syncope A diagnostic

Syncope A Diagnostic and Treatment Strategy Developed by: David G. Benditt, M.D. University of Minnesota Medical Center Richard Sutton, DScMed Royal Brompton Hospital, London, UK Presentation Overview I. Prevalence & Impact II. III. IV. V. VI. Etiology Diagnosis & Evaluation Options Specific Conditions Treatment Options Insights into more efficient and effective diagnosis and treatment of patients with syncope Section I: Prevalence and Impact The Significance of Syncope The only difference between syncope and sudden death is that in one you wake up.1 1 Engel GL. Psychologic stress, vasodepressor syncope, and sudden death. Ann Intern Med 1978; 89: 403-412. The Significance of Syncope 1 National Disease and Therapeutic Index on Syncope and Collapse, ICD-9-CM 780.2, IMS America, 1997 J-J, L‟her C, Touiza A, et al. Eur Heart J, 2002; 23: 815-820. 2 Blanc 3 Day SC, et al, AM J of Med 1982 4 Kapoor W. Evaluation and outcome of patients with syncope. Medicine 1990;69:160-175 Syncope Reported Frequency  Individuals <18 yrs 15%  Military Population 17- 46 yrs  Individuals 40-59 yrs*  Individuals >70 yrs* Brignole M, Alboni P, Benditt DG, et al. Eur Heart J, 2001; 22: 1256-1306. 20-25% 16-19% 23% *during a 10-year period The Significance of Syncope infrequent, unexplained: 38% to 47% 1-4 explained: 53% to 62%  500,000 new syncope patients each year 5  170,000 have recurrent syncope 6  70,000 have recurrent, infrequent, unexplained syncope 1-4 1 Kapoor W, Med. 1990;69:160-175. 2 Silverstein M, et al. JAMA. 1982;248:1185-1189. 3 Martin G, et al. Ann Emerg. Med. 1984;12:499-504. 4 Kapoor W, et al. N Eng J Med. 1983;309:197-204. 5 National Disease and Therapeutic Index, IMS America, Syncope and Collapse #780.2; Jan 1997-Dec 1997. 6 Kapoor W, et al. Am J Med. 1987;83:700-708. The Significance of Syncope  Some causes of syncope are potentially fatal  Cardiac causes of syncope have the highest mortality rates 25% 20% 15% 10% 5% 0% Overall 1 2 Syncope Mortality Due to Cardiac Causes Day SC, et al. Am J of Med 1982;73:15-23. Kapoor W. Medicine 1990;69:160-175. 3 Silverstein M, Sager D, Mulley A. JAMA. 1982;248:1185-1189. 4 Martin G, Adams S, Martin H. Ann Emerg Med. 1984;13:499-504. Impact of Syncope 100% 80% 60% 37% 2 73% 1 71% 2 60% 2 40% 20% 0% Anxiety/ Depression Alter Daily Activities Restricted Driving Change Employment 1Linzer, 2Linzer, J Clin Epidemiol, 1991. J Gen Int Med, 1994. Section II: Etiology Syncope: A Symptom…Not a Diagnosis  Self-limited loss of consciousness and postural tone  Relatively rapid onset  Variable warning symptoms  Spontaneous complete recovery Causes of Syncope1 Cause Reflex-mediated: Vasovagal Situational 18 5 8-37 1-8 Prevalence (Mean) % Prevalence (Range) % Carotid Sinus Orthostatic hypotension Medications Psychiatric Neurological Organic Heart Disease 1 8 3 2 10 4 0-4 4-10 1-7 1-7 3-32 1-8 Cardiac Arrhythmias Unknown 1Kapoor 14 34 4-38 13-41 W. In Grubb B, Olshansky B (eds) Syncope: Mechanisms and Management. Armonk NY; Futura Publishing Co, Inc: 1998; 1-13. Syncope: Etiology NeurallyMediated 1 • Vasovagal • Carotid Sinus • Situational Cough Postmicturition Orthostatic Cardiac Arrhythmia Structural CardioPulmonary 4 • Aortic Stenosis • HOCM • Pulmonary Hypertension NonCardiovascular 5 • Psychogenic • Metabolic e.g. hyperventilation • Neurological 2 • Drug Induced • ANS Failure Primary Secondary 3 • Brady Sick sinus AV block • Tachy VT* SVT • Long QT Syndrome 24% 11% 14% Unknown Cause = 34% 4% 12% DG Benditt, UM Cardiac Arrhythmia Center Causes of Syncope-like States         Migraine* Acute hypoxemia* Hyperventilation* Somatization disorder (psychogenic syncope) Acute Intoxication (e.g., alcohol) Seizures Hypoglycemia Sleep disorders * may cause „true‟ syncope Section III: Diagnosis and Evaluation Options Syncope Diagnostic Objectives  Distinguish „True‟ Syncope from other „Loss of Consciousness‟ spells:  Seizures  Psychiatric disturbances  Establish the cause of syncope with sufficient certainty to:  Assess prognosis confidently  Initiate effective preventive treatment Initial Evaluation (Clinic/Emergency Dept.)  Detailed history  Physical examination  12-lead ECG  Echocardiogram (as available) Syncope Basic Diagnostic Steps  Detailed History & Physical  Document details of events  Assess frequency, severity  Obtain careful family history  Heart disease present?  