Dr. Maurizio GaspariniDr. Maurizio Gasparini UO Elettrofisiologia ed ElettrostimolazioneUO Elettrofisiologia ed Elettrostimolazione

Istituto Clinico HumanitasIstituto Clinico Humanitas,, IRCCS, Rozzano-Milano IRCCS, Rozzano-Milano

ADVANCES IN CRT ADVANCES IN CRT

What Is The Patient Profile Who What Is The Patient Profile Who Can Benefit from CRT-P only? Can Benefit from CRT-P only?

Progressi nella CRTProgressi nella CRT

Quale è il profilo del paziente che può Quale è il profilo del paziente che può beneficiare della sola CRT ?beneficiare della sola CRT ?

Eur Heart J 2007; 28: 2256-95Eur Heart J 2007; 28: 2256-95

Cardiac resynchronization therapy Cardiac resynchronization therapy guidelines published for the first time in 2007 guidelines published for the first time in 2007 ……

Few months later , American GL Few months later , American GL published…published…

So very simple and clear indications So very simple and clear indications for CRT-P in HF patients !for CRT-P in HF patients !

Thank you for your attention Thank you for your attention

NYHA III-IV pts on OPTNYHA III-IV pts on OPT

LV EF LV EF << 35% 35%

QRS ≥ 120 msecQRS ≥ 120 msec Sinus rhythmSinus rhythm

However reading carefully…. However reading carefully….

The ESC and AHA/ACC/HRS Guidelines on indications for The ESC and AHA/ACC/HRS Guidelines on indications for device therapydevice therapy do not clearly indicate which patients are do not clearly indicate which patients are candidates tocandidates to CRT-P onlyCRT-P only

Solved dilemma by recent HF Solved dilemma by recent HF Guidelines ??!!Guidelines ??!!

……Once Once againagain

On the other hand,On the other hand, following GL in the clinical following GL in the clinical practice, it is mandatory to control if in the practice, it is mandatory to control if in the same field (i.e. ICD therapy) some other same field (i.e. ICD therapy) some other guidelines existguidelines exist ::

in patients within patients with severely compromised severely compromised left ventricular functionleft ventricular function

regardless of underlyingregardless of underlying etiologyetiology… …

in primary as well as in secondary in primary as well as in secondary preventionprevention

as clearly demonstrated by several studiesas clearly demonstrated by several studies

ICDICD therapy has been demonstrated to be therapy has been demonstrated to be particularly effective in preventing sudden particularly effective in preventing sudden cardiac death (SD) and thus reducing total cardiac death (SD) and thus reducing total mortality :mortality :

COMPANIONIsch/non EF ≤ 35%; NYHA III- IV; CRT-D mortality by 36%

NE

JM 2

004;

350:

2140

-50

SCD-HeFTIsch/non isch;EF ≤ 35%; NYHAII-III ICD mortality by 23%

NE

JM 2

005;

352:

225-

37

NE

JM 2

004;

350:

2151

-8

DEFINITENon isch DCM; NYHA I/III; EF Non isch DCM; NYHA I/III; EF ≤ 36%; ICD mortality by 35%

MADIT IIPost-MI, FE ≤ 30%, any NYHAICD mortality by 31%

NE

JM 2

002;

346

(12

); 8

77-8

3

ICD decreases total mortality in pts with systolic dysfunction of any etiology regardless NYHA functional class

How to combine both these 2 statements?

85% of CRT

candidates are in

NYHA III !!

Maurizio Gasparini Istituto Clinico Humanitas - Rozzano, Milano

(Italy)

Long-term follow up after cardiac Long-term follow up after cardiac resynchronization therapy: resynchronization therapy: poor clinical outcome in patients poor clinical outcome in patients enrolled in advanced NYHA class IVenrolled in advanced NYHA class IV

Presented at AHA Congress 2003 Published on theHeart.org

268 268 consecutiveconsecutive CRT pts CRT pts

October 1999 / July 2003October 1999 / July 2003

NYHA II: 34 pts (13%)NYHA II: 34 pts (13%)

NYHA III: 194 pts (72%)NYHA III: 194 pts (72%)

NYHA IV: 40 pts (15%)NYHA IV: 40 pts (15%)

