SINCOPE. La terapia della sincope (secondo il GIMSI) Michele Brignole Centro Aritmologico, Ospedali del Tigullio, Lavagna

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1 SINCOPE La terapia della sincope (secondo il GIMSI) Michele Brignole Centro Aritmologico, Ospedali del Tigullio, Lavagna

2 ESC Guidelines on Management of Syncope Version 2009 Treatment of syncope Diagnostic evaluation Reflex and Orthostatic Intolerance Cardiac Unexplained and high risk of SD Unpredictable or highfrequency Predictable or low-frequency Cardiac arrhythmias Structural (cardiac or cardiopulmonary) i.e., CAD, DCM, HOCM, ARVC, Channelopathies Consider specific therapy or delayed treatment (guided by ECG documentation) Education, reassurance avoidance of triggers usually sufficient Specific therapy of the culprit arrhythmia Treatment of underlying disease Consider ICD therapy according current ICD guidelines

3 Neurally-mediated syndromes: therapy Recommendations Initial treatment: education and reassurance No treatment Additional treatments Sufficient for most Single syncope and no high risk setting High risk or high frequency settings ESC Guidelines on Management of Syncope Update 2004

4 Life-style advice for Reflex Syncopes Reassurance Education regarding awareness and possible avoidance of triggers (e.g. hot crowded environments, volume depletion) Early recognition of prodromal symptoms Performing maneuvers to abort the episode (e.g. supine posture, physical counterpressure maneuvers). If possible, triggers were addressed directly, such as avoiding micturition in standing position ESC Guidelines on Management of Syncope Update 2004

5 Europace (2010) 12, Population 100 VVS pts, mean age 38 Results The median number of syncopal recurrences was lower in the first year of non-pharmacological treatment compared with the last year before treatment (median 0 vs 3; p=0.001) Nevertheless, 49% of patients experienced at least one recurrence. In multivariable analysis, a higher syncope burden prior to inclusion was significantly associated with syncopal recurrence.

6 Neurally-mediated syndromes: therapy Additional treatment (high risk or high frequency) syncope is very frequent, e.g. alters the quality of life syncope is recurrent and unpredictable (absence of premonitory symptoms) and exposes patients at high risk of trauma syncope occurs during the prosecution of a high risk activity (e.g., driving, machine operation, flying, competitive athletics, etc) ESC Guidelines on Management of Syncope Update 2004

7 Drug therapy for vasovagal syncope To date there are not sufficient data to support the use of any pharmacological therapy for vasovagal syncope

8 POST trial Sheldon R et al. Circulation 2006; 113;

9 Etilefrine Placebo

10 double-blind 3-month cross-over treatment starting either with Midodrine or placebo 23 patients mean age 31 (87% females) 6 syncopal episodes per years Europace (2011) 13,

11 Physical therapy for orthostatic intolerance syndromes Tilt training Physical counterpressure maneuvers Elastic bendage

12 Van Dijk et al. J Am Coll Cardiol 2006; 48: PC-TRIAL: Syncope-free survival p= The resulting Hazard ratio was 1.7 ( ). Log rank. p= Hazard ratio 1.7 ( ).

13 PC-TRIAL: Syncope burden Episodes per patient/year 0.6 (0-1.3) p= (0-0.7) Conventional PCM J Am Coll Cardiol 2006; 48:1652 7

14 Podoleanu et al. J Am Coll Cardiol 2006; 48:

15 HR BP Placebo Active HR BP Leg bandage Leg + abdomen 178 Leg bandage Leg + abdomen min 10 min BA, 79 f, 13/5/2005

16 Specific symptom score for Orthostatic Intolerance (SSS-OI) in patients and control Symptom (score during last month) Controls Patient baseline p Patient treatment P Dizziness and presyncope 1.6± ± ± Visual disturbances 1.2± ± ± Syncope 0.2± ± ± Hearing disturbance 0.9± ± ± Pain in the neck, low back pain 1.7± ± ± Weakness, fatigue, lethargy 2.4± ± ± Palpitations, hyperhydrosis 2.4± ± ± Total Score 10.4± ± ± Podoleanu et al. J Am Coll Cardiol 2006; 48:

17 % CSS: syncope recurrence rate Blanc 84 Brignole 92 No therapy Pacemaker Claesson 07 Claesson 07 Menozzi 93 Brignole 92 Crilley 97 Morley 82 Claesson 07 Walter 78 Sugrue 86 Brignole 92 Sugrue 86 Brignole 92 Lopes 11 Claesson 07 Blanc 84 Stryjer 86 Years Brignole M, Menozzi C. Europace (2011) 13,

18 CSS: metanalysis of controlled trials Study PM group n/n No PM group n/n Relative risk 95% CI Relative risk 95% CI Sugrue 1986 Brignole 1992 (a) Claesson /23 7/33 3/32 16/28 3/30 12/ ( ) 0.16 ( ) 0.33 ( ) Total 8/85 35/ ( ) Test for heterogeneity: p= PM better No PM better Europace (2011) 13,