Physical exam  ECG: long QT, WPW, conduction system disease  Echo: LV function, valve status, HOCM  Follow a diagnostic plan... Conventional Diagnostic Methods/Yield Test/Procedure History and Physical (including carotid sinus massage) Yield (based on mean time to diagnosis of 5.1 months 7 49-85% 1, 2 ECG Electrophysiology Study without SHD* Electrophysiology Study with SHD 2-11% 2 11% 3 49% 3 Tilt Table Test (without SHD) Ambulatory ECG Monitors:    Holter External Loop Recorder (2-3 weeks duration) 11-87% 4, 5 2% 7 20% 7 65-88% 6, 7 Insertable Loop Recorder (up to 14 months duration) † Neurological (Head CT Scan, Carotid Doppler) 1 2 3 4 0-4% 9 Day 10 4,5,8,9,10 Kapoor, et al N Eng J Med, 1983. Kapoor, Am J Med, 1991. Linzer, et al. Ann Int. Med, 1997. Kapoor, Medicine, 1990. 5 6 7 Kapoor, JAMA, 1992 S, et al. Am J Med. 1982; 73: 15-23. Krahn, Circulation, 1995 Krahn, Cardiology Clinics, 1997. Stetson P, et al. PACE. 1999; 22 (part II): 782. * † Structural Heart Disease MRI not studied 8 Eagle K,, et al. The Yale J Biol and Medicine. 1983; 56: 1-8. Syncope Evaluation and Differential Diagnosis History – What to Look for  Complete Description  From patient and observers  Type of Onset  Duration of Attacks  Posture  Associated Symptoms  Sequelae 12-Lead ECG  Normal or Abnormal?  Acute MI  Severe Sinus Bradycardia/pause  AV Block  Tachyarrhythmia (SVT, VT)  Preexcitation (WPW), Long QT, Brugada  Short sampling window (approx. 12 sec) Carotid Sinus Massage  Site: Carotid arterial pulse just below thyroid cartilage  Method:  Right followed by left, pause between  Massage, NOT occlusion  Duration: 5-10 sec  Posture – supine & erect Carotid Sinus Massage  Outcome:  3 sec asystole and/or 50 mmHg fall in systolic blood pressure with reproduction of symptoms = Carotid Sinus Syndrome (CSS)  Contraindications  Carotid bruit, known significant carotid arterial disease, previous CVA, MI last 3 months  Risks  1 in 5000 massages complicated by TIA Conventional AECG Low Yield, Poor Symptom / Arrhythmia Concordance*  8 studies, 2612 patients  19% pts had symptoms with AECG Only 4% had arrhythmia with symptoms  79% pts were without symptoms 14% had arrhythmia despite absence of symptoms * ACC/AHA Task Force, JACC 1999;912-948 Ambulatory ECG Method Holter (24-48 hours) Event Recorder Comments Useful for infrequent events Useful for infrequent events Loop Recorder Limited value in sudden LOC Useful for infrequent events Implantable type more convenient (ILR) In development Wireless (internet) Event Monitoring Head-up Tilt Test (HUT)  Unmasks VVS susceptibility  Reproduces symptoms  Patient learns VVS warning symptoms  Physician is better able to give prognostic / treatment advice Head-Up Tilt Test (HUT) DG Benditt, UM Cardiac Arrhythmia Center Electroencephalogram  Not a first line of testing  Syncope from Seizures  Abnormal in the interval between two attacks – Epilepsy  Normal – Syncope Value of Event Recorder in Syncope *Asterisk denotes event marker Linzer M. Am J Cardiol. 1990;66:214-219. Reveal Plus Insertable Loop Recorder ® Patient Activator Reveal® Plus ILR 9790 Programmer ILR Recordings* 56 yo woman with syncope accompanied with seizures. Infra-Hisian AV Block: Dual chamber pacemaker 65 yo man with syncope accompanied with brief retrograde amnesia. VT and VF: ICD and meds *Medtronic data on file Randomized Assessment of Syncope Trial Unexplained Syncope after history, physical exam, ECG, Holter Low Risk (EF > 35%) ILR - + Usual care including: External loop recorder Tilt test, EPS and others External loop recorder Tilt test, EPS, others + ILR Diagnosis Krahn A, Klein GJ, Skanes Y. Circulation 2001; 104:46-51. RAST Methods  Prospective randomized trial  60 patients with unexplained syncope referred for cardiac investigation  Inclusion:  Recurrent unexplained syncope  Referred to the arrhythmia service for cardiac investigation  No clinical diagnosis after history, physical, ECG and at least 24 hours of cardiac monitoring  Exclusion:  LVEF < 35%  Unable to give informed consent  Major morbidity precluding one year of follow-up Krahn A, Klein GJ, Skanes Y. Circulation 2001; 104:46-51. RAST Results Unexplained Syncope n=60 ILR n=30 Conventional n=30 In Follow-up Diagnosed Undiagnosed Diagnosed Undiagnosed n=3 n=14 n=13 n=6 n=24 Krahn A, Klein GJ, Skanes Y. Circulation 2001; 104:46-51. RAST Crossover Results Unexplained Syncope n=60 13/30 24/30 Undiagnosed after monitoring 6 accepted crossover to conventional Undiagnosed after conventional 21 accepted crossover to ILR Diagnosed n=1 Undiagnosed n=5 Diagnosed n=8 Undiagnosed n=5 In follow-up n=8 Krahn A, Klein GJ, Skanes Y. Circulation 2001; 104:46-51. RAST - Diagnoses 14 12 number of patients 