Obesity and AF Risk Adjusted HR 1.5 with obesity, attributable to increased LA size Wang et al, JAMA 2004; 292:2471
Causes of AF Anything that damages or stretches the atria: – Htn, Aging – Obstructive Sleep Apnea, Pulm Dz – Ischemia, CHF, Myocarditis, Valvular Dz (MS, MR), CABG – Thyrotoxicosis, Ethanol (Holiday Heart) – Obesity BMI>30 – Accessory Pathway – Genetics
Classifications of AF 1. Paroxysmal: “self terminating” – Episodes of AF <7days. 2. Persistent – Episodes of AF >7days 3. Permanent – Rhythm control failed 4. “Lone” – Describes any of the classifications above that occur in individuals without structural cardiac or pulmonary disease.
NORMAL 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.
AF begets AF Electrical Remodeling: Reversible – Tachy Cellular Ca load Decrease ARP and WCL – Triggered Activity Structural Remodeling: Not reversible – Fibrous tissue deposition Local conduction abnormality Reentry – This is sufficient for AF maintenance – Preventable but not reversible – Irreversibility may necessitate early intervention AF is a moving target: if SR maintenance is the intention, earlier intervention may be particularly effective and important.
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: The longer we wait to control rhythm the harder it is to regain SR Patients in sinus rhythm (%) 82% 36% 67% 27% 1 month P<.02 6 months P<.07
AF causes Histologic Remodeling of Atria as Early as 4 Months Enlarged atrial cells Severe myolysis Glycogen accumulation Sinus Rhythm AF Reduction in Connexin 40 expression
Gap Junctions In heart cells the signal to contract is passed efficiently through gap junctions
Stroke and AF Framingham data: 4-5 fold increased risk Risk may be higher if silent multi-infarction cognitive impairment included Chronic AF and paroxysmal AF carry same risk Stroke associated with AF: more severe with higher mortality Coumadin only prevents 65% of strokes.
Prevention of AF AF Genetics (Chromosome 4q25) Predictors (Who is at higher risk?) – Sex, Age, BMI, Syst BP, PR interval, Murmur – LA size, LV wall thickness Risk Prediction Models may help identify patients for primary prevention. –
AF Genetics Wolff described three brothers with AF in Increasing evidence of a heritable component of lone AF. Presence of AF in 1 st 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.
Having at least 1 affected parent approximately doubled the risk of predicted AF Fox…Benjamin JAMA 2004;291:2851
Management Medical therapy – Rate control: AVN blockers – Rhythm control: Anti-arrhythmics – CVA prevention: Warfarin New antithrombotics LAA occlusion vs resection. – PROTECT-AF (Watchman) Ablation – Catheter Ablation: AF ablation: PVAI, Substrate modification AVN ablation and PPM – Surgical Ablation
Other Anticoagulants Xa inhibitor – Apixaban ARISTOTLE: Apixaban vs Warfarin AVERROES: Apixaban vs ASA in pts who can’t take coumadin – Rivaroxaban – RECORD (Canada, Europe 9/08) Direct Thrombin Inhibitors: – Dabigatran – PETRO phase III, RE-LY Study Very few drug-drug interaction (PPIs). No antidote. 110mg same CVA but less hge 150mg less CVA but same hge – Ximelagatran – SPORTIF – as good as Warfarin but not FDA approved due to Liver Toxicities
Dabigatran Direct Thrombin Inhibitor Approved by the FDA in October 19, 2010 for prevention of CVA in AF Dose: – 150 mg twice daily – If 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.
