Disclosures. Advances in Cardiac Electrophysiology. CVA Risk by Type of AF. Outline

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1 Disclosures Advances in Cardiac Electrophysiology Research Grant: NIH KL2 RR2413 Honoraria (minor): Biotronik St. Jude Medical Advances in Internal Medicine UCSF Department of Medicine, School of Medicine 21 June 21 Zian H. Tseng, M.D., M.A.S. Assistant Professor of Medicine Cardiac Electrophysiology Section University of California, San Francisco Outline CVA Risk by Type of AF Advances in atrial fibrillation management Stroke prevention Rate vs. Rhythm control Dronedarone Catheter ablation Advances in ventricular arrhythmia management New risk stratifiers for SCD Advances in device therapy Implantable cardioverter defibrillators (ICDs) Cardiac resynchronization therapy (CRT) Tasers and sudden death Current guidelines emphasize that type of AF should not be taken into account when deciding oral anticoagulation Paroxysmal AF pts have higher risk of stroke than persistent AF pts No difference in CVA risk with asx or sx AF Nieuwlaat, R et al Eur Heart J 26 Nieuwlaat, R et al Eur Heart J 28 Savalieva I et al JICE 2 1

2 Thromboembolic Prophylaxis by CHADS2 Score CHADS2 score: CHF, Hypertension, Age >75, Diabetes: 1 pt Stroke/TIA hx: 2 pts Rx by CHADS2 score: CHADS2 : ECASA 325mg CHADS2 1-2: warfarin (INR 2.-3.) > ECASA CHADS2 >3: warfarin unless contraindicated Dabigatran vs. Warfarin for AF Dabigatran: oral direct thrombin inhibitor Pros: No INR monitoring, fewer dietary/drug interactions Cons: bid, no long-term safety data, high cost, no antidote, dose adj for renal disease Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Connolly SJ et al. NEJM 29 18,113 pts, mean CHADS2 score 2, 2 y F/U first trial to demonstrate superiority over warfarin hemorrhagic CVA, major bleeding equal or lower for dabigatran Not yet approved but may be attractive for those with difficulty with warfarin (INR monitoring) Nonpharmacologic Alternatives to Warfarin ~2% of pts with AF have a contraindication to warfarin (bleeding, noncompliance, pregnancy) Surgical LAA ligation standard at the time of MV surgery or MAZE Percutaneous approach: WATCHMAN device Self-expanding nitinol frame deployed via transseptal catheter Warfarin for 45 days, then ECASA + clopidogrel x 6 mo PROTECT AF (Holmes DR, et al. Lancet 29) 7 pts with AF (CHADS2 > 1) randomized 2:1 to device or warfarin Implantation successful in 91% Non-inferior to warfarin (stroke, CV death, embolism) 7% more adverse safety events, mostly due to pericardial effusion Rhythm vs. Rate control In patients with paroxysmal or persistent AF, is restoration of SR superior to rate control? AFFIRM, NEJM 22; 347: paroxysmal or persistent AF pts Mean 7y, 4% female, 25% CHF, 5% HTN, 5% CAD 3.5 y F/U, trend toward lower mortality in rate control arm, fewer hospitalizations RACE, NEJM 22; 347: persistent AF pts 2.3 y F/U, trend toward lower composite end point of CV death, CHF, CVA in rate control arm These trends likely due to inadequate anticoagulation in rhythm control arm, thus both approaches require chronic warfarin if indicated 2

3 All-Cause Mortality in AFFIRM Rhythm vs. Rate control in CHF Patients CHF pts with AF have an especially poor prognosis compared with similar pts in SR 1,376 pts with CHF and EF < 35% randomized to rhythm vs. rate control (Roy et al. NEJM 28) Rhythm control: CV + amiodarone (82%), sotalol, or dofetilide Rate control: ß blockers +/- digitalis NEJM 22; 347: Rhythm vs. Rate control in CHF Patients Which Patients for Rhythm Control? Over a mean 37 mo F/U, no significant differences in: primary end point of CV death secondary outcomes of overall survival, CVA, or worsening HF 27% prevalence of AF in rhythm control group, but 58% had > 1 recurrence of AF Therefore, as with AFFIRM and RACE, it remains unknown whether actually achieving SR would result in better outcomes Roy et al. NEJM 28 The major reason to pursue rhythm control is to improve symptoms and quality of life Although SR was associated with better survival in AFFIRM, no studies have shown a reduction in stroke or CHF with rhythm control approach For older pts, persistent/chronic AF, or with structural heart disease: Careful assessment of sx in rate control Warfarin per CHADS2 score DCCV + AAD if sx For younger pts, paroxysmal AF, and structurally normal hearts Often sx even with rate control Goal is restoration of SR AAD, radiofrequency catheter ablation (RFCA) 3