10 ILR 8 6 4 2 0 Bradycardia Tachycardia Conventional Vasovagal Seizures Krahn A, Klein GJ, Skanes Y. Circulation 2001; 104:46-51. Conventional EP Testing in Syncope  Limited utility in syncope evaluation  Most useful in patients with structural heart disease  Heart disease……..50-80%  No Heart disease…18-50%  Relatively ineffective for assessing bradyarrhythmias Brignole M, Alboni P, Benditt DG, et al. Eur Heart Journal 2001; 22: 1256-1306. EP Testing in Syncope: Useful Diagnostic Observations  Inducible monomorphic VT  SNRT > 3000 ms or CSRT > 600 ms  Inducible SVT with hypotension  HV interval ≥ 100 ms (especially in absence of inducible VT)  Pacing induced infra-nodal block ISSUE Study International Study of Syncope of Uncertain Etiology  Objectives: • Understand the mechanism of syncope in tilt-positive and tiltnegative (isolated) patients • Use the ILR to assess the correlation of rhythms captured during tilt testing and spontaneous recurrent episodes  Inclusion Criteria: • Patients with three or more syncopal episodes in the last 2 years • Groups matched in age, sex, history of syncope, ECG, Echo abnormalities, SHD and arrhythmias Moya A. Circulation. 2001; 104:1261-1267 ISSUE Study Design  Multicenter, prospective 111 syncope patients 3 episodes in 2 years, first and last episode >6 months apart History, physical exam, ECG, CSM, echo, Holter (24 hr), other tests as appropriate Tilt test followed by implant of Reveal Insertable Loop Recorder Follow-up to recurrent spontaneous episode Moya A. Circulation. 2001; 104:1261-1267 ISSUE Study Results Results Recurrent Event Occurrence (#) Mean Time to Recurrent Event (range) ILR ECG Documented (#) Tachyarrhythmia Bradycardia Tilt-Negative Syncope (Isolated) Tilt-Positive Syncope n=82 34% (28) 105 days (47-226) 29% (24) n=29 34% (10) 59 (22-98) 28% (8) 21% (6) 2% (2) 16% (13) –Sinus Brady –Sinus Arrest 2% (2) 12% (10) 3% (1) 17% (5) 21% (6) –AV Block 1% (1) 18% (15) Total Arrhythmic Normal Sinus Rhythm Moya A. Circulation. 2001; 104:1261-1267 11% (9) 7% (2) ISSUE Study  Conclusions: • Homogeneous findings from tilt-negative and tiltpositive syncope patients were observed (clinical characteristics and outcomes). Most frequent finding was asystole secondary to progressive sinus bradycardia, suggesting a neuromediated origin • In this study tilt-negative patients had as many arrhythmias (18%) as tilt-positive patients (21%) • In tilt-positive patients the spontaneous episode ECG was more frequently asystolic than what was predicted by tilt test Moya A. Circulation. 2001; 104:1261-1267 ISSUE Study Implications  HUT outcome was not predictive of vasodepressor vs. cardioinhibitory response  Bradycardia is common in spontaneous VVS - independent of HUT outcome  Bradycardia is more prevalent in spontaneous events vs. HUT induced VVS • Clinical Implication: Consider a strategy of postponing treatment until a spontaneous episode can be documented Moya A. Circulation. 2001; 104:1261-1267 Symptom-Rhythm Correlation Auto Activation Point Patient Activation Point Diagnostic Limitations  Difficult to correlate spontaneous events and laboratory findings  Often must settle for an attributable cause  Unknowns remain 20-30% 1 1Kapoor W. In Grubb B, Olshansky B (eds) Syncope: Mechanisms and Management. Armonk NY; Futura Publishing Co, Inc: 1998; 1-13. Unexplained Syncope Diagnosis History and Physical Exam Surface ECG ENT Evaluation CV Syncope Workup Endocrine Evaluation Other CV Testing • Angiogram • Exercise Test • SAECG Neurological Testing • Head CT Scan • Carotid Doppler • Holter • ELR or ILR • Tilt Table • Echo • EPS • MRI • Skull Films • Brain Scan • EEG Psychological Evaluation Adapted from: W.Kapoor.An overview of the evaluation and management of syncope. From Grubb B, Olshansky B (eds) Syncope: Mechanisms and Management. Armonk, NY: Futura Publishing Co., Inc.1998. Typical Cardiovascular Diagnostic Pathway Syncope History and Physical, ECG Known SHD No SHD > 30 days; > 2 Events < 30 days Echo EPS Tilt/ILR + Treat Tilt ILR Tilt Holter/ ELR ILR Adapted from: Linzer M, et al. Annals of Int Med, 1997. 127:76-86. Syncope: Mechanisms and Management. Grubb B, Olshansky B (eds) Futura Publishing 1999 Zimetbaum P, Josephson M. Annals of Int Med, 1999. 