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Cardiac Resynchronization Therapy with
Implantable Cardioverter Defibrillator (CRT-D)
for Mildly Symptomatic Heart Failure
Medtronic CRT FDA-Approved Labeling*
QRS Duration
LVEF
Optimal Medical Therapy
Approved Device(s)
NYHA III/IV**
NYHA II
Prolonged
LBBB***, QRS ≥ 130 ms
≤ 35%
≤ 30%
Yes
Yes
CRT-P, CRT-D
CRT-D only
* See www.manuals.medtronic.com for complete labeling7. This is the “expanded indication” population approved
for Medtronic in April, 2012.
** NYHA Class IV patients should be ambulatory with no admissions for HF in the last month and have a reasonable
expectation of survival.
***LBBB = Left bundle branch block
2
Recent Medtronic Studies Supporting
CRT-D Expansion
Study Design
REVERSE1
RAFT2
Randomized 2:1;
CRT±D ON vs. OFF;
Double-blinded
Randomized 1:1;
CRT-D vs. ICD;
Double-blinded
610 randomized
1,798 randomized
12 months
18 months minimum;
Mean 40 months
HF Clinical Composite
Total mortality + HF
hospitalization
I and II
II and III
Size
Randomized Duration
Primary Endpoint
NYHA Class
1
Linde C, et al. JACC. 2008;52:1834-1843.
2
Tang A, et al. N Engl J Med. 2010;363:2385-2395.
33
1
REVERSE :
REsynchronization ReVErses
Remodeling in Systolic Left
VEntricular Dysfunction
1
Linde C, et al. JACC. 2008;52:1834-1843.
1 Linde, C, Abraham, WT, Gold, MR, et al., JACC, Dec 2, 2008; 52 (23): 1834-1843.
4
REVERSE: Study Design
• Prospective, randomized, double-blind, multicenter
– 73 international centers
• 37 US, 35 Europe, 1 Canada
– 610 randomized 2:1 (CRT ON : CRT OFF)
• Enrollment
– September 2004 through September 2006
• Follow-up
– 40 ± 5 months
5
REVERSE: Key Inclusion/Exclusion Criteria
Inclusion
•
•
•
•
•
•
NYHA Class II or I (ACC/AHA Stage C)
QRS  120 ms
LVEF  40%; LVEDD  55 mm
Optimal medical therapy
Without permanent cardiac pacing
With or without an ICD indication
82%
NYHA Class II
83% received
CRT-D
Exclusion
•
•
•
•
NYHA Class III or IV within 90 days prior to enrollment
HF hospitalization within 90 days prior to enrollment
ACS, acute MI, CABG, or PCI within 90 days prior to enrollment
Persistent or permanent atrial arrhythmias
6
Definition: Clinical Composite Response
Did the patient die?
Hospitalized for worsening HF?
Crossover due to worsening HF?
Worsening NYHA Classification?
Answer YES
to Any
Patient classified
as worsened
Answer YES
to Any
Patient classified
as improved
Moderately or markedly worse on Patient
Global Assessment?
Answer NO
to ALL
Improved NYHA Classification?
Moderately or markedly improved on Patient
Global Assessment?
Answer NO
to ALL
Patient classified as unchanged
7
Baseline Assessment
(n = 684)
11 exits after
implant
Successful CRT Implant
(n = 621)
42 ineligible
or withdrew
97% successful
implants
Randomization 2:1
(n = 610)
CRT OFF (OMT  ICD)
(n = 191)
CRT ON (OMT ± ICD)
(n = 419)
12 Months – North American
Randomization complete
(US n = 343; Canada n = 5)
99% follow-up
compliance at
12 months
24 Months – European
Randomization complete
(Europe n = 262)
8
Primary Endpoint: Clinical Composite Response (CCR)
Full Cohort % Worsened at 12 Months1 and Full Distribution*
p = 0.004
54%
40%
39%
30%
p = 0.10
21%
16%
Improved
Unchanged
CRT OFF (n = 191)
1
Linde C, et al. JACC. 2008;52:1834-1843.
