1. What Is The Patient Profile Who Can Benefit from CRT-P only?
ADVANCES IN CRT
What Is The Patient Profile Who Can Benefit from CRT-P only?
Progressi nella CRT
Quale è il profilo del paziente che può beneficiare della sola CRT ?
Dr. Maurizio Gasparini
UO Elettrofisiologia ed Elettrostimolazione
Istituto Clinico Humanitas, IRCCS, Rozzano-Milano

2.  Cardiac resynchronization therapy guidelines published for the first time in 2007 …
Eur Heart J 2007; 28:

4.  Few months later , American GL published…

6. So very simple and clear indications for CRT-P in HF patients !
 NYHA III-IV pts on OPT
 LV EF < 35%
 QRS ≥ 120 msec
 Sinus rhythm
Thank you for your attention 

7. However reading carefully….

8. The ESC and AHA/ACC/HRS Guidelines on indications for device therapy do not clearly indicate which patients are candidates to CRT-P only
Solved dilemma by recent HF Guidelines ??!!

9. …Once again

10. On the other hand, following GL in the clinical practice, it is mandatory to control if in the same field (i.e. ICD therapy) some other guidelines exist :
ICD therapy has been demonstrated to be particularly effective in preventing sudden cardiac death (SD) and thus reducing total mortality :
 in primary as well as in secondary prevention
 in patients with severely compromised left ventricular function
 regardless of underlying etiology…
as clearly demonstrated by several studies

11. MADIT II
Post-MI, FE ≤ 30%, any NYHA
ICD  mortality by 31%
NEJM 2002; 346 (12);
NEJM 2004;350:2151-8
DEFINITE
Non isch DCM; NYHA I/III; EF ≤ 36%; ICD  mortality by 35%
ICD decreases total mortality in pts with systolic dysfunction of any etiology regardless NYHA functional class
SCD-HeFT
Isch/non isch;EF ≤ 35%; NYHAII-III
ICD  mortality by 23%
NEJM 2005;352:225-37
COMPANION
Isch/non EF ≤ 35%; NYHA III- IV;
CRT-D  mortality by 36%
NEJM 2004;350:
Sappiamo ora che l’ ICD riduce la mortalità totale nei pz con disfunzione sistolica di qualunque eziologia e classe funzionale

12. How to combine both these 2 statements?

13. 85% of CRT candidates are in NYHA III !!

14. 85% of CRT candidates are in NYHA III !!

15. Long-term follow up after cardiac resynchronization therapy: poor clinical outcome in patients enrolled in advanced NYHA class IV
Maurizio Gasparini
Istituto Clinico Humanitas - Rozzano, Milano (Italy)
Presented at AHA Congress Published on theHeart.org

16. STUDY POPULATION 268 consecutive CRT pts (267 endo, 1 epi )
CRT between October 1999 and July 2003
Population was divided in 3 groups according to NYHA class at enrollment
NYHA II
NYHA III
NYHA IV
34 pts
(13%)
194 pts
(72%)
40 pts
(15%)

17. 268 consecutive CRT pts October 1999 / July 2003 NYHA II: 34 pts (13%)
NYHA III: 194 pts (72%)
NYHA IV: 40 pts (15%)

18. Total mortality rate according to NYHA class at baseline
m.r. 0%
.001
.04
m.r. 5.7%
m.r. 16.6%
.01
H.R. 3-4 = 1.7
H.R. 2-4 = 4.5
Log rank p= .002

19. Cardiac mortality rate according to NYHA class at baseline
m.r. 0%
.003
m.r. 4.7% ns
m.r. 14.7%
.01
H.R. 3-4 = 1.7
H.R. 2-4 = 4.1
Log rank p= .004

20. Low mortality rate in NYHA III (5.7%/yr)
No deaths in NYHA II
(mortality rate 0 %/yr)
Low mortality rate in NYHA III (5.7%/yr)
High mortality rate in NYHA IV (16.7%/yr)
Too high??
Cost-effectiveness ?

21. NYHA IV pt into details :
NYHA IV: 40 pts
33 pts IV
7 pts IV advanced
No ev amine
No mechanical ventilation
4 ev amine + mech. vent
3 ev amine no mech. vent
deaths :3/33
deaths :5/7

22. Cardiac mortality rate according to NYHA class at baseline
m.r. 0%
m.r. 4.7%
.02 ns
All p=
m.r. 7.8% ns
Log rank p=
m.r. 80.8%
Non advanced NYHA IV survival rate:similar to NYHA III !!

