Transcript Journal Review-CRT

Journal Review-CRT
Dr Pradeep Sreekumar
Senior Resident
Cardiology
Rationale for CRT



Presence of a bundle branch block or other
intraventricular conduction delay can worsen
HF due to systolic dysfunction by causing
ventricular dyssynchrony
Ventricular dyssynchrony exacerbates left
ventricular dysfunction
Hemodynamic benefits follow the correction of
dyssynchrony with CRT
CARE-HF trial

Randomly assigned 813 patients (mean age 67)
with NYHA class III or IV HF (94 percent class
III, 62 percent nonischemic), an LVEF ≤35
percent (median 25 percent), and QRS
prolongation (median QRS duration 160 msec)
to CRT with biventricular pacing and medical
therapy or medical therapy alone .

The primary end point
Time of death from any cause
Unplanned hospitalization for a major
cardiovascular event

Major secondary end point was death from any
cause.

Significant benefits were noted with CRT at a
mean of 29 months:
A reduction in the primary end point (39 versus 55
percent, hazard ratio [HR] 0.63, 95% CI 0.51-0.77).
 The benefit increased over time and did not vary
with age, sex, NYHA class, baseline systolic
pressure, LVEF, QRS duration, or routine therapies
for HF


A reduction in mortality (20 versus 30 percent,
HR 0.64, 95% CI 0.48-0.85).

The mortality benefit increased over time and
was largely due to a reduction in deaths due to
worsening HF (8.1 versus 13.9 percent), with a
lesser reduction in SCD (7.1 versus 9.4 percent).

The mortality benefit for both HF and SCD increased
slightly at extended follow-up of 38 months .

An increase in LVEF relative to the control arm of 3.7
percent at 3 months and 6.9 percent at 18 months.
This was associated with a rise in systolic pressure of
about 6 mmHg compared to no CRT (median baseline
110 mmHg) and a reduction in plasma N-terminal-probrain natriuretic peptide


At 90 days, improvements in quality of life and NYHA
class was noted.
COMPANION trial

The COMPANION trial was a study of CRT with and
without an ICD in 1520 patients (mean age 67) with




285.
NYHA class III or IV HF
a QRS duration ≥120 msec
LVEF ≤35 percent (median 21 percent) who had had a
hospitalization for HF within the year prior to enrollment .
Bristow MR, Feldman AM, Saxon LA. Heart failure management using
implantable devices for ventricular resynchronization: Comparison of
Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure
(COMPANION) trial. COMPANION Steering Committee and COMPANION Clinical Investigators. J Card Fail.
2000;6:276–

Half of patients enrolled had a nonischemic etiology of HF.

Patients were randomly assigned to optimal medical therapy,
CRT alone, or CRT with an ICD.

Medical therapy for HF included angiotensin converting enzyme
inhibitors or angiotensin receptor blockers in 89 percent, beta
blockers in 66 percent, and spironolactone in 55 percent.

During the course of the study, a significant number of
patients in the medical therapy only arm of the trial
withdrew to receive a device because of arrhythmia or
HF

Mean follow-up of 12 months

There was a significant reduction in the incidence of the primary
composite end point of all-cause mortality and all-cause
hospitalization in the two arms receiving CRT compared to the
medical therapy only arm (HR 0.80, 95% CI 0.68-0.95) .

On subgroup analysis according to baseline characteristics, the
primary end point benefit for device versus medical therapy did
not vary with age, sex, NYHA class, ischemic or nonischemic
origin of the cardiomyopathy, LVEF, or other routine therapies
for HF (eg, angiotensin converting enzyme inhibitors, beta
blockers etc).

Characteristics associated with an increased absolute rate of SCD
included male gender, renal dysfunction, NYHA class IV HF,
and an LVEF ≤20 percent .

The CRT plus ICD arm and the CRT only arm experienced a
significant and an almost significant improvement, in the
secondary end point of all-cause mortality alone
(12 and 15 versus 19 percent in the medical therapy only arm, HR
for CRT plus ICD versus medical therapy 0.64, 95% CI 0.48-0.86,
HR for CRT only versus medical therapy 0.76, 95% CI 0.58-1.01) .

All-cause mortality for CRT plus ICD compared to CRT alone
was significantly lower (odds ratio 0.79, 95% CI 0.60-1.06 )

On subgroup analysis ,the mortality benefit of CRT plus ICD as
compared to medical therapy was significant in nonischemic
cardiomyopathy (HR 0.50) and not quite significant in ischemic
cardiomyopathy (HR 0.73).