Worsened
CRT ON (n = 419)
* Post-hoc analysis.
9
9
Primary Endpoint: Clinical Composite Response (CCR)
Expanded Indication* % Worsened at 12 Months**
65%
47%
35%
30%
p = 0.004
18%
5%
Improved
Unchanged
CRT OFF (n = 60)
Worsened
CRT ON (n = 119)
* FDA-approved cohort.
**Post-hoc analysis.
10
10
Secondary Endpoint: Significant Reduction in LV End
Systolic Volume Index (LVESVi)1 – Full Cohort
CRT OFF
(n = 165)
110
Delta:
-1.6 23.4
LVESVi (ml/m2)
100
90
CRT ON
(n = 328)
80
70
p < 0.0001
Delta:
-18.2 29.4
CRT Off
Acutely
60
Pre-Implant Baseline
1
12 Months
Linde C, et al. JACC. 2008;52:1834-1843.
11
Significant Reduction in HF Hospitalization or All-Cause
Death – Full Cohort and Expanded Indication Population*
% with HF Hospitalization or Death
30%
25%
20%
CRT OFF
15%
10%
5%
CRT ON
0%
0
6
12
18
24
Months Since Randomization
Yellow = All patients (n = 610); RRR = 51%
Blue = Expanded indication cohort (n = 179); RRR = 73%
* Post-hoc analysis.
12
REVERSE Clinical Composite Response
Worsened Subgroup Analysis – Full Cohort*
All Patients
Ischemic
Non-ischemic
CRT-P
CRT-D
NYHA I
NYHA II
Male
Female
< 65 years
≥ 65 years
Non-white
White
LBBB
non-LBBB
QRS duration (ms)
120-129
130-149
≥ 150
0.1
* Post-hoc analysis.
CRT ON Better
1
CRT OFF Better
10
Worsened Clinical Composite Response Odds Ratio
13
REVERSE Safety: Left Ventricular Lead
Complication Rate Similar to Previous Trials
14
REVERSE: Conclusions
• Primary endpoint not met at 12 months in full cohort (p = 0.10)
However…
• Primary endpoint met at 12 months in expanded indication*
cohort (p = 0.004)
• Totality of data demonstrates CRT-D can safely improve patient
outcomes in expanded indication population:
– Clinical composite response*
– LV structural changes (LVESVi)
– Time to first HF hospitalization or all-cause death*
* Post-hoc analysis.
15
2
RAFT :
Resynchronization/Defibrillation
for Ambulatory Heart Failure Trial
2
Tang A, et al., N Engl J Med. 2010;363:2385-2395.
16
RAFT: Study Design
• Prospective, randomized, double-blind, multicenter
– 1,798 enrolled and randomized patients
– 34 international centers
• 24 Canada, 8 Western Europe/Turkey, 2 Australia
– Randomization 1:1 (ICD:CRT-D)
• Enrollment
– January 2003 through February 2009
• Follow-up
– 40 ± 20 months
17
RAFT: Key Inclusion/Exclusion Criteria
Inclusion Criteria
•
•
•
•
•
•
NYHA Class II or III (changed to NYHA Class II only as of February 2006)
QRS  120 ms or Paced QRS  200 ms
LVEF  30%
Optimal medical therapy
ICD indication
With or without persistent atrial tachycardia
Exclusion Criteria
• NYHA Class I or IV
• Existing ICD
18
RAFT: Endpoints
• Primary Endpoint
– HF hospitalization or all-cause mortality
• Key Secondary Endpoint
– Mortality
19
Enrollment
(n = 1,798)
All patients included
in the primary
analysis
Randomization 1:1
(ICD n = 904; CRT-D n = 894)
Device Implant
ICD or CRT-D
CRT-D
(n = 888)
ICD
(n = 899)
95% successful
LV implants
(n = 841)
18-month
Minimum Follow-Up
Mean follow-up 40 months ± 20 months
20
HF Hospitalization or All-cause Death
Primary Endpoint: Significant Reduction in
7
HF Hospitalization or All-cause Death (Full Cohort)
60%
P = 0.014*
HR = 0.75 (0.67-0.96)
50%
ICD
40%
CRT-D
30%
20%
10%
0%
0
12
24
36
48
60
Months Since Randomization
Number 904
remaining 894
770
779
572
615
384
429
214
278
101
130
* Adjusted p-value.