4 Dronedarone Dronedarone Multichannel blocker (class 3) similar to amiodarone but does not contain iodine Avoids iodine-related adverse reactions Low risk of proarrhythmia and torsade de pointes Significantly reduces CrCl, due to inhibition of specific renal tubular cation transporters rather than a true reduction in GFR FDA approval in July 29 for low- to intermediate-risk pts with nonpermanent AF or AFL but no advanced or recently decompensated HF ANDROMEDA (Kober et al. NEJM 28) 627 pts with class 3/4 CHF and AF randomized to dronedarone 4 bid vs. placebo Excess deaths in dronedarone arm, mostly due to worsening CHF ATHENA (Hohnloser et al. NEJM 29) 4,628 pts, 25% in AF/AFL, 6% with structural heart disease, 2y F/U Hosp/death lower in dronedarone group (32%) vs. placebo (39%), p<.1 Small, statistically significant reduction in ACS in dronedarone arm bradycardia, QT prolongation, increase in Cr but no increase in pulmonary or thyroid abnormalities ACC/AHA/ESC 26 Guidelines for Treatment of Atrial Fibrillation Catheter Ablation for AF Dronedarone Dronedarone Dronedarone Dronedarone Catheter ablation can relieve sxs and improve QOL in pts with paroxysmal and permanent AF Success rates for AF recurrence highly dependent on mode and intensity of monitoring Trial hard endpoints such as mortality, CHF, hospitalization, CVA, and costs are lacking Relative efficacy of ablation vs. AAD as first line therapy has never been studied Best data in pts with symptomatic AF and no or minimal structural heart disease 4

5 ACC/AHA/ESC 26 Guidelines for Treatment of Atrial Fibrillation Current Ablation Approaches Current guidelines recommend RFCA as a Rx option after AAD failure Ablation targets: Circumferential PV isolation (PVI) LA ablation CFAE ablation Ganglionic plexi ablation Hybrid therapy: RFCA + AADs PVI: Major complications (tamponade, CVA) ~3% Success rates after 1 mo F/U: 85% paroxysmal AF in SR 68% permanent AF in SR Chronic AF: Overall 63% SR after 21 mo F/U structural heart disease: 25% SR structurally normal hearts: 74% SR ~4% require at least 1 repeat ablation Pappone C Circ 21 Sanders P Eur Heart J 27 Current Status of Catheter Ablation for AF Not yet studied as primary therapy Appropriate candidates are symptomatic pts who: have failed at least 1 AAD understand risks of procedures, unknowns of long-term effects Up to 5% of RFCA pts will take AADs anyway No data for D/C of warfarin, thus even after successful ablation, pts are risk stratified by CHADS2 score Taking evidence-based approach may delay some pts for ablation until techniques improve, long-term outcomes are known Magnitude of Sudden Cardiac Death in the U.S. # deaths/year 5, 4, 3, 2, 1, AIDS Breast Cancer Lung Cancer Stroke 1 U.S. Census Bureau, Statistical Abstract of the United States: American Cancer Society, Inc., Surveillance Research, Cancer Facts and Figures Heart and Stroke Statistical Update, American Heart Association. SCD 4 Circulation. 21;14:

6 GROUP Incidence of SCD in Specific Populations HAT: SCD Prevention with AED General population Patients with high coronary-risk profile Patients with previous coronary event Patients with EF < 35%, congestive heart failure Patients with previous out-of-hospital cardiac arrest Patients with previous MI, low EF and VT Incidence of Sudden Death (% of group) 3 1, 2, SCD-HeFT AVID, CASH, CIDS MADIT, MUSTT, MADIT II No. of Sudden Deaths Per Year 3, Most cardiac arrests occur at home HAT (Home External Defibrillator Trial) Bardy G et al. NEJM 28 7,1 pts with anterior MI randomized to home AED vs. no AED All pts had spouse/companion undergo CPR training Median F/U 37 mo, no difference in mortality (6.4% vs. 6.5%) Only 38% of deaths due to VT/VF Why negative results? Less power due to substantially lower overall mortality and SCA than anticipated All received CPR training Only 5% of home SCA were witnessed Myerburg RJ. Circulation.1998;97: The $15 Billion Question Relative Reduction in Mortality (%) Trial Summary: Reduction in All-Cause Mortality with ICDs 7% 6% 5% 4% 3% 2% 1% % Absolute reduction in all-cause mortality ~2% 54% 55% 31% MADIT 1 MUSTT 2 MADIT-II 3 36% COMPANION 4 23% SCD-HeFT 5 1. Moss AJ, et al. N Engl J Med. 1996;335: Buxton AE, et al. N Engl J Med. 1999;341: Moss AJ, et al. N Engl J Med. 22;346: Bristow MR, et al. N Engl J Med. 24;35: Bardy, GH, et al. N Engl. J Med. 25; 352:

