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“ICD Patients/Recalled ICDS: What to do?”
Gerald V. Naccarelli M.D.Research support: Boston-Scientific, Medtronic,
sanofi-aventis, Boehringer-Ingelheim, ARYX, Glaxo-Smith-Kline, St. Jude’s
Consultant: Glaxo-Smith-Kline, Medtronic, Boston-Scientific, Pfizer, Xention, sanofi-aventis, Wyeth-Ayerst, Novartis, Astellas, Cardiome, CV Therapeutics, Transoma, Paracor, Astra Zeneca
How do physicians and industry manage innovation, device benefits and inherent risks?
Electrophysiology Has Unique Issues
• Industry-wide, product advisories since 2002 affected:– ~650,000 devices1
– ~240,000 leads1
– Potential risk of over-reaction: inappropriate surgery and underutilization of life-saving technology
• Device innovation saves and improves lives each day – Despite proven benefits, all technology is subject to unexpected
failure– Patient care decisions need to be evidence-based
1 Source: fda.gov.
Sudden Cardiac Death: ICDs Proven to Save Lives
16,316
41,000
310,000
160,390
• ICDs terminate 98% of
fatal arrhythmias
• ICDs are 99% reliable
• ICDs are Class I
indicated for most
at-risk patients
AIDS
SCD
Breast Cancer
Lung Cancer
217,706
SCD Risk ICD Benefit
SCA kills more than
lung cancer, breast
cancer, and AIDS
combined
SCA is 95% fatal. Only defibrillation has been shown to prevent SCD.
Sources: American Cancer Society, American Heart Association, American College of Cardiology
1 The AVID Investigators. N Engl J Med. 1997;337:1576-1583. 3 Connolly S. ACC98 News Online. April, 1998. Press release.2 Kuck K. ACC98 News Online. April, 1998. Press release. 4 Moss AJ. N Engl J Med. 1996;335:1933-1940.
AVID1
3 Years
CASH2
2 Years
CIDS3
3 Years
MADIT4
2 Years
MUSTT5
5 Years
% M
ort
alit
y R
edu
cti
on
MADIT 2
3 Years
SCD-HeFT
5 Years
COMPANION
1 Year
CRT-D only - Secondary
31%
37%
20%
54%
60%
31%
23%
36%
0%
10%
20%
30%
40%
50%
60%
70%
Reductions in Mortality with ICDs
Pacemaker Innovation Over Last 4 Decades
19701 parameter
2008> 200 parameters
Increasing Functionality, Increasing Benefit
1989 2008
ICD Innovation: Increasing Complexity With Smaller Device
ICDs today have ~59 million transistors
ICD Innovation and Continuous Improvement
Today, ICDs are proven 98% effective and 99% reliable
1989 2008
Implant death rate 3.2% < 1%
Implant infection rates > 10% < 1%
Device battery longevity 1-2 years 8-9 years
209 cc 40 cc
Sources: Zipes, Circulation, 1995 and Medtronic Product Performance Report.
100.0%
99.5%
99.0%
98.5%
98.0%
97.5%
97.0%
99.985% 99.888%
One-year
ICDsIPGs
99.908%99.562%
Five-year
ICDsIPGs
2007 Medtronic pacemaker and ICD reliability data.
ICDs and IPGs are Reliable
• Is 100% product reliability expected, or realistic?
• How do we apply and assure consistent standards across the industry?
• What should be done to set realistic expectations?
What are realistic expectations for device reliability?
Unrealistic Expectations of Device Function by PhysiciansUnrealistic Expectations of Device Function by Physicians
• Recent survey of heart rhythm specialists: up to 30% responding recommended replacement of ICDs if the malfunction rate was 1/10,000 (0.01%). – Experienced practitioners expect a very high degree of reliability
of implantable devices. – Survey results suggest that both physicians and industry need to
develop a consensus for dealing with the reality of malfunctions in manufactured devices.
• Perfection of device function is assumed and desirable although this manufacturing gold standard can never be reached – In 1997, ICDs had Expected Life Reliability of 93% at 3 years
and an average failure rate of 0.20% failures/month. – Current Expected Life Reliability for ICDs is 96.18% at 5 years
and average failure rate is 0.065% failures/month. – We will continue to approach 100% reliability but never achieve
it
Maisel WH. PACE 2004; 27:437-442
ICDs and Pacemakers Explanted After Recalls[Mean Percent of Subject Products Explanted after Recalls]
0
5
10
15
20
25
30
35
40
Pe
rce
nt
MDTMarquis
ICD
MDTMarquisC
RT-D
GDTPrizm2 DR
ICD
GDTContak
RenewalCRT-D
GDTPacemakers
31%33%
27%24%
39%
[Reproduced courtesy of Eric Prystowsky, MD. These data are based on the reported experience of 37 implanting physicians who responded to a survey on this question, and may not reflect general experience or that subsequent to the survey. The data were presented at the HRS/FDA Policy Conference on Pacemaker and ICD Performance, Washington, DC, September 16, 2005.]