23. Which pts are candidates to CRT-P only ??
 So ambulatory NYHA IV behaviour is like NYHA III patients
Which pts are candidates to CRT-P only ??

24. Which data in the literature? Care HF
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

25. Which studies from the literature ??
Available studies in details…
Scissors CRT-D /CRT at days
Scissors CRT-P / OPT at 240 days
COMPANION - Bristow NEJM 2004;350:

26. NYHA III-IV, EF< 35%, QRS > 120
Inclusion criteria :
NYHA III-IV, EF< 35%, QRS > 120
191 pts CRT-D
Results ( fu:2 yrs):
at least 1 appropriate therapy
21% primary prevention
120 primaryprevention
71 secondary prevention
Quello che ci si puo’ aspettare applicando un CRT-D in prevenzione primaria in attesa dei dati dei nostri registri ongoing
35% secondary prevention
No predictors

27. MILOS STUDY 4 European Centers 1303 pts
All cause mortality reduction  by 17%
Sudden death reduction  by 96%

28. Further 9% of mortality reduction with CRT-D!!!
Data from metanalisis
Further 9% of mortality reduction with CRT-D!!!
CRT-D with respect to OPT  mortality by 43%
CRT-P with respect to OPT  mortality by 34%
ICD with respect to OPT  mortality by 31%

29. Further 9% of mortality reduction with CRT-D!!!
Data from metanalisis
Further 9% of mortality reduction with CRT-D!!!
CRT-D with respect to OPT  mortality by 43%
CRT-P with respect to OPT  mortality by 34%
ICD with respect to OPT  mortality by 31%

32. IB IA
IA even in the upcoming European GL

33. 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%

34. CRT-P Similar behaviour in USA
(small rate of CRT-P implant with respect to CRT-D)

35. Aside from costs considerations
If ICD back up seems reasonable… we should consider the possibility of….
disadvantages of CRT-D systems in CRT candidates
Aside from costs considerations
No major technical differences between CRT and CRT D implantation
1) No significant increased risk of complications (implant - related)
2) No significant increased complications during follow up

36. 1 a Complications (COMPANION trial, Bristow et al., NEJM 2004)
Parameter
OPT
n=308
OPT +
CRT
n=617
CRT-D
n=595
Implant Success (%) –
88.3
92.0
Total Implant Time (minSD)†
200
116
213
131
Moderate or Severe Adverse Events (% of total patients) 55 58 60
30 day crude mortality (%), from randomization or implantation
1.0
{–}
1.8
{2.1}
0.9
{0.7}
Absolutely no differences in severe implant-related adverse events between device type adverse events are mainly associated to LV lead positioning...

37. 2) DFT can be safely delayed
1 b Complications related to defibrillation testing (DT)
1) DFT can be avoided
2) DFT can be safely delayed

38. 2) No significant difference in QOL! (during f.u)
A correct device programming allows reduction of inappropriate shocks and “minimize” appropriate shocks
 improving ATP in ICD for VT:
 PAINFREE algorithms:
1) fast VT in CAD: 2 bursts of 8 pulses, 88% [Wathens et al, Circulation 2001]
2) fastVT in all etiologies: 1 burst of 8 pulses, 88% [Wathens et al, Circulation 2004]
 ATP algorithms in CRT-D :
ADVANCE CRT-D trial (RV vs BiV ATP in CRT-D)
[Schwab JO, Gasparini M, JCE 2006; Gasparini M., late breaking trial HRS S Francisco 2008]
 Increasing VT detection time in selected cases where VTs tend to self-terminate [Relevant Study Gasparini M. et al HRS S Francisco 2008]
 algoritms for atrial tachiarrhythmias discrimination(PR logic ™)
 atrio-ventricular junction ablation for permanent AF

39. The CARE-HF & CARE-HF extension phase data
So…at this point … which arguments for not associate ICD function to CRT-P?
It has been postulated that CRT-P per se  mortality due to sudden death … …especially in the “long term” f.u.
The CARE-HF & CARE-HF extension phase data

40. Companion Does CRT-P really  sudden death ?
Scissors CRT-D /CRT at days
Scissors CRT-P / OPT at 240 days
COMPANION - Bristow NEJM 2004;350:

