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Tilt asistolico VASIS 2B Pro

Francesco Arabia U.O. Cardiologia – UTIC

Emodinamica e Cardiologia Interventistica Presidio Ospedaliero “A. Pugliese” Catanzaro

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Tipo  2  A  ,  cardioinibitoria    senza    asistolia:'la  frequenza  cardiaca  scende    a  meno  di  40  bpm  per  più  di  10  s,  ma    non    si    verifica    asistolia  maggiore    di    3    secondi.  La  pressione  cala    prima    della    diminuzione    della    frequenza    cardiaca.      Tipo  2    B  ,  cardioinibitoria    con    asistolia:  Si    verifica    asistolia      maggiore    di    3    secondi.  Il  calo    pressorio    coincide  con    la    diminuzione  della    frequenza    cardiaca  o    la    precede  

Tipo  2A  :    'la  frequenza  cardiaca  scende    a  meno  di  40  bpm  per  più  di  10  s  o  si  verifica  asistolia  per  più  di  3  s;  la  pressione  arteriosa  scende  prima  della  frequenza  cardiaca        Tpo  2B:  la  frequenza  cardiaca  scende  a    meno  di  40  bpm  per  più  di  10  s  o  si  verifica  asistolia  per  più  di  3  s;  la  caduta  della  pressione  arteriosa  coincide  con  la  caduta  della  frequenza  cardiaca  

Vasis  1992   Vasis  2000    

SuJon  R,  Petersen  M,  Brignole  M,  Raviele  A,  Menozzi  C,  Giani  P.  Proposed  classificaPon  for  Plt  induced  vasovagal  syncope.  Eur  J  Cardiac  Pacing  Electrophysiol  1992;  2:  180–3.  

M.  Brignole,  C.  Menozzi,A.  Del  Rosso,  S.  Costa,  G.  Gaggioli,  N.  BoJoni,P.  Bartoli  and  R.  SuJonNew  classificaPon  of  haemodynamics  of  vasovagal  syncope:  beyond  the  VASIS  classificaPon  Europace  (2000)  2,  66–76  

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www.gimsi.it M.  Brignole,  C.  Menozzi,A.  Del  Rosso,  S.  Costa,  G.  Gaggioli,  N.  BoJoni,P.  Bartoli  and  R.  SuJonNew  classificaPon  of  haemodynamics  of  vasovagal  syncope:  beyond  the  VASIS  classificaPon  Europace  (2000)  2,  66–76  

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   The Role of Pacing as Therapy for VVS  VVS with +HUT and cardioinhibitory response: Class IIb indication for pacing  Three randomized, prospective trials reported benefits of pacing in select VVS patients:  

 – VPS I  

 – VASIS  

 – SYDIT  Subsequent study results less clear:    

 – VPS II  

 – Synpace  

1Connolly SJ. J Am Coll Cardiol. 1999;33:16-20. 2Sutton R. Circulation. 2000;102:294-299. 3Ammirati F. Circ. 2001;104:52-57.

4Connolly 5Giada 6Occhetta E, et al. Europace. 2004;6:538-547.

Double  blind  

Open  label  

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     VPS I North American Vasovagal Pacemaker Study      

 Objective: To evaluate pacemaker therapy for  severe recurrent vasovagal syncope

 

 Randomized, prospective, single centre  

 N=54 patients      – 27: DDD pacemaker with rate drop response

     – 27: No pacemaker

 

 Inclusion: Vasodepressor response  

 Primary outcome: First recurrence of syncope Connolly SJ. J Am Coll Cardiol. 1999;33:16-20.

!  6  syncopal  events  ever  

!  +HUT  !  RelaPve  bradycardia  

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Cum

ulat

ive

Ris

k (%

)

100    90  80  70  60  50  40    30  20  10    0

0 3 12 15  6 9 Time in Months

Connolly SJ. J Am Coll Cardiol. 1999;33:16-20.

