Sincopi ricorrenti: diagnosi differenziale e management. Alessandro Proclemer SOC Cardiologia Az. Osp.-Univ. Udine

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1 Sincopi ricorrenti: diagnosi differenziale e management Alessandro Proclemer SOC Cardiologia Az. Osp.-Univ. Udine

2 DISCLOSURE INFORMATION Dr. Alessandro Proclemer negli ultimi due anni ho avuto i seguenti rapporti anche di finanziamento con soggetti portatori di interessi commerciali in campo sanitario: Sperimentatore senza profitto in studi multicentrici supportati da Boston, Medtronic, St. Jude e LivaNova

3 Causes of True Syncope Neurally- Mediated Orthostatic Cardiac Arrhythmia Structural Cardio- Pulmonary 1 VVS CSS Situational Cough Post- Micturition 2 Drug-Induced ANS Failure Primary Secondary 3 Brady SN Dysfunction AV Block Tachy VT SVT Long QT Syndrome 4 Acute Myocardial Ischemia Aortic Stenosis HCM Pulmonary Hypertension Aortic Dissection Unexplained Causes = Approximately 1/3

4 Recurrent syncope: differential diagnosis and management Bennett et al Heart 2015;101:1591 9

5 Syncope: Outcomes-Conditions Related with Hospitalization Joy PS, Am J Med 2017 (in press) California Statewide Inpatient Database ICD9-CM code (syncope or collapse) 1.52% of syncope related admissions per year In 42.1% the cause of syncope remained unknown 23% of admissions for reccurrent episodes Hospital mortality where lower for primary vs secondary syncope (0.2% vs 1.4%; p<0.0001)

6 Syncope: Outcomes-Conditions Related with Hospitalization Joy PS, Am J Med 2017 (in press)

7 Syncope: Outcomes-Conditions Related with Hospitalization Joy PS, Am J Med 2017 (in press) Multivariable logistic model for mortality of patients with primary diagnosis of syncope

8 Twenty per cent of unexplained fallers demonstrate an arrhythmia which is attributable as the cause of their fall. Patients who have cardiac arrhythmia are significantly more likely to experience future falls Bhangu J, et al. Heart 2016;102:

9 Heart Rhythm 2017;14:234 9 et al.

10 Heart Rhythm 2017;14:234 9 ILR in all patients; mean FU 16 m et al. Mechanism of syncope of No prodromes group: low adenosine plasma level with up-regulation of A1 receptors

11 Female, 67 yrs, no HD, 3 syncope in 2 years

12 After ILR and before therapy Heart Rhythm 2017;14:234 9 et al. No prodrome group Rx: PM in 10 pts, theophylline in 8 pts

13 The Role of Pacing as Therapy for Reflex Syncope 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 1 VASIS 2 SYDIT 3 Subsequent study results less clear VPS II 4 Synpace 5 INVASY 6 1 Connolly SJ. J Am Coll Cardiol. 1999;33: Sutton R. Circulation. 2000;102: Ammirati F. Circ. 2001;104: Connolly S. JAMA. 2003;289: Giada F. PACE. 2003;26:1016 (abstract). 6 Occhetta E, et al. Europace. 2004;6:

14 The role of Pacing as Therapy for Reflex Syncope: Comments Three earlier studies single blind Bias? Pacemaker implantation may modulate reflex syncope and autonomic responses 1 Study results may differ based on pre-implant selection criteria and tilt-testing techniques Pacing therapy is effective in some but not all (cardioinhibition vs. vasodepression) In five pacing studies, syncope recurred in 33/156 (21%) of paced patients, 72/162 (44%) in non-paced patients (p<0.000) 2 1 Kapoor W. JAMA. 2003;289: Brignole M, et al.. Europace. 2004;6:

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17 SEEDS: Syncope Evaluation in the Emergency Department Study Long-Term Clinical Outcomes Survival Free from Death Survival Free from Recurrence 100% 100% 90% 90% 80% Syncope Unit Group Standard Care Group 80% Syncope Unit Group Standard Care Group 70% 0 P=0.30 Results: 1 Years 2 70% 0 P= Years Syncope unit improved diagnostic yield in the ED and reduced hospital admission and length of stay S 2 Shen W, et al. Circ. 2004;110(24):

18 40,0% AIAC Italian PM and ICD Registry ICD Indication by Symtomps in Secondary Prevention N First implants in ,0% 30,0% 25,0% 20,0% 15,0% 10,0% 5,0% 0,0% Syncope Dizzy spells Cardiac arrest Palpitation Other