At three and six months, both CRT arms showed significant
improvements in NYHA class, six minute walk distance, and
systolic pressure compared to medical therapy alone .

All-cause, cardiac, and HF hospitalization rates were significantly
reduced in both CRT arms compared to medical therapy alone observed within days or weeks of CRT initiation and was
sustained throughout the trial

The mortality benefit in COMPANION began immediately in
the CRT plus ICD group compared to eight months with CRT
alone.

Delayed benefit was seen with CRT alone in CARE-HF also.

Suggest that the ICD prevents sudden death from the beginning,
while the mortality benefit of CRT requires time for reverse
ventricular remodeling .

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

PATH-CHF






First randomised controlled trial,2001
42 patients,NYHA III/IV ,SinusRhythm,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 &secondary
endpoints 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 endpoint-6-min walked distance
Secondary end point-peak Vo2, quality of life, NYHA
class,worsening HF,total mortality
Significant improvement in primary and secondary end points
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(MIRACLEICD)
CONTAK-CD







Randomized controlled, double-blind study
6-month parallel control study design
NYHA II–IV ,LVEF< 35%, QRS>120 ms
581 patients were randomized, 248 into 3 mth crossover study
and 333 into the 6-month parallel controlled trial.
Primary endpoint was a composite of mortality,
hospitalizations for HF &VT/VF
Secondary endpoints-peak Vo2, 6-min.walk distance, quality
of life, and NYHA class-significant improvement in CRT grp
Improvement in NYHA class III–IV subgroup
CRT plus ICD versus CRT alone

Most patients who are eligible for CRT also meet criteria for
ICD implantation.

COMPANION trial - CRT plus ICD showed an significant
trend toward lower all-cause mortality compared to CRT alone in
patients with NYHA class III or IV HF
REVERSE and MADIT-CRT trial results support the use of
CRT plus ICD (CRT-D) in preference to ICD alone to reduce



rehospitalization
heart failure events
remodeling in patients
in NYHA class I or II HF, QRS ≥120 (particularly ≥150), and
LVEF ≤30-40 percent
In NYHA class I or II HF

The largest trial of CRT in patients with mild HF -MADIT-CRT
trial

Demonstrated a beneficial impact of cardiac resynchronization
therapy on heart failure events and remodeling in patients with
mild or no HF symptoms.




The study population consisted of 1820 patients with an LVEF
≤30 percent, QRS ≥130 msec, and NYHA class I (15 percent)
or II (85 percent) HF who were randomly assigned to CRT-D or
ICD alone.
The study included patients with ischemic (55 percent; NYHA
class I or II) or nonischemic (45 percent; NYHA class II )
cardiomyopathy.
The primary endpoint was death from any cause or a nonfatal
HF event (whichever came first).
At average follow-up of 29 months, CRT-D produced a decrease
in the primary endpoint as compared to ICD alone (17 versus 25
percent)




At 40 months mean follow-up, CRT-D decreased the primary
outcome compared to ICD alone (33 versus 40 percent).
The CRT-D group had significantly fewer deaths (21 versus 26
percent) and hospitalizations for HF (20 versus 26 percent).
Adverse events (hemothorax or pneumothorax and device
pocket hematoma or infection, or lead dislodgement requiring
intervention, and coronary sinus dissection) were more frequent
in the CRT-D than in the ICD group (13 versus 7 percent) in the
30 days after device implantation.
The benefit was observed primarily in patients with a QRS
duration ≥150 msec.
Predictive value of QRS duration

A meta-analysis that included the COMPANION, CARE-HF,
REVERSE, MADIT-CRT, and RAFT trials found that CRT
reduced adverse clinical events in patients with HF and a
baseline QRS interval of ≥150 msec but not in those with HF
and a baseline QRS interval of <150 msec.

This difference in response between those with QRS ≥150 msec
and those with QRS interval of <150 was seen in patients with
NYHA functional class I and II HF (P<0.001 and P=0.72,
respectively) as well as those in those with NYHA class III and
IV HF (P<0.001 and P=0.38).
Sex




In the MADIT-CRT trial, CRT plus a defibrillator (CRT-D)
versus ICD alone was associated with significantly greater benefit
in women than in men.
In women as compared to men, there were significantly greater
reductions with CRT-D in the primary endpoint of heart failure
or death, in heart failure alone, and in death alone.
Significantly reduced mortality with CRT-D was seen in women
but not men.
Improvements in echocardiographic volumes and left ventricular
ejection fraction with CRT-D were also greater in women than in
men.