130:848-856. Krahn A et al. ACC Current Journal Review,1999. Jan/Feb:80-84. Section IV: Specific Conditions Neurally-Mediated Reflex Syncope (NMS)  Vasovagal syncope (VVS)  Carotid sinus syndrome (CSS)  Situational syncope  post-micturition  cough  swallow  defecation  blood drawing  etc. NM Reflex Syncope: Pathophysiology  Multiple triggers  Variable contribution of vasodilatation and bradycardia NMS – Basic Pathophysiology Cerebral Cortex Feedback via Carotid Baroreceptors Other Mechanoreceptors Parasympathetic (+) Baroreceptors Heart sympathetic (+) ¯ Heart Rate ¯ AV Conduction Vascular Bed _ Vasodilatation Bradycardia/ Hypotension Benditt DG, Lurie KG, Adler SW, et al. Pathophysiology of vasovagal syncope. In: Neurally mediated syncope: Pathophysiology, investigations and treatment. Blanc JJ, Benditt D, Sutton R. Bakken Research Center Series, v. 10. Armonk, NY: Futura, 1996 Vasovagal Syncope (VVS): Clinical Pathophysiology  Neurally Mediated Physiologic Reflex Mechanism with two Components:  Cardioinhibitory ( HR )  Vasodepressor ( BP )  Both components are usually present Prevalence of VVS  Prevalence is poorly known  Various studies report 8% to 37% (mean 18%) of cases of syncope (Linzer 1997)  In general:  VVS patients younger than CSS patients  Ages range from adolescence to elderly (median 43 years)  Pallor, nausea, sweating, palpitations are common  Amnesia for warning symptoms in older patients Spontaneous VVS 16.3 sec Continuous Tracing 1 sec DG Benditt, UM Cardiac Arrhythmia Center Management Strategies for VVS  Optimal management strategies for VVS are a source of debate  Patient education, reassurance, instruction  Fluids, salt, diet  Tilt Training  Support hose  Drug therapies  Pacing  Class II indication for VVS patients with positive HUT and cardioinhibitory or mixed reflex VVS: Tilt-Training  Objectives  Enhance Orthostatic Tolerance  Diminish Excessive Autonomic Reflex Activity  Reduce Syncope Susceptibility / Recurrences  Technique  Prescribed Periods of Upright Posture  Progressive Increased Duration 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 Etiology of CSS  Sensory nerve endings in the carotid sinus walls respond to deformation  “Deafferentation” of neck muscles may contribute  Increased afferent signals to brain stem Carotid Sinus  Reflex increase in efferent vagal activity and diminution of sympathetic tone results in bradycardia and vasodilation Carotid Sinus Hypersensitivity(CSH)  Abnormal response to CSM  Absence of symptoms attributable to CSS  CSH reported frequent in „fallers‟ (Kenny) CSH  CSS CSS and Falls in the Elderly  30% of people >65 yrs of age fall each year1  Total is 9,000,000 people in USA  Approximately 10% of falls in elderly persons are due to syncope2  50% of fallers have documented recurrence3  Prevalence of CSS among frequent and unexplained fallers unknown but…  CSH present in 23% of >50 yrs fallers presenting at ER 3 1Falling in 2 the Elderly: U.S. Prevalence Data. Journal of the American Geriatric Society, 1995. Campbell et al: Age and Aging 1981;10:264-270. 3Richardson DA, Bexton RS, et al. Prevalence of cardioinhibitory carotid sinus hypersensitivity in patients 50 years or over presenting to the Accident and Emergency Department with “unexplained” or “recurrent” falls. PACE 1997 Section V: Treatment Options VVS: Pharmacologic Rx  Salt /Volume  Salt tablets, „sport‟ drinks, fludrocortisone  Beta-adrenergic blockers  1 positive controlled trial (atenolol),  1 on-going RCT (POST)  Disopyramide  SSRIs  1 controlled trial  Vasoconstrictors (e.g., midodrine)  1 negative controlled trial (etilephrine) Midodrine for Neurocardiogenic Syncope 100 Symptom – Free Interval 80 60 40 Midodrine Fluid 20 p < 0.001 0 0 20 40 60 80 Months 100 120 140 160 180 Journal of Cardiovascular Electrophysiology Vol. 12, No. 8, Perez-Lugones, et al. Status of Pacing in VVS  Perception of pacing for VVS changing:  VVS with +HUT and cardioinhibitory response a Class IIb indication1  Recent clinical studies demonstrated benefits of pacing in select VVS patients:  VPS I  VASIS  SYDIT  VPS II –Phase I  ROME VVS Trial 1Gregoratos G, et al. ACC/AHA Guidelines for Implantation of Cardiac Pacemakers and Antiarrhythmic Devices. Circulation. 1998; 97: 1325-1335. Status of Pacing in VVS  Benefits of specific device features evolving:  Some success with DDD/DDI hysteresis • • 1 “False positives” may result in prolonged high rate intervention Tied to lower rate intervention  Rate drop therapies designed for treating VVS syncope appear to be successful 2-4 1 Sutton 2 R, et al. Circulation. 2000; 102:294-299. Connolly S, et al. J Am Coll Cardiol 1999; 33:16-20. et al. Circulation. 2002; 104: 52-57. 3 Ammirati F, 4 Ammirati F, et al. NASPE Abstract #307. PACE, Vol. 24, April 2002, Part II. 