7 Incidence of Appropriate Shocks New Risk Stratifiers for SCD Probability of ICD Therapy AVID MADIT-II MADIT SCD-HeFT Myocardial scar quantification: MRI Autonomic dysfunction indices, BNP Genetic predictors: GWAS Microvolt T wave alternans Years after Randomization ICD shock rates overestimate arrhythmic death rates by 2x Recent MWTA Studies Noninvasive test of arrhythmia vulnerability Previous observational studies have shown some promise for negative tests (lower risk) Prospective substudy of SCD-HeFT (Gold MR, et al. Circulation 28) MTWA in 49 of 2,521 pts with EF 35%, NYHA II or III MTWA did not predict the composite primary end point of SCD, sustained VT/VF, or appropriate ICD shock 1% primary event rate in MTWA-negative pts Recent MWTA Studies MASTER trial (Chow T et al. JACC 28) 575 pts meeting MADIT-II criteria (prior MI, EF < 3%) underwent MTWA testing and ICD implantation Over a mean 2.1 y F/U, MTWA failed to discriminate between those who had SCD or ICD shock Total mortality 2x greater in MTWA non-negative pts 7

8 MTWA Testing Not Clinically Useful for SCD Risk Stratification MTWA testing has low predictive power for SCD events MTWA testing does not identify low risk SCD-HeFT or MADIT II type patients Available evidence thus far does not allow for extrapolation to routine clinical use for risk stratification of primary prevention ICD patients Search continues for markers other than ejection fraction for patients at high risk for SCD Prognostic Significance of ICD Shocks All-cause mortality of pts in MADIT II and SCD-HeFT receiving any ICD shocks was 4-6x higher than those without Inappropriate shocks (due to AF or SVT) increased all-cause mortality 2x Adverse psychological consequences Direct myocardial damage VT/VF may be a marker of end-stage heart disease Implications for internists: Optimize AF therapy, esp rate control Optimize CHF therapy Selecting Appropriate Patients for ICD Consideration What to Tell the Patient? ICD implant is often thought of as a life or death decision If we put an ICD in 1 pts with heart disease like yours, over the next 5 years we would expect: 3 pts will die anyway 7-8 pts will be saved by the ICD 1-2 pts will receive unnecessary shocks 5-15 pts will have other complications rest of pts may never use their ICD Removes an opportunity for quick, painless death Some pts will request ICD be turned off to allow for natural death Stevenson, L, et al J Card Fail. 26 Aug;12(6):47-12 Age itself is not a contraindication for consideration of ICD, but less than 2% of pts in trials were > 75 y 8

9 Current State of Cardiac Resynchronization Therapy Current guidelines: NYHA class 3-4 HF, LVEF < 35%, and QRS >12 ms with sxs despite optimal medical therapy Randomized trials and other studies have consistently shown that CRT improves LVEF, QOL, and functional status At least 3% of pts do not benefit from CRT Active research into: Other measures of mechanical dyssynchrony (echo, nuclear) other than wide QRS CRT use in milder HF to forestall progression Recent CRT Studies RethinQ trial (Beshai et al. NEJM 27) CRT in HF pts w/ mechanical dyssynchrony but narrow QRS At 6 mo, no benefit in functional status or HF events MADIT-CRT trial (Moss et al. NEJM 29) ICD vs. CRT-ICD in class I/II HF pts, LVEF< 35%, QRS > 12 ms 41% reduction in HF events with CRT-ICD over 2.5 y FDA Advisory Panel recommends broader CRT indications: NYHA II (LVEF < 35%, LBBB QRS > 12) NYHA I (ischemic, LVEF < 3%, LBBB QRS > 13) What is the Taser? Risks of Taser Use: Background Trade name for stun gun with electrodes ejected as darts High-voltage, low-current stimulation: short-duration (small fraction of a millisecond) repetitive pulses (5-3 pulses/s) 5, V Causes involuntary muscle contractions, intense pain, feeling of exhaustion Eye injury, miscarriage, rhabdomyolysis, brain penetration Risk for cardiac arrhythmias leading to sudden death: Immediate: cardiac capture --> VT, or T shock --> VF Late: pain, adrenaline, acidosis, QT changes Possibility for increase in risk of death due to excited delirium Temporal association with over 3 deaths worldwide >12, law enforcement agencies use Taser Taser claims weapon is non-lethal No regulatory agency oversees Tasers 9

