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Vasovagal syncope management Mexico City 2016
1. Vasovagal Syncope:Vasovagal Syncope:
Current Management and Role ofCurrent Management and Role of
Cardiac PacingCardiac Pacing
Antonio Raviele, MD, FESC, FHRSAntonio Raviele, MD, FESC, FHRS
ALFA – Alliance to Fight Atrial fibrillation, Mestre – Venice, ItalyALFA – Alliance to Fight Atrial fibrillation, Mestre – Venice, Italy
Curso de Actualizaciòn en Arritmias, Mexico City, Mexico - 16-18 November, 2016
12. Van Dijk N et al.J Am Coll Cardiol. 2006;48:1652-1657
Kaplan-Meier syncope-free survival curve of
time to first syncopal recurrence
31.6%31.6%
50.9%50.9%
FU = 14 mthsFU = 14 mths
13. Comparison between Kaplan–Meier curves of freedom from syncope recurrence in patients
who performed PCM training and control untreated group of patients.
Tomaino M et al. Europace 2014;16:1515-1520
PCM
No Therapy
ISSUE-3 trial subanalysis
15. HUTT / Tilt Training
• 5 in-hospital head-up tilt sessions for a planned
duration of 10-50 minutes at 60° (once a day for
5 days)
• daily tilt training at home by standing against a
wall for a planned duration of up to 40 minutes
(twice a day)
16. Tilt TrainingTilt Training
In the literature there are discordant results
regarding the real efficacy of this measure
17. Vyas A, et al. Int J Cardiol 2012; 167: 1906-1911
• However, the effect is lost if only randomized studies are included.
• Moreover, tilt training is hampered by the low compliance of the patients to
continue the treatment for a long period of time.
A recent metanalysis of all studies performed with tilt training has shown that
this therapy is effective in preventing recurrences of VVS with 70% decrease
18. HUTT /HUTT / Tilt TrainingTilt Training
• Tilt training, at best, and if really effective,
may be recommended only in a very selected
group of highly motivated patients.
20. VVS Open Studies – Drug EfficacyVVS Open Studies – Drug Efficacy
• alpha-agonists 73% 86% 12
• betablockers 74% 81% 15
• fludrocortisone 47% 68% 13
• serotonin inhibitors 55% 92% 13
• disopyramide 87% 91% 24
• scopolamine 44% 93% 14
• teophylline 33% 50% 11
Drug Acute Chronic FU
21. In all these studies, with only few exceptions, no difference was found in the recurrence rate of syncope
during follow-up between pts treated with drugs and those treated with placebo
Placebo – Controlled Trials
Ammirati F et al. In: Alboni P, Furlan R (eds), Vasovagal Syncope, Springer 2015; 237-245
22. Liao Y, et al. Acta Paediatrica 2009; 98: 1194-1200
Midodrine
This drug has given positive results in 4 studies, with a consistent risk reduction of syncopal
recurrences of more than 60%,
23. • These studies are not placebo-controlled
• Studied children or extraordinarily symptomatic pts
• Used tilt test outcomes as the main measure
• Regarded a limited number of patients
• Had a short period of follow-up
Midodrine & VVS / Positive results
25. Metanalysis of prespecified, prestratified substudy of POST I and a large earlier
observational study showed evidence of benefit of metoprolol in pts older than 42 years
Sheldon RS et al. Circ Arrhythm Electrophysiol. 2012;5:920-926
(Metoprolol) (Metoprolol)
Metoprolol
26. • However, these data need to be confirmed by an
ongoing prospective, multicenter, randomized trial
(POST 5) with results expected in 2017, before they
can be largely applied in daily clinical practice.
Metoprolol & VVS / Positive results
27. Sheldon R. et al.J Am Coll Cardiol. 2016; 68: 1-9
49%
Fludrocortisone
Fludrocortisone, at a dose of 0.2 mg daily, significantly reduced by 49% the syncopal
recurrence rate after the initial 2 weeks of dose stabilization.
