Download the MADIT-CRT Trial Slides

Early CRT Intervention Reduces Death and Heart
Failure Events :
Updated Insight from MADIT-CRT
Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy
© 2010 Boston Scientific. All rights reserved.
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MADIT-II: Easier to Qualify for SCD Protection
31%
MADIT-II
Size: 1218 U.S. patients
Endpoint: All-cause mortality
(patient follow-up = 20 months)
Published: NEJM 2002
Reduction in the risk of death
in heart attack survivors with ICDs, when
compared to conventional medical
therapy (CMT) alone (p = 0.016).
Building to the Next Question:
• ICD therapy in patients with chronic ischemic
heart disease improved survival but were the same
patients with increased risk of heart failure (HF) events.1
*Compared to CMT alone. Goldenberg I, et al. Presented 5/14/2009, HRS 2009. http://www.heartrhythmondemand.org/webcasts/heartrhythm2009/sessions/090502SP11.7552/
session.html. 1. Goldenberg I, et al. Circulation, June 2006. http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.105.577262/DC1.
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SCD-HeFT: Preventing SCD in Heart Failure Patients
SCD-HeFT
Size: 2521 patients in North America
and New Zealand
Endpoint: All-cause mortality
Published: NEJM 2005
23%
Reduction in the risk of all-cause mortality
when using an ICD, in combination with
conventional drug therapy (CDT), when
compared to CDT alone (p = 0.007)
Building to the Next Question:
• ICD therapy saved NYHA Class II/III patients’ lives from tachyarrhythmias – but a
major cause of mortality remained: heart failure
(31% of deaths, evenly distributed among treatment arms).1
1 Packer DL, Bernstein R, Wood F, et al. Impact of Amiodarone versus implantable cardioverter defibrillator therapy on the mode of death in
congestive heart failure patients in the SCD-HeFT trial. Heart Rhythm. 2005;2:S38. Abstract AB20-2.
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COMPANION: Providing New Access to CRT
COMPANION
Size: 1520 U.S. patients
Endpoint: All-cause mortality or first
hospitalization
Published: NEJM 2004
20%
Reduction in the risk of all-cause
mortality or first hospitalization with
CRT-D, in combination with OPT,
compared to OPT alone (p = 0.011)
Building to the Next Question:
• CRT-Ds save lives in NYHA Class III/IV HF patients, but
pump failure was the most common cause of death (44.4%).1
• 70% of HF patients are in NYHA Class I/II.2 There is a need to slow
their progression to symptomatic heart failure.
1.
2.
Carson P, et al, JACC, 2005 Dec 20; 46(12): 2329-34.
O'Connell JB, Bristow MR. Economic impact of heart failure in the United States: time for a different approach. J Heart Lung Transplant. 1994 JulAug;13(4):S107-12.
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Key Learning
Bottom Line:
MADIT II
Ability to save lives from
sudden cardiac death…
SCD-HeFT
…heart failure
remains an issue
COMPANION
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Multicenter Automatic Defibrillator
Implantation Trial with Cardiac
Resynchronization Therapy (MADIT-CRT)
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CRM6-4403-0810
Introduction
• Heart failure remains a significant health concern; a heart failure event
is associated with a five-fold increase in mortality in 5 years.
• Cardiac resynchronization therapy with defibrillation (CRT-D) has been
demonstrated to reduce mortality and hospitalizations, improve
symptoms, and increase exercise capacity.