10 Taser Animal Studies 2 Taser-funded swine studies show no VF induction (Lakkireddy, et al JACC 26; McDaniel, et al PACE 25) Taser simulator used 3 independent swine studies show VT and VF induction during Taser discharge (Nanthakumar et al, JACC 26; Dennis et al, J Trauma 27; Walter et al, AED 28) Vector over heart is critical, up to 81% VT/VF rate Taser Human Studies 3 studies in resting, healthy police volunteers, typically Tasered in the back show tolerability Taser-induced rapid ventricular myocardial capture demonstrated by pacemaker (Cao et al, JCE 27) University funded Vector across chest Myocardial capture at >24 bpm Am J Cardiol. 29 Mar 15; 13(6):877-8) Rates of In-Custody Sudden Death p=.34 p=.6 In the real world setting, do Tasers impact rates of: In-custody sudden deaths Lethal force deaths Officer injuries Survey sent to 126 CA agencies recently adopting Tasers and the 1 largest US cities 113 (9%) survey response rate 8 cities confirmed deployment of Taser 9 of 1 largest US cities refused to provide data Events per 1, arrests (44) -4 (49) -3 (5) -2 (5) p=.73-1 (5).93 (47) (4) 2 (5) Years since deployment of Taser (Number of cities contributing data) 3 (29) 4 (19) 5 (9) 1.44 Event rates recorded for each city from 5 y before through 5 y after Taser use Mean rate of in-custody sudden deaths in pre-deployment period =.93/1, arrests Mean rate of in-custody sudden deaths in post-deployment years 2-5 = 1.44/1, arrests Lee BK Tseng ZH. American Journal of Cardiology 29 1

11 Rates of Lethal Force (Firearm) Deaths Rates of Officer Injuries p=.23 p=.3 Events per 1, arrests (18) -4 (19) -3 (21) -2 (21) p= (21) (21) (21) 2 (21) 3 (1) 4 (9) (5) Years since deployment of Taser (Number of cities contributing data) Mean rate of lethal force deaths in pre-deployment period = 6.66/1, arrests Mean rate of lethal force deaths in post-deployment years 2-5 = 9.1/1, arrests Lee BK Tseng ZH. American Journal of Cardiology 29 Lee BK Tseng ZH. American Journal of Cardiology 29 Implications of Taser Research Recommendations for Taser Use Definitive risk for both mechanisms of lethal arrhythmias demonstrated in animal models: VT and VF Vector critically important Taser use is associated with significant early increase in sudden death rates Low absolute risk for sudden death, but not nonlethal Tasers may serve a useful role in law enforcement, but policy should be designed taking into account the risks Due the direct and possible additive risk for lethal events, Tasers should only be deployed for situations in which subjects are in imminent threat of significant harm to self or others Avoid vector across chest Avoid repeated shocks which increase risk for VT/VF Mandate AED availability with Taser use 11

12 Atrial fibrillation Take-Home Points Type of AF should not be taken into account when deciding oral anticoagulation Dabigatran is the first warfarin alternative to show superiority for ischemic stroke and bleeding safety; not yet approved but may be attractive for those with difficulty taking warfarin Rate control is equivalent to rhythm control in pts with and without HF, however due to high recurrence of AF with rhythm control, it remains unknown whether actually achieving SR would result in better outcomes The major reason to pursue rhythm control is to improve symptoms and QOL, not mortality benefit Atrial fibrillation Take-Home Points Dronedarone recently approved for nonpermanent AF (to prevent hospitalizations), but is contraindicated in HF patients; has less efficacy but less side effects relative to amiodarone Guidelines recommend catheter ablation as a second option for patients who are symptomatic and have failed > 1 AAD Ablation patients should be treated with anticoagulation based on CHADS2 score, even after apparent success Take-Home Points Take-Home Points SCD/ventricular arrhythmias CPR remains the most useful intervention for post AMI patients to prevent SCD Microvolt T wave alternans has not proven clinically useful for risk stratification of patients for SCD; the search is ongoing for alternative markers of SCD risk Device therapy ICD patients receiving any shock have a 2-6x higher risk of death, therefore optimizing CHF, AF treatment and rate control are critical Only 8/1 ICD patients will be saved by the ICD over 5 years, thus a realistic and informed discussion of risks and benefits with eligible patients is important CRT has shown a consistent LV remodeling and functional benefit for NYHA III/IV pts with LVEF < 35% and QRS > 12 ms Recent trials show that narrow QRS patients with mechanical dyssnchrony do not benefit from CRT, but HF patients with milder HF (class I/II) do 12

13 Take-Home Points Tasers and sudden death Taser use is associated with a low absolute but significant early increase in sudden death Cardiac vector is critically important for arrhythmic risk 13