19 Israel Med Ass J VOL 18 june 2016

20 Israel Med Ass J VOL 18 june 2016

21 et al

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23 Arrhythmic syncope incidence in 705 pts (history of syncope before ICD in 33%) Heart Rhythm 2016;13:

24 RECURRENT SYNCOPE Differential diagnosis and Management Final comments In recent Real Word database, 42 % of admission causes for syncope remain unknown and mortality-morbidity rates are lower for primary syncope. In patients with normal heart and normal ECG the mechanisms of syncope are related to the presence or absence of prodromes. In both reflex syncope and low adenosine pattern the pacemaker therapy appears effective. In patients with primary prevention indication to ICD, history of syncope indicates an increased risk VA/ICD Rx. In patients with secondary prevention indication to ICD, new ICD programming are not related to high risk of syncope.

25 % Syncope-Free VASIS (VAsovagal Syncope International Study) 100 Pacemaker (PM) p= No Pacemaker Years Results: 1 (5%) with PM had recurrence vs. 14 (61%) without PM Sutton R. Circulation. 2000;102:

26 % Syncope-Free SYDIT (SYncope DIagnosis and Treatment) 1.0 Pacemaker (PM) p= Drug Time (Days) Results: 2 (4%) with PM had syncope recurrence vs. 12 (26%) without PM Ammirati F. Circulation. 2001;104:52-57.

27 Cumulative Risk VPS II (Vasovagal Pacemaker Study II) Only Sensing Without Pacing (ODO) Dual Chamber Pacing (DDD) Results: Months Since Randomization 33% with pacing had recurrence vs. 42% with only sensing (not statistically significant) Connolly S. JAMA. 2003;289:

28 ISSUE Patients with Isolated Syncope and Tilt-Positive Syncope 111 Patients with Syncope No SHD, Normal ECG Tilt Test Followed by Insertable Loop Recorder 82: Tilt-Negative Isolated Syncope 29: Tilt-Positive Follow-Up to Recurrent Spontaneous Episode Moya A. Circulation. 2001;104:

29 % Syncope-Free INVASY (INotropy Controlled Pacing in VAsovagal SYncope) 100 Closed Loop Stimulation (CLS) 0 60 P < Control (DDI only) 3m 6m 9m 1y 2y 3y Time Since Randomization Results: Patients with CLS had no syncope recurrence and improved quality of life Occhetta E, et al. Europace. 2004;6:

30 ISSUE Patients with Bundle Branch Block and Negative EP Test 52 Pts with BBB and Insertable Loop Recorder Syncope: 22 Pts (42%)* Stable AVB: 3 Pts (6%) ILR-Detected Pre-Syncope: 2 Pts (4%)** Death: 1 Pt (2%) ILR-Detected: 19 Not Detected: 3 AVB: 2 (4%) AVB: 12 (63%) SA: 4 (21%) Asystole-undefined: 1 (5%) NSR: 1 (5%) Sinus tachy: 1 (5%) Brignole M., ET AL.,Circulation. 2001;104: * 5 of these also had 1 presyncope ** Drop-out before primary-end point

31 Impact of Syncope: US Trends (000s) 900 Emergency Department Visits* (000s) 80 Hospital Outpatient Visits* '96 '97 '98 '99 '00 '01 ' '96 '97 '98 '99 '00 '01 '02 *Syncope and collapse (ICD-9 Code:780.2) listed as primary reason for visit. NHAMCS Not available

32 Diagnostic Flow Diagram for TLOC Initial Evaluation Syncope Not Syncope Certain Diagnosis Suspected Diagnosis Unexplained Syncope Cardiac Likely Neurally-Mediated or Orthostatic Likely Frequent or Severe Episodes Single/Rare Episodes Confirm with Specific Test or Specialist Consultation Cardiac Tests Tests for Neurally- Mediated Syncope Tests for Neurally- Mediated Syncope No Further Evaluation Re-Appraisal Re-Appraisal Treatment Treatment Treatment Treatment Brignole M, et al. Europace, 2004;6:

33 ISSUE Patients with Heart Disease and a Negative EP Test 35 Pts with Heart Disease and Insertable Loop Recorder Syncope: 6 Pts (17%) Pre-Syncope: 13 Pts (37%) ECG-Documented: 6 Pts (17%) ECG-Documented: 8 Pts (23%) AV block + asystole: 1 A.Fib + asystole: 1 Sinus arrest: 1 Sinus tachycardia: 1 Rapid A.Fib: 2 Sustained VT: 1 Parox. A.Fib/AT: 1 Post tachycardia pause: 1 No rhythm variations: 4 Sinus tachycardia: 1 Menozzi C, et al. Circulation. 2002;105:

