Download Current indications for resynchronisation therapy.

Take home messages from recent heart failure clinical trials
Current indications for
resynchronisation therapy
Panos E. Vardas
President Elect of the ESC
Professor of Cardiology
Heraklion University Hospital
Crete, Greece
Declaration of conflict of interest
Modest teaching fees from
Bayer, Medtronic, Menarini, Servier,
and Pfizer.
ESC / EHRA Guidelines for Cardiac Pacing
and Cardiac Resynchronization Therapy
ESC Guidelines for Cardiac Pacing and Resynchronization Therapy 2007 (EHJ 2007)
Recommendation for the use of cardiac resynchronization therapy
by CRT-P and CRT-D in HF patients
Heart failure patients, who remain symptomatic in NYHA classes III – IV,
despite optimal medical therapy, with:
 LVEF < 35 %
 LV dilatation
 QRS complex > 120 ms
 Normal sinus rhythm
Class I, level of evidence A
for CRT-P to reduce morbidity and mortality.
CRT-D is an acceptable option for patients who have expectancy of
survival > 1 year
CRT for specific issues
ESC/EHRA 2007 Guidelines
Class
LoE
Patients with mild HF or asymptomatic LV systolic
dysfunction
III
C
Patients with permanent AF and indication of AVJ
ablation
IIa
C
Patients with bradycardic indications for pacemaker
implantation
IIa
C
IIa
C
I
B
Patients who already have a pacemaker implanted
Should all CRT patients have an ICD back-up?
New ESC Guidelines for CRT
 New data derived from recent clinical trials necessitate the
update of the previous 2007 ESC guidelines for cardiac
resynchronization therapy.
 The 2010 focused update of ESC guidelines on device therapy in
heart failure was developed with the special contribution of the
Heart Failure Association and the European Heart Rhythm
Association.
CRT-P/CRT-D in patients with HF in NYHA
function class III/IV
2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure (EHRA/HFA)
Patient Population
• NYHA function class III/IV
• LVEF≤35%,
• QRS≥120 ms,
• SR
• Optimal medical therapy
• Class IV patients should be
ambulatory
Recommendation
CRT-P/CRT-D*
is recommended
to reduce morbidity
and mortality
Class
LoB
I
A
Reasonable expectation of survival with good functional status for >1
year for CRT-D. Patients with a secondary prevention indication for an
ICD should receive a CRT-D
Ambulatory: No admissions for HF during the last month and a
reasonable expectation of survival >6 months
CRT-P/CRT-D in patients with HF in NYHA
function class III/IV
2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure (EHRA/HFA)
Key points:
What about
 New: LV dilatation no longer required in the
recommendation
 New: Class IV patients should be ambulatory: No
scheduled or unscheduled admissions for HF during the
last month and a life expectancy >6 months
 New: Reasonable expectation of survival with good
functional status for >1 year for CRT-D
 Similar level of evidence for CRT-P and CRT-D
 Evidence is strongest for favourable outcomes for patients
with typical LBBB
NYHA class I-II
patients ??
Clinical evidence in mildly symptomatic patients
CRT in patients with mild heart failure
REVERSE study
 REVERSE trial enrolled 610 NYHA class II patients and class
I patients with previous HF symptoms, with QRS ≥ 120 ms
and EF < 40%.
 The primary endpoint was the HF clinical composite
response that scored patients as improved, unchanged, or
worsened over a relatively short follow-up of 12 months.
CRT in patients with mild heart failure
REVERSE study
The study did not meet the primary endpoint: 16% of patients worsened
in the CRT-ON compared with 21% in the CRT-OFF (p=0.10) group.
Linde C. J Am Coll Cardiol 2008
CRT in patients with mild heart failure
REVERSE study
In secondary analyses, the time-to-first HF hospitalization during 12month follow-up was significantly delayed in the CRT-ON group
(hazard ratio: 0.47, p = 0.03).
Linde C. J Am Coll Cardiol 2008
CRT in patients with mild heart failure
REVERSE study
Patients assigned to CRT-ON experienced a greater
improvement in LV end-systolic volume index and
other measures of LV remodeling.