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* *a trough heart rate <60/min if no isoproterenol used, <70/min if up to 2 mcg/min isoproterenol used, or <80/min if over 2 mcg/min isoproterenol used Connolly S, et al. J Am Coll Cardiol 1999; 33: 16-20. VPS- I  Endpoints: Time to first syncope  Outcome: PACEMAKER RESULTS (n= 27) CONTROL (n=27) Number of patients w/syncopal recurrence Mean time to first recurrence (days) Relative risk reduction of syncope* *2p = 0.000022 6 (22%) 112 85.4% 19 (70%) 54 - Connolly S, et al. J Am Coll Cardiol 1999; 33: 16-20. VPS- I 100 90 80 Control (No Pacemaker) 70 60 Cumulative Risk 50 (%) 40 30 Pacemaker 2P=0.000022 20 10 0 0 Number At Risk C 27 P 27 3 9 21 6 9 Time in Months 4 17 2 12 12 1 11 15 0 8 Connolly S, et al. J Am Coll Cardiol 1999; 33: 16-20. VPS-I  Conclusion: Dual-chamber pacing with rate drop response reduces the likelihood of syncope in patients with recurrent VVS. Connolly S, et al. J Am Coll Cardiol 1999; 33: 16-20. VASIS Vasovagal Syncope International Study  Study Design:  42 patients, randomized, prospective, multicenter _ _ 19 DDI pacemaker (80 bpm) with rate hysteresis (45 bpm) 23 no pacemaker  Patient Inclusion Criteria:  > 3 syncopal events in 2 years and last event occurring within 6 months of enrollment and,  Positive VASIS type 2A or 2B cardioinhibitory response to HUT and,  Age > 40 years or drug refractory if < 40 years Sutton, R, et al. Circulation. 2000; 102:294-299. VASIS  Endpoints: Time to first syncope  Outcome: RESULTS Pacemaker (n= 19) No Pacemaker (n=23) 14 (61%) 5 Number of patients w/syncopal recurrence Median time to first recurrence (months)* *P= 0.0006 1 (5%) 15 Sutton, R, et al. Circulation. 2000; 102:294-299. VASIS 100 % syncope-free Pacemaker 80 60 40 No-Pacemaker 20 p=0.0004 0 # of pts 40 2 3 Years 15 4 5 6 31 23 14 12 7 Sutton, R, et al. Circulation. 2000; 102:294-299. VASIS  Conclusion: Dual-chamber pacing (at a rate of 80 bpm ) with rate hysteresis reduces the likelihood of syncope in patients with tilt-positive, cardioinhibitory syncope. Sutton, R, et al. Circulation. 2000; 102:294-299. SYDIT Syncope Diagnosis and Treatment Study  Study Design: 93 patients randomized, prospective, multicenter _ 46 DDD pacemaker with rate drop response (RDR) _ 47 Atenolol 100 MG/D  Patient Inclusion Criteria:  > 55 yrs > 3 syncopal episodes in 2 years + HUT with relative bradycardia (trough HR <60 bpm) Ammirati F, et al. Circulation. 2001; 104:52-57. SYDIT  Endpoints:  Time to first syncope  Outcome: PACED DRUG RESULTS Number of patients w/syncopal recurrence* Median time to first recurrence (days) *P=0.004 (n= 46) 2 (4%) 390 (n= 47) 12 (25%) 135 Ammirati, et al. Circulation. 2001; 104:52-57. SYDIT Syncope-free Survival: Intention-to-Treat (n=46/paced, 47/drug). 1.0 0.9 % of syncope free pts drug pacemaker 0.8 P = 0.0032 0.7 0.6 0 100 200 300 400 500 600 700 800 900 1000 Time (days) Ammirati F, et al. Circulation. 2001; 104:52-57. SYDIT  Conclusion: Dual-chamber pacing + RDR is superior to Atenolol in prevention of recurrent syncope in highly symptomatic patients with relative bradycardia during tilt-induced syncope. Ammirati F, et al. Circulation. 2001; 104:52-57. VPS-II: Phase I Vasovagal Pacemaker Study-II  Study Design: 100 patients, randomized, prospective, multicenter _ 50 DDD pacemaker with rate drop response (RDR) _ 50 ODO pacemaker (inactive mode)  Patient Inclusion Criteria: > 6 syncope events ever or > 3 syncope events in 2 years or > 1 syncope event in 6 months and, Positive HUT with syncope or presyncope and a heart rate blood pressure product <9000 Presented at the 23rd Annual Scientific Sessions of the North American Society of Pacing and Electrophysiology. Late Breaking Clinical Trials, May 11, 2002. VPS-II: Phase I  Endpoints:  Time to first syncope  Outcome: DDD Pacemaker RESULTS Number of patients w/syncopal recurrence (n= 50) 16 (32%) ODO Pacemaker (n= 50) 22 (44%) Relative Risk Reduction* *P=0.153 28.7% - Presented at the 23rd Annual Scientific Sessions of the North American Society of Pacing and Electrophysiology. Late Breaking Clinical Trials, May 11, 2002. VPS-II: Phase I 0.4 0.3 Cumulative Risk of Syncope ODO DDD 0.2 P = 0.153 (one-sided) 0.1 0.0 0 1 2 3 4 5 6 Number at Risk ODO DDD 40 39 37 36 35 34 32 33 31 33 21 17 Presented at the 23rd Annual Scientific Sessions of the North American Society of Pacing and Electrophysiology. Late Breaking Clinical Trials, May 11, 2002. VPS-II: Phase I  Conclusions:  Lower than anticipated syncope event rate in the control arm.  Higher than anticipated event rate in the treatment group.  