Kaplan Meier survival estimatesaccording to NYHA at baseline

follow-up time (months)0 6 12 18 24 30 36

0.00

0.25

0.50

0.75

1.00nyha 2

nyha 3

nyha 4

.00.0011

H.R. 3-4 = 1.7H.R. 3-4 = 1.7

H.R. 2-4 = 4.5H.R. 2-4 = 4.5

Log rank p= .002Log rank p= .002

Total mortality rate according to NYHA class at baselineTotal mortality rate according to NYHA class at baseline

.04.04

.0.011

m.r. 0%

m.r. 5.7%

m.r. 16.6%

NYHA IV: 40 pts

33 pts IV33 pts IV

No ev amine

No mechanical ventilation

7 pts IV advanced

4 ev amine + mech. vent

3 ev amine no mech. vent

deaths :3/33 deaths :5/7

NYHA IV pt into details :NYHA IV pt into details :

Kaplan Meier cardiac survival estimates according to NYHA at baseline

follow-up time (months) 0 6 12 18 24 30 36

0.00

0.25

0.50

0.75

1.00 nyha 2

nyha 3

nyha 4

Advanced nyha 4

Cardiac mortality rate according to NYHA class at baseline

Log rank p= .00001

ns

.02

All p= .00001

Non advanced NYHA IV survival rate:similar to NYHA III !!

ns

m.r. 0%m.r. 4.7%

m.r. 7.8%

m.r. 80.8%

Which pts are candidates to CRT-P only ??

So ambulatory NYHA IV behaviour is like NYHA III patients

Which data in the literature?

Clealand NEJM 2005

Care HF

CRT-P 37% mortality with respect to OPT

Bristow NEJM 2004

COMPANION:Risk of secondary endpoint

death from any cause 24 % CRT (p=0.059) vs OPT 36 % CRT-D (p=0.003) vs

OPT

Inclusion criteria :

NYHA III-IV, EF< 35%, QRS > 120

191 pts CRT-D

120 primaryprevention

71 secondary prevention

Results ( fu:2 yrs):

• at least 1 appropriate therapy

35% secondary prevention

21% primary prevention

• No predictors

All cause mortality reduction by 17%

Sudden death reduction by 96%

1303 pts

4 European Centers

MILOS STUDY

Data from metanalisis

ICD with respect to OPT mortality by 31%

CRT-P with respect to OPT mortality by 34%

CRT-D with respect to OPT mortality by 43% Further 9% of mortality reduction with CRT-D!!!

IBIB IA IA IA even in the upcoming European IA even in the upcoming European

GLGL

Which is the behaviour in real world ?

1303 pts

Progressive dramatic increase in % of CRT-D in Europe !!

CRT-D allows all cause mortality reduction by 17%

Avg = 88Avg = 76

USAItaly

NetherlandsGermanyBelgium

DenmarkAustria

SwedenWestern Europe

FranceUK

SwitzerlandNorwayIrelandSpain

PortugalFinland

0 50 100 150 200 250 300

CRT-D CRT-P 2007 WE Average 2006 WE Average

CRT-P

Similar behaviour in USA

(small rate of CRT-P implant with respect to CRT-D)

disadvantages of CRT-D systems in CRT disadvantages of CRT-D systems in CRT candidatescandidates

Aside from costs considerationsAside from costs considerations

1) No significant increased risk of 1) No significant increased risk of complications (implant - related)complications (implant - related)

2) No significant increased complications 2) No significant increased complications during follow upduring follow up

If ICD back up seems reasonable… we should If ICD back up seems reasonable… we should consider the possibility of….consider the possibility of….

No major technical differences between CRT and CRT D implantation

1 a1 a ComplicationsComplications ((COMPANION trial, Bristow et al., NEJM 2004)COMPANION trial, Bristow et al., NEJM 2004)

ParameterParameter OPTOPT

n=308n=308

OPT +OPT +CRTCRT

n=617n=617

OPT + OPT + CRT-DCRT-D

n=595n=595

Implant Success (%)Implant Success (%) –– 88.388.3 92.092.0

Total Implant Time (minTotal Implant Time (minSD)†SD)† –– 200200

116116

213213

131131

Moderate or Severe Adverse Events (% Moderate or Severe Adverse Events (% of total patients)of total patients)

5555 5858 6060

30 day crude mortality (%), from 30 day crude mortality (%), from randomization or implantationrandomization or implantation

1.01.0

{–}{–}

1.81.8

{2.1}{2.1}

0.90.9

{0.7}{0.7}

Absolutely Absolutely no differences in severe implant-related in severe implant-related adverse events between device typeadverse events between device type adverse events adverse events are mainly associated to LV lead positioning...are mainly associated to LV lead positioning...