• Prior to MADIT-CRT, Boston Scientific CRT-Ds were indicated by FDA
for the treatment of patients with the following conditions:
– Moderate to severe heart failure (NYHA Class III/IV) despite optimal
pharmacological therapy
– Reduced systolic function (LVEF  35%)
– Wide QRS (QRS duration ≥ 120 ms)
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Rationale for Undertaking MADIT-CRT
• Currently, patients with severe left ventricular systolic dysfunction, a
wide QRS complex, and asymptomatic or mildly symptomatic heart
failure are indicated for prophylactic ICD therapy without CRT
• Although ICD therapy is effective for the prevention of sudden cardiac
arrest, it does not slow the progression of heart failure
However, progression of heart failure in these patients is associated
with increased mortality and diminished quality of life
• Retrospective studies of CRT-D in NYHA Class I/II patients reported
improvement in echocardiographic variables, suggesting a potential
role for CRT-D earlier in the disease process
• Accordingly, MADIT-CRT was undertaken to determine if early
intervention with CRT-D in patients with asymptomatic or mild heart
failure could reduce death and heart failure events
Higgins et al, JACC (2001)
Abraham et al, Circulation (2004)
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MADIT-CRT Primary/Secondary Effectiveness Hypotheses
• Primary:
It was hypothesized that CRT-D would reduce the risk of the combined endpoint
of all-cause mortality or heart failure event, whichever came first, when
compared with ICD in patients with asymptomatic or mildly symptomatic heart
failure with left ventricular dysfunction and wide QRS
• A heart failure event was defined as a patient having signs and symptoms of
heart failure, with either:
– Intravenous decongestive therapy in an outpatient setting, or
– Augmented intravenous or oral decongestive therapy during in-hospital
stay
• Secondary:
Evaluate the effects of CRT-D, relative to ICD, on the patient-specific rates of
recurrent heart failure events over the full study period
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Study Design
• Designed to detect a 25% reduction in the risk of the primary
end point
– Wang-Tsiatis group-sequential design
– 95% power at a two-sided significance level of 5%
– Sample size requirement of 1820 patients
• Randomized controlled trial
– Randomization on a 3:2 basis to CRT-D/ICD
– Stratified by ischemic status and clinical center
• Data analyzed on an intention-to-treat basis
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Main Inclusion Criteria
• Ischemic heart disease (NYHA Class I or II) or non-ischemic
heart disease (NYHA Class II) for at least three months prior to
entry
• Optimal pharmacologic therapy
– Beta blockers, ACE/ARB, and statins (ischemic patients)
unless not tolerated or contraindicated
• Left ventricular ejection fraction ≤ 30%
• QRS duration ≥ 130 ms
• Sinus rhythm
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Main Exclusion Criteria
• Currently implanted pacemaker, ICD, or CRT device
• Current indication for CRT
• Atrial fibrillation within one month of entry
• NYHA Class III/IV within three months of entry
• CABG, PCI, or MI within three months of entry
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MADIT-CRT: Methods
•
Led by Dr. Arthur J. Moss
•
Largest randomized NYHA
Class I/II CRT-D trial to date
•
Enrollment
– 1820 patients, 110 centers,
14 countries
•
Baseline Evaluation
To document inclusion/exclusion criteria and establish
baseline heart statusa
Randomization (3:2 CRT-D:ICD)
Stratified by center and ischemic status
CRT-D + OPT
(1089 patients)
ICD + OPT
(731 patients)
Average follow-up
– 34.3 months
•
Commercially available devices
provided by Boston Scientific
were used
Clinic Follow-up Visits
1 month post-enrollment/randomization, 3 months postrandomization, and quarterly thereafter to a common study
closure dateb
aBaseline
evaluation includes history and physical exam, electrocardiogram, and echocardiogram. Patients are randomized and then
baseline testing is completed including BNP (US only), quality-of-life assessment, 6-minute walk test, and Holter monitor recording
(CRT-D patients only).
bThe 12-month follow-up visit includes echocardiogram, BNP (US only), 6-minute walk test, Holter monitor recording (CRT-D patients only),
and device interrogation. Other follow-up visits include history and physical exam, clinical events, and device interrogation. Quality-oflife assessments were conducted at 6-month intervals.
Moss AJ, et al. N Engl J Med. 2009;361:1329-1338.
