3AF: an age related condition Go et al JAMA 2001;285:
4AF: a growing problem Doubling of patients with AF from 1995 to 2030 Reasons for epidemic: Aging population, Improved longevity from CAD, Improved detection, Rising obesity rateDoubling of patients withAF from 1995 to 2030Go et al JAMA 2001;285:
5Risk Factors Clinical: Subclinical: Non-modifiable: Age, Sex, Ethnicity, GeneticModifiable: Htn, DM, CAD, Obesity, OSA, TobSubclinical:LVH, Systolic/Diastolic dysfunction, LA size/functionBNP, CRP
6Obesity and AF RiskAdjusted HR 1.5 with obesity, attributable to increased LA sizeWang et al, JAMA 2004; 292:2471
7Causes of AF Anything that damages or stretches the atria: Htn, Aging Obstructive Sleep Apnea, Pulm DzIschemia, CHF, Myocarditis, Valvular Dz (MS, MR), CABGThyrotoxicosis, Ethanol (Holiday Heart)Obesity BMI>30Accessory PathwayGenetics
8Classifications of AF 1. Paroxysmal: “self terminating” 2. Persistent Episodes of AF <7days.2. PersistentEpisodes of AF >7days3. PermanentRhythm control failed4. “Lone”Describes any of the classifications above that occur in individuals without structural cardiac or pulmonary disease.
9NORMAL RHYTHM AF MORE AF ADVERSE OUTCOMES Once AF begins, there are multiple adverse outcomes and therefore prevention is imperative.There are currently several potentially modifiable risk factors for AF that may provide strategies for population based interventions.
10AF begets AF Electrical Remodeling: Reversible Tachy Cellular Ca load Decrease ARP and WCLTriggered ActivityStructural Remodeling: Not reversibleFibrous tissue deposition Local conduction abnormality ReentryThis is sufficient for AF maintenancePreventable but not reversibleIrreversibility may necessitate early interventionAF is a moving target: if SR maintenance is the intention, earlier intervention may be particularly effective and important.
11The longer we wait to control rhythm the harder it is to regain SR Pts Converted to SR in 3 Mo of Onset Are More Likely to Remain in SR Dittrich HC et al. Am J Cardiol. 1989;63:82%67%Patients in sinus rhythm (%)36%27%1 monthP<.026 monthsP<.07The longer we wait to control rhythm the harder it is to regain SR
12AF causes Histologic Remodeling of Atria as Early as 4 Months Sinus RhythmAFEnlarged atrial cellsSevere myolysisGlycogen accumulationReduction in Connexin 40 expression
13Gap Junctions In heart cells the signal to contract is passed efficiently through gap junctions
14Stroke and AF Framingham data: 4-5 fold increased risk Risk may be higher if silent multi-infarction cognitive impairment includedChronic AF and paroxysmal AF carry same riskStroke associated with AF: more severe with higher mortalityCoumadin only prevents 65% of strokes.
15Prevention of AF AF Genetics (Chromosome 4q25) Predictors (Who is at higher risk?)Sex, Age, BMI, Syst BP, PR interval, MurmurLA size, LV wall thicknessRisk Prediction Models may help identify patients for primary prevention.
16AF Genetics Wolff described three brothers with AF in 1943. Increasing evidence of a heritable component of lone AF.Presence of AF in 1st degree relatives was associated with an increased risk of developing AF.Positive F/H of AF in 1/3 of pts with lone AF indicating that familial AF is more common than previously recognized.
17Having at least 1 affected parent approximately doubled the risk of predicted AF Fox…Benjamin JAMA 2004;291:2851
19Management Medical therapy Ablation Rate control: AVN blockers Rhythm control: Anti-arrhythmicsCVA prevention:WarfarinNew antithromboticsLAA occlusion vs resection.PROTECT-AF (Watchman)AblationCatheter Ablation:AF ablation: PVAI, Substrate modificationAVN ablation and PPMSurgical Ablation
20Other Anticoagulants Xa inhibitor Direct Thrombin Inhibitors: Apixaban ARISTOTLE: Apixaban vs WarfarinAVERROES: Apixaban vs ASA in pts who can’t take coumadinRivaroxaban – RECORD (Canada, Europe 9/08)Direct Thrombin Inhibitors:Dabigatran – PETRO phase III, RE-LY StudyVery few drug-drug interaction (PPIs). No antidote.110mg same CVA but less hge150mg less CVA but same hgeXimelagatran – SPORTIF – as good as Warfarin but not FDA approved due to Liver ToxicitiesIdeal: no drug interactions, no monitoring levels, and has an antidote.
