Syncope. Peter Netzler AnMed Health Arrhythmia Specialists February 22, 2014

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1 Syncope Peter Netzler AnMed Health Arrhythmia Specialists February 22, 2014

2 Syncope I have no disclosures 1. Incidence and prevalence 2. Broad differential 3. Risk Stratification 4. Work up and treatment for vasovagal syncope 5. Conclusions

3 Syncope Transient, abrupt, loss of consciousness, with rapid, usually complete, recovery, with or without a prodrome, caused by cerebral hypoperfusion Derives from the Greek word synkoptein, meaning to cut short A common, non-specific, alarming, debilitating, symptom with diverse causes and the key in making the diagnosis is in the History and Physical Dilemma: Avoid over-testing yet avoid underdiagnosing life-threatening causes 1 Engel GL. Psychologic stress, vasodepressor syncope, and sudden death. Ann Intern Med 1978; 89:

4 Cause of Syncope* - Recent Data Framingham Cohort 727 patients* Cause Prevalence % Men Women Vasovagal Orthostatic Cardiac Seizure Stroke/TIA Medication Other Unknown *Soteriades ES et al. N Engl J Med 2002;347: **Linzer M et al Ann Int Med 1997;126:989 Pooled Data Five Studies** Cause % Vasovagal 18 Situational 5 Orthostatic 8 Cardiac 18 Medication 3 Psychiatric 2 Neurologic 10 Carotid sinus 1 Unknown 34 *Full differential diagnosis beyond scope of talk

5 SYNCOPE Background Syncope is common in the general population 1 Syncope accounts for 3-5% of Emergency Department (ED) visits and 1-3% of all hospital admissions 2,3 Not created equal Cardiac syncope doubled the risk of death from any cause with a 6 mo mortality rate>10% 4 Soteriades ES. N Engl J Med 2002;347:

6 Syncope Impact on the Medical Community Incidence: 500,000/year >1,000,000 evaluated annually 10% of falls due to syncope 10.2 visits/year, 3.2 specialists Cause for disability * * 20-50% of adults experience syncope at least once in a lifetime *Krahn AD Am Heart Journal 1999;137:870 ** L inzer, J Clin Epidemiol, 1991;44: Linzer, J Gen Int Med, 1994;9:181-6

7 Syncope: Economic Burden Per recent data, the overall cost per hospital admission was estimated to be about $10,600. One study found $17,000 of unnecessary testing to diagnosis vasovagal syncope Overall cost in US estimated to be in excess of $1 billion. Costs of Test Troponin $156 EKG $274 Telemetry $2,325/d Head CT $1901 MRI brain $3947 Carotid US $1294 EST $1156 Echocardiogram $1835 EEG $978

8 Syncope: Pathophysiology Common final pathway is decreased cerebral perfusion Cessation of cerebral perfusion for as little as 3-5 seconds can result in syncope Decreased cerebral perfusion may occur as a result of decreased cardiac output or decreased systemic vascular resistance.

9 Syncope: Etiology Neurally- Mediated Orthostatic Cardiac Arrhythmia Structural Cardio- Pulmonary Non- Syncopal 1 Vasovagal Carotid Sinus Situational Cough Postmicturition Defaecation Swallow 2 Drug Induced Volume Depletion ANS Failure Primary Secondary 3 Brady Sick sinus AV block Tachy VT* SVT Inherited 4 Aortic Stenosis HOCM Pulmonary Hypertension 5 Psychogenic Metabolic Epilepsy Intoxications TIA Falls 66% 10% 11% 5% 6% Unknown Cause = 2% Brigole et al. Heart 2007;93:

10 Cause of Syncope By Age Younger patient Neurocardiogenic Situational Psychiatric Long QT* Brugada s syndrome* WPW syndrome* RV dysplasia* Hypertrophic cardiomyopathy* Older patient Cardiac** Mechanical Arrhythmic Orthostatic hypotension Drug-induced Neurally mediated Multifactorial Underlined: generally benign *infrequent but not benign **generally not benign

11 RISK STRATIFICATION Etiology can be benign or deadly that s the rub HISTORY alone identifies the cause up to 85% of the time POINTS to CONSIDER Previous episodes Character of the events, witnesses Events preceding the syncope Events during and after the episode

12 Short-Term High Risk Criteria Severe structural or CAD (CHF, low EF, prior MI) Clinical or EKG ->Arrhythmia During exertion or supine Palpitations NSVT Bifascicular block Bradycardia Pre-excited QRS complex RBBB with ST elevation in V1-V3 (Brugada pattern) Long or short QT Negative T waves in right precordial leads, epsilon waves or ventricular late potentials suggestive of ARVC Severe anemia Electrolyte disturbance