21
Primary Endpoint: Significant Reduction in HF Hospitalization or
All-Cause Death – NYHA II vs. Expanded Indication Population*
% with HF Hospitalization or Death
50%
40%
ICD
30%
CRT-D
20%
10%
0%
0
12
24
36
48
60
Months Since Randomization
Yellow = NYHA II cohort (n = 1,438); RRR = 27%
Blue = Expanded indication cohort (n = 850); RRR = 42%
* Post-hoc analysis.
22
Secondary Endpoint: Significant Reduction in Mortality –
NYHA II vs. Expanded Indication Population*
40%
% Mortality
30%
ICD
20%
CRT-D
10%
0%
0
12
24
36
48
60
Months Since Randomization
Yellow = NYHA II cohort (n = 1,438); RRR = 29%
Blue = Expanded indication cohort (n = 850); RRR = 42%
* Post-hoc analysis.
23
RAFT Conclusions
• Among ICD-indicated patients with mildly symptomatic
HF/systolic dysfunction/QRS prolongation, CRT-D:
– Reduces heart failure hospitalization or all-cause
mortality
– Reduces mortality alone
• Consistently strong evidence in full cohort, NYHA II
cohort, and expanded indication population
• Findings support expanded use of CRT-D in mildly
symptomatic heart failure
24
Medtronic Experience with CRT
FDA Approval
CRT and CRT-D
Late 1990s
MIRACLE and
MIRACLE ICD
Clinical Studies
2001
2002
FDA Approval
For REVERSE
and RAFT
2005
2012
CARE-HF
25
More than a Decade of Experience
With CRT in Mild Heart Failure
2010: RAFT
Average 40 mos, n = 1,438
2009: MADIT CRT
Average 29 mos, n = 1,820
2008: REVERSE
12 mos, n = 610;
24 mos, n = 262
2004: MICD II
6 mos; n = 186
2003: CONTAK CD
6 mos; n = 263
26
More than a Decade of Experience
With CRT in Mild Heart Failure
2010: RAFT2
Average 40 mos, n = 1,438
2009: MADIT CRT4
• Mortality
Average 29 mos, n = 1,820
benefit
2008: REVERSE1
• Mortality benefit
12 mos, n = 610;
in LBBB
24 mos, n = 262
population*
2004: MICD II5
6 mos; n = 186
2003: CONTAK CD6
6 mos; n = 263
* Post-hoc analysis.
1
Linde C, et al. JACC. 2008;52:1834-1843.
Tang A, et al. N Engl J Med. 2010;363:2385-2395.
3 Moss AJ, et al. N Engl J Med. 2009;361:1329-1338.
4 Young JB, et al. JAMA. 2003;289:2685-2694.
5 Higgins S, et al. JACC. 2003;42:1454-1459.
2
27
More than a Decade of Experience
With CRT in Mild Heart Failure
2010: RAFT
Average 40 mos, n = 1,438
2009: MADIT CRT
• Mortality
Average 29 mos, n = 1,820
benefit
•
Reduced HF
2008: REVERSE
• Mortality benefit hospitalizations
12 mos, n = 610;
in LBBB
24 mos, n = 262
population*
2004: MICD II
6 mos; n = 186
2003: CONTAK CD
6 mos; n = 263
• Improved CCR
• Reduced HF
hospitalizations*
• Improved CCR*
• Reduced HF
hospitalizations
* Post-hoc analysis.