21Dabigatran Direct Thrombin Inhibitor Approved by the FDA in October 19, 2010 for prevention of CVA in AFDose:150 mg twice dailyIf severe renal impairment (CrCl 15-30): 75 mg twice daily (dose Not studied in RELY!!)No specific antidote.Due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity.In life-threatening bleeding: recombinant activated factor VII and prothrombin complex concentrates can be considered.
23New Antiarrhythmic Drugs DronedaroneSimilar to Amiodarone but less lipophilic, no iodine, & half life 24hr.No significant organ toxicitiesRanolazine (Na channel blocker)Alters the trans-cellular late Na current, indirectly prevents the Ca overload, inhibits triggered activityApproved as anti-anginal.Vernakalant (K channel blocker)Atria selectiveAccepted for review by the FDAThe ideal anti-arrhythmic is atria selective.
24Rate Control vs Rhythm Control AFFIRM (AF f/u Investigation of Rhythm Management) , NEJM 2002RACE (Rate Control vs. cardioversion for persistent AF) – NEJM 2002PIAF (Pharmacologic Intervention in Atrial Fibrillation) – Lancet 2000STAF (Strategies of Treatment of Atrial Fibrillation) – JACC 2003HOT CAFÉ ( How to Treat Chronic Atrial Fibrillation) – Chest 2004
25Rate Control vs Rhythm Control Favor attempts to maintain SR:First or infrequent episodes of persistent AFYoung active patientSignificant symptomsDifficult rate controlContraindication to long term warfarinFavor rate control:Asymptomatic sedentary elderly patientContraindication to anti-arrhythmics or ablation
26AFFIRM TRIAL4060 patients Persistent AF Age >65, Mean 70 Other risk factors for stroke Patients with contraindications for anticoagulant therapy were excluded Primary endpoint: all-cause mortality. Mean 3.5 years follow up. For rhythm control group anticoagulant encouraged but could be discontinued
27AFFIRM TRIAL No difference in mortality Similar incidence of stroke: 1% per year in each groupMost strokes occurred in pts off warfarin or subtherapeutic INRAFFIRM Investigators NEJM 2002;347:
28WHAT AFFIRM DOES NOT TELL US Optimal management for:Pts with mod-severe disabling AF symptomsYounger pts with paroxysmal AFOutcome if better tools to maintain sinus rhythm were availableLong-term implications of rate vs rhythm control (mean duration of follow-up only 3.5 years)
29What DOES AFFIRM tell us? Do not stop coumadin in rhythm control pts.Elderly pts with asymptomatic persistent AF are less likely to benefit from antiarrhythmics.Unfortunately we don’t have good antiarrhythmic agents.
30Limitations of the AFFIRM Study May not be applicable to all pts with AF. Results cannot be generalized to :Younger patientsPts without other RF for strokeParoxysmal AFPts with severe symptoms might have been considered unsuitable for a rate control strategy and may not have been enrolled (Selection Bias).In the rhythm control group, continuous anticoagulation was encouraged but could be stopped at the physician’s discretion if SR had been maintained for at least 4-12 weeksMost strokes occurred in pts in whom warfarin was stopped or were sub-therapeuticAverage follow-up was only 3.5 years and treatment of AF is a life-long processA large proportion of pts in the rate control arm remained in SR. Does not reflect typical outcome in pts with AF treated with rate control.