MDT = Medtronic GDT = Guidant
High Replacement Rates Due to Physicians High Replacement Rates Due to Physicians Lack of UnderstandingLack of Understanding
• “The experience with a low-frequency rate of malfunctions, in the setting of defined clinical benefits of the therapy, creates a broad range of dilemmas. The major conflict is between the financial impact of an aggressive replacement policy on corporate business and the fiscal status of the health care system and the ethical drive to preserve a single life, in accordance with individual patient preferences. Despite the low probability of manifest adverse events, high replacement rates occurred as a result of potential device malfunctions for a number of devices recently reported by device manufacturers. These numbers speak to the absence of a baseline of information that would provide clinicians with a balanced insight into the entire scope of the issue, in the context of risk/benefit ratios. It is likely that clinical judgment would drive the numbers down, with appropriate physician awareness and education on actual risk. “
Guidant Independent Panel Report
Importance of Root Cause Analysis
Root Cause Analysis reduced from a potential> 165,000 US Sigma IPGs to 6,650 active US implants
Exhaustive Root Cause Search, Thousands of Variables and Scenarios
• Affected devices implanted around two time periods
• Isolated specific manufacture dates
• Discovered outside supplier’s cleaning solvent contained anti-oxidant additive not present in previous shipments
Sig
ma
April 2001
April 2008
January 2003
APR 2001: Marquis launched
JAN 2003: battery shorts while being
used to test new manufacturing equipment
Mar
qu
is
First indication of potential battery issue, root cause unknown
• No field failures observed
Random Component Failures
• All technology has an inherent rate of failure
• Important to understand if failure is random– Root cause analysis reveals the mechanism of failure
in 65%1 of cases
– 1/10,0002 devices incur a random component failure
1 Guidant data.2 Maisel. JAMA. 2006.
Despite best efforts, random failures still occur
Mar
qu
is
Crack in cathode
Short @grid hole
Ragged edge ofcathode crack
SeparatorGrid hole
Separator compressedbetween edges ofcathode crack and hole in anode grid
Cathode Crack
Mesh Anode Grid Shorting MechanismM
arq
uis
• Solid anode current collector removes edges in previous design
• Additional 3.5mil spacer added to increase distance between anode current collector and cathode
Anode Grid
New Battery Design Testing
Battery Design
Batteries Tested
Shorts Observed
Comment
Original
Mesh Grid> 2800 27
Rate of shorting under highly accelerated testing is variable across population
New Solid Grid
> 2700 0 Instituted new design
Approved Design ChangesM
arq
uis
Theoretic clinical shorting mechanism solved
First Field Failures
April 2001
Sept 2004
APR 2004First failureconfirmed DEC 2004
April 2008
Mar
qu
is
Potential concern of device reliability raised
Timeline of Marquis Battery Confirmations
Mar-04 Jun-04 Sept-04 Jan-05
Calendar Date
* * *******
• Between September and December, 8 additional device failures confirmed
• Exceeds typical random component failure rate
DEC 2004 – JAN 2005
Available data modeled a 0.2% - 1.5% risk
April 2001
Results of Bench Testing
April 2008
Mar
qu
is
Panel actions:
a) Reviewed results of extensive device testing
b) Unanimously recommended product advisory
c) Assisted with patient management recommendations
April 2001
Independent Medical Advisory Panel
JAN - FEB 2005
April 2008
Mar
qu
is
Panel integral to recall and patient management recommendations
April 2001
Patient Management
Medtronic Recommended Physicians Consider the Following Patient Management Options:
• Continue to conduct routine follow-up• Turn on Patient Alert™ indicator• Patients should seek care if they experience warmth in the ICD area• Consider providing a handheld magnet to patients • Should the physician decide to replace an affected device in a
specific patient (e.g., a patient who is pacemaker dependent), Medtronic will provide a device at no cost
FEB 2005
April 2008
Mar
qu
is
Advisory Communicated
US
Mar
quis
Ret
urns
20,000 devices explanted within 6 months
April 2001
Physician Over-reaction to Product Advisory
April 2008
FEB – SEPT 2005
Mar
qu
is
US
Dev
ice
retu
rns
April 2001Only known patient injuries resulted from explants
April 2001 September 2005
Early Explant of ICDS Resulted in More Adverse Effects than Just Monitoring Patient As Per Advisory
April 2008
First 6 months of Advisory
Mar
qu
is
• Patient impact:– Confirmed failures = 95– 37,000 devices explanted worldwide– Known patient injuries from field failures = 0
• Failure rates:– Last half of device life at lower bounds of
forecast (~ 0.2%)– Total observed battery shorting
mechanism (Mar-08) is 0.09%
Marquis PerformanceM
arq
uis
CRDM Product Performance Report, 2nd edition 2007.