• 6 (22%) with PM had recurrence vs. 19 (70%) without PM • 84% RRR (2p=0.000022)

 VPS I North American Vasovagal Pacemaker Study

           No Pacemaker (PM)

           2P=0.000022

                 Pacemaker

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       VASIS    Vasovagal Syncope International Study      

Objective: To evaluate pacemaker therapy for severe cardioinhibitory tilt-positive neurally mediated syncope  Randomized, prospective, multi-centre  N=42 patients    – 19: DDI pacemaker (80 bpm) with rate hysteresis (45 bpm)    – 23: No pacemaker  Inclusion: Positive cardioinhibitory response   Primary outcome: First recurrence of syncopeope

Sutton R. Circulation. 2000;102:294-299.

!  >  3  syncopal  events  in  2  years  and  last  event  occurring  within  6  months  of  enrollment  and,  

!  PosiPve  VASIS  type  2A  or  2B  cardioinhibitory  response  to  HUT  and,  !  Age  >  40  years  or  drug  refractory  if  <  40  years  

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% S

ynco

pe-F

ree

Sutton R. Circulation. 2000;102:294-299.

100          80            60        40        20

0 2 3 4 5 6  Years Results:

• 1 (5%) with PM had recurrence vs. 14 (61%) without PM

VASIS VAsovagal Syncope International Study

   Pacemaker (PM)              

     p=0.0004              

   No Pacemaker

Sutton R. Circulation. 2000;102:294-299. •  2-year estimated syncope recurrence rate was 6%  

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   SYDIT    Syncope Diagnosis and Treatment

   

Objective: To compare the effects of cardiac pacing with pharmacological therapy in patients with recurrent vasovagal syncope  Randomized, prospective, multi-centre  N=93 patients    – 46: DDD pacemaker with rate drop response    – 47: Atenolol 100 mg/die Inclusion: Positive HUT with relative bradycardia  Primary outcome: First recurrence of syncopee Ammirati F. Circulation. 2001;104:52-57.

>  55  yrs  >  3  syncopal  episodes  in  2  years        

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% S

ynco

pe-F

ree

Ammirati F. Circulation. 2001;104:52-57.

1.0          0.9          0.8          0.7          0.6

0 100 200 300 400 500 600 700 800 900 1000

 SYDIT Syncope Diagnosis and Treatment      

     Pacemaker (PM)                

   p=0.0032          

       Drug

 Time (Days) • 2 (4%) with PM had syncope recurrence vs. 12 (26%) without PM •  2-year estimated syncope recurrence rate was 7,2%  

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     VPS II    Vasovagal Pacemaker Study II    

Objective: To determine if pacing therapy reduces the risk of syncope in patients with vasovagal syncope  Randomized, double-blind, prospective, multi-centre  N=100 patients    – 52: Only sensing without pacing    – 48: DDD pacemaker with rate drop response  Inclusion: Positive HUT with (HRxBP) < 6000/min x mmHg

! 6  syncope  events  ever  or    ! >  3  syncope  events  in  2  years  or  !   >  1  syncope  event  in  6  months

 Primary outcome: First recurrence of syncope

Connolly S. JAMA. 2003;289:2224-2229.

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Cum

ulat

ive

Ris

k

1.0        0.8          0.6            0.4              0.2                0

Months Since Randomization 6543 210

Connolly S. JAMA. 2003;289:2224–2229.

Results: 33% recurrence with pacing vs. 42% with only sensing (p=ns)

 VPS II Vasovagal Pacemaker Study II                        

   Only Sensing Without    Pacing (ODO)

               Dual Chamber Pacing    (DDD)

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SYNPACE Vasovagal Syncope and Pacing

 

Objective: To determine if pacing therapy will reduce syncope relapses in patients with recurrent vasovagal syncope, compared with those having a pacemaker programmed OFF Randomized, double-blind, prospective, multi-centre, placebo-controlled N=29 patients  – 16: DDD PM with rate drop response    programmed ON  – 13: PM programmed OFF (OOO mode) Inclusion: Recurrent VVS and +HUT with asystolic or mixed response Primary outcome: First recurrence of syncope

Raviele A.. Europace. 2001;3:336–341. Raviele A, et al. Eur Heart J. 2004;25:1741-1748.

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% S

ynco

pe-F

ree

Raviele A, et al. Eur Heart J. 2004;25:1741-1748.

