EP Summit 2014: Atrial Fibrillation: Rate or Rhythm Control

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Tristram Bahnson, MD

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EP Summit 2014: Atrial Fibrillation: Rate or Rhythm Control

  1. 1. Rate vs Rhythm Control in 2014 a moving target Tristram D. Bahnson, MD Professor of Medicine, Duke University Director, Duke Center for Atrial Fibrillation Duke University Medical Center
  2. 2. Disclosures •  Grant support –  –  –  –  NIH; NHLBI Medtronic Boston Scintific St. Jude Medical •  Consulting –  ChanRx
  3. 3. AFFIRM Trial Primary Endpoint: All-Cause Mortality 30 P=0.08 25 20 Rhythm control Mortality 15 (%) Rate control 10 total N=4060 5 0 0 Deaths (no.) Rhythm Rate 1 2 3 4 5 257 (13) 210 (11) 314 (18) 275 (16) 352 (24) 306 (21) Years 0 0 80 (4) 78 (4) 175 (9) 148 (7) AFFIRM Investigators: NEJM 347:1825, 2002
  4. 4. Rate vs Rhythm Control in HF Patients Patients with heart failure, depressed EF (27%), 2/3 persistent AF. Total N=1376 Roy et al. N Engl J Med 2008;358:2667-77
  5. 5. AFFIRM, RACE, AF-CHF Rhythm control and rate control are equivalent therapy strategies for: -Elderly patients (69.7±9y) with normal EF (AFFIRM); 1/3 new onset -Elderly patients (68±9y) with persistent AF (309-337 d median duration) and normal EF (RACE) -Elderly patients (66-67±11) with AF (33-30% PAF) and HF (EF 27±6) (AF-CHF)
  6. 6. Safety of Rate Control 62 72
  7. 7. Warfarin Use in AFFIRM 100 Warfarin Use (%) 80 60 Rate Rhythm 40 20 0 1 2 3 4 5 Follow-up (years) O’Hara GE, et al. Am J Cardiol. 2005;815-21.
  8. 8. Stroke occurrence in prior trials Trial n % Pts in SR Followup (yrs) Age Stroke/Embolism (%) (rate vs rhythm) Rate Rhythm AFFIRM (2002) 4060 3.5 70±9 35 vs 63 4.3 4.6 RACE (2002) 522 2.3 68±9 10 vs 39 2.7 6 200 1.6 66±8 11 vs 26 2 5 205 1.7 61±11 NR vs 64% 1 2.9 STAF (2003) HOT CAFÉ (2004) Fuster et al. ACC/AHA/ESC Practice Guidelines. JACC (2006)
  9. 9. Poor Efficacy of AA drugs for AF control Verma & Natale, Circulation 2005;112:1214
  10. 10. Safety Outcome for AF Drug Therapy (Meta Analysis) Overall Outcomes Mortality Death overall Sudden death Treatment-related death Not treatment-related death Adverse events CV events Bradycardia GI Neuropathy Thyroid dysfunction Torsades Q-T prolongation Total no. of pt with events Discontinuations Total Due to AE Due to inefficacy Due to noncompliance Calkins et al: Circ A&E 2:349, 2009 t No. % 33 21 22 20 120/4291 18/2900 15/3179 40/3023 2.8 0.6 0.5 1.3 10 19 16 4 5 12 12 24 58/1572 44/2349 97/1499 48/969 19/576 16/2238 5/2034 989/3318 3.7 1.9 6.5 5.0 3.3 0.7 0.2 29.8 32 32 12 4 1035/4347 384/3682 229/1694 19/457 23.8 10.4 13.5 4.2
  11. 11. •  Factors to consider: –  These studies did not show inferiority of rhythm control or superiority of rate control –  “young” subjects were not included – limited generalizability –  In AFFIRM and RACE the majority of strokes in rhythm control occurred with patient off anticoagulation or with sub-therapeutic anticoagulation; anticoagulation use was less in the rhythm control arms •  Race – 29/35 strokes occurred in those off anticoagulation or with sub-therapeutic anticoagulation •  AFFIRM – most patients treated with rhythm control and deemed to be in NSR had warfarin stopped after about 1 month –  Rhythm control success was limited and many patients analyzed by ITT in the rhythm control arm had a significant burden of AF (NSR: RACE 39%, AFFIRM 63% at 5y) –  AA drugs have toxicity and amiodarone use was high for rhythm control treated patients (AF-CHF 82%; RACE 32% of those in whom NSR maintained; AFFIRM ≈ 2/3 had amiodarone at some time)
  12. 12. Rate v Rhythm Control Revisited: a large retrospective case control study •  •  26,130 patient in Quebec with first hospitalization for AF/first treatment of AF from 1/1/1999 – 3/31/2007; average f/u 3.1±2. y Age >66; mean age 77 (rhythm) and 80 (rate); about half with CHD and about half with HTN Ionescu-Ittu. Arch Intern Med 2012;172(13):997
  13. 13. Therapy History for AF
  14. 14. How might ‘new’ therapies alter the riskbenefit analysis of Rate vs Rhythm control; is there mortality benefit of any particular therapy? What is the role of non-pharmacologic therapies such as LA ablation for AF?