AT 5 years there was a 1.8% increased risk of ICD malfunction
“ICD generator replacement in patients with advisory devices is associated with a substantial rate of complications, including death. These complications need to be considered in the development of guidelines determining the appropriate treatment of patients with advisory devices.”
Risk/Benefit of Intervention
Table 4. Complications From 533 Elective Advisory Device Replacements
Severity and Complications No. (%)*
Minor 9 (1.7) Incisional infection, medically managed Significant site pain, medically 1 (0.2) managed Heart failure requiring admission 1 (0.2) Major psychological morbidity, 1 (0.2)
Major Pocket infection requiring 10 (1.9) extraction Postextraction deaths 2 (0.4) Hematoma requiring reoperation 12 (2.3) System malfunction requiring 8 (1.5) reoperaton Significant site pain requiring 1 (0.2) reoperation
*Number of patients with the complication.
1Krahn et al, JAMA 2006:295
Is a 5.8% Major Complication Rate a Risk Reasonable For Early Replacement of “Recalled Device”?
Medtronic Marquis ICD Accelerated battery depletion from internal battery short
0.01%
Guidant Ventak Prizm 2 DR ICD
Short circuit caused by wire insulation problem
0.1%
Guidant Ventak Prizm, Vitality, Contak Renewal AVT ICDs
Random memory error limiting delivery of therapies
00095%
Guidant Contak Renewal 3,4; 3,4 AVT; RF ICDs
Magnetic switch faulty limiting delivery of therapies
0.009%
St. Jude Photon DR; Micro VR/DR; Atlas VR/DR ICDs
Memory chip affected by cosmic radiation limiting delivery of therapies
0.167%
ELA Alto ICD Metal migration that can impair delivery of therapies
2.6%
Gould PA, et al. JAMA 2006;295:1907-1911
Device Advisory Risk of Failure
Cost/Risk of ICD Advisory Explant
• 533 ICDs replaced * @ $20,000 each = $10,660,000– Your Canadian tax dollars at work
• 8.1% complications• 2 deaths and 8 other patients that no longer have an ICD
due to device extraction for infection• Benefit: 3 devices had minor issues that were not life
threatening• Let me know when complete transparency is a good
idea?
*Gould PA, et al. JAMA 2006;295:1907-1911
ICD Replacement Complications in Response to Recall Advisories
• 533/2915 (18.3%) had advisory ICDs replaced• During a 2.7 month mean follow-up, complications
occurred in 43 patients(8.1%)• Major complications occurred in 31 patients (5.8%)
– 2 deaths after pocket extraction of infected device– Pocket infection requiring extraction 10 (1.9%)
• There were 3 device (0.1%) advisory-related device malfunctions, without clinical consequence
Gould PA, et al. JAMA 2006;295:1907-1911
Decision Models for Any IPG or ICD Device Replacement
Results:• Decision to replace a recalled device depends on:
– Primary factors: Advisory's estimated device failure rate and likely effects of device failure on mortality
– Secondary factor: procedural mortality – Least influence: patient age and remaining generator life
Conclusions:• Device replacement warranted when advisory
device failure rates exceed:– 0.3% (IPG) for pacemaker-dependent patients– 3% (ICD), decreasing to 0.1% as risk of fatal
arrhythmias increase to near 20% per year
Mo
del
"device replacement in the setting of an advisory is not inconsequential and frequently has a greater risk than continued device follow-up"
Amin M, Matcher D, Wood M, Ellenbogen KA. JAMA 2006;296:412-420
Risk/Benefit of Intervention
Table 1. Current ICD Advisories Included in the Survey and Associated Risk
Date Current Risk Company/Device* of Advisory Advisory Issue† of Failure, %†
Medtronic February 2005 Accelerated battery depletion caused 0.01 Marquis ICD by internal battery short
Guidant Ventak Prizm 2 DR ICD June 2005 Short circuit caused by wire insulation 0.1problem within lead connector block
Guidant Ventak Prizm AVT, Vitality AVT, June 2005 Random memory error, limited delivery 0.0095 and Contak Renewal AVT ICDs of therapies
Guidant Contak Renewal 3, 4, Renewal 3,June 2005 Magnetic switch faulty, impairing delivery 0.009 4 AVT, and Renewal RF ICDs of therapies
St. Jude Photon DR, Photon Micro VR/DR,October 2005 Memory chip affected by atmospheric 0.167 and Atlas VR/DR ICDs radiation, which can impair pacing
and delivery of therapies
ELA Alto ICD August 2001 Migration of metal, which can impair 2.6‡pacing and delivery of therapies 0.1§