 SYNPACE Vasovagal Syncope and Pacing  1.0

0 200 400 600 800 1000

0.9  0.8  0.7  0.6  0.5  0.4  0.3  0.2  0.1  0.0

 p=0.58            Pacemaker OFF      Pacemaker ON

 Days Since Randomization  50% recurrence with pacing ON vs. 38% with pacing OFF (p=ns)

Recurrent VVS and +HUT with asystolic or mixed

response 2A+2B Age : 53

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Context and Background:  THE EFFICACY OF CARDIAC PACING FOR PREVENTION OF SYNCOPAL    RECURRENCES IN PATIENTS WITH NEURALLY MEDIATED SYNCOPE

   Multicenter, randomized studies with results in favour of pacing (open-label)

-          -

SYDIT. Circulation 2001    2-year estimated syncope recurrence rate was 7,2%  

 VASIS. JAMA 2003    2-year estimated syncope recurrence rate was 6%

- SYDIT Circulation 2001    Randomized double-blind controlled trials failed to prove superiority of cardiac

 pacing over placebo

 VPS II trial. JAMA 2003    6-months syncope recurrence rate was 31%

SYNPACE trial. Eur Heart J 2004    1-year syncope recurrence rate was 29%

ISSUE 2

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3

Implanted ILR

Eligible 442 25 No ILR implant

 53  ILR-based specific Rx: • Pacemaker #47 • Defibrillator #1 • Catheter ablation #4 • Antiarrhythmic drug #1

 50  Non- specific Rx

417

 25 No follow-up    

 15 Drop-out  • Asystole, # 57 • Bradycardia, # 4 • No or slight rhythm variations # 29 • Progressive sinus tachycardia #7 • Tachyarrhythmia, # 9

No follow-up Started Phase II 103

         Started Phase I FU 392    

           Syncopal recurrence 143    

ECG-documented syncope 106

ISSUE  2  

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ISSUE 2

1-year estimated syncope recurrence rate was 5% ( burden 0,05 ±0,15)  

" Pacing potentially effective in patients with documented asystole " The mechanism of spontaneus NMS documentated by ILR was riproducible " Asystolic NMS treated with pacemaker showed a > 80% relative risk reduction of syncopal recurrence Studio  mulPcentrico  prospebco  osservazionale  

ISSUE-2 was not a formal controlled double-blind trial

Eur Heart J 2006; 27, 1085–1092

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Europace.  2007  Jan;9(1):31-­‐3.  Pacing  for  neurally  mediated  syncope:  is  placebo  powerless?  Brignole  M,  SuJon  R.  

CONCLUSIONS:    

Placebo  is  not  an  effecPve  therapy  for  neurally  mediated  syncope.  Different  selecPon  criteria  in  paPents  who  are  candidates  for  cardiac  pacing-­‐for  example,  presence,  absence,  or  severity  of  the  cardioinhibitory  reflex  may  separate  posiPve  from  negaPve  trials.  

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ISSUE 3"

SYNCOPE"

ISSUE  3  International Study on Syncope of Uncertain Etiology 3  

Pacemaker    therapy  for  paPents  with    

neurally-­‐mediated  syncope  and  documented  asystole  

 A  randomized  controlled  double-­‐blind  trial  

Objective: to determine if pacing therapy reduces recurrences in patients with severe documented spontaneous asystolic NMS

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ISSUE  3  International Study on Syncope of Uncertain Etiology 3  

ISSUE 3"

SYNCOPE"

Total  29  centers  

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ISSUE  3  International Study on Syncope of Uncertain Etiology 3  

Study  hypothesis:  

Pacing  therapy  is  effecPve  for  prevenPng  syncope  recurrence  in  paPents  with  NMS  and  documented  asystole  

Background:  

Two  RCTs*  failed  to  prove  superiority  of  cardiac  pacing  over  placebo  of  unselected  NMS  paPents  with  posiPve  Plt  tesPng    

*  VPS  II  trial.  JAMA  2003;  289:  2224-­‐2229                  Synpace  trial.  Eur  Heart  J  2004:  25:  1741–1748        