41. Care HF
Mean f.u. = 29,4 months
CRT-P diverges from OPT only at 240 days !!
NEJM 2005;352:

42. Between day 120 and 240 gg CRT-D begins to saves lifes……
COMPANION - Bristow NEJM 2004
COMPANION: same behaviour of CRT-P of CARE-HF !!!!
Clealend NEJM 2005

43. The identical behaviour is based on the typical temporal pattern of the “reverse remodeling” process conferred by CRT… SR
AF + AVJ Ablation
AF no AVJ Ablation
Baseline mos
Baseline mos
(Gasparini et al., JACC 2006)

44. SD in HF patients treated with CRT-P
Mode of death in CRT-P
COMPANION
Other
2 different studies with SAME CRT-P curve behaviour
32%
CHF
Sudden
47%
1/3 pts die for SD
in CRT-P
-with SAME SD % in CRT-P
death
21%
OPT
CRT-P
Other
22%
CHF
Sudden
45%
death
CARE-HF
32%

45. SCD in HF patients treated with CRT
What about the earlier phases of CRT when reverse remodeling has still to take place?
COMPANION
6 mos
Would you take the CRT leap…
With a parachute (ICD)
or without a parachute…
Would it be worthwhile to stratify arrhythmic risk?
(“ethical” issue this day and age)
2) Simply implant a CRT-D system !!
Benefits from ICD back up to protect from SD between 120 and 240 days after CRT clearly demonstrated by Care HF and Companion

46. Does really CRT-P  sudden death in the long term follow up ?!
CARE HF
John G.F. Cleland
N Engl J Med 2005;352:
Does really CRT-P  sudden death in the long term follow up ?!
CARE HF extension phase
John G.F. Cleland
EHJ (2006) 27, 1928–1932
Mean f.u. = 37,4 months
Mean f.u = 29,4 months .
Questi sono i risultati del CARE HF, a sx il follow up esteso, a destra i risultati dello studio iniziale del 2005.
SI OSSERVANO DUE COSE ESTREMEMENTE IMPORTANTI: 1) LA MORTALITà NON VIENE MINIMAMENTE RIDOTTA NEI PRIMI 12 MESI DALLA CRT; LA SEPARAZIONE DELLE CURVE è TARDIVA. MA LA RIDUZIONE DI MORTALITà è IMPORTANTE E SIGNIFICATIVA

47. CAREfully looking inside CARE HF extended
Mean f.u = 29,4 months
At the end of the study: n of deaths:
200 pts
E SAPPIAMO ORA CHE LA CRT EFFETTIVAMENTE SALVA LA VITA.
Questi sono i risultati del CARE HF, a sx il follow up esteso, a destra i risultati dello studio iniziale del 2005.
SI OSSERVANO DUE COSE ESTREMEMENTE IMPORTANTI: 1) LA MORTALITà NON VIENE MINIMAMENTE RIDOTTA NEI PRIMI 12 MESI DALLA CRT; LA SEPARAZIONE DELLE CURVE è TARDIVA. MA LA RIDUZIONE DI MORTALITà è IMPORTANTE E SIGNIFICATIVA
Due to the demonstrated benefit of CRT-P CRT-P strongly recommanded at the end of CARE HF for pts randomized in OPT group

48. Recommendation letter
CRT-P strongly recommended at the end of CARE HF for pts randomized in OPT group !!!!
However…..

49. statistically significant and statistically correct…
Optimal drug therapy
404 pts / 154 deaths:
CRT
409 pts / 101 deaths:
35%
32%
E questi sono i dati di mortalità assoluta del CARE. Riduzione del rischio di WHF…, ma anche marcata riduzione di morti imprivvise che continuano a rappresentare un 35% circa del totale in entrambi i gruppi. .
Risk reduction of death from HF by 45% ( HR = 0,55)
Risk reduction of death from SCD by 46% ( HR = 0,54)
statistically significant and statistically correct…
but clinically uncorrect…

50. Does really CRT-P  sudden death in the long term f.u.?
Why such a big spaceball ?!

51.  Considering pts still alive… for them LONGER f.u (~ 10 months)
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 ???