13 Risk Stratification Short-term Risk (1 week 1 month) Study San Francisco Quinn JV, et al. Ann Emerg Med 2004;43:224. Rose rule Reed MJ,et al. J Am Coll Cardiol. 2010;55:713 StePs Costantino G, et al.j Am Coll Cardiol 2008; 51: Clinical Markers Abnormal ECG, Low Blood Pressure, CHF, SOB, Hematocrit <30% Abnormal ECG, Elevated BNP, Chest pain Fecal blood Abnormal ECG, Trauma, No warning, Male gender

14 From: The ROSE (Risk Stratification of Syncope in the Emergency Department) Study J Am Coll Cardiol. 2010;55(8): doi: /j.jacc Figure Legend: The ROSE Rule With BRACES Mnemonic Aide Memoire A patient should be considered high-risk and admitted if any of the 7 criteria in the ROSE (Risk stratification Of Syncope in the Emergency department) rule are present. BNP = B-type natriuretic peptide; ECG = electrocardiogram. Date of download: 2/22/2014 Copyright The American College of Cardiology. All rights reserved.

15 Diagnostic Algorithm Syncope History and Physical ECG Known SHD No SHD - Echo EPS + > 30 days; > 2 Events Tilt ILR < 30 days Tilt Holter/ ELR ILR Tilt/ILR Treat

16 Neurological Tests Carotid Dopplers, EEG, Head CT / MRI Little value in syncope evaluation Imaging only if there is concern re head injury from fall or seizure EEG only if seizure concern, but interictal EEG may be non-diagnostic Neurological consultation is advised prior to tests

17 Lower Risk Patient Overall normal EKG??? Normal ECHO or no/little concern for structural heart disease No high risk features

18 NEURALLY MEDIATED SYNCOPE Vasovagal, carotid sinus, situational Represents 66% of patients with syncope No increased risk for cardiovascular morbidity or mortality associated with reflex mediated syncope.

19 Features suggestive of Neurally- Mediated causes? Prolonged standing in a crowded, warm place Preceding nausea, feeling cold and sweaty After exertion or post-prandial Tonic-clonic movements are short in duration and occur after the loss of consciousness Long duration of symptoms >4years

20 Indications: Tilt-Table Test If a neurocardiogenic cause is suspected Recurrent syncope, no apparent cause, any age Other evaluation unrevealing Treating other potential causes ineffective Do not tilt if etiology is clear or if tilt has dangers 1. Delepine S. Am J Cardiol 2002; 5: Raviele, A. Am J Cardiol 2000;85: Calkins H. J Cardiovasc Electrophysiol 2001;12: Saadjian, A. Y Circulation 2002;106:569-74

21 Head-Up Tilt Test (HUT) Protocols vary some use provocative drugs Isuprel or nitrogylcerin Goals: Unmask VVS susceptibility Reproduce symptoms Patient learns VVS warning symptoms Patient more confident of diagnosis Not recommended for predicting treatment benefit

22 VVS: Typical HUT Protocols Basic Preparation 4 hour fast Continuous ECG monitor Continuous BP monitor Finometer or equivalent preferred Arterial line if placed >1 hour before Sphygmomanometer BP discouraged Minimally Disruptive Beat-to beat BP disruptive to Autonomic Nervous system Moya A et al, ESC Syncope Guidelines, Eur Heart J 2009; 30:

23 Typical HUT Protocol Supine rest period 5-20 min Tilt to for 20 min Positive end-point: Syncope with reproduction of symptoms If negative, then add drug provocation while still upright Nitroglycerine 0.4mg SL, or Isoproterenol 1-5 mcg/min, to increase HR to 125% baseline Extend tilt after drug, duration minutes Test completion without syncope is a negative result Moya A et al, ESC Syncope Guidelines, Eur Heart J 2009; 30:

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25 Tilt-Table Findings Neurocardiogenic Sudden hypotension with or without bradycardia Dysautonomic Gradual parallel decline in systolic and diastolic blood pressure POTS An excessive heart rate response to maintain a low normal BP Cerebral syncope Syncope associated with cerebral vasoconstriction in the absence of systemic hypotension Psychogenic No change in heat rate, BP, EEG, transcranial blood flow

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27 Neurocardiogenic Responses Vasovagal International Study Group Vasovagal International Study Group Type 1-Mixed: BP falls then HR (<3 sec pause) Type 2A - Cardioinhibitory: BP falls then HR Type 2B - Cardioinhibitory: HR falls >10 sec or >3 sec pause before BP falls Type 3 - Pure vasodepressor: BP falls What does it all mean? Is it reproducible? How do we treat it?