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Screening  phase  

Study  phase  

77        randomized   12      refused  randomizaPon  

38        assigned  and  received                                          Pm  ON  

39      assigned  and  received                                          Pm  OFF  

511      met  inclusion  criteria                        and  received  an  ILR  

89        had  ECG  documentaPon  of:                  -­‐  syncopal  recurrence    with  asystole  of  12±10  s  (#72)                                                                                    or                  -­‐  non-­‐syncopal  asystole  of  10±6  s    (#17)  

8  had  Pm  reprogrammed    DDD/VVI  in  absence    of  

             primary  end-­‐point  

38      analysed   39      analysed  

9          followed-­‐up  (registry):                6        implanted  Pm                3        no  therapy  

9      analysed  

3      lost  to  follow-­‐up  

ISSUE 3"

SYNCOPE"

ISSUE 3"

SYNCOPE"ILR  screening  phase:  documented  events

Asystole  Normal  SR  

10%  

Tachicardia  

Asystole  (11  ±  4  s)  

Bradycardia  

Normal  SR  

Tachycardia  

Total  end-­‐points:  158  

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ISSUE 3"

SYNCOPE"

EsDmated  prevalence:  9%  of  paPents  affected  by  NMS  referred  to  Syncope  Clinic  

ISSUE  3  populaPon    

Features:  • Mean  age  at  presentaPon:  >60  years  

• History  of  recurrent  syncopes  beginning  in  middle  or  older  age    

• Severe  clinical  presentaPon  requiring  treatment  (high  risk  and/or  high  frequency)  

• Atypical  presentaPon  without  warning  • Frequent  injuries  related  to  presentaPon  without  warning  • ILR  documentaPon  of  long  pauses  (mean  11  seconds)  

0

.1

.2

.3

.4

.5

.6

.7

.8

.9

1

Free

dom

from

syn

copa

l rec

urre

nce

38 32 27 22 16 14 13 13 11Pm ON39 31 25 21 21 18 15 12 8Pm OFF

Number at risk

0 3 6 9 12 15 18 21 24Months

Kaplan-Meier survival estimates

log rank: p=0.039 RRR at 2 yrs: 57%

Pm  ON  

Pm  OFF  

First  syncope  recurrence  (intenDon-­‐to-­‐treat)  

ISSUE 3"

SYNCOPE"

25%  

37%  

25%  

57%  

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ISSUE  3  International Study on Syncope of Uncertain Etiology 3  

ISSUE 3"

SYNCOPE"

Conclusions  

•   Dual-­‐chamber  permanent  pacing  is  effecPve  in  reducing  recurrence  of  syncope  in  paPents  ≥40  years  with  severe  asystolic  NMS.    

•   The  observed  32%  absolute  and  57%  relaPve  syncope  reducPon  rate  support  the  use  of  this  invasive  treatment  for  the  relaPvely  benign  NMS.  

•   The  overall  strategy  of  using  an  ILR  in  order  to  determine  indicaPon  for  pacing  likely  contributed  to  the  posiPve  findings  and  explains  the  discrepancy  with  the  negaPve  results  of  some  previous  report.  

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www.gimsi.it Heart  2013;99:1825-­‐1831  doi:10.1136/heartjnl-­‐2013-­‐304399  

According  to  the  ILR  findings,  the  accuracy  of  the  diagnosis  of  NMS  made  on  iniPal  evaluaPon  was  87%.  The  diagnosPc  accuracy  of  Plt  table  test  was  low:  TT  was  posiPve  in  56%  NMS,  43%  non-­‐NMS;  an  asystolic  response  was  present  in  21%  NMS  and  0%  non-­‐NMS  

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ON-TREATMENT ANALYSIS  The recurrence of syncope occurred in 10 paced patients (17%) 40 non-paced patients (46%). At 21 months, the estimated product-limit syncope recurrence rates were 27% and 54% respectevely. Risk of recurrence with cardiac pacing was reduced by 57%

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-Positive TTT is more likely correlated with a higher frequency of recurrences of syncope in the group treated using a PM, while a negative response seems to predict the success of the pacing therapy.        -The results of our study show the capacity of TTT to identify patients with a possible concomitant vasodepressive form ( !?!? )    Consequently PM is not sufficient in a group of patients with positive TTT response.