19 ISSUE 3" SYNCOPE" ISSUE 3 International Study on Syncope of Uncertain Etiology 3 Pacemaker therapy for patients with neurally-mediated syncope and documented asystole A randomized controlled double-blind trial Circulation 2012;125:

20 SYNCOPE" ISSUE 3" Study design ILR screening phase Pts affected by severe, recurrent reflex syncopes, aged >40 yrs ILR implantation (Reveal DX/XT) ILR follow-up (max 2 yrs) ISSUE 3 study phase ILR eligibility criteria: Asystolic syncope 3 s, or Non-syncopal asystole 6 s R Pm ON Pm OFF

21 SYNCOPE" ISSUE 3" Screening phase: documented events Tachycardia Tachicardia 10% Normal Normal SR SR 23% 56% Asystole (11 ± 4 s) Bradycardia 10% Total end-points: 158

22 ISSUE 3" ISSUE 3 population SYNCOPE" 3.5 s 6.5 s >13 s LAV25, f

23 ISSUE 3" SYNCOPE" Freedom from syncopal recurrence Number at risk Pm OFF Pm ON First syncope recurrence (intention-to-treat) Kaplan-Meier survival estimates 25% 37% log rank: p=0.039 RRR at 2 yrs: 57% 25% 57% Months Pm ON Pm OFF

24 Recommenda9ons: Treatment of reflex syncope Class Level Explana9on and reassurance. Triggers or situaions must be avoided. Hypotensive drugs must be modified or disconinued Isometric PCM are indicated in paients with prodrome I B Cardiac pacing should be considered in paients with dominant cardioinhibitory CSS Cardiac pacing should be considered in paients with frequent recurrent reflex syncope, age > 40 years and documented spontaneous cardioinhibitory response during monitoring Midodrine may be indicated in paients with VVS refractory to lifestyle measures Tilt training may be useful for educaion of paients but long- term benefit depends on compliance Cardiac pacing may be indicated in paients with Ilt- induced cardioinhibitory response with recurrent frequent unpredictable syncope and age > 40 ayer alternaive therapy has failed Cardiac pacing is not indicated in the absence of a documented cardioinhibitory reflex Beta- adrenergic blocking drugs are not indicated III A I IIa IIa IIb IIb IIb III C B B B B C C

25 Syncope Unit Project (SUP) Management Reflex (neurally-mediated syncope) 602 pts Education, reassurance & avoidance of triggers alone Physical manœuvres (tilt training or counterpressure manœuvres) 253 (42%) 247 (41%) Tilt training 69 (11%) Pacemaker 61 (10%) Modification or discontinuation of hypotensive drugs 53 (9%) Vasoconstrictor drugs 9 (1%) Brignole et al. Europace 2010; 12:

26 Syncope Unit Project (SUP) Management Orthostatic hypotension 32 pts Modification or discontinuation of hypotensive drugs 21 (66%) Education & avoidance of triggers 20 (62%) Physical (counterpressure manœuvres, elastic stockings) 18 (56%) Volume expansion 15 (47%) Vasoconstrictor drugs 1 (3%)

27 ESC Guidelines on Management of Syncope Version 2009

28 Treatment of Cardiac Arrhythmias as Primary Cause Cardiac arrhythmia Documented -Standard ECG -ECG monitoring -Exercise test -ILR Suspected -Clinical features - EP study - Other tests ESC Guidelines on Management of Syncope Update 2004

29 Treatment of Cardiac Arrhythmias as Primary Cause 1. Syncope is due to documented cardiac arrhythmia (ECG-symptom correlation) 2. An asymptomatic arrhythmia/abnormality is documented which is likely to be responsible for syncope (no ECG-symptom correlation) 3. An arrhythmia is likely but still undocumented

30 Treatment of Cardiac Arrhythmias as Primary Cause 2 - An asymptomatic arrhythmia/abnormality is documented (no ECG-symptom correlation) Mechanism Alternating RBBB and LBBB (ECG) Pause >3 sec awake (Monitoring) Treatment Pacemaker (VVI/DDD) Pacemaker (VVI/DDD) 2 nd or 3 rd AV block awake (Monitoring) Pacemaker (VVI/DDD) Rapid paroxysmal tachicardia (Monitoring) Abnormal SNRT function (EPS) Abnormal His-Purkinje (EPS) Induction of SV tachicardia (EPS) Induction of V. tachicardia (EPS) Catheter ablation / ICD Pacemaker (DDDR) Pacemaker (VVI/DDD) Catheter ablation ICD

31 Recommenda9ons: Indica9ons for ICD in pa9ents with unexplained syncope and a high risk of SCD (1) Clinical situa+on Class Level In paients with ischaemic cardiomyopathy with severely depressed LVEF or HF ICD therapy is indicated according to current guidelines for ICD- cardiac resynchronizaion therapy implantaion In paients with non- ischaemic cardiomyopathy with severely depressed LVEF or HF ICD therapy is indicated according to current guidelines for ICD- cardiac resynchronizaion therapy implantaion I I A A