The overall adverse events rate was higher in women as
compared to men (10.5 versus 7.9 percent)
Women more likely to have pneumothorax (3 versus 0.73
percent)
Men more likely to have lead dislodgement (1.7 versus 3.2
percent).
Age

Randomized trials have not specifically addressed the benefit of
CRT in elderly patients.

In two major CRT trials (CARE-HF and COMPANION), the
mean age was about 65 years and the benefit from CRT was
similar in patients above and below the mean age.

Equivalent benefits were also noted in an observational studies
of patients ≥70 years of age (mean age 76) compared to patients
<70 years of age (mean age 59)
Right bundle branch block




The efficacy of CRT in patients with right bundle branch block
(RBBB) is not established.
Most patients in the controlled CRT trials had LBBB; RBBB was
present in 5 to 13 percent of patients .
The guidelines note that there is not yet sufficient evidence to
provide specific recommendations for patients with right bundle
branch block.
In the MADIT-CRT trial, benefit was observed in only in the
subgroup with LBBB.
Lead position



The position of the left ventricular and right ventricular pacing
leads may affect the efficacy of CRT
A retrospective study of 86 patients with QRS ≥120 ms and
NYHA class III or IV HF found that the three-dimensional
separation between the left ventricular and right ventricular lead
tips was associated with reduction in NYHA class by one or
more .
A response rate of 88 percent was achieved in patients with QRS
≥160 ms and lead separation of ≥100 mm compared with 60
percent with QRS ≥160 ms with lead separation <100 mm

An analysis of MADIT-CRT data for patients with QRS ≥120
ms and NYHA class I or II HF found that an apical left
ventricular lead position as compared with a basal or
midventricular position was associated with a significantly
increased risk for heart failure or death (HR=1.72, 95% CI, 1.09
to 2.71) and increased risk of death (HR=2.91, 95% CI, 1.42 to
5.97)
Major society guidelines

CRT is recommended for patients with LVEF ≤35 percent, a
QRS duration ≥120 msec, and NYHA functional class III or
ambulatory class IV symptoms with optimal medical therapy .

CRT is reasonable for patients with LVEF ≤35 percent with
NYHA functional class III or ambulatory class IV symptoms
who are receiving optimal recommended medical therapy and
who have frequent dependence on ventricular pacing.

CRT may be considered for patients with LVEF ≤35 percent
with NYHA functional class I or II symptoms who are receiving
optimal recommended medical therapy and who are undergoing
implantation of a permanent pacemaker and/or ICD with
anticipated frequent ventricular pacing .

CRT is not indicated for asymptomatic patients with reduced
LVEF in the absence of other indications for pacing . CRT
is not indicated for patients whose functional status and life
expectancy are limited predominantly by chronic noncardiac
conditions
Meta-analysis of CRT

Meta-analysis of 14 randomized, controlled trials
of 4420 patients
CARE-HF , COMPANION , MIRACLE and
MIRACLE ICD , MUSTIC-SR and MUSTIC-AF ,
PATH-CHF , VENTAK CHF/CONTAK CD ,
and HOBIPACE

Benefits of CRT were noted

A greater likelihood of improving at least one
NYHA class (59 versus 37 percent, relative risk
[RR] 1.6, 95% CI 1.3-1.9), with improvements in
six minute walk distance (mean difference 24
meters) and quality of life.

A reduced rate of hospitalizations for HF (RR
0.63, 95% CI 0.43-0.93).

A reduced rate of all-cause mortality (RR 0.78,
95% CI 0.67-0.91), primarily due to fewer deaths
from progressive HF (RR 0.64, 95% CI 0.490.84).
Summary of CRT benefit

The above randomized trial data support the use of CRT in
patients with NYHA class III or IV HF, left ventricular ejection
fraction (LVEF) ≤35 percent, and QRS duration ≥120 to 140
msec to reduce symptoms, reduce hospitalizations and improve
survival.

The symptomatic benefit (improvement by about one NYHA
class or increased six minute walk distance) occurs early.
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
THANK YOU