28
More than a Decade of Experience
With CRT in Mild Heart Failure
2010: RAFT
Average 40 mos, n = 1,438
2009: MADIT CRT
• Mortality
Average 29 mos, n = 1,820
benefit
•
Reduced HF
2008: REVERSE
• Mortality benefit hospitalizations
12 mos, n = 610;
in LBBB
24 mos, n = 262
population*
• Reduced HF
• Reduced HF
hospitalizations
hospitalizations* • Improved cardiac
• Improved CCR*
function*
• Improved CCR • Improved cardiac
• Improved
function
cardiac function
2004: MICD II
6 mos; n = 186
2003: CONTAK CD
6 mos; n = 263
• Improved
cardiac function
* Post-hoc analysis.
29
CRT Shown to Slow HF Progression in Mild
or Moderate/Severe HF
Mortality
HF or CV Hospitalizations
Cardiac Function/
Structure
CARE-HF1,2
+
+
+
COMPANION3
+
+
Not collected
MIRACLE4
MIRACLE ICD5
REVERSE6
+
Not powered for
mortality or hospitalization
Not powered
Not powered
+*
+
RAFT7
+
+
Not collected
MADIT CRT8
+*
+
+*
1
4
7
2
5
8
Cleland J, et al. N Engl J Med. 2005;352:1539-1549.
Cleland J, et al. Eur Heart J. 2006;27:1928-1932.
3 Bristow M, et al. J Card Fail. 2000;6:276-285.
Abraham W, et al. N Engl J Med. 2002;346:1845-1853.
Young J, et al. JAMA. 2003;289:2685-2694.
6 Linde C, et al. JACC. 2008;52:1834-1843.
Tang A, et al. N Engl J Med. 2010;363:2385-2395.
Moss A, et al. N Engl J Med. 2009;361:1329-1338.
* Post-hoc analysis.
30
Similar Results for CRT in Patients
with Mild Symptoms
REVERSE: Linde C, et al. JACC. 2008;52:1834-1843.
RAFT: Tang A, et al. N Engl J Med. 2010;363: 2385-2395.
MADIT-CRT: Moss A, et al. N Engl J Med. 2009;361:1329-1338.
31
Consistent Benefit of CRT for Patients
with LBBB within Study Cohorts*
Death or Heart Failure Hospitalization/Event
LBBB:
REVERSE
RAFT Class II
MADIT-CRT
Non-LBBB:
REVERSE
RAFT Class II
MADIT-CRT
0.1
0.48
0.63
0.43
0.53
1.10
1.32
CRT-D Better
1
10
Odds Ratio with 95% CI
REVERSE: Linde C, et al. JACC. 2008;52:1834-1843.
RAFT: Tang A, et al. N Engl J Med. 2010;363:2385-2395.
MADIT-CRT: Cognis 100-D Physician’s Technical Manual, Boston Scientific, Inc.
Retrieved from http://www.accessdata.fda.gov/cdrh_docs/pdf/P010012S230c.pdf
* Post-hoc analysis for all 3 trials.
32
32
Totality of Evidence: Conclusion
In the expanded indication patient population,
CRT-D:
• Reduces mortality
• Reduces heart failure hospitalization
• Improves cardiac function
33
References
1
REVERSE: Linde C, Abraham WT, Gold MR, et al. Randomized trial of cardiac resynchronization in
mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction
and previous heart failure symptoms. JACC. Dec 2, 2008;52(23):1834-1843.
2 RAFT: Tang A, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart
failure. N Engl J Med. Dec 16, 2010;363(25):2385-2395.
3 COMPANION: Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or
without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004:350:21402150.
4 MADIT CRT: Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the
prevention of heart-failure events. N Engl J Med. October 1, 2009; 361(14):1329-1338.
5 MIRACLE ICD: Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and
implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial.
JAMA. May 28, 2003; 289(20):2685-2694.
6 CONTAK CD: Higgins S, Hummel J, et al. Cardiac resynchronization therapy for the treatment of heart
failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias.
JACC. 2003;42:1454-1459.