Linde C. J Am Coll Cardiol 2008
CRT in patients with mild heart failure
REVERSE study
 European investigators of
this trial followed 262 of
the patients up to 24
months and the primary
endpoint of worsening was
found to be significantly
lower in the CRT-ON group
than in the CRT- -OFF
group (19% vs 34%,
respectively, p = 0.01)
 Time to first HF hospital
stay or death in the
European cohort was
significantly delayed by
CRT.
Daubert C. J Am Coll Cardiol 2009
CRT in patients with mild heart failure
MADIT-CRT
 In high risk, asymptomatic or mildly symptomatic, NYHA
Class I and II patients, LVEF ≤0.30, and QRS duration ≥130
ms, CRT-Ds associated with a significant 29% reduction in
death or heart failure interventions when compared to
traditional ICDs.
 Early use of CRT in milder heart failure patients might be
beneficial in improving LV function, leading to a reduction in
symptoms, hospitalizations, and mortality.
Moss AJ, N Engl J Med 2009; 361:1329–38
.
CRT in patients with mild heart failure
MADIT-CRT
A significant 41% reduction in the risk of HF events
whereas there was no significant difference in mortality
between the CRT-D and ICD-only arms.
Moss AJ, N Engl J Med 2009; 361:1329–38
.
CRT in patients with mild heart failure
MADIT-CRT
 Patients with a wide QRS duration ≥ 150 ms as well as
females had significantly more benefit from CRT-D than
patients with QRS < 150 ms and males.
 Further analyses revealed that patients with LBBB, derived
a significant benefit from CRT-D whereas patients with a
wide QRS complex and RBBB or indeterminate ventricular
conduction disturbances (regardless of QRS duration) did
not demonstrate reduction in primary events.
Moss AJ, N Engl J Med 2009; 361:1329–38
.
CRT in patients with mild to moderate heart failure
RAFT
 RAFT enrolled 1,798 NYHA class II or III HF patients with
an EF <30% and an intrinsic QRS ≥ 120 ms or a paced QRS
≥ 200 ms, and randomized them 1:1 to an implantable
cardioverter-defibrillator (ICD) alone or an ICD plus CRT
(CRT-D).
 20% of patients had NYHA class III heart failure at study
entry.
Tang A, N Engl J Med 2010
.
CRT in patients with mild to moderate heart failure
RAFT
Kaplan-Meier estimates of hospitalization for heart failure or death
The risk of primary endpoint was significantly
reduced by 25%, from 40.3% in the ICD-only group
to 33.2% in the CRT-D group.
Tang A, N Engl J Med 2010
.
CRT in patients with mild to moderate heart failure
RAFT
Kaplan-Meier estimates of hospitalization for heart failure or death
NYHA class II
NYHA class III
Tang A, N Engl J Med 2010
.
CRT in patients with mild to moderate heart failure
RAFT
Subgroup Analyses of Death or Hospitalization for Heart Failure


Patients with LBBB benefit more than patients with RBBB, IVCD or paced QRS.
Females also showed a trend toward more significant benefit than men.
Tang A, N Engl J Med 2010
.
CRT in patients with mild to moderate heart failure
RAFT
 Mortality was also reduced by 25% (hazard ratio: 0.75; p =
0.003), from 26.1% in the ICD-only patients to 20.8% in CRT-D
patients.
Tang A, N Engl J Med 2010
.
CRT in patients with mild to moderate heart failure
RAFT
In NYHA class II patients RAFT showed,
a significant 29% reduction in mortality.
In NYHA class III patients RAFT showed,
a non-significant 21% reduction in mortality.
Tang A, N Engl J Med 2010
.
CRT in patients with mild heart failure
Clinical Trials Comparison
 When comparing two-year mortality rates in patient
treated with CRT devices RAFT showed about 20% twoyear mortality in the CRT-D arm, which is comparable with
about 18% two-year mortality in the CARE-HF, the trial
enrolling class III and IV patients, and comparable with a
25% two-year mortality observed in the CRT-D arm in the
COMPANION trial, also enrolling class III and IV patients.
 These rates are much higher than the 6% two-year
mortality observed in MADIT-CRT patients randomized to
CRT-D therapy.
CRT in patients with mild heart failure
Clinical Trials Comparison
What do the
 RAFT seems to be more similar to CARE-HF or
COMPANION than to MADIT-CRT, which probably explains
the differences between trials regarding the magnitude of
the effect of CRT-D on HF events and differences in the
effect on mortality.
