“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