Circ  Arrhythm  Electrophysiol.  2014  Feb;7(1):10-­‐6  

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Physical  counter-­‐pressure  manoeuvres  in  prevenDng  syncopal  recurrence  in  paDents  older  than  40  years  with  recurrent  neurally  mediated  syncope:  a  controlled  study  from  the  Third  InternaDonal  Study  on  Syncope  of  Uncertain  EDology  (ISSUE-­‐3)  Marco  Tomaino,  CrisDna  Romeo,  Elena  Vitale,  Teresa  Kus,  Angel  Moya,  Nynke  van  Dijk,  Silvia  Giuli,  Giorgia  D'Ippolito,  Alessandra  GenDli,  Richard  Suaon,  DOI:  hap://dx.doi.org/10.1093/europace/euu125  1515-­‐1520  First  published  online:  6  June  2014    

Issue-3 population: - OLDER PATIENTS - ABSENCE OF PRODROME

At 21 months, the estimated product-limit syncope recurrence rates were 42% (95% CI 29-62) and 64% (95% CI 48-80 respectively (p=0.30)

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Bolzano

SYNCOPE TAKE HOME MESSAGES

ISSUE 3 TRIAL

"   Clinical evaluation "   Diagnostic iter guided by ILR "   Selection of patients who undergo to PM implantation "   Reducing of recurrences and improvement of QOL by pacing DDD RDR

"   PCM Therapy

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SUP 2

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The recurrence rate was similar in the 65 CSM+ (11%), 32 TT+ (7%) and 23 ILR+ (7%) patients.

The actuarial total syncope recurrence rate was : 9% (95% CI 6-12 at 1 years and 15% (95% CI, 10-20) at two years and when significantly lower than that observed in the control group of 124 patients with unspleined syncope who did not receive pacemaker i.e. 22% (95% CI, 18-26 ai 1 year and 37% (95%, CI 30-43) at 2 years ( p=0,004)

recurrence rate was 9%

SUP 2

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About half of older patients with severe recurrent syncopes without prodromes have an asystolic reflex for which cardiac pacing is effective in preventing syncopal recurrences. The recurrence rate is low irrespective of the index diagnostic test

.

Asystolic Tilt Test and PM

SUP 2

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0  

5  

10  

15  

20  

25  

30  

35  

40   2008  

2009  

2010  

2011  

2012  

2013  

2014  

Lineare  (2008)  

Lineare  (2009)  

Lineare  (2010)  

Lineare  (2011)  

Lineare  (2012)  

Lineare  (2014)  

Syncope  Unit    CZ    Aevità  2008  -­‐  2014    

Totale  1610  pz  

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0  

100  

200  

300  

400  

500  

600  

700  

800  

900  

1000  

NegaPvi   Tipo  I   Tipo  2A   Tipo  2B   Tipo    3   MSC  pos  

1004;  61%  

175  14%  %  

57;  5%  

110;  7%  

133;    8%  71;  5%  

39%  

RISULTATI  

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0  

20  

40  

60  

80  

100  

120  

140  

160  

180  

Tipo  I   Tipo  2A   Tipo  2B   Tipo    3   MSC  pos   Altri  

175;  30%  

57  10%  %  

110;  19%  133;  22%  

71;    12%  

20;  3%  

RISULTATI  

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0  

10  

20  

30  

6  mesi   12  mesi   18  mesi   24  mesi  

TraJaP  con  PM  

No  PM  

PZ  

PazienP  con  risposta  Ppo  2B  

33%  

50%  

4%  10%  

48  pz    età  media    68  aa              Pz    DDD  PM    rate  drop  response  

60  pz  età  media  30  aa                  Misure  comportamentali   3  

SINCOPE 2 0 1 5

www.gimsi.it

SINCOPE 2 0 1 5

www.gimsi.it

0  

50  

100  

150  

200  

250  

300  

350  

0-­‐17   18-­‐39   40-­‐69   >70  

Donne  

Uomini  

DISTRIBUZIONE  PER  FASCE  DI  ETA’