1908 JAMA, April 26, 2006—Vol 295, No. 16 (Reprinted) ©2006 American Medical Association. All rights reserved.
The Heart Rhythm Society believes that patient and physicianknowledge, confidence, and trust can be enhanced and strengthenedthrough:
• Transparency in post-market surveillance, analysis, and reporting of information,
• Systems to increase the return of devices to manufacturers and to improve the analysis and reporting of device performance and malfunction information, and
• Cooperation among industry, the FDA, and physicians to make every effort to prevent injuries and deaths due to device malfunctionsHeart Rhythm Society
Task Force on Device Performance Policies and Guidelines April 26, 2006
HRS Guidelines
Consensus on approach to future advisories
Fid
elis
Sprint Fidelis versus Quattro® Lead SLS Survival Probability
Sprint Fidelis Lead Advisory
• Reviewed analyses of returned product, System Longevity Study information and data from over 25,000 CareLink-enrolled patients
• 97.7% all-cause lead survival at 30 months
• 268,000 implants
Independent physician advisory panel consultedFid
elis
Voluntarily suspended distribution of leads (October 2007)
Sprint Fidelis Lead Patient Management Recommendations
• Programming parameters to:– Improve effectiveness of lead impedance alert– Reduce likelihood of inappropriate shocks
• Independent Physician Quality Panel believed prophylactic removal inappropriate except in unusual circumstances– Lead extraction risk from published literature suggests
major complications range from 1.4–7.3%1,2
1 Byrd CL, Wilkoff BL, et al. PACE May 2000.2 Bracke FA, et al. Europace, May 2004.
Fid
elis
Sprint Fidelis Update – May 2008
• Medtronic continues Performance trend reported May 2008 continues as described in October 2007 communication
• Patient management recommendations remain unchanged• Future plans include:
– Device enhancement with Lead Integrity Alert (pending FDA Approval)– Quarterly updates posted to Internet
Fid
elis
Lead Integrity Alert (LIA)
LIA will increase the likelihood of fracture detection prior to inappropriate therapy
– Prior to LIA, approximately 49% of Sprint Fidelis lead patients are expected to receive an alert two or more days prior to inappropriate therapy due to a lead fracture.
– With the Lead Integrity Alert, approximately 75% of Sprint Fidelis lead patients will receive an alert three or more days prior to inappropriate therapy due to a lead fracture.
Fid
elis
Communication: Instantly to Everyone
Manufacturers
Regulators
Patients
Physicians
Media
Public
Device Recalls: Arguments Against Full Device Recalls: Arguments Against Full TransparencyTransparency
• Physicians are not trained or knowledgeable enough about device malfunctions to make an informed decision
• If the industry standard was full transparency, the information overload to the physician would be overwhelming and ignored
• Devices save lives even if they are not perfect– Current devices have lower malfunction rates than ever
• Hysteria around “recalls” cause many device to be explanted that should not be explanted– Cost– Risk of re-operation
• Current “Recall” nomenclature is misleading• Depends on your definition of full “transparency”• Bad press makes patients reluctant to give consent for a
life-saving therapy• Medico-legal implications
Risk of Telling Docs Too Much?Risk of Telling Docs Too Much?
• Do Physicians Know How To React to a Recall?Do Physicians Know How To React to a Recall? • Maximal risk of the device not functioning in a life saving situation of
recently recalled devices is maximally 0.65% against a >2% risk of infection, 1% risk of damaging an existing lead at a cost greater than $20,000 per re-implant. This would put the cost for two USA Guidant re-implants at a staggering $181,250,000. – One is re-implanting a device with an unknown error rate of between
0-1%– Patients have an even poorer understanding of the above problem. – Physicians have overreacted to recent device recall creating huge
cost and risk to patients• Medico-legal issues obviously add to a disproportionate number of
recalled devices being taken out and replaced.