Consequence: treatment effect was less than VPS-I.  Results favored pacing but the treatment effect was not statistically significant. Presented at the 23rd Annual Scientific Sessions of the North American Society of Pacing and Electrophysiology. Late Breaking Clinical Trials, May 11, 2002. VVS Pacing Trials Conclusions DDD pacing reduces the risk of syncope in patients with recurrent, refractory, highly-symptomatic, cardioinhibitory vasovagal syncope. SAFE PACE Study Design  Randomized controlled trial (N=175):  Pacing (87) vs. No Pacing (88)  Single center: Royal Victoria Infirmary, Newcastle, UK  Recruitment began: April 1998  12 month follow-up per patient  Study concluded: May 2000 Kenny RA, J Am Coll Cardiol 2001; 38:1491-1496. SAFE PACE Inclusion Criteria  Consecutive adults attending accident and emergency department • > 50 Years - Experienced non-accidental fall •Positive response to CSM Kenny RA, J Am Coll Cardiol 2001; 38:1491-1496. SAFE PACE Screening Process Accident and Emergency Attendees > 50 Yrs Falls or Syncope Non-accidental Fall CSM Performed Cardioinhibitory or Mixed CSH RCT Control Kenny RA, J Am Coll Cardiol 2001; 38:1491-1496. Pacemaker SAFE PACE Screening Results RCT (n=175) Control (n=88) • No pacing intervention Pacemaker (n=87) • Medtronic Thera DR (Rate Drop Response Algorithm) Kenny RA, J Am Coll Cardiol 2001; 38:1491-1496. SAFE PACE Results Number of Falls Control n=87 Pacemaker n=84 % Participants w/Falls Total Number of Falls* Mean Number of Falls** 60% 699 9.3 58% 216 4.1 70% Reduction [OR 0.42; 95% CI: 0.23, 0.75] * Falls during 12 months post randomization ** Crude adjustment calculation Kenny RA, J Am Coll Cardiol 2001; 38:1491-1496. SAFE PACE Results Number of Syncopal Episodes Control N=87 Pacemaker N=84 % Participants w/Syncopal Events Total Number of Syncopal Events Mean Number Syncopal Events 22% 11% 47 22 50% Reduction [OR 0.53; 95% CI 0.23; 1.20 ns] 1.14 0.20 * Syncopal events 12 months past randomization ** Crude adjustment calculation Kenny RA, J Am Coll Cardiol 2001; 38:000-000. SAFE PACE Results Number of Injury Events Control Pacemaker n= 87 % Participants w/Injurious Events 41% n= 84 35% Total Number Injury Events -Fractures 202 61 70% Reduction 4 3 -Soft Tissue Injury 198 58 * Injurious events 12 months post randomization Kenny RA, J Am Coll Cardiol 2001; 38:1491-1496. SAFE PACE Conclusions In patients with unexplained falls and a diagnosis of Cardioinhibitory CSH, cardiac pacing reduced the total number of:  Falls by 70%  Syncopal events by 53%  Injurious events by 70% Kenny RA, J Am Coll Cardiol 2001; 38:1491-1496. Role of Pacing in CSS -Syncope Recurrence Rate 75% 57% 50% Class I indication for pacing (AHA and BPEG) Limit pacing to CSS that is: •Cardioinhibitory •Mixed 0% No Pacing Pacing Brignole et. Al. Diagnosis, natural history and treatment. Eur JCPE. 1992; 4:247-254 %6 25% DDD/DDI superior to VVI (Mean follow-up = 6 months) Section VI: Insights into More Efficient and Effective Diagnosis and Treatment Principal Causes of Orthostatic Syncope  Drug-induced (very common)  diuretics  vasodilators  Primary autonomic failure  multiple system atrophy  Parkinsonism  Secondary autonomic failure  diabetes  alcohol  amyloid  Alcohol  orthostatic intolerance apart from neuropathy Syncope Due to Arrhythmia or Structural CV Disease: General Rules  Often life-threatening and/or exposes patient to high risk of injury  May be warning of critical CV disease  Aortic stenosis, Myocardial ischemia, Pulmonary hypertension  Assess culprit arrhythmia / structural abnormality aggressively  Initiate treatment promptly Principal Causes of Syncope due to Structural Cardiovascular Disease  Acute MI / Ischemia  Acquired coronary artery disease  Congenital coronary artery anomalies     HOCM Acute aortic dissection Pericardial disease / tamponade Pulmonary embolus / pulmonary hypertension  Valvular abnormalities  Aortic stenosis, Atrial myxoma Syncope Due to Cardiac Arrhythmias  Bradyarrhythmias  Sinus arrest, exit block  High grade or acute complete AV block  Tachyarrhythmias  Atrial fibrillation / flutter with rapid ventricular rate (e.g. WPW syndrome)  Paroxysmal SVT or VT  Torsades de pointes Rhythms During Recurrent Syncope Bradycardia 36% Normal Sinus Rhythm Normal Sinus Rhythm 58% 58% Tachyarrhythmia 6% Krahn A, et al. Circulation. 