28. However, the study did not meet its primary objective of demonstrating that fludrocortisone reduces the likelihood of
vasovagal syncope by the specified risk reduction of 40%. Indeed the reduction was more modest, only 31%
31%
29. Drug Therapy for Vasovagal SyncopeDrug Therapy for Vasovagal Syncope
“To date there are not sufficient data to
support the use of any pharmacological
therapy for vasovagal syncope”
ESC Guidelines on Management of Syncope
Brignole et al. Eur Heart J 2001; 22: 1256-1306
31. VVS / Rationale for pacingVVS / Rationale for pacing
To counteract
the cardioinhibitory component
of the pathological reflex
32. Pacing for VVS / StudiesPacing for VVS / Studies
• Randomized open-label controlled
• Randomized double-blind placebo-controlled
33. VPS VASIS SYDIT
Pts no. 54 42 93
Mean age 43 60 58
Median no. of syncopes 14-35 5.5 7-8
Tilt test + + +
Control arm no pm no pm atenol
Recurrence (Pm arm) 22% 5% 4%
Recurrence (control arm) 70% 61% 25%
p value 0.000 0.000 0.004
Pacemaker RDR DDI
45-80
RDR
Randomized open-label controlled studies
VPS. J Am Coll Cardiol 1999; 33: 16-20
VASIS. Circulation 2000; 102: 294-299 SYDIT. Circulation 2001;104:52-57
RiskRisk ↓↓
83%83%
92%92%
Mean FU: few mo – 3.7 yrs
34. VPS II SYNPACE
Pts no. 100 29
Mean age 49 53
Median no. of syncopes 16 14-10
Tilt test + / - +
Control arm pm off pm off
Recurrence (Pm arm) 33% 50%
Recurrence (control arm) 42% 38%
p value ns ns
Pacemaker RDR RDR
Randomized double-blind placebo-controlled trials
RiskRisk ↓↓
-21%-21%
+32%+32%
VPS II. JAMA 2003; 289: 2224-2229 SYNPACE. Eur Heart J 2004; 25: 1741-8
35. a substantial placebo effect
of pacemaker implantation
Randomized double-blind placebo-controlled trials
36. VVS / Limitation of pacingVVS / Limitation of pacing
The vasodepressor component
is not affected by pacing and may be
responsible for the LoC at the time
the pathological reflex develops
37. It has been suggested that selecting patients
with vasovagal syncope for PM implantation
on the basis of the results of implantable loop
recorder may give better results
Pacing for VVSPacing for VVS
39. Brignole M et al. Eur Heart J 2006; 27: 1085-92
90%
59%
1 year
Patients with documentation of
asystole by ILR at the time of
spontaneous syncope
PM
40. Time to first recurrence of syncope according to the intention-to-
treat analysis (ISSUE III)
Brignole M et al. Circulation. 2012;125:2566-2571
75%
43%
PM
2 years
41. Patients who seem to benefit mostly from pacemaker implantation are those with tilt test negative.
Brignole M et al. Circ Arrhythm Electrophysiol. 2014;7:10-16
This is because a positive tilt test might identify patients who are likely to also have a
vasodepressor response during VVS, and therefore not respond as well to permanent pacing
43. VVS / Pacing indication
Class IIa recommendation
Cardiac pacing is recommended in patients 40 years of
age or older, with frequently recurrent and unpredictable
syncope, and with documented spontaneous pauses during
electrocardiographic monitoring (≥3 sec if symptomatic
and ≥6 sec if asymptomatic).
Moya A et al. Eur Heart J 2009; 30: 2631-2671
44. VVS / Pacing indication
However, owing to the risk of complications following
pacemaker implantation and the fact that electrical
therapy may be ineffective in a significant percentage of
patients considered to be appropriate candidate (25% at 2
years in ISSUE III trial), pacing should be considered
only in highly selected patients, especially those with
repeated injury and limited or absent prodromes.
Sheldon RS et al. Heart Rhythm 2015; 12(6): e41-e63
48. It consists in performing a transcatheter endocardial ablation of the parasympathetic post-ganglionic
neurons located inside the atrial wall that allows selective vagal denervation and elimination or
attenuation of the cardioinhibitory reflex of the vasovagal syncope
Pachon JCM et al. Europace 2011;13:1231-1242
49. Pachon JCM et al. Europace 2011;13:1231-1242
Cardioneuroablation was performed in 43 patients with recurrent VVS and
important cardioinhibition at tilt testing
93% of syncopal recurrence during a mean follow-up of 41 months
50. Considerations
• It is clear that these results, although interesting, need to
be confirmed by future randomized, multicenter trials
before considering cardioneuroablation a consolidated
therapy for vasovagal syncope
Editor's Notes
Mister Chairmen, Ladies and Gentlemen, the topic of my presentation today is “Vasovagal syncope: current management and role of cardiac pacing”.