52. CAREfully looking inside CARE HF extended
CRT: 32/409 (7.8%)
2.5%/y
SD: 32% in CRT SD
OPT: 54/404 (13.4%)
4.3% / y
2.5%
1 yr
2.5%
1 yr
2.5%
2 yr
2.5%
2 yr
3 yr
2.5%
2.5%
4 yr
3 yr
8 % 8%
4 yr

53. 42.7% mortality CAREfully looking inside CARE HF extended
82 † (29.4 months)
20% mortality
CRT arm
102 † (37.4 months)
25% mortality
409 pts
DESPERATE OPT
120 † (29.4 months)
29.7% mortality
OPT arm
154 † (37.4 months)
38% mortality
404 pts
42.7% mortality
309 pts: 132 † (DESPERATE OPT!!)
BUT…
404 pts
95 OPT CONVERTED to CRT:22 †
23.2% mortality

54. CARE HF investigators postulated that CRT-P SCD during long term f.u
I honestly think that it is not true
but SD rate in CRT-P REMAIN THE SAME over time !!
If CRT-P would protect from SD this would be the pattern of the survival curve
Pts left on OPT (despite recommendations!) continues to dramatically die like flies… that the only reason for the supposed reduction of SD with CRT !!!

55. In conclusions….
1) CRT-D undeniably reduce mortality with respect to OPT
2) All studies comparing CRT-P and CRT-D, CRT-D arm has shown greater benefit with respect to CRT-P in terms of SD reduction
3) Metanalisys data undeniably shown that CRT-D saves more lives than CRT-P (9% more!!)
4) We should offer to any HF pt the best possible therapy, i.e complete therapy  CRT-D
5) Last but not least, more than 85% of CRT candidates satisfy a class IA indication for ICD !!!

56. Is there still place for CRT-P ?

57. CRT-P FOR WHOM?  consider 1) LIFE EXPECTANCY
 if life expectancy < 1 yr
 very advanced anagraphic age (at least > 80 years)
 very advanced biological age
due to severe comorbidities
cachexia
neurological diseases
severe COPD / severe renal/epatic insufficiency
complicated insulin dependent diabetes
peripheral vascular disease
Reasonable NOT to provide an ICD back-up
Aim of the intervention:  QOL for the remaining life

58. 2) PREVIOUS VVI or DDD PM CAUSING “IATROGENIC” LV DYSFUNCTION at a reasonably advanced age (>75 yrs)
Often rapid clinical /echo improvement after upgrading to CRT-P
A rapid response after CRT may reduce the arrhythmic risk
Not infrequent venous access difficulties in those settings
Increased risks of complications if LV lead AND RV defib coil insertion necessary

59. 3) PREVIOUS DDD pm with two unipolar leads
CS lead
PM DDD
Unipolar lead
Risk/benefit ratio evaluation-> which is better : CRT-D with 3 more leads or CRTP with only one more LV lead ???

60. Subclavian vein occlusion is not an unusual finding after lead insertion
Collateral vessels
Collateral vessels

61. Lead burden of the Ventricle Subclavian vein occlusion
The problem of lead burden” is not uncommon… and upgrading from CRT-P to CRT-D may involve technical problems
Mr. A.I. After 17 years of device history…
1996: DDD
1997: ICD-DDD
2003: CRT-D
1994: VVI
1989: Epi-ICD
Lead burden of the Ventricle
Subclavian vein occlusion

62. After several decubitus, lead surgical extraction… and right sided new implant
New ICD
New LV epi lead
New RA lead
New RV lead

63. CONCLUSIONS Since all patients eligible for CRT present a CLASS IA
In summary, aside from costs considerations
indication to CRT-P should be limited to
 life expectancy < 1 yr (advanced age, comobidities)
 HF due to iatrogenic asynchronous RV pacing
 difficult venous access
Since all patients eligible for CRT present a CLASS IA
indication for an ICD device

64. New technology to contain costs
InSync III Protect:
 a full-feature Cardiac Resynchronization System + “simplified programmable “ICD
 allows to reduce costs by around 30-40%
Protect RescueSetTM
VF/VT treatment window: 270, 300, 330 (nom.), 360, 400 ms
VT monitor only window: 370 ms (fixed)
(240)
400
Shocks
1 ATP + Shocks

65. Principal investigator: M Gasparini Results (Recorded episodes)
RELEVANT Study
Principal investigator: M Gasparini
Presented at HRS 2008
Results (Recorded episodes)
Total episodes recorded on device memory
884
in 126 patients
PROTECT
CONTROL
330 episodes
554 episodes
20 INAPP. episodes
310 APP. episodes
242 INAPP. episodes
312 APP. episodes
Same number of appropriate detections
Dramatically lower inapp. detections in PROTECT
RELEVANT