1999; 99: 406-410 AECG: 74 yr Male, Syncope From the files of DG Benditt, UM Cardiac Arrhythmia Center Syncope: Torsades From the files of DG Benditt, UM Cardiac Arrhythmia Center 28 yo man in the ER multiple times after falls resulting in trauma VT: ablated and medicated 83 yo woman Bradycardia: Pacemaker implanted Reveal ® ILR recordings; Medtronic data on file. Infra-His Block From the files of DG Benditt, UM Cardiac Arrhythmia Center Drug-Induced QT Prolongation  Antiarrhythmics  Class IA ...Quinidine, Procainamide, Disopyramide  Class III…Sotalol, Ibutilide, Dofetilide, Amiodarone, (NAPA)  Antianginal Agents  (Bepridil)  Psychoactive Agents  Phenothiazines, Amitriptyline, Imipramine, Ziprasidone  Antibiotics  Erythromycin, Pentamidine, Fluconazole  Nonsedating antihistamines  (Terfenadine), Astemizole  Others  (Cisapride), Droperidol Treatment of Syncope Due to Bradyarrhythmia  Class I indication for pacing using dualchamber system wherever adequate atrial rhythm is available  Ventricular pacing in atrial fibrillation with slow ventricular response Treatment of Syncope Due to Tachyarrhythmia  Atrial Tachyarrhythmias;  AVRT due to accessory pathway – ablate pathway  AVNRT – ablate AV nodal slow pathway  Atrial fib– Pacing, linear / focal ablation, ICD selected pts  Atrial flutter – Ablation of reentrant circuit  Ventricular Tachyarrhythmias;  Ventricular tachycardia – ICD or ablation where appropriate  Torsades de Pointes – withdraw offending Rx or ICD (longQT/Brugada)  Drug therapy may be an alternative in many cases Conclusion Syncope is a common symptom, often with dramatic consequences, which deserves thorough investigation and appropriate treatment of its cause. Disclaimer INDICATIONS 9526 Reveal® Plus Insertable Loop Recorder The Reveal Plus Insertable Loop Recorder (ILR) is an implantable patient activated monitoring system that records subcutaneous ECG and is indicated for patients who experience transient symptoms that may suggest a cardiac arrhythmia. 9790 Programmer The Medtronic 9790 Programmers are portable, microprocessor based instruments used to program Medtronic implantable devices. 6191 Activator The Model 6191 Activator is intended for use in combination with a Medtronic Model 9525 Reveal ® and the Model 9526 Reveal Plus Insertable Loop Recorders. CONTRAINDICATIONS There are no known contraindications for the implantation of the Reveal Plus ILR. However, the patient‟s particular medical condition may dictate whether or not a subcutaneous, chronically implanted device can be tolerated. WARNINGS/PRECAUTIONS 9526 Reveal Plus Insertable Loop Recorder Patients with the Reveal Plus ILR should avoid sources of magnetic resonance imaging, diathermy, high sources of radiation, electrosurgical cautery, external defibrillation, lithotripsy, and radiofrequency ablation to avoid electrical reset of the device, and/or inappropriate sensing. 6191 Activator Operation of the Model 6191 Activator near sources of electromagnetic interference, such as cellular phones, computer monitor s, etc., may adversely affect the performance of this device. See the appropriate technical manual for detailed information regarding indications, contraindications, warnings, and precautions. Caution: Federal law (U.S.A.) restricts this device to sale by or on the order of a physician. Disclaimer INDICATIONS Medtronic.Kappa 700 Series Pacemakers The Medtronic.Kappa 700 Series pacemakers are indicated for rate adaptive pacing in patients who may benefit from increased p acing rates concurrent with increases in activity and are also indicated for dual chamber and atrial tracking modes in patients who may b enefit from maintenance of AV synchrony. Dual chamber modes are specifically indicated for treatment of conduction disorders that require restoration of both rate and AV synchrony, which include various degrees of AV block to maintain the atrial contribution to cardiac output a nd VVI intolerance (e.g., pacemaker syndrome) in the presence of persistent sinus rhythm. 9790 Programmer The Medtronic 9790 Programmers are portable, microprocessor based instruments used to program Medtronic implantable devices. 