First of all, let me start by emphasizing (stressing) that a specific treatment of VVS is only rarely necessary in clinical practice.
Indeed, in the majority of subjects, vasovagal syncope is a benign condition that does not represent a threat to life and that does not significantly impair quality of life
and syncope may be easily prevented by patient reassurance about the benign nature of his or her condition and other educational measures, in particular recognition of premonitory symptoms, and avoidance of precipitating conditions
such as prolonged sitting – standing, crowded – hot places, strenous exercise in warm enviroment, dehydration – volume depletion, potentially hypotensive drugs, venipuncture and emotional – stressful situations.
So, a specific treatment is only indicated in patients with frequent syncopal episodes, absence of predictable circumstances or warning symptoms that allow the patient to assume supine position or other evasive action, important physical injury and potential occupational hazard.
The main therapeutical mesaures, that are currently available for the treatment of vasovagal syncope, include non pharmacological, pharmacological, and electrical options.
Among the non pharmacological options, besides patient reassurance and counseling, we have to mention, high salt diet, increased water intake, support stocking, counter-pressure maneuvers, and tilt training,
Counterpressure maneuvers are simple measures, such as handgrip, arm muscle tensing, leg crossing and muscle tensing, squatting, bending forward, and crash position, that patients may activate at the time prodromal symptoms develop
All these maneuvers act in interrupting the vasovagal reaction by increasing venous return, cardiac output and blood pressure.
The effectiveness of these maneuvers have been confirmed in a multicentre prospective trial, the PC Trial in 2006
During a mean follow-up of 14 months patients trained in counterpressure maneuvers had a significantly lower syncopal recurrence rate compared to patients conventionally treated: 31.6% vs 50.9%.
However, in a recent subanalysis of ISSUE-3 trial, no statistical difference in terms of freedom from syncope recurrence was found between patients who performed PCM training and control untreated patients.
Tilt training was initially proposed by Ector and coworkers in 1998
and consists of 5 in-hospital head-up tilt sessions for a planned duration of 10-50 minutes at 60° (once a day for 5 days), followed by daily tilt training at home by standing against a wall for a planned duration of up to 40 minutes (twice a day)
In the literature there are discordant results regarding the real efficacy of this measure.
A recent metanalysis of all studies performed with tilt training has shown that this therapy is effective in preventing recurrences of VVS. However, the effect is lost if only randomized studies are included. Moreover, tilt training is hampered by the low compliance of the patients to continue the treatment for a long period of time.
So, tilt training, at best, and if really effective, may be recommended only in a very selected group of highly motivated patients.
Coming to pharmacological options, several drugs with different effects have been proposed for the prevention of vasovagal syncope. They include alpha-agonists, betablockers,fludrocortisone, serotonin inhibitors, disopyramide, scopolamine, teophylline/clonidine, and ACE-I.
In open studies, almost all these drugs have shown to be quite helpful, as you can see in this slide, with an acute efficacy during tilt testing ranging from 33% to 87%, and with a chronic efficacy during the follow-up ranging from 50% to 93%
These apparently good results of open studies are in sharp contrast with those of the long-term placebo-controlled trials that have been performed till now in patients with vasovagal syncope. Indeed, in all these studies, with only few exceptions, no difference was found in the recurrence rate of syncope during follow-up between patients treated with drugs and those treated with placebo, raising serious doubts about the real value of current drug therapy for treatment of vasovagal syncope.
One of the few drugs that has shown some efficacy is midodrine. This drug, has given positive results in 4 studies, with a consistent risk reduction of syncopal recurrences of more than 60%,
However, these studies are not placebo-controlled, studied children or extraordinarily symptomatic pts, used tilt test outcomes as the main measure, regarded a limited number of patients, and had a short period of follow-up.
Moreover, the effectiveness of midodrine was not confirmed in STAND-trial, a randomized cross-over trial of Midodrine against placebo in patients with VVS not responding to non-pharmacological treatment.
Another drug that can be used but only in patients older than 42 years is metoprolol. Indeed, a metanalysis of prespecified, prestratified substudy of POST I and a large earlier observational study, has shown benefit of metoprolol in these patients, differently from younger patients who did worse with beta-blockers..