1 b Complications related to defibrillation testing (DT)1 b Complications related to defibrillation testing (DT)1) DFT can be avoided

2) DFT can be safely delayed

So…at this point … which arguments for So…at this point … which arguments for not associate ICD function to CRT-P?not associate ICD function to CRT-P?

The CARE-HF The CARE-HF && CARE-HF extension phase data CARE-HF extension phase data

It has been postulated that It has been postulated that CRT-P per se CRT-P per se mortalitymortality due to due to sudden deathsudden death … …

…especially in the “long term” f.u. …especially in the “long term” f.u.

COMPANION - Bristow NEJM 2004;350:2140-50

Scissors CRT-P / OPT at 240 days

Scissors CRT-D /CRT at 120-240 days

CompanionCompanion Does CRT-P really Does CRT-P really sudden sudden

death ?death ?

Mean f.u. = 29,4

months

NEJM 2005;352:1539-49

Care HFCare HF

CRT-P diverges from OPT only at 240 days !!

Clealend NEJM 2005

COMPANION - Bristow NEJM 2004

COMPANION: same behaviour of CRT-P of

CARE-HF !!!!

Between day 120 and 240 gg CRT-D begins to saves lifes……

The identical behaviour is The identical behaviour is based on based on the the typical temporal pattern typical temporal pattern of of thethe “reverse “reverse remodeling”remodeling” processprocess conferred by CRT conferred by CRT……

0

10

20

30

40

50

60

1 2 3 4 5 6

Lef

t ve

ntr

icu

lar

ejec

tio

n

frac

tio

n (

%)

-15

-10

-5

0

5

1 2 3 4 5 6

Left

Ven

tric

ular

End

Dia

stol

ic

Dia

met

er C

hang

e (%

)

Baseline 6 12 24 36 48 mos Baseline 6 12 24 36 48

mos

SR

AF + AVJ Ablation

AF no AVJ Ablation

(Gasparini et al., JACC 2006)

Mode of death in CRT-PMode of death in CRT-P

SD in HF patients treated with CRT-P

COMPANIONCOMPANION

CARE-HFCARE-HF

OPTOPT CRT-PCRT-P

Sudden death21%

CHF47%

Other32%

Sudden death32%

CHF45%

Other22%

2 different studies 2 different studies with SAME CRT-P with SAME CRT-P curve behaviourcurve behaviour

-with SAME SD % in -with SAME SD % in CRT-PCRT-P

1/3 pts die for SD1/3 pts die for SDin CRT-Pin CRT-P

What about the earlier phases of CRT when What about the earlier phases of CRT when reverse remodeling has still to take place?reverse remodeling has still to take place?

SCD in HF patients treated with CRT

Would you take the Would you take the CRT leap…CRT leap…

With a parachute With a parachute (ICD)(ICD)

or without a or without a parachute… parachute…

1)1) Would it be worthwhile to stratify Would it be worthwhile to stratify arrhythmic risk?arrhythmic risk?

(“ethical” issue this day and age)(“ethical” issue this day and age)

2) Simply implant a CRT-D 2) Simply implant a CRT-D system !!system !!

COMPANION

6 mos Benefits from ICD back up to protect from SD between 120 and Benefits from ICD back up to protect from SD between 120 and 240 days after CRT clearly demonstrated by Care HF and 240 days after CRT clearly demonstrated by Care HF and Companion Companion

CARE HFJohn G.F. ClelandN Engl J Med 2005;352:1539-49

CARE HF extension phaseJohn G.F. Cleland

EHJ (2006) 27, 1928–1932

Mean f.u. = 37,4 months

Mean f.u = 29,4 months

Does Does really really CRT-P CRT-P sudden death in sudden death in the long term follow up ?!the long term follow up ?!