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Study Milestones
• Primary endpoint was met on June 22, 2009
• Results were published online on Sep. 1, 2009, in the NEJM and
presented as a late-breaker at ESC
• Published in print in the NEJM on Oct. 1, 2009
• PMA submitted to the FDA in December 2009
• FDA requested updated results through Dec. 31, 2009
• FDA panel took place on Mar. 18, 2010, and there was
unanimous recommendation for approval of the expanded
CRT-D indication for the MADIT-CRT left bundle branch block
(LBBB) sub-population
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Previously Published and Updated Results
57%
34%
•
MADIT-CRT met its endpoint in June 2009
and results were published in the September
2009 NEJM online addition.
•
Results showed that CRT-D was associated
with a 34% reduction in the relative risk of the
primary endpoint
•
Primary effectiveness endpoint achieved
•
The FDA requested to see additional 6 months
of data analyzed (through December 2009)
•
It was subsequently discovered and validated
that in the LBBB subgroup, patients received
substantial benefit from CRT-D. Non-LBBB
patients did not show evidence of benefit. The
LBBB sub-group made up approximately 70%
of the total MADIT-CRT population.
N Engl J Med. 2009 Oct 1;361(14):1329-38. Epub 2009 Sep 1. Cardiac-resynchronization therapy for the prevention of heart-failure events.
Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NA 3rd, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W; MADIT-CRT
Trial Investigators.
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Consistent Results with LBBB across Subgroups
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LBBB Sub-population Baseline Demographics
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Exploratory Analysis - Hypothesis Generating Only:
LBBB Echocardiographic Outcomes
CRT therapy was ON during echocardiographic measurements and may have influenced the results.
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Results
In asymptomatic or mild heart failure, patients with wide QRS,
LV dysfunction, and LBBB on stable optimal heart failure
pharmacologic therapy, CRT-D, as compared to ICD, was
significantly associated with:
– An acceptable safety profile
– Primary endpoint showed:
57% reduction (p < 0.001) in the risk of a composite of allcause mortality or heart failure events. This was driven by:
• 35% reduction (p = 0.048) in the risk of all-cause mortality, and a
• 63% reduction (p < 0.001) in the risk of heart failure events
– Secondary endpoint showed:
43% reduction (p = 0.001) in the risk of recurrent heart failure
events
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New Boston Scientific CRT-D Indication
Boston Scientific Cardiac Resynchronization Therapy Defibrillators
(CRT-Ds) are indicated for patients with heart failure who receive
optimal pharmacologic therapy (OPT) for heart failure and who
meet any one of the following classifications:
– Moderate to severe heart failure (NYHA Class III/IV) with EF ≤ 35%
and QRS duration ≥ 120 ms
– Left bundle branch block with QRS ≥ 130 ms, EF ≤ 30% and mild
(NYHA Class II) ischemic or nonischemic heart failure or
asymptomatic (NYHA Class I) ischemic heart failure
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Identification of patients
• In order to successfully identify NYHA Class I and II heart failure
patients most likely to benefit from CRT-D therapy, begin with an
ECG analysis to screen for LBBB and a wide QRS
• How many NYHA Class I and II patients do you see in a week?
• How many of those have LBBB and a wide QRS?
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Thank you
Questions?
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CRT-D Systems from Boston Scientific CRM
Indications and Usage
Boston Scientific Cardiac Resynchronization Therapy Defibrillators (CRT-Ds) are indicated for patients with heart failure who receive stable optimal pharmacologic therapy (OPT) for
heart failure and who meet any one of the following classifications:
Moderate to severe heart failure (NYHA Class III-IV) with EF ≤ 35% and QRS duration ≥ 120 ms
Left bundle branch block (LBBB) with QRS ≥ 130 ms, EF ≤ 30%, and mild (NYHA Class II) ischemic or nonischemic heart failure or asymptomatic (NYHA Class I) ischemic heart
failure
CONTAK RENEWAL® 3 CRT-Ds Indications and Usage: Cardiac Resynchronization Therapy Defibrillators (CRT-Ds) are indicated for patients with moderate to severe heart failure
(NYHA III/IV) who remain symptomatic despite stable, optimal heart failure drug therapy, and have left ventricular dysfunction (EF  35%) and QRS duration  120 ms.