28 ILR Small subcutaneous implantable monitoring device 2009 ESC Guidelines recommend for: Early phase evaluation Recurrent syncope with absence of high risk features Suspected or proven reflex syncope before pacing Late evaluation High risk syncope without eitology after exhaustive w/u

29 Insertable Cardiac Monitors (ICM) Reveal System, Medtronic Inc. Minneapolis, MN -manual/auto trigger -remote download (CareLink ) Confirm, St Jude Medical St Paul, MN -manual/auto trigger -remote download (Merlin )

30 Clinical Trials RAST (Randomized Assessment of Syncope Trial) 1 EasyAs 1 (Eastbourne Syncope Assessment Study) 2 ISSUE 1 (International Study on Syncope of 3,4,5 Unexplained Etiology) ISSUE 2 and ISSUE 3 6,7 PICTURE 8 1 Krahn AD, et al. Circ. 2001;104: Krahn AD, et al. JACC 2003;42: Farwell D et al. Eur Heart J 2006; 27: Moya A. Circulation 2001; 104: Menozzi C. Circulation 2002; 105: Brignole M. Circulation 2001; 104: Brignole M et al, Eur Heart J 2006; 27: Brignole M, Circulation 2012;125: Edvardsson N et al, Europace 2011;13:262 9 Hong PS et al, PACE 2010; 33;763-5

31 Randomized Assessment of Syncope Trial (RAST) 60 Patients Unexplained Syncope EF > 35% 30 Patients 30 Patients Primary Strategy ILR Diagnosis Conventional Testing (AECG, Tilt, EPS) Crossover AECG, Tilt, EP Study + + ILR Results: Combining primary strategy with crossover, the diagnostic yield is 43% ILR only vs. 20% conventional only 1 Cost/diagnosis is 26% less than conventional testing 2 1 Krahn AD, et al. Circ. 2001;104: Krahn AD, et al. JACC 2003;42:

32 Neurocardiogenic Syncope First line: Treatment Options Tilt +, High suspicion (pretest probability despite tilt -) Patient education about pathophysiology of VVS and benign prognosis Increase salt and water intake If prodrome, sit or lie down Tilt-training or counterpressure manuevers Leg compression Tilt training: > 90% effective Di Girolamo E Circulation 1999;100: Reybrouck T PACE 2000;23: Ector H et al PACE 1998; 21:193-6.

33 Tilt-Training: Clinical Outcomes Neurocardiogenic Syncope Of 42 tilt positive patients (21±13 min), home training: two 30 minute sessions daily Outcome: 41/42 ->45 min asymptomatic tilt Follow-up: 15.1±7.8 mos 36 syncope free; 4 presyncope ; 1 recurrence Reybrouck et al. PACE 2000; 23:493-8

34 Neurocardiogenic Syncope Drug Therapies: Second Line Beta-blockers SSRIs Midodrine Fludrocortisone Anticholinergics (disopyramide, scopolamine) Desmopressin Erythropoietin Theophylline

35 Beta Blockers Initial observations suggest syncope reduction Rationale is that B-receptor involvement in ventricular baroreceptor reflexes Isuprel (B agonist) can trigger hypotension and bradycardia and BB can prevent the Isuprel effect At least 4 randomized trials have failed to show benefit but difficult to demonstrate statistical benefit when placebo effect is so high Best data from the POST trial

36 208 patients with recurrent syncope and an abnormal tilt table test Placebo vs metoprolol (avg dose 122mg daily) with 1 year follow up Recurrent syncope occurred in 36 percent of both groups. Withdrawal rates were 22 percent in both groups. Prespecified analyses according to age (categorized as <42 versus 42 years) and tilt table test results did not identify any subgroups that benefited with metoprolol.

