow up
• Primary Composite endpoint : all-cause
mortality, HF hospitalizations, crossover
due to worsening HF, NYHA class, and the
patient global assessment assessed in
double blind manner
• Secondary: Left Ventricular End Systolic
Volume Index
• No significant difference primary end point
• Significant degree of reverse LV remodelling was
observed in CRT, manifested by decreases in the
LVESV&LVEDV and increase in LVEF
• LV end-systolic volume index was significantly smaller
in CRT grp
• MADIT-CRT and REVERSE enrolled a small
proportion of asymptomatic patients, only
15% and 18%, respectively
• NYHA class I, MADIT-CRT did not show
significant reduction in the all-cause mortality
or HF by CRT over ICD
• REVERSE-trend toward less clinical efficacy
conferred by CRT among class I compared to
class II
ESC guidelines
CRT in AF
• Prevalence of AF in patients with HF-5% in
NYHA I as compared with 25–50% in NYHA
III/IV
• Intrinsic AF rhythm reduces the percentage of
effectively biventricular paced captured beats
(BVP%).
• Effective ‘CRT-dose’ may be reduced
compared to atrial-synchronous rhythm with a
short AV interval (as in SR)
• MUSTIC AF first randomized trial demonstrating
possible benefits of CRT in HF in pts with permanent AF
• Two trials comparing CRT in SR Vs AF-comparable but
benefit more in SR-Leclercq et al (AJC 2000),Molhoek
et al (AJC 2004)
• OPSITE trial- ‘rate control’ by AVJ ablation significantly
improved symptoms &functional status
• PAVE trial-‘ablate and pace’ approach-greater benefit
of the BVP mode in patients with depressed LVEF (45%)
and/or in NYHA functional class III
• 5 studies followig a total of 1,164 patients
• Mortality was not significantly different at 1
year
• NYHA class improved similarly both groups
• SR patients showed greater relative
improvement in 6-min walk&Minnesota score
• AF patients-statistically significant greater
change in ejection fraction
ESC guidelines
Upgradation to biventricular pacing
• small prospective studies
• Clinical benefit of upgrading to biventricular
pacing with long-standing right ventricular
pacing, severe ventricular dysfunction, NYHA
class III symptoms, regardless of QRS durationVatankulu MA et al(AJC 2009),Paparella G(Pacing
clin ele 2010)
• Detrimental effects of RV pacing on symptoms
and LV function in patients with HF of ischaemic
origin and preserved LVEF (Kindermann M et al
,HOBIPACE-JACC 2006)
• In patients with a conventional indication for
pacing, NYHA III/IV symptoms, an LVEF of
≤35%, and a QRS width of ≥120 ms,CRT-P/CRTD is indicated.
• RV pacing will induce dyssynchrony
• Chronic RV pacing in patients with LV
dysfunction should be avoided
• CRT may permit adequate up-titration of Bblocker
ESC guidelines
CRT in narrow QRS
• RethinQ study
• Patients with a indication for ICD,LVEF<35%, NHYA class
III heart failure,QRS<130 ms,echo evidence of
dyssynchrony
• 172 patients,6 months follow up
• Primary end point was the proportion of patients with
an increase in peak oxygen consumption
• CRT group and the control group did not differ
significantly in proportion of patients with the primary
end point (46% Vs 41%)
• No significant difference in HF events
Echocardiographic assessment of
dyssynchrony
PROSPECT
• 498 patients with standard CRT indications
• Twelve echocardiographic parameters of dyssynchrony
• Positive CRT response were improved clinical
composite score and 15% reduction in LVESV at 6
months
• Ability of the 12 echo parameters to predict clinical
composite score response– sensitivity ranging from 6% to 74%
– specificity ranging from 35% to 91%
• No single echocardiographic measure of dyssynchrony
may be recommended to improve patient selection for
CRT beyond current guidelines
Role of CMR in CRT
• Venous anatomy
– assessed noninvasively to determine whether a
transvenous approach is feasible or surgical
approach should be used for LV lead placement
• Assessment of dyssynchrony:
– 77 patients undergoing CRT, those with a CMR-TSI
≥ 110 ms were more likely to meet the endpoints
of death or adverse cardiac events
– Leyva F et al:JACC 2007
• Internal flow fraction fraction (IFF) is defined as
the total internal flow as a percentage of stroke
volume
• IFF of 10 ± 5% in typical CRT patients (NYHA class
III or IV,LVEF < 35%, QRS > 150 ms) and of 1 ± 1%
in the healthy controls (p < 0.001)
• IFF cut-off of 4% discriminated b/w patients and
controls with 90% sensitivity and 100%
specificity.
• Fornwalt et al (JMRI,2008)
• Assessment of scar
– White et al-scar burden < 15% as the best cut-off
for predicting a clinical response to CRT
• LV lead placement
– pacing outside the LV free wall scar is associated
with a better response than pacing over thescar
(86% vs 33%, p = 0.004)
Conclusion
• CRT is an accepted modality of treatment with
mortality benefit in NYHA III/IV HF
• Reduce morbidity in NYHA II
• No evidence of benefit in HF with narrow QRS
• In AF with III/IV HF reduces morbidity&AV nodal
ablation may be necessary
• Echo parameters of dyssynchrony not proven to
be useful
• CMR may prove to be useful to assess
dyssynchrony and feasibility of CRT