31Rhythm Control In theory converting someone to NSR should: Improve cardiac hemodynamicsPrevent LV dysfunctionMaintain proper cardiac outputReduce risk of thromboembolism -> reduce risk of death
32AF Adversely Affects Qaulity of Life Dorian P et al. J Am Coll Cardiol
33Clinical Trials Showed the Survival Advantage of Sinus Rhythm STAF: The Strategies for Treatment of AF studySR maintained in 30% of rhythm control patientsMortality:2.5% per year in the rhythm control group4.9% per year in rate control groupResult was NOT statistically significantFramingham Heart Study cohortCHF-STATSOLVDDIAMOND
34AF increases mortality Framingham Heart Study cohort : Follow-up of the originalAF was associated with a 1.5- to 1.9-fold mortality risk after adjustment for preexisting cardiovascular conditionsSOLVD: Studies of LV Dysfunction Prevention and Treatment Trial– retrospective analysisEvaluated whether AF in pts with low EF was associated with higher mortality.AF pts had greater:All-cause mortality (34% vs 23%, P < 0.001)
35SR Decreases Mortality DIAMOND: The Danish Investigations of Arrhythmia and Mortality ON Dofetilide study 3028 pts with severe CHF or recent MIPresence of SR was associated with a significant reduction in mortality (RR 0.44, 95% CI, , P < )CHF-STAT : The CHF Survival Trial of Antiarrhythmic TherapyAF pts who converted to SR (n=16) had a lower mortality rate (P = 0.04) than those who did not (n=35)AFFIRM Study Post Hoc Analyses: SR is a Predictor of SurvivalSR was associated with a lower risk of death (47% reduction)Anticoagulant use associated with a decreased risk of death (50% reduction)
36Sustaining Sinus Rhythm Is Associated With Decreased Mortality Reduction in mortality (%)AFFIRMDIAMONDThe AFFIRM Investigators. Circulation. 2004;109: ;Circulation. 2001;104: ; Lancet. 2006;367:
37CAN SINUS RHYTHM IMPROVE SURVIVAL? Predictors ofMortality in AFFIRMEpstein et al, Circulation 2004;109:1509
38CABANA Trial Ablation Vs Anti-Arrhythmic Drug Therapy for AF Designed to test the hypothesis that the treatment strategy of Afib ablation will be superior to current therapy with either rate control or rhythm control drugs for reducing total mortality.3000 Pts randomized to Ablation or Pharmacologic TherapyCABANA Trial will disclose:The role of medical and non-pharmacologic therapies for AFEstablish the cost and impact of therapy on quality of lifeDetermine if AF is a modifiable risk factor for increased mortality.
39AVN ablation and Pacemaker Implantation Advantages:adequate rate control without drugsregularizes ventricular rateDisadvantagesrequires permanent pacemakerfibrillation continues: anticoagulation neededrisk of torsade de pointes early after sudden rate decreaserisk of hemodynamic deterioration from RV pacingGN Kay et al Ablate and Pace J Intervent Card Electrophy 1998Brignole et al Circulation Geelen P, et al. VF and sudden death after AVJ ablation. PACE 1997;20:343–8.Jordaens L, et al. Sudden death and long term survival . Eur J Card EP 1993;21:102–9.Gasparini M, et al. Long-term follow-up after AV ablation…PACE 2000;23:1925–9.Ozcan C, et al. Long-term survival. NEJM 2001;344: 1043–51.
40A New Idea Came AlongHaissguerre et al. NEJM1998;339:659-66
41Mechanistic Approach to AF Ablation- Some Simplifications AF is predominantly driven by the LA.AF is predominantly driven by 2 mechanisms:I. Focal Rapid Firing from the PVs (Paroxysmal AF).II. Multiple Reentry Circuits around anatomical obstacles (Chronic AFIB).
42Ectopic Foci Haissguerre et al. NEJM1998;339:659-66 Chen Circ1999;100:
45Pulmonary Vein Isolation Electrophysiological Breakthroughs From the Left Atriumto the Pulmonary VeinsMichel Haïssaguerre, MD; Dipen C. Shah, MD; Pierre Jaïs, MD; Mélèze Hocini, MD;Teiichi Yamane, MD; Isabel Deisenhofer, MD; Michel Chauvin, MD;Stéphane Garrigue, MD; Jacques Clémenty, MDGoing…Going…Gone !Haïssaguerre, M. et al., Circulation. 2000;102:2463–2465.