7 REVERSE and RAFT Clinical Studies: Summary of Clinical Results. See www.manuals.medtronic.com.
34
Brief Statement
Medtronic CRT-D Systems
Indications: Medtronic Cardiac Resynchronization Therapy Implantable Cardioverter-Defibrillators (CRT-Ds) are indicated for ventricular
antitachycardia pacing and ventricular defibrillation for automated treatment of life-threatening ventricular arrhythmias and for providing cardiac
resynchronization therapy in heart failure patients who remain symptomatic despite optimal medical therapy, and meet any of the following
classifications: • New York Heart Association (NYHA) Functional Class III or IV and who have a left ventricular ejection fraction ≤ 35% and a prolonged
QRS duration, • Left bundle branch block (LBBB) with a QRS duration ≥ 130 ms, left ventricular ejection fraction ≤ 30%, and NYHA Functional Class II
Contraindications: CRT-Ds are contraindicated in patients whose ventricular tachyarrhythmias may have transient or reversible causes; patients with
incessant VT or VF; patients who have a unipolar pacemaker. The leads are contraindicated for patients with coronary venous vasculature that is
inadequate for lead placement, as indicated by venogram. The lead is also contraindicated in patients for whom a single dose of 1.0 mg of
dexamethasone acetate and/or dexamethasone sodium phosphate may be contraindicated.
Warnings and Precautions: For the CRT-Ds, changes in a patient’s disease and/or medications may alter the efficacy of the device’s programmed
parameters. Patients should avoid sources of magnetic and electromagnetic radiation to avoid possible underdetection, inappropriate sensing and/or
therapy delivery, tissue damage, induction of an arrhythmia, device electrical reset, or device damage. Do not place transthoracic defibrillation paddles
directly over the device. Certain programming and device operations may not provide cardiac resynchronization. For the leads, people with metal
implants such as pacemakers, ICDs, and accompanying leads should not receive diathermy treatment. The interaction between the implant and
diathermy can cause tissue damage, fibrillation, or damage to the device components, which could result in serious injury, loss of therapy, or the need
to reprogram or replace the device.
Potential Complications: Potential complications include, but are not limited to, acceleration of ventricular tachycardia, air embolism, bleeding, body
rejection phenomena which includes local tissue reaction, cardiac dissection, cardiac perforation, cardiac tamponade, chronic nerve damage,
constrictive pericarditis, death, device migration, endocarditis, erosion, excessive fibrotic tissue growth, extrusion, fibrillation or other arrhythmias, fluid
accumulation, formation of hematomas/ seromas or cysts, heart block, heart wall or vein wall rupture, hemothorax, infection, keloid formation, lead
abrasion and discontinuity, lead migration/ dislodgement, mortality due to inability to deliver therapy, muscle and/or nerve stimulation, myocardial
damage, myocardial irritability, myopotential sensing, pericardial effusion, pericardial rub, pneumothorax, poor connection of the lead to the device,
which may lead to oversensing, undersensing, or a loss of therapy, threshold elevation, thrombosis, thrombotic embolism, tissue necrosis, valve
damage (particularly in fragile hearts), venous occlusion, venous perforation, lead insulation failure, or conductor or electrode fracture.
See the device manual for detailed information regarding the implant procedure, indications, contraindications, warnings, precautions, and potential
complications/adverse events. For further information, please call Medtronic at 1 (800) 328-2518 and/or consult Medtronic’s website at
www.medtronic.com.
Caution: Federal law (USA) restricts these devices to sale by or on the order of a physician.
35
World Headquarters
Medtronic, Inc.
710 Medtronic Parkway
Minneapolis, MN 55432-5604
USA
Tel:
(763) 514-4000
Fax:
(763) 514-4879
Medtronic USA, Inc.
Toll-free: 1 (800) 328-2518
(24-hour technical support for
physicians and medical professionals)
UC201206402 EN Medtronic, Inc. 2012. All Rights Reserved. 04/2012
www.medtronic.com