New Antiarrhythmic Drugs Dronedarone – Similar to Amiodarone but less lipophilic, no iodine, & half life 24hr. – No significant organ toxicities Ranolazine ( Na channel blocker) – Alters the trans-cellular late Na current, indirectly prevents the Ca overload, inhibits triggered activity – Approved as anti-anginal. Vernakalant (K channel blocker) – Atria selective – Accepted for review by the FDA
Rate Control vs Rhythm Control AFFIRM (AF f/u Investigation of Rhythm Management), NEJM 2002 RACE (Rate Control vs. cardioversion for persistent AF) – NEJM 2002 PIAF (Pharmacologic Intervention in Atrial Fibrillation) – Lancet 2000 STAF (Strategies of Treatment of Atrial Fibrillation) – JACC 2003 HOT CAFÉ ( How to Treat Chronic Atrial Fibrillation) – Chest 2004
Rate Control vs Rhythm Control Favor attempts to maintain SR: – First or infrequent episodes of persistent AF – Young active patient – Significant symptoms – Difficult rate control – Contraindication to long term warfarin Favor rate control: – Asymptomatic sedentary elderly patient – Contraindication to anti-arrhythmics or ablation
AFFIRM TRIAL 4060 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
AFFIRM TRIAL No difference in mortality Similar incidence of stroke: 1% per year in each group Most strokes occurred in pts off warfarin or subtherapeutic INR AFFIRM Investigators NEJM 2002;347:
WHAT AFFIRM DOES NOT TELL US Optimal management for: –Pts with mod-severe disabling AF symptoms –Younger pts with paroxysmal AF Outcome if better tools to maintain sinus rhythm were available Long-term implications of rate vs rhythm control (mean duration of follow-up only 3.5 years)
What 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.
Limitations of the AFFIRM Study May not be applicable to all pts with AF. Results cannot be generalized to : – Younger patients – Pts without other RF for stroke – Paroxysmal AF Pts 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 weeks – Most strokes occurred in pts in whom warfarin was stopped or were sub-therapeutic Average follow-up was only 3.5 years and treatment of AF is a life-long process A 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.
Rhythm Control In theory converting someone to NSR should: – Improve cardiac hemodynamics – Prevent LV dysfunction – Maintain proper cardiac output – Reduce risk of thromboembolism -> reduce risk of death
AF Adversely Affects Qaulity of Life Dorian P et al. J Am Coll Cardiol. 2000;36:
Clinical Trials Showed the Survival Advantage of Sinus Rhythm STAF: The Strategies for Treatment of AF study – SR maintained in 30% of rhythm control patients – Mortality: 2.5% per year in the rhythm control group 4.9% per year in rate control group Result was NOT statistically significant Framingham Heart Study cohort CHF-STAT SOLVD DIAMOND
AF increases mortality Framingham Heart Study cohort : Follow-up of the original – AF was associated with a 1.5- to 1.9-fold mortality risk after adjustment for preexisting cardiovascular conditions SOLVD: Studies of LV Dysfunction Prevention and Treatment Trial– retrospective analysis – Evaluated 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)
SR Decreases Mortality DIAMOND: The Danish Investigations of Arrhythmia and Mortality ON Dofetilide study – 3028 pts with severe CHF or recent MI – Presence of SR was associated with a significant reduction in mortality (RR 0.44, 95% CI, , P < ) CHF-STAT : The CHF Survival Trial of Antiarrhythmic Therapy – AF 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 Survival – SR was associated with a lower risk of death (47% reduction) – Anticoagulant use associated with a decreased risk of death (50% reduction)
Sustaining Sinus Rhythm Is Associated With Decreased Mortality DIAMOND AFFIRM Reduction in mortality (%) The AFFIRM Investigators. Circulation. 2004;109: ; Circulation. 2001;104: ; Lancet. 2006;367:
CAN SINUS RHYTHM IMPROVE SURVIVAL? Predictors of Mortality in AFFIRM Epstein et al, Circulation 2004; 109:1509
CABANA 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 Pts randomized to Ablation or Pharmacologic Therapy CABANA Trial will disclose: – The role of medical and non-pharmacologic therapies for AF – Establish the cost and impact of therapy on quality of life – Determine if AF is a modifiable risk factor for increased mortality.
Advantages: – adequate rate control without drugs – regularizes ventricular rate Disadvantages – requires permanent pacemaker – fibrillation continues: anticoagulation needed – risk of torsade de pointes early after sudden rate decrease – risk of hemodynamic deterioration from RV pacing AVN ablation and Pacemaker Implantation GN Kay et al Ablate and Pace J Intervent Card Electrophy 1998 Brignole 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.
Haissguerre et al. NEJM1998;339: A New Idea Came Along
Mechanistic 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).
Ectopic Foci Haissguerre et al. NEJM1998;339: Chen Circ1999;100:
Pulmonary Vein Antral Isolation
Pulmonary Vein Isolation Haïssaguerre, M. et al., Circulation. 2000;102:2463–2465. Going…Going… Gone !