34 ISSUE Patients with Heart Disease and a Negative EP Test Conclusions Patients with unexplained syncope, overt heart disease, and negative EP study had a favorable medium-term outcome Mechanism of syncope was heterogeneous Ventricular tachyarrhythmia was unlikely ILR-guided strategy seems reasonable, with specific therapy safely delayed until a definite diagnosis is made. Menozzi C, et al. Circulation. 2002;105:

35 ISSUE Patients with Bundle Branch Block and Negative EP Test Conclusion: In patients with BBB and negative EP study, most syncopal recurrences have a homogeneous mechanism that is characterized by prolonged asystolic pauses mainly attributable to sudden-onset paroxysmal AV block Brignole M. Circulation. 2001;104:

36 VPS I (North American Vasovagal Pacemaker Study) Objective: To evaluate pacemaker therapy for severe recurrent vasovagal syncope Randomized, prospective, single center 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.

37 Cumulative Risk (%) VPS I (North American Vasovagal Pacemaker Study) No Pacemaker (PM) 2P= Connolly SJ. J Am Coll Cardiol. 1999;33: Pacemaker Time in Months Results: 6 (22%) with PM had recurrence vs. 19 (70%) without PM 84% RRR (2p= )

38 VASIS (VAsovagal Syncope International Study) Objective: To evaluate pacemaker therapy for severe cardioinhibitory tilt-positive neurally mediated syncope Randomized, prospective, multi-center 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 syncope Sutton R. Circulation. 2000;102:

39 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-center N=93 patients 46: DDD pacemaker with rate drop response 47: Atenolol 100 mg/d Inclusion: Positive HUT with relative bradycardia Primary outcome: First recurrence of syncope Ammirati F. Circulation. 2001;104:52-57.

40 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-center N=100 patients 52: Only sensing without pacing 48: DDD pacemaker with rate drop response Inclusion: Positive HUT with (HRxBP) < 6000/min x mm Hg Primary outcome: First recurrence of syncope Connolly S. JAMA. 2003;289:

41 SYNPACE (Vasovagal SYNcope and PACing) Objective: To determine if pacing therapy will reduce syncope relapses in patients with recurrent vasovagal syncope, compared to those with a pacemaker programmed to OFF Randomized, double-blind, prospective, multi-center, 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: Raviele A, et al. Eur Heart J. 2004;25:

42 % Syncope-Free SYNPACE (Vasovagal SYNcope and PACing) p= Pacemaker OFF Pacemaker ON Results: Raviele A, et al. Eur Heart J. 2004;25: Days Since Randomization 50% with pacing ON had recurrence vs. 38% with pacing OFF (not statistically significant)

43 INVASY (INotropy Controlled Pacing in VAsovagal Syncope) Objective: To evaluate Closed Loop Stimulation (CLS), a form of rate-adaptive pacing using RV impedance, in preventing recurrence of VVS Randomized, prospective, single-blind, multi-center N=50 patients 41: CLS therapy 9: Control (pacemaker programmed in DDI) Inclusion: Recurrent VVS and +HUT with cardioinhibition Primary outcome: Recurrence of two VVSs during a minimum of 1 year of follow-up Occhetta E, et al. Europace. 2004;6:

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46 Impact of Syncope 40% will experience syncope at least once in a lifetime 1 1-6% of hospital admissions 2 1% of emergency room visits per year 3,4 10% of falls by elderly are due to syncope 5 Major morbidity reported in 6% 1 eg, fractures, motor vehicle accidents Minor injury in 29% 1 eg, lacerations, bruises 1 Kenny RA, Kapoor WN. In: Benditt D, et al. eds. The Evaluation and Treatment of Syncope. Futura;2003: Kapoor W. Medicine. 1990;69: Brignole M, et al. Europace. 2003;5: Blanc J-J, et al. Eur Heart J. 2002;23: Campbell A, et al. Age and Ageing. 1981;10:

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48 Syncope: Outcomes-Conditions Related with Hospitalization Joy PS, Am J Med 2017 (in press) Patient factors related to major adverse event versus proportional increase in number of syncope admissions

49 AIAC Italian ICD Registry ICD by Symptoms N First implants % 80% % 60% 50% 40% 30% 20% 10% 0% Primary prevention Syncope/Dizzy spells Cardiac arrest Palpitation Other