Mean f.u = 29,4 months

CAREfully looking inside CARE HF extended

At the end of the study:

n of deaths:

200 pts

Due to the demonstrated benefit of CRT-P CRT-P strongly recommanded at the end of CARE HF for pts randomized in OPT group

Recommendation letterRecommendation letter• CRT-P strongly recommended at the end of

CARE HF for pts randomized in OPT group !!!!

However…..

Optimal drug therapy

404 pts / 154 deaths:

CRT

409 pts / 101 deaths:

• Risk reduction of death from HF by 45% ( HR = 0,55)

32%35%

• Risk reduction of death from SCD by 46% ( HR = 0,54)

statistically significant and statistically statistically significant and statistically correct…correct… but clinically but clinically

uncorrect…uncorrect…

DoesDoes really really CRT-P CRT-P sudden death in the long term sudden death in the long term f.u.? f.u.?

Why such a big Why such a big spaceball ?! spaceball ?!

CARE HF extended

Mean f.u. = 37,4 months

8 months longer than CARE HF… BUT CONSIDER that n of pts is LOWER due to the 200 deaths..

Considering pts still alive… for them LONGER f.u (~ 10 months) WITHOUT protection of CRT: ETHICAL ???

CAREfully looking inside CARE HF extended

SDOPT: 54/404 (13.4%) 4.3% / y

2.5%

1 yr

2.5%

2 yr 3 yr

2.5%

CRT: 32/409 (7.8%) 2.5%/y SD: 32% in CRT

2.5%

4 yr

2.5%

1 yr

2.5%

2 yr 3 yr

8 %8%

4 yr

CAREfully looking inside CARE HF extended

CRT arm

409 pts

82 † (29.4 months) 20% mortality

102 † (37.4 months) 25% mortality

OPT arm

404 pts

120 † (29.4 months) 29.7% mortality

154 † (37.4 months) 38% mortality

95 OPT CONVERTED to CRT:22 † 23.2% mortalityBUT…404 pts

42.7% mortality

309 pts: 132 † (DESPERATE OPT!!)

DESPERATE OPT

CARE HF investigators postulated that CRT-P SCD during long term f.u

but SD rate in CRT-P REMAIN THE SAME over time !!

Pts left on OPT (despite recommendations!) continues to dramatically die like flies… that the only reason for

the supposed reduction of SD with CRT !!!If CRT-P would protect from SD this would be the pattern

of the survival curve

I honestly think that it is not true

In conclusions….In conclusions….1) 1) CRT-DCRT-D undeniably reduce mortality with respect to undeniably reduce mortality with respect to OPTOPT

2) All studies comparing CRT-P and 2) All studies comparing CRT-P and CRT-D, CRT-DCRT-D, CRT-D armarm has shown greater benefit with respect to CRT-P in has shown greater benefit with respect to CRT-P in terms of SD reductionterms of SD reduction

4) We should offer to any HF pt the best possible 4) We should offer to any HF pt the best possible therapy, i.e complete therapy therapy, i.e complete therapy CRT-DCRT-D

5) Last but not least, more than 85% of CRT candidates 5) Last but not least, more than 85% of CRT candidates satisfy a class satisfy a class IAIA indication for ICD !!! indication for ICD !!!

3) Metanalisys data undeniably shown that CRT-D 3) Metanalisys data undeniably shown that CRT-D saves more lives than CRT-P (9% more!!)saves more lives than CRT-P (9% more!!)

Is there still place for CRT-P ?Is there still place for CRT-P ?