Lt Inferior Pulmonary Vein
Side-by-Side Geometry Electroanatomic Map & 3-D CT: Cranial View ESI Nav-X 3-D Geometry 3-D CT via CardEP (Cranial View) LA Roof Esophagus Left PVs Right PVs LAA
AF ablation How is procedure performed? – Out pt, 3-5hr, moderate-heavy sedation – Discharged home next am – Coumadin mandatory 6-8 weeks after – Four vein sheaths: 2 RFV (Lasso, Ablation) LFV (ICE) RIJ (Duo-deca)
Visualization: Intracardiac Ultrasound Facilitate trans-septal access to LA Visual guidance of catheters at PV ostium Direct visualization of: – PV ostial size – Anatomic abnormalities – Pericardial effusion – Thrombus
Left Atrial Mapping and Catheter Ablation Visualization: Intracardiac Ultrasound Transeptal Access to LA Tenting of the intra-atrial septum during transeptal catheterization AcuNav 10 Fr Phased Array Diagnostic Ultrasound Catheter (by Acuson)
Left Atrial Mapping and Catheter Ablation Visualization : Intracardiac Ultrasound Optimizing Catheter Placement at PV Os
Trans-septal Puncture with LA entry
Intracardiac Echo Tenting of Interatrial septumEsophagus posterior to LA
Lasso on Lt Inf PV
Lasso on Lt Sup PV
So why ablate? Our best drugs are: – Only moderately effective (30-50%) – Have side effects/toxicities Many patients despite adequate rate control remain symptomatic in AF Sustaining SR may be associated with decreased mortality
AF ablation Pappone, JACC, 2003
Risks vs Benefits Potential benefits Symptomatic benefit No need for AADs Thromboembolic benefit Mortality benefit? Potential harm Stroke LA flutters Tamponade TE fistula PV stenosis
Post Ablation Care Early AF recurrence (not uncommon) –20-50% of patients –More than half will resolve within 3 mos –Antiarrhythmic drugs usually continued for first 2-6 months Atrial tachycardias post ablation Anticoagulation –High risk of CVA in first month post RFA Redo procedures in 20% of pts (after 3 mo)
AF case 1 67y old female, school teacher Recurrent symptomatic AF with RVR – Admitted to hospital several times, twice in 10/08 – Tachypalpitations several times a week Failed amiodarone and sotalol AFib RFA 11/08 Post RFA: – One AF episode 2 days after ablation (blanking period) – No tachypalpitations since then – A 2 wk MCOT 2 & 6 months later shows no AF – Off amiodarone and coumadin
MCOT 2mo after ablatioin
AF case 2 Middle age female, Nurse Paroxysmal AF with RVR, once/1-2months Failed anti-arrhythmics A fib ablation in 12/08 Follow up: – No episodes since ablation – MCOT 2/16-2/24 showed 0% AF – Tikosyn was stopped four months after ablation
Case 3 50y old female Frequent tachypalpitations, with significant symptoms Propafenone helped a little – Dose increased but still significantly symptomatic – Palpitations occur if one dose is delayed 2hr – Max dose of AA caused metallic taste
Higher dose only decreased episodes Propafenone 225mgPropafenone 150mg
A fib ablation 3/09 Follow up: – No more palpitations immediately after ablation – 2 month: No palpitations even when misses AA dose Feels great and more energetic – 3 months: Propafenone was discontinued three months after ablation Repeat MCOT showed no AF
Case 4 51y old man with symptomatic persistent AF On amiodarone for >6 mo Amiodarone stopped given his age, and 2 mo later started on tikosyn AF ablation 3/09
MCOT 2 months post RFA
Remains AF free 5 months after
Case 5 66y old female Persistent symptomatic AF for >1 year Failed multiple AA therapy Success rate with ablation less than paroxysmal AF
AF Ablation on AF burden decreased gradually weeks after PVAI
Case 6 60 y old man with persistent AF. Amiodarone started DC CV AF ablation
Case 7 65y old man failed two anti-arrhythmics AF ablation in 5.09
MCOT 4 months later Propafenone was discontinued
Conclusion These 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.