Naccarelli, GV. Subanalysis to Guidant Independent Panel
Lawsuits Filed within Hours of Field Action Announcement
Fid
elis
Patient Impact of a Change in Terminology from Device “Recall” to Device “Advisory”
Murray, CM, et. al. “Device “Recall” Terminology: Results of a Patient Study.” Presented at 2008 HRS.
Pat
ien
t P
erce
pti
on
http://vm.cfsan.fda.gov/~lrd/recall2.html
Definition Problems: All FDA “Recalls” Are Not the Same
• Class I– Reasonable probability that if a device is malfunctioning there
will be a serious adverse health consequence or death– Does not necessarily require removal of the device– Sponsor needs to disclose the device malfunction to patients
and doctors and provide additional instructions for safe use of the device
• Class II Recall– The malfunctioning product may cause temporary or medically
reversible adverse health consequences; however, the probability of serious adverse health consequences is remote
Costea A, J Cardiovasc Electrophysiol, 19: 266-269, 2008
Reasons for Device Replacement
20.7%
14.4%
17.6%18.5%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
Priorappropriate
shock
Pacemakerdependency
Patientrequest
Prior cardiacarrest
Patient Request is the third-largest reason for device replacement
Pat
ien
t P
erce
pti
on
Murray, CM, et. al. “Device “Recall” Terminology: Results of a Patient Study.” Presented at 2008 HRS.
Significantly More Patients Want a “Recall” Device Removed than an “Advisory” Device
Patients who want the device removed no matter what:• 2.5% if there was a “safety advisory”• 5.0% if there was a “recall”• p=0.01, Chi-square and Fisher’s exact tests
A change in the terminology could potentially reduce the number of complications by half
Pat
ien
t P
erce
pti
on
Murray, CM, et. al. “Device “Recall” Terminology: Results of a Patient Study.” Presented at 2008 HRS.
Definition Issues: Are All Device Malfunctions Definition Issues: Are All Device Malfunctions the Same?the Same?
• Device Failure: The inability of the device to provide the therapy that is intended for the survival or avoidance of major medical morbidities.
• Device Malfunction: A deviation from the intended function or response to a clinical event that the device is intended to provide. Malfunctions in the extreme may be device failures as defined above, or may be of lesser clinical significance but still requiring mitigation.
• Random: A defect unique to a specific component that causes non-repetitive malfunctions or failures. This may be due to manufacturing error during construction of a single device or a single defective component.
• Systematic: Repetitive malfunctions or failures due to a design flaw or inherent component defect.
• Manifest vs potential life-threatening events: “Manifest” refers to the occurrence of one or more actual fatal or near-miss events as a result of device failure or malfunction. “Potential” refers to a flaw or defect that creates a realistic potential for a fatal or near-miss event in the future, if not mitigated or replaced.
Guidant Independent Panel Report
Medtronic CareLink Remote Monitoring
250,000 PatientsEnrolled
Product Performance Report
70 MillionPatient Years
Industry’s Tracking of Device Performance
System Longevity Study
75,000 PatientsData
Returned Products Analysis System Longevity Study
Product Complaints and Physician Input
Post Market Studies
Performance Monitoring
• Passive assessment
• Hard feedback on specific returns • 25 years, 75,000 patients
• Prospective view and trending
• Registries
• RV Optimize (3830 Select Secure)
• Conditions of Approval (4195 Starfix)
• Technical Services calls
• MAUDE Industry database
• Physician studies and registries
Device Recalls/Transparency:Device Recalls/Transparency: Final Thoughts Final Thoughts
• Not all devices need to be explanted STAT or maybe at all– Monitor risk/benefit e.g. risk of infection, compatibility of
new device with other hardware, coexisting anticoagulation, age, co-morbidities
– Is the patient dependent on the device or not– When is the EOL (if only 1 year to go, elective
replacement reasonable)• Monitor the situation
– The problem may be worse or better than you initially thought as more information comes available
– Increase device monitoring of patients• Although we expect a 0% failure tolerance, what is realistic
(<1%)• HRS, FDA and industry have set new standards for
reporting etc.• Future transparency will depend on massive physician
education campaign and redefinition of device malfunctions