9462 The Model 9462 Remote Assistant is intended for use in combination with a Medtronic implantable pacemaker with Remote Assista nt diagnostic capabilities. CONTRAINDICATIONS The Medtronic.Kappa 700 Series pacemakers are contraindicated for the following applications: · Dual chamber atrial pacing in patients with chronic refractory atrial tachyarrhythmias. · Asynchronous pacing in the presence (or likelihood) of competitive paced and intrinsic rhythms. · Unipolar pacing for patients with an implanted cardioverter-defibrillator (ICD) because it may cause unwanted delivery or inhibition of ICD therapy. WARNINGS/PRECAUTIONS Medtronic.Kappa 700 Series patients should avoid sources of magnetic resonance imaging, diathermy, high sources of radiation, electrosurgical cautery, external defibrillation, lithotripsy, and radiofrequency ablation to avoid electrical reset of the device, inappropriate sensing and/or therapy. See the appropriate technical manual for detailed information regarding indications, contraindications, warnings, and precaut ions. Caution: Federal law (U.S.A.) restricts this device to sale by or on the order of a physician. Additional Slides Falls -- Incidence, Recurrence, CHS* 75% 50% 1 50% 30% 1 23% 2 25% 0% Incidence > 65 yrs. old Recurrence CSH* present in fallers > 50 yrs. presenting at ER * Carotid Sinus Hypersensitivity 1 Falling 2 in the Elderly, 1995. Richardson, PACE, 1997. VVS Pacing Trials Comparison Summary Pacing in VVS Two randomized, controlled trials suggest benefit in selected patients with multiple (>5 lifetime) syncope recurrences and one or more of: prominent cardioinhibitory features asystolic pause >10 seconds sustained HR<40/minute VVS Recurrences  35% of patients report syncope recurrence during follow-up ≤3 years  Positive HUT with >6 lifetime syncope episodes: recurrence risk >50% over 2 years Sheldon et al. Circulation 1996; 93: 973-81. Savage et al. STROKE 1985; 16: 626-29. SAFE PACE 2: Syncope and Falls in the Elderly  30% of individuals >65 yrs fall each year  5% of falls result in fractures  1% of falls result in hip fractures  SAFEPACE Pilot Study 18% prevalence of CSH in unexplained „fallers‟ 31% in „fallers‟ >80 yrs Kenny RA, J Am Coll Cardiol 2001; 38:1491-1496. Rate Drop Response Overview Detection Options Drop Detect Detects relative heart rate drops of a predetermined size Both Detection occurs when either Drop Detection or Low Rate Detection criteria are met Low Rate Detect Detects heart rate that falls to a user-defined lower rate Rate Drop Detection in Medtronic Kappa® Series Pacemakers Drop Detection with Intervention Drop Detection Method: Drop Size 25, Drop Rate 70 110 100 90 Peak Rate=90 bpm Ventricular Rate 80 70 60 50 40 Drop Size=25 bpm Drop Rate 2 consecutive beats < Drop Size and Drop Rate Rate Drop Detection in Medtronic Kappa® Series Pacemakers Drop Detect Peak Rate Drop Detection Method: Drop Size 25 120 110 Peak Rate=90 bpm Ventricular Rate 100 90 80 70 60 50 40 Drop Size=25 bpm Rate Drop Detection in Medtronic Kappa® Series Pacemakers Low Rate Detect Low Rate Detection Method: Lower Rate 40, Detection beats 2 110 100 90 Ventricular Rate 80 70 60 50 2 consecutive paced beats at Lower Rate 40 Lower Rate 30 Rate Drop Detection in Medtronic Kappa® Series Pacemakers Using Both Detection Algorithms  When both detection algorithms are used:  Detection occurs when either Drop Detection or Low Rate Detection criteria are met  Intervention Rate, Duration and Termination are programmed the same as when using the individual detection modes Rate Drop Detection in Medtronic Kappa® Series Pacemakers Rate Drop Intervention Therapy  DDD or DDI pacing  Pacing intervention  Paces at programmed Intervention Rate for programmed duration  Pacing termination  Pacing rate decreases until there are three consecutive atrial senses or Lower Rate is reached Rate Drop Detection in Medtronic Kappa® Series Pacemakers Challenges of Syncope  Cost  Cost/year  Cost/diagnosis  Quality of Life Implications  Work/financial  Mobility (automobiles)  Psychological  Diagnosis & Treatment  Diagnostic yield and repeatability of tests  Frequency and clustering of events  Difficulty in managing/treating/controlling future events  Appropriate risk stratification  Complex Etiology Diagnosing VVS  Patient history and physical exam  Positive tilt table test (ACC Consensus Protocol)  Overnight fast  ECG  Blood pressure  Supine and upright  Tilt to 60-80 degrees  Isoproterenol  Re-tilt DG Benditt, Tilt Table Testing, 1996. 60° - 80° VVS: Treatment Overview  Education  symptom recognition  reassurance  situation avoidance  Tilt-Training  prescribed upright posture  Pharmacologic Agents  salt/volume management  beta-adrenergic blockers  SSRIs  vasoconstrictors (e.g., midodrine)  Cardiac Pacemakers Tilt-Training: Clinical Outcomes  42 HUT positive (21±13 min) VVS patients  Home training: two 30 minute sessions daily  Outcomes 41/42 pts --->45 min asymptomatic HUT  Clinical follow-up: 15.1±7.8 mos  • 36 pts syncope free • • 4 pts: presyncope 1 pt: syncope recurrences Reybrouck et al. PACE 2000; 23:493-8