32 ESC Guidelines on Management of Syncope - Version 2009 Recommenda9ons: Indica9ons for ICD in pa9ents with unexplained syncope and a high risk of SCD (2) Clinical situa+on Class Level Comments IIa C In non high risk, consider ILR In hypertrophic cardiomyopathy ICD therapy should be considered in paients at high risk In right ventricular cardiomyopathy ICD therapy should be considered in paients at high risk In Brugada syndrome ICD therapy should be considered in paients with spontaneous type I ECG IIa C In non high risk, consider ILR IIa B In the absence of type I pa`ern, consider ILR In long QT syndrome ICD therapy,., should be considered in paients at high risk IIa B In non high risk, consider ILR

33 Syncope Unit Project (SUP) Management Cardiac arrhythmias 53 pts Cardiac pacing 29 (58%) Cardioverter-defibrillator (ICD) 8 (16%) Antiarrhythmic drug therapy 5 (10%) Modification or discontinuation of antiarrhythmic/hypotensive drugs 5 (10%) Catheter ablation 1 (1%) Brignole et al. Europace 2010; 12:

34 Syncope Unit Project (SUP) Management Case mix Reflex Orthostatic hypotension Cardiac Arrhythmia Structural Cardio- Pulmonary Non-syncopal 1 Vasovagal CSS Situational Atypical Likely reflex 2 Classical OH form Delayed OH form (progressive) 3 Brady Ø Sick sinus Ø AV block Ø PM dysf * Tachy Ø VT Ø SVT High risk of SCD 4 ACS Aortic Stenosis Atrial myxoma Pulmonary embolism Others 5 Metabolic Epilepsy Intoxications Drop-attacks Psychogenic TIA Falls 67% 4% 5% 1% 5% Unknown Cause = 18%

35 Evaluation of Guidelines in SYncope Study 2 (EGSYS-2) Recurrence of syncope in 398 patients 1,00 Survival free from syncope 0,95 0,90 0,85 0,80 0,75 arrhythmic unexplained structural heart disease neuroreflex orthostatic 0, Ungar A et al. Eur Heart J 2010 Days

36 Syncope Unit Project (SUP) Limits of current management (I) Diagnosis at initial evaluation n=191 Early diagnosis with tests n=541 No diagnosis n=159 p value Age, median Males (%) 54% 51% 62% 0.05 Number of syncopes, median History of syncope, years No prodromes (%) 9% 30% 43% Structural heart disease (%) 8% 16% 48% ECG abnormalities (%) 9% 21% 47% OESIL risk score, median EGSYS risk score, median Brignole et al. Europace 2010; 12:

37 Syncope Unit Project (SUP) Limits of current management (II) Initial diagnosis Assigned diagnosis Reflex OH Unknown Cardiac Non-sycopal 5 5 Brignole et al. Europace 2010; 12:

38 By e9ology (clinical forms) Reflex (neurally- mediated) Vasovagal SituaIonal CaroId sinus Atypical forms (Ilt- posiive) Orthosta9c hypotension Primary autonomic failure Secondary autonomic failure Drug- induced Volume depleion Cardiac cardiovascular Arrhythmia as primary cause Bradycardia Tachycardia Drug- induced Structural cardiac (e.g., aoric stenosis, atrial mixoma, etc) By mechanism (ECG/BP documenta9on) Bradycardia Asystole Sinus arrest Sinus bradycardia plus AV block AV block Bradycardia (sinus) Tachycardia Progressive sinus tachycardia Atrial fibrillaion Atrial tachycardia (except sinus) Ventricular tachycardia No or slight rhythm varia9ons- (Hypotension)

39 A new strategy for the management of the patient with unexplained syncope after the initial evaluation ECG-guided Diagnosis and therapy delayed Initial risk stratification required (safety issue) Laboratory driven Diagnosis and therapy immediate Risk of misdiagnosis

40 Eastbourne Syncope Assessment Study (EaSyAS) European Heart Journal 2006; 27, ILR (101 pts) P=0.04 Conv (97 pts) Time to second syncope recurrence

41 Long term outcome after specific therapy guided by ILR in patients with syncope Furukawa et al. (JCE 2011) 100 Cumulative incidence % Actuarial recurrence rate 1year 5 year Total 3% 8% Pace maker 4% 4% Total 0 Total patients Pacemaker PM Months

42 La terapia della sincope Take home messages : La terapia è tanto piu efficace quanto piu la diagnosi è precisa La terapia specifica guidata dal meccanismo è piu efficace della terapia guidata dalla eziologia Nonostante la terapia specifica, una minoranza di pazieni coninueranno ad avere recidiva sincopale nel follow- up a lungo termine. Tu`avia in genere la terapia specifica è in grado di ridurre il burden delle recidive SINCOPE