  15. 15. Maintenance of NSR with Dofetilide (SAFIRE-D) Structural HD in 57-77% Singh et al. Circulation. 2000;102:2385-2390 TDB Duke EP
  16. 16. Dofetilide is Safe in Individuals with Structural Heart Disease •  TdP in 3.3% (4.8% before adjusting dose; 2.9% after) •  All patients with CHF; most with class II or III Sx’s •  Pederson et al. Circulation 2001;104:292 - no increase in mortality in subset of patients with AF/AFL receiving dofetilide Torp-Pedersen et al. New England Journal of Medicine. 341(12):857-65, 1999 Sep 16 TDB Duke EP
  17. 17. Initiation of Atrial Fibrillation by Ectopic Atrial Tachycardia Originating in Pulmonary Veins - II Sites of 69 ectopic atrial tachycardia foci associated with AF Haissaguerre et al. NEJM 1998;339:659
  18. 18. Anatomy of Pulmonary Veins: Muscular Sleeves From Saito, Waki, and Becker J Cardiovasc Electrophysiol 2000;11:66 Adapted from J .M .T . de Bakker et al . / Cardiovascular Research 2002;54:287– 294
  19. 19. PV Muscle Tissue is Unique •  Short Refractory Period -- enable rapid AT’s (S Nattel, Montreal Heart) •  Enhanced Automaticity – enable rapid AT’s (S Nattel, Montreal Heart) •  Localized near sites of cardiac autonomic innervation – ganglionated plexi (GP’s) (BJ Scherlag, Univ. Oklahoma)
  20. 20. TDB Duke EP
  21. 21. PV in “fib” with exit block TDB Duke EP
  22. 22. Ablation Works for Rhythm Control in Drug Refractory Patients * *primary therapy Piccini et al. Circ Arrhythm Electrophysiol. 2009;2:626-633.)
  23. 23. Restoration of NSR may Improve Survival (DIAMOND substudy) 148 dofetilide treated and 86 placebo, of 506/1518 in AF/AFL, converted. Of these, maintenance of NSR associated with decreased mortality Pederson et al. Circulation 2001;104:292
  24. 24. AFFIRM Survival by Actual Rhythm 0.39 0.5 P<0.001 0.72 Sinus 0.37 0.5 0.69 Warfarin 1.49 AAD 1.06 Age (per year) 1.57 CHF 1.56 CAD 0.25 0.50 0.75 1.00 1.25 Higher survival 1.50 1.75 2.00 Lower survival Hazard ratio N=3,677 AFFIRM Investigators, Circulation 2004;109:1509
  25. 25. While ablation has been shown to improve symptoms in drug refractory patients, it is not known whether ablation will impact long term health or health care costs; what is the impact of ablation on hospitalization, stroke and cost? What about mortality?