CRT-P FOR WHOM?

considerconsider

1) LIFE EXPECTANCY1) LIFE EXPECTANCY if life expectancy < 1 yrif life expectancy < 1 yr

Aim of the intervention: Aim of the intervention: QOL for the remaining life QOL for the remaining life

very advanced anagraphic age (at least > 80 years)very advanced anagraphic age (at least > 80 years)

very advanced biological agevery advanced biological age

Reasonable NOT to provide an ICD back-upReasonable NOT to provide an ICD back-up

due to severe comorbidities due to severe comorbidities cachexiacachexia

neurological diseasesneurological diseases severe COPD / severe renal/epatic insufficiencysevere COPD / severe renal/epatic insufficiency

complicated insulin dependent diabetescomplicated insulin dependent diabetes peripheral vascular diseaseperipheral vascular disease

2) PREVIOUS VVI or DDD PM CAUSING “IATROGENIC” LV DYSFUNCTION at a reasonably 2) PREVIOUS VVI or DDD PM CAUSING “IATROGENIC” LV DYSFUNCTION at a reasonably advanced age (>75 yrs)advanced age (>75 yrs)

Often rapid clinical /echo improvement after upgrading to CRT-POften rapid clinical /echo improvement after upgrading to CRT-P

Not infrequent venous access difficulties in those settingsNot infrequent venous access difficulties in those settings

A rapid response after CRT may reduce the arrhythmic risk A rapid response after CRT may reduce the arrhythmic risk

Increased risks of complications if LV lead Increased risks of complications if LV lead AND AND RV defib coil insertion necessaryRV defib coil insertion necessary

3) PREVIOUS DDD pm with two unipolar leads3) PREVIOUS DDD pm with two unipolar leads

Unipolar lead

Unipolar lead

PM DDD

Risk/benefit ratio evaluation-> which is better : CRT-D with 3 Risk/benefit ratio evaluation-> which is better : CRT-D with 3 more leads or CRTP with only one more LV lead ???more leads or CRTP with only one more LV lead ???

CS lead

Subclavian vein occlusion is not an unusual finding after lead insertion

Collateral vessels

Collateral vessels

Subclavian vein occlusion

Mr. A.I. After Mr. A.I. After 17 years17 years of device history… of device history…

1994: VVI1994: VVI

1996: DDD1996: DDD

1989: Epi-ICD1989: Epi-ICD

1997: ICD-DDD1997: ICD-DDD

2003: CRT-D2003: CRT-D

Lead burden of the VentricleLead burden of the Ventricle Subclavian vein occlusionSubclavian vein occlusion

The problem of lead burden” is not uncommon… and The problem of lead burden” is not uncommon… and upgrading from CRT-P to CRT-D may involve technical upgrading from CRT-P to CRT-D may involve technical problemsproblems

After several decubitus, lead surgical extraction… and After several decubitus, lead surgical extraction… and right sided new implant right sided new implant

New ICD

New RV lead

New RA lead

New LV epi lead

CONCLUSIONSIn summary, aside from costs considerations

indication to CRT-P should be limited to life expectancy < 1 yrlife expectancy < 1 yr (advanced age, comobidities) (advanced age, comobidities)

HF due to iatrogenic asynchronous RV pacingHF due to iatrogenic asynchronous RV pacing

difficult venous accessdifficult venous access

Since all patients eligible for CRT presentSince all patients eligible for CRT present aa CLASS IACLASS IA indication for an ICD deviceindication for an ICD device

New technology to contain costsNew technology to contain costs

InSync III Protect: InSync III Protect:

a full-feature Cardiac Resynchronization System + a full-feature Cardiac Resynchronization System + “simplified programmable “ICD“simplified programmable “ICD

allows to reduce costs by around allows to reduce costs by around 30-40%30-40%

(240)

Shocks 1 ATP + Shocks

Protect RescueSetProtect RescueSetTMTM

VF/VT treatment window: 270, 300, 330 (nom.), VF/VT treatment window: 270, 300, 330 (nom.), 360, 400 ms360, 400 ms

VT monitor only window: 370 ms (fixed)VT monitor only window: 370 ms (fixed)

400

Results Results (Recorded episodes)(Recorded episodes)

Total episodes recorded on device memory

884in 126 patients

330 episodes 554 episodes

20 INAPP. episodes

310 APP. episodes

242 INAPP. episodes

312 APP. episodes

PROTECTPROTECT CONTROLCONTROL

RELEVANTRELEVANT

Dramatically lower inapp. detections in Dramatically lower inapp. detections in PROTECTPROTECT

SameSame number of number of appropriate detectionsappropriate detections

RELEVANT StudyRELEVANT StudyPrincipal investigator: M GaspariniPrincipal investigator: M Gasparini

Presented at HRS 2008Presented at HRS 2008