37 Sheldon R et al. Circulation 2006;113:

38 FLUDROCORTISONE Corticosteroid with primarily mineralcorticoid activity Sodium and water retention and potassium excretion POST II (multinational, randomized, controlled) 211 pts (fludrocortisone vs placebo) for 1yr Trend of less events in the fludrocortisone group but NO statistical difference

39 MIDODRINE Pro-drug- active metabolite is a peripheral alpha- 1 adrenergic receptor Causes venoconstriction and arteriolar constriction Increases cardiac output and incresases peripheral resistance More effective than Na/volume therapy alone Challenge is frequent dosing compliance POST 4 (placebo vs midodrine) results due in 2017

40 SSRIs High serotonin levels in the nervous system Serotonin modulates the CNS BP and HR Di Gerolamo et al conducted a randomized, double-blind, placebo-controlled trial Paroxetine (20mg QD) vs placebo over ~25 mo Reduction in syncope recurrence 18% with Paxil vs 53% with placebo Other studies have found other SSRIs of no benefit Can be helpful in psychosocial stressors due to syncope

41 Pacemakers Any role? Often a significant bradycardic response in VVS But severe vasodepressor reactions often coexist

42 Does Asystole Cause Syncope? Tilt Passed out Asystole

43 VPS-I Vasovagal Pacemaker Study I Study Design: 54 patients randomized, prospective, single center 27 DDD pacemaker with rate drop response (RDR) 27 no pacemaker Patient Inclusion Criteria: 6 syncopal events ever +HUT Relative bradycardia* Connolly S, et al. J Am Coll Cardiol 1999; 33:

44 Cumulative Risk (%) Risk of Syncope Recurrence The VPS I Study No Pacemaker 2P= Pacemaker Inclusion: vasodepressor response Time in Months Control Group n = Pacemaker Group n = Connolly SJ. J Am Coll Cardiol 33:16-20, 1999

45 VPS II Trial Big Placebo Effect Time to First Recurrence of Syncope Syncope > 5 total or > 2 episodes in 2 years, positive tilt, age > 19 RR reduction 29% Connolly S. JAMA 2003:289:

46 ILR FIRST THEN PM??? ISSUE 3 Population Diagnosis: Reflex (neurally-mediated) VVS Mean age at presentation: >60 years Recurrent syncope beginning in middle or older age Clinical presentation sufficiently severe to require treatment (high risk and/or high frequency) Atypical presentation without warning Injuries related to presentation without warning ILR documentation of marked bradycardia (mean pause duration, 11 seconds) Brignole M, Circulation 2012;125:

47 ISSUE-3 Study design ILR screening phase ILR eligibility criteria: Asystolic syncope 3 s, or Non-syncopal asystole 6 s -mediated syncope ILR implantation (Reveal DX/XT) ILR follow-up (max 2 yrs) ISSUE 3 study phase Endpoint Randomization PM ON PM OFF Time to first syncope recurrence Brignole M, Circulation 2012;125:

48 ISSUE-3: Intention-to-Treat Freedom from syncopal recurrence Number at risk Pm OFF Pm ON Kaplan-Meier survival estimates 37% 25% log rank: p=0.039 RRR at 2 yrs: 57% 25% 57% Months PM ON PM OFF Brignole M, Circulation 2012;125:

49 ISSUE-3 Conclusion In patients 40 years with severe asystolic NMS: Dual-chamber pacing reduces recurrence of syncope The 32% absolute and 57% relative syncope reduction rate support use pacing. The strategy of using ILR to determine indication for pacing likely explains the positive outcome and difference from prior negative results in pacemaker studies. Brignole M, Circulation 2012;125:

50 Carotid Sinus Syndrome (CSS) Syncope clearly associated with carotid sinus stimulation is rare ( 1% of syncope) CSS may be an important cause of unexplained syncope / falls in older individuals Brignole et al. Eur Heart J 2001;22:

51 CSS Proposed Mechanisms Carotid Sinus Sensory nerve endings in the carotid sinus walls respond to deformation Deafferentation of neck muscles may contribute as the CNS doesn t realize the neck is moving Afferent signals to brain stem interpreted as arterial pressure Reflex increase in efferent vagal activity and diminution of sympathetic tone results in bradycardia and vasodilation

52 CSS - Carotid Sinus Syndrome Diagnosis Carotid Sinus Hypersensitivity (CSH) implies positive response to carotid massage: 50 mmhg drop in systolic pressure 6 sec asystolic pause CSS = CSH + Reproduction of symptoms CSH without symptoms is not treated CSS needs a DDD PM Moya A et al, ESC Syncope Guidelines, Eur Heart J 2009; 30:

53 Conclusion Syncope is common Risk stratification important High risk patients require further testing and hospitalization Low risk patients can be discharged for further evaluation as an outpatient

54 Etiology can be difficult to decipher Requires good history and physical Treatment is education first Remember that placebo has been very effective thus education and empowerment should be as effective Tilt studies and ILR monitoring can be helpful PMs for >3s asystolic syncope, asymptomatic >6s pause and Carotid Sinus Syndrome

55 Questions?