  26. 26. Mortality and AF Therapy: Randomized Trials of RFA vs AAD where deaths reported * ** § § § “post hoc” analyses; N=930; *chronic AF; **DM only; §First line Rx Dagres et al. AHJ 2009;158:15
  27. 27. Does AF Ablation Reduce Mortality or Stroke? Mortality Stroke 4,212 prospectively followed consecutive AF ablation patients compared to: 16,848 age/gender matched controls with AF (no RFA) and 16,848 age/gender matched controls w/o AF Bunch et al. JCE 2011;22:839-845
  28. 28. Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA)
  29. 29. Design of the CABANA Pivotal Study Inclusion Criteria Atrial fibrillation Warranting Therapy •  ≥2 paroxysmal AF episodes (≥1 hour) over 6 mos or >1 persistent AF episode (>1 week) •  ≥65 yr of age, or <65 yr with ≥1 risk factors Hypertension >65 yr of age or <65 yr with ≥1 CVA risk factor Eligible for ablation and/ or drug therapy N=1100 Drug Rx and AC •  Rate control •  Rhythm Rx N=1100 R 1° ablation & AC •  PV isolation •  Adjunctive Follow-up CABANA Study; ACC 2010, modified 2013 Diabetes Heart failure Prior CVA or TIA LA size >5.0 cm (Vol In ≥40 cc/m2) EF ≤35 % •  Eligible for ablation and ≥2 rhythm control and/or ≥2 rate control drugs Endpoints (Pivotal): Primary – Composite of Death, disabling stoke, serious bleeding, cardiac arrest Secondary – total mortality; total mortality or CV hospitalization; total mortality, stroke, or CV hospitatlization; stroke, CV cause specific death; AF burden, QOL, Cost Sub-studies – CABANA gene; CT / MRI LA substrate/remodelling
  30. 30. Any patient with AF > 65 years old OR Any patient with AF < 65 years old with a CHADS2 score of greater than 0*, or left atrial enlargement could be eligible *If under 65 and the only risk factor is HTN, they must also have LVH
  31. 31. CABANA Enrollment Distribution Status (as of October 25, 2013) Patients Randomized U.S. Germany Russia Italy China Canada United Kingdom South Korea Czech Republic Australia As of 1/24/14, 1409 1308 824 (63%) 188 (14%) 135 (10%) 40 ( 3%) 35 ( 3%) 30 ( 2%) 21 ( 2%) 18 ( 1%) 9 (<1%) 8 (<1%)
  32. 32. Rate vs Rhythm Control in 2014 RATE •  Advantages RHYTHM •  –  Implementation does not require INPT hospitalization –  Drugs have low toxicity –  Reduced utilization –  HR not dependent on SN function •  –  Optimization of C.O., eliminate Sx’s –  Assured adequate ‘rate control’ and avoidance of tachycardia-mediated myopathy –  Achieve best functional capacity and QoL –  Prevent future atrial fibrosis –  Long term health benefits? Disadvantages –  Rate control might not be achieve able –  Variable loss in functional capacity if diastolic/systolic HF or very active –  Drugs have significant side effects, poor QoL with BB, CA blocker –  Atrial remodelng will occur limiting ability to achieve NSR if desired or required in the future –  Possible increased mortality and/or stroke risk? Advantages •  Disadvantages –  Therapies have toxicity or risk •  •  •  Pro-arrhythmia Extra-cardiac effects of AA drugs (minimized with newer agents) Procedural complications –  INPT care and increased utilization •  •  •  Drug loading Procedures DCCV’s –  May unmask SND; need for pacemaker
  33. 33. Rhythm Control with Drug vs Ablation in 2014 DRUG •  Advantages ABLATION •  –  Initial cost low –  Newer agents with limited extra-cardiac toxicity, well tolerated •  –  When successful, restoration of NSR and peak functional capacity without ongoing cumulative toxicity or side effects of therapy –  Together with surgical ablation, only options for drug refractory symptomatic patients –  Possible reduction in mortality and stroke? Disadvantages –  Long term cumulative risks •  •  Pro-arrhythmia Toxicity –  Long term cost –  Efficacy failures are common •  •  Adjunctive DCCV Adjunctive rate control therapy needed –  Exacerbate SND, brady-arrhythmias –  Drug side effects QoL •  •  •  •  •  •  •  Neurologic Bradycardia Dysguesia Liver Lung Thyroid photosensitivity Advantages •  Disadvantages –  Invasive with procedural risk •  •  •  •  Stroke (symptomatic and asymptomatic) PV stenosis Cardiac perforation/tamponade Collateral thoracic injury –  –  –  –  –  ESO injury Phrenic nerve injury Pulmonary injury Pericarditis Gastroparesis –  Efficacy failures are not uncommon •  •  Adjunctive AA drug use Adjunctive rate control therapy often needed
  34. 34. Who should get rhythm control •  Patients with symptoms not alleviated by rate control –  Remember patients can become accustomed to mild to moderate reduction in C.O. •  Patients with uncontrolled V rates independent of initial symptom status •  ? Young patients who would have a long exposure to AF with a rate control strategy – cardiac remodeling –  LA size –  QoL
  35. 35. The fundamental challenge of contemporary AF care is to individualize assessment of the risks vs benefits of rate vs rhythm control in order to choose the ‘best’ overall treatment strategy for the patient, and if rhythm control is recommended, to choose the least risky and most efficacious approach based on the patient’s clinical characteristics. Ongoing treatment decisions are often iterative and depend upon the patients history of response to therapy. As therapy options evolve, so will the relative merits of Rate vs Rhythm control
  36. 36. thank you !

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