However, these data need to be confirmed by an ongoing prospective, multicenter, randomized trial (POST 5) with results expected in 2017, before they can be largely applied in daily clinical practice.
Finally, also fludrocortisone seems to be useful at least in young patients. Indeed, in the POST2 trial recently published in JACC, fludrocortisone, at a dose of 0.2 mg daily, significantly reduced by 49% the syncopal recurrence rate after the initial 2 weeks of stabilization.
However, the study did not meet its primary objective of demonstrating that fludrocortisone reduce the likelihood of vasovagal syncope by the specified risk reduction of 40%. Indeed the reduction was more modest, only 31%.
Thus, according to the initial 2001 ESC guidelines on management of syncope, we can still state that to date there are not sufficient data to support the use of any pharmacological therapy for vasovagal syncope
Finally, electrical options . To this regard, we have 2 possibilities, pacemaker and ablation. Let me start with pacemaker implantation.
The rationale for using a pacemaker for vasovagal syncope is to counteract the cardioinhibitory component of the pathological reflex
The main studies performed on the value of pacing for vasovagal syncope include prospective randomized open-label studies and randomized double—blind placebo-controlled trials.
In the three randomized open-label controlled studies, VPS VASIS and SYDIT, a highly significant reduction of syncopal recurrence was observed in patients treated with dual-chamber pacemaker, from 83% to 92%, during a mean follow-up ranging from few months to 3.7 years
By contrast, in the two randomized double-blind placebo-controlled trials, the VPS II and the SYNPACE, no significant benefit of active pacing over inactive pacing was found in the prevention of syncopal recurrence,
thus indicating a substancial placebo effect of pacemaker implantation.
This is not surprising because the vasodepressor component, that is always present and often precedes the carioinhibitory component, is not affected by pacing and, thus, may be responsible for the loss of consciousness, despite the correction of bradycardia, at the time the pathological reflex develops.
However, it has been suggested that selecting patients with vasovagal syncope for pacemaker implantation on the basis of the results of implantable loop recorder, may give better results
This seems to be confirmed by the results of the ISSUE trials. In the ISSUE 2 trial
patients with documentation of asystole by ILR at the time of spontaneous syncope that were assigned to pacemaker therapy showed a significantly higher freedom from syncopal recurrence compared to patients that were not treated with pacemaker, 90% vs 59% at 1 year.
Similarly, in the ISSUE III trial, the freedom from syncopal recurrence was significantly higher in patients randomized to pacemaker on than in those randomized to pacemaker off, 75% vs 43% at 2 years.
Patients who seem to benefit mostly from pacemaker implantation are those with tilt test negative. This is because a positive tilt test might identify patients who are likely to also have a vasodepressor response during VVS, and therefore not respond as well to permanent pacing.
According to these data, the 2009 Guidelines on syncope management of the ESC
give a Class IIa recommendation for cardiac pacing in patients 40 years of age or older, with frequent and unpredictable syncope, and with documented spontaneous pauses during electrocardiographic monitoring (≥3 sec if symptomatic and ≥6 sec if asymptomatic).
However, owing to the risk of complications following pacemaker implantation and the possibility that pacing is ineffective in a significant percentage of patients considered to be appropriate candidate (25% in ISSUE III trial) pacing should be considered only in highly selected patients, especially in those with repeated injury and limited or absent prodromes.
Finally, cardioneuroablation for vaso-vagal syncope.
This therapy was first proposed da Pachon in 2005
and subsequently utilized also by other brazilian groups, in particular Sao Paulo group.
It consists in performing a transcatheter endocardial ablation of the parasympathetic post-ganglionic neurons located inside the atrial wall that allows selective vagal denervation and elimination or attenuation of the cardioinhibitory reflex of the vasovagal syncope
In the last publication of Pachon in Europace in 2011, cardioneuroablation was performed in 43 patients with recurrent VVS and important cardioinhibition at tilt testing and was associated with a 93% reduction of syncopal recurrence during a mean follow-up of 41 months.
It is clear that these results, although interesting, need to be confirmed by future randomized, multicenter trials before considering cardioneuroablation a consolidated therapy for vasovagal syncope .
Thank you very much for your attention.
Finally, class III indications, that is contraindications to therapy are represented by the use of beta-blocking abents and cardiac pacing in the absence of a documwnted cardioinhibitory reflex.