Contraindications
There are no contraindications for this device.
Warnings
Read the product labeling thoroughly before implanting the pulse generator to avoid damage to the system. Such damage can result in patient injury or death. Program the pulse
generator Tachy Mode to Off during implant, explant or postmortem procedures to avoid inadvertent high voltage shocks. Always have sterile external and internal defibrillator
protection available during implant. If not terminated in a timely fashion, an induced tachyarrhythmia can result in the patient's death. Ensure that an external defibrillator and medical
personnel skilled in CPR are present during post-implant device testing should the patient require external rescue. Advise patients to seek medical guidance before entering
environments that could adversely affect the operation of the active implantable medical device, including areas protected by a warning notice that prevents entry by patients who have
a pulse generator. Do not expose a patient to MRI device scanning. Strong magnetic fields may damage the device and cause injury to the patient. Do not subject a patient with an
implanted pulse generator to diathermy since diathermy may cause fibrillation, burning of the myocardium, and irreversible damage to the pulse generator because of induced
currents. Do not use atrial-tracking modes in patients with chronic refractory atrial tachyarrhythmias. Tracking of atrial arrhythmias could result in VT or VF. Do not use atrial-only
modes in patients with heart failure because such modes do not provide CRT. LV lead dislodgment to a position near the atria can result in atrial oversensing and LV pacing inhibition.
Physicians should use medical discretion when implanting this device in patients who present with slow VT. Programming therapy for slow monomorphic VT may preclude CRT
delivery at faster rates if these rates are in the tachyarrhythmia zones. Do not kink leads. Kinking leads may cause additional stress on the leads, possibly resulting in lead fracture. Do
not use defibrillation patch leads with the CRT-D system, or injury to the patient may occur. Do not use this pulse generator with another pulse generator. This combination could
cause pulse generator interaction resulting in patient injury or lack of therapy delivery. For specific models, when using a subpectoral implantation, place the pulse generator with the
serial number facing away from the ribs. Implanting the pulse generator subpectorally with the serial number facing the ribs may cause repetitive mechanical stress to a specific area
of the titanium case, potentially leading to a component failure and device malfunction.
Precautions
For information on precautions, refer to the following sections of the product labeling: clinical considerations; sterilization, storage and handling; implant and device programming;
follow-up testing; explant and disposal; environmental and medical therapy hazards; hospital and medical environments; home and occupational environments. Advise patients to
avoid sources of electromagnetic interference (EMI) because EMI may cause the pulse generator to deliver inappropriate therapy or inhibit appropriate therapy.
Potential Adverse Events
Potential adverse events from implantation of the CRT-D system include, but are not limited to, the following: allergic/physical/physiologic reaction, death, erosion/migration, fibrillation
or other arrhythmias, lead or accessory breakage (fracture/insulation/lead tip), hematoma/seroma, inappropriate or inability to provide therapy (shocks/pacing/sensing), infection,
procedure related, and component failure. Patients may develop psychological intolerance to a pulse generator system and may experience fear of shocking, fear of device failure, or
imagined shocking. In rare cases severe complications or device failures can occur.
Refer to the product labeling for specific indications, contraindications, warnings/precautions and adverse events. Rx only.
(Rev. M)
© 2010 Boston Scientific. All rights reserved.
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ICD Systems from Boston Scientific CRM
ICD Indications and Usage
ICDs are intended to provide ventricular antitachycardia pacing and ventricular defibrillation for automated treatment of life-threatening ventricular arrhythmias. ICDs with atrial therapies
are also intended to provide atrial antitachycardia pacing and atrial defibrillation treatment in patients who have or are at risk of developing atrial tachyarrhythmias.