Guidelines
 Long-term follow-up of MADIT-CRT patients will possibly
allow us to determine whether in these mild HF patients,
CRT-D also reduces mortality, which would be expected
after about a 40% reduction the risk of HF events.
say ??
Current indications for CRT-D in patients with HF
in NYHA function class II
2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure (EHRA/HFA)
Patient Population
• NYHA function class II
• LVEF≤35%
• QRS≥150 ms
• SR
• Optimal medical therapy
Recommendation
Class
LoE
CRT preferentially
by CRT-D
is recommended to reduce
morbidity or to prevent
disease progression*
I
A
* The guideline indication has been restricted to patients with HF in
NYHA function class II with a QRS width ≥150 ms, a population with a
high likelihood of a favourable response
Current indications for CRT-D in patients with HF
in NYHA function class II
2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure (EHRA/HFA)
Key points:
 Two recent, randomised, prospective, multicentre trials in
mild HF (MADIT-CRT and REVERSE) demonstrate reduced
morbidity.
 18% of patients in REVERSE and 15% of patients in MADITCRT were in NYHA I class at baseline although most of
these patients had been previously symptomatic.
 Recommendation restricted to patients in NYHA II
Current indications for CRT-D in patients with HF
in NYHA function class II
2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure (EHRA/HFA)
 Improvement primarily seen
QRS≥150 ms and typical LBBB.
in
patients
with
 In MADIT-CRT the extent of reverse remodelling was
concordant with and predictive of improvement in
clinical outcomes.
 Survival advantage not established.
Current indications for CRT in patients
with HF and permanent AF
2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure (EHRA/HFA)
Patient population
Recommendations
Class LoE
• NYHA class III/IV
• LVEF≤35%, QRS≥130 ms
• Pacemaker dependency
induced by AV nodal ablation
CRT-P/CRT-D
should be considered
to reduce morbidity
IIa
B
• NYHA class III/IV
• LVEF≤35%, QRS≥130 ms
• Slow ventricular rate and
frequent pacing
CRT-P/CRT-D
should be considered
to reduce morbidity
IIa
C
Reasonable expectation of survival with good functional status for >1
year
Frequent pacing is defined as ≥95% pacemaker dependency
Current indications for CRT in patients
with HF and permanent AF
2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure (EHRA/HFA)
Key points:
 Approximately 20% of CRT implantations in Europe are
in patients with permanent AF
 NYHA class III/IV symptoms and an LVEF ≤35% are
well-established indications for ICD
 Frequent pacing is defined as ≥95% pacemaker
dependency
 AV nodal ablation may be required to assure adequate
pacing
 Evidence strongest for patients with an LBBB pattern
 Insufficient evidence for mortality recommendation
Current indications for CRT in patients
with HF and a conventional pacemaker indication
2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure (EHRA/HFA)
Patient population
Recommendations
NYHA III/IV
LVEF≤35%
QRS≥120 ms
CRT-P/CRT-D
is recommended
to reduce morbidity
NYHA III/IV
LVEF≤35%,
QRS<120 ms
NYHA II
LVEF≤35%
QRS<130 ms
Class LoE
I
B
CRT-P/CRT-D
should be considered
to reduce morbidity
IIa
C
CRT-P/CRT-D
may be considered
to reduce morbidity
IIb
C
Current indications for CRT in patients
with HF and a conventional pacemaker indication
2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure (EHRA/HFA)
Key points:
 In patients with an indication for pacing, NYHA III/IV
symptoms, an LVEF ≤35% and a QRS width ≥ 120 ms, a
CRT-P/CRT-D is indicated
 RV pacing will induce dyssynchrony
 Chronic RV pacing in patients with LV dysfunction
should be avoided
 CRT may permit adequate uptitration of β-blocker
treatment
Open Issues for CRT implantation
CRT Implantation Issues
 CRT-P or CRT-D?
 Importance of operator experience and lead placement?
 Role of imaging to determine optimal lead placement?
 Skills in optimal AV, VV programming?
 Adequate follow-up programme?
 Which factors in patient selection predict a poor response?
 Health Resource Utilisation and cost/benefit ratio?
Thank You