49AF ablation How is procedure performed? Out pt, 3-5hr, moderate-heavy sedationDischarged home next amCoumadin mandatory 6-8 weeks afterFour vein sheaths:2 RFV (Lasso, Ablation)LFV (ICE)RIJ (Duo-deca)
50Visualization: Intracardiac Ultrasound Facilitate trans-septal access to LAVisual guidance of catheters at PV ostiumDirect visualization of:PV ostial sizeAnatomic abnormalitiesPericardial effusionThrombusFacilitate safe and rapid transeptal LA accessVisual guidance for placement of diagnostic loop catheter at PV ostiumOptimization of RF energy delivery via “bubble” monitoringDoppler flow assessment of PV flow to assess for stenosisVisualization of PV ostial size, anatomic abnormalities, pericardial effusion, thrombus
51Left Atrial Mapping and Catheter Ablation Visualization: Intracardiac Ultrasound Tenting of the intra-atrial septum during transeptal catheterizationAn 8 Fr model also was announced in June 2004 (?release date?)Transeptal Access to LAAcuNav 10 Fr Phased Array Diagnostic Ultrasound Catheter (by Acuson)
52Left Atrial Mapping and Catheter Ablation Visualization : Intracardiac Ultrasound Optimizing Catheter Placement at PV OsIntracardiac echo facilitates PV isolation by:1. Rendering transseptal access easier and safer.2. Helping in proper placement of the circular mappingcatheter at the vein ostium.3. Optimizing power titration during radiofrequencyenergy delivery through detection of bubbles at thecatheter-tissue interface. Prompt detection of densebubbles (type 2 bubbles) could also prevent impedancerise and avoid the milieu for thrombus formation.In addition, monitoring PV flow velocity offers thepotential to prevent excessive swelling at the PV ostium,which could lead to chronic PV stenosis. In this respect,ablation at the PV ostium should be abortedwhen the PV diastolic flow velocity exceeds 1 m/s.
58So why ablate? Our best drugs are: Only moderately effective (30-50%) Have side effects/toxicitiesMany patients despite adequate rate control remain symptomatic in AFSustaining SR may be associated with decreased mortality
60Risks vs Benefits Potential benefits Potential harm Symptomatic benefitNo need for AADsThromboembolic benefitMortality benefit?Potential harmStrokeLA fluttersTamponadeTE fistulaPV stenosis
61Post Ablation Care Early AF recurrence (not uncommon) 20-50% of patientsMore than half will resolve within 3 mosAntiarrhythmic drugs usually continued for first 2-6 monthsAtrial tachycardias post ablationAnticoagulationHigh risk of CVA in first month post RFARedo procedures in 20% of pts (after 3 mo)
62AF case 1 67y old female, school teacher Recurrent symptomatic AF with RVRAdmitted to hospital several times, twice in 10/08Tachypalpitations several times a weekFailed amiodarone and sotalolAFib RFA 11/08Post RFA:One AF episode 2 days after ablation (blanking period)No tachypalpitations since thenA 2 wk MCOT 2 & 6 months later shows no AFOff amiodarone and coumadin
64AF case 2 Middle age female, Nurse Paroxysmal AF with RVR, once/1-2monthsFailed anti-arrhythmicsA fib ablation in 12/08Follow up:No episodes since ablationMCOT 2/16-2/24 showed 0% AFTikosyn was stopped four months after ablation
65Case 350y old femaleFrequent tachypalpitations, with significant symptomsPropafenone helped a littleDose increased but still significantly symptomaticPalpitations occur if one dose is delayed 2hrMax dose of AA caused metallic taste
67Higher dose only decreased episodes Propafenone 225mgPropafenone 150mg
68A fib ablation 3/09 Follow up: No more palpitations immediately after ablation2 month:No palpitations even when misses AA doseFeels great and more energetic3 months:Propafenone was discontinued three months after ablationRepeat MCOT showed no AF
69Case 4 51y old man with symptomatic persistent AF On amiodarone for >6 moAmiodarone stopped given his age, and 2 mo later started on tikosynAF ablation 3/09
72Case 5 66y old female Persistent symptomatic AF for >1 year Failed multiple AA therapySuccess rate with ablation less than paroxysmal AF
73AF Ablation on 5.28.09 AF burden decreased gradually weeks after PVAI
74Case 6 60 y old man with persistent AF. Amiodarone started 7. 28. 09 Case 6 60 y old man with persistent AF. Amiodarone started DC CV AF ablation
75Case 7 65y old man failed two anti-arrhythmics AF ablation in 5.09
76MCOT 4 months later Propafenone was discontinued
77ConclusionThese advances may yet tip the balance back in favor of a rhythm control strategy.RFA of the PVs has been successful in long-term maintenance of SR, representing a curative strategy that eliminated the need for pharmacotherapy for AF in drug-refractory patients.