Contraindications
Use of ICD systems are contraindicated in: Patients whose ventricular tachyarrhythmias may have reversible cause, such as 1) digitalis intoxication, 2) electrolyte imbalance, 3) hypoxia,
or 4) sepsis, or whose ventricular tachyarrhythmias have a transient cause, such as 1) acute myocardial infarction, 2) electrocution, or 3) drowning. Patients who have a unipolar
pacemaker.
Warnings
Read the product labeling thoroughly before implanting the pulse generator to avoid damage to the ICD system. Such damage can result in patient injury or death. Program the pulse
generator ventricular Tachy Mode to Off during implant, explant or post-mortem procedures to avoid inadvertent high voltage shocks. Always have sterile external and internal defibrillator
protection available during implant. If not terminated in a timely fashion, an induced tachyarrhythmia can result in the patient’s death. Ensure that an external defibrillator and medical
personnel skilled in cardiopulmonary resuscitation (CPR) are present during post-implant device testing should the patient require external rescue. Patients should seek medical
guidance before entering environments that could adversely affect the operation of the active implantable medical device, including areas protected by a warning notice that prevents
entry by patients who have a pulse generator. Do not expose a patient to MRI device scanning. Strong magnetic fields may damage the device and cause injury to the patient. Do not
subject a patient with an implanted pulse generator to diathermy since diathermy may cause fibrillation, burning of the myocardium, and irreversible damage to the pulse generator
because of induced currents. Do not use atrial tracking modes (or an AVT device) in patients with chronic refractory atrial tachyarrhythmias. Tracking of atrial arrhythmias could result in
VT or VF. (Applies to dual-chamber devices only.) Do not use this pulse generator with another pulse generator. This combination could cause pulse generator interaction resulting in
patient injury or lack of therapy delivery. Do not kink leads. Kinking leads may cause additional stress on the leads, possibly resulting in lead fracture. For specific models, when using a
subpectoral implantation, place the pulse generator with the serial number facing away from the ribs. Implanting the pulse generator subpectorally with the serial number facing the ribs
may cause repetitive mechanical stress to a specific area of the titanium case, potentially leading to a component failure and device malfunction.
Precautions
For information on precautions, refer to the following sections of the product labeling: clinical considerations; sterilization, storage and handling; implantation and device programming;
follow-up testing; explant and disposal; environmental and medical therapy hazards; home and occupational environments. Advise patients to avoid sources of electromagnetic
interference (EMI) because EMI may cause the pulse generator to deliver inappropriate therapy or inhibit appropriate therapy.
Potential Adverse Events
Potential adverse events from implantation of the ICD system include, but are not limited to, the following: allergic/physical/physiologic reaction, death, erosion/migration, fibrillation or
other arrhythmias, lead or accessory breakage (fracture/insulation/lead tip), hematoma/seroma, inappropriate or inability to provide therapy (shocks/pacing/sensing), infection, procedure
related, psychologic intolerance to an ICD system - patients susceptible to frequent shocks despite antiarrhythmic medical management/imagined shocking, and component failure. In
rare cases severe complications or device failures can occur.
Refer to the product labeling for specific indications, contraindications, warnings/ precautions and adverse events. Rx only.
(Rev. M)
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Back up slide
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COMPANION: Providing New Access to CRT Therapies
Clinical Question
COMPANION
Size: 1520 U.S. patients
Endpoint: All-cause mortality or
first hospitalization
Published: NEJM 2004
Does CRT therapy, used in combination
with optimal pharmacologic therapy
(OPT), significantly improve the quality
and duration of life for patients with latestage symptomatic heart failure versus
using OPT alone? 1
36%
Reduction in the risk of all-cause
mortality when using a CRT-D, in
combination with OPT, when compared
to OPT alone
(p value:0.004) 1
1 Bristow
MR, et al, NEJM, 2004 ; 350 (21): 2140-2150.
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