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Atrial Fibrillation The Last Big Hurdle in Treating SVT

Atrial Fibrillation The Last Big Hurdle in Treating SVT. Esam Baryun , MD, FACC, FHRS. Ever Felt Like This?. AF: an age related condition. Go et al JAMA 2001;285:2370-2375. AF: a growing problem. Doubling of patients with AF from 1995 to 2030. Go et al JAMA 2001;285:2370-2375.

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Atrial Fibrillation The Last Big Hurdle in Treating SVT

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  1. Atrial FibrillationThe Last Big Hurdle in Treating SVT EsamBaryun, MD, FACC, FHRS

  2. Ever Felt Like This?

  3. AF: an age related condition Go et al JAMA 2001;285:2370-2375

  4. AF: a growing problem Doubling of patients with AF from 1995 to 2030 Go et al JAMA 2001;285:2370-2375

  5. Risk Factors • Clinical: • Non-modifiable: Age, Sex, Ethnicity, Genetic • Modifiable: Htn, DM, CAD, Obesity, OSA, Tob • Subclinical: • LVH, Systolic/Diastolic dysfunction, LA size/function • BNP, CRP

  6. Obesity and AF Risk Adjusted HR 1.5 with obesity, attributable to increased LA size Wang et al, JAMA 2004; 292:2471

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. Pts Converted to SR in 3 Mo of Onset Are More Likely to Remain in SRDittrich HC et al. Am J Cardiol. 1989;63:193-197 82% 67% Patients in sinus rhythm (%) 36% 27% 1 month P<.02 6 months P<.07 The longer we wait to control rhythm the harder it is to regain SR

  12. AF causes Histologic Remodeling of Atria as Early as 4 Months Sinus Rhythm AF Enlarged atrial cells Severe myolysis Glycogen accumulation Reduction in Connexin 40 expression

  13. Gap JunctionsIn heart cells the signal to contract is passed efficiently through gap junctions

  14. 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.

  15. 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. • www.framinghamheartstudy.org/risk/index.html

  16. AF 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.

  17. Having at least 1 affected parent approximately doubledthe risk of predicted AF Fox…Benjamin JAMA 2004;291:2851

  18. Therapeutic Options

  19. 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

  20. Other Anticoagulants • Xa inhibitor • Apixaban • ARISTOTLE: ApixabanvsWarfarin • AVERROES: Apixabanvs 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

  21. 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.

  22. Anti-arrhythmic Choice

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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 TRIAL AFFIRM Investigators NEJM 2002;347:1825-33

  28. 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)

  29. 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.

  30. 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.

  31. 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

  32. AF Adversely Affects Qaulity of Life Dorian P et al. J Am Coll Cardiol. 2000;36:1303-1309

  33. 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

  34. 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)

  35. 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, 0.30-0.64, P < 0.0001) • 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)

  36. Sustaining Sinus Rhythm Is Associated With Decreased Mortality Reduction in mortality (%) AFFIRM DIAMOND The AFFIRM Investigators. Circulation. 2004;109:1509-1513;Circulation. 2001;104:292-296; Lancet. 2006;367:262-272.

  37. CAN SINUS RHYTHM IMPROVE SURVIVAL? Predictors of Mortality in AFFIRM Epstein et al, Circulation 2004; 109:1509

  38. CABANA TrialAblation 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 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.

  39. AVN ablation and Pacemaker Implantation • 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 GN Kay et al Ablate and Pace J Intervent Card Electrophy 1998 Brignole et al Circulation 1998. 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.

  40. A New Idea Came Along Haissguerre et al. NEJM1998;339:659-66

  41. 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).

  42. Ectopic Foci Haissguerre et al. NEJM1998;339:659-66 Chen Circ1999;100:1879-86

  43. AF ablation

  44. Pulmonary Vein Antral Isolation

  45. Pulmonary Vein Isolation Going… Going… Gone ! Haïssaguerre, M. et al., Circulation. 2000;102:2463–2465.

  46. Lt Inferior Pulmonary Vein

  47. Side-by-Side GeometryElectroanatomic Map & 3-D CT: Cranial View Esophagus Left PVs Right PVs LA Roof LAA ESI Nav-X 3-D Geometry 3-D CT via CardEP (Cranial View)

  48. 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)

  49. 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

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