Controversies with regard to 'upstream therapy of atrial fibrillation Barbara Casadei Department of Cardiovascular Medicine John Radcliffe Hospital University of Oxford No conflict of interest to declare
Ionic remodelling in atrial fibrillation iapd and atrial ERP iwave length Re-entry icontraction
Upstream treatment of atrial fibrillation is aimed at molecular targets that are upstream (or independent) of ion channels RAS inhibition Omega-3 Fatty Acids Statins Wholistic Added value (lowering BP & lipids, antiinflammatory effects) Safer (less likely to be pro-arrhythmic)
AF: one arrhythmia, different substrates Focal activity Lone /Paroxysmal AF Electrical Remodelling AERP shortening icontractility RAS inhibition LV dysfunction/lvh Atrial Structural Remodelling Fibrosis Metabolic changes Atrial Structural Remodelling Sustained Atrial Fibrillation
Angiotensin II Antagonist Prevents Electrical Remodeling in Atrial Fibrillation Nakashima et al. Circ 2000
Candesartan has no effect on atrial electrical and structural remodelling in a goat model of lone AF Atrial effective refractory period Duration of burst pacing required to induce AF Hall et al. JRAAS 2010
Valsartan in the secondary prevention of AF Kaplan-Meier Curves for the Time to the First Recurrence of Atrial Fibrillation 1442 patients at least 40 y of age with either 2 or more episodes of symptomatic AF in the previous 6 months (40%) or a successful AF cardioversion 14 2 days before randomization (88%), in addition to: heart failure or left ventricular dysfunction (LVEF<40%); 8% hypertension > 6 months; 85% type 2 diabetes; 15% stroke or peripheral artery disease; 4% coronary artery disease; 15-9% AF with left atrial dilatation; 12% The GISSI-AF Investigators. N Engl J Med 2009
Secondary prevention of AF by RAS Inhibition Using the log-rank method 0.83 (0.69, 0.99) Modified from Schmieder et al. JACC 2010 Pretreatment with ACEIs and ARBs may be considered in patients with recurrent AF undergoing electrical conversion and receiving antiarrhythmic drug therapy ARBs or ACEIs may be useful for prevention of recurrent paroxysmal AF or in patients with persistent AF undergoing electrical cardioversion in the absence of significant structural disease if these agents are indicated for other reasons; eg, hypertension IIb IIb B B
AF: one arrhythmia, different substrates Focal activity Lone /Paroxysmal AF Electrical Remodelling AERP shortening icontractility RAS inhibition LV dysfunction/lvh Atrial Structural Remodelling Fibrosis Metabolic changes Atrial Structural Remodelling Sustained Atrial Fibrillation
ACE inhibition prevents atrial structural remodelling and AF in dogs with ventricular tachypacing (VTP)-induced heart failure Control Atrial Conduction Heterogeneity Index VTP VTP+Enalapril VTP VTP + Enalapril Control Li et al Circulation 2001
Primary prevention of AF in CHF by RAS Inhibition Modified from Schmieder et al. JACC 2010 Using the log-rank method 0.67 (0.58, 0.79) ACEIs and ARBs should be considered for prevention of new-onset AF in patients with heart failure and reduced ejection fraction ACEIs and ARBs should be considered for prevention of new-onset AF in patients with hypertension, particularly with left ventricular hypertrophy IIa IIa A B
Summary Inhibition of the RAS prevents the new onset of AF in patients with LVH or failure but these are mostly ancillary findings... Whether RAS inhibition is effective in the secondary prevention of AF (postcardioversion) remains uncertain Better AF detection? Longer follow-up? Earlier intervention? Data in patients with PAF are promising but inconclusive...awaiting the results of ANTIPAF (RCT of olmesartan in PAF) Tuesday HotLine
0.60 0.70 0.80 0.90 1.00 Omega-3 Fatty Acid and AF Epidemiological Evidence The Cardiovascular Health Study Tuna or Other Broiled or Baked Fish 5+/wk 1-4/wk 1-3/mo <1/mo The Rotterdam Study 0 2 4 6 8 10 12 Years N= 4,815 >65 yrs; follow up12 yrs. Mozaffarian et al., Circulation 2004 N=5,184 >55 yrs; follow up:6.4 yrs. Brower et al. Am Heart J 2006
AF: one arrhythmia, different substrates Focal activity Omega-3 fatty acid LV dysfunction/lvh Lone /Paroxysmal AF Electrical Remodelling AERP shortening icontractility Atrial Structural Remodelling Fibrosis Metabolic changes Atrial Structural Remodelling Sustained Atrial Fibrillation
Omega-3 Fatty Acids prevent AF associated with HF but not atrial tachycardia remodelling Sakabe et al. Circulation 2007
Where does this leave us? The effect of Omega-3 on AF prevention in patients with HF remains to be directly investigated. However, the results of the post-hoc analysis of the GISSI-HF trial (6,975 patients, NYHA Class II-IV) will be communicated soon. Some (but not all) trials in patients undergoing cardiac surgery have suggested a beneficial effect of Omega-3 in preventing post-operative AF.
A randomized, double-blind, placebo controlled clinical trial to determine whether perioperative administration of oral n-3 PUFA (8 g over 2-4 days pre-op and then 2 g/d for 10 days or until hospital discharge) reduces the occurrence of postoperative AF in 1,516 patients undergoing cardiac surgery FOR ARD Trial A randomized, double-blind, placebo controlled clinical trial to evaluate the effect of oral n-3 PUFA in the secondary prevention of AF (entry criteria similar to those in the GISSI-AF Valsartan Trial)
Inflammation, oxidative stress, and atrial remodelling in AF + ATRIAL FIBRILLATION RAPID ATRIAL ACTIVATION INFLAMMATION & OXIDATIVE STRESS AF begets AF ELECTROPHYSIOLOGICAL REMODELLING
Inflammation, oxidative stress, and AF There is evidence of enhanced oxidative stress in atrial samples from patients with AF (Mihm et al. Circ 2001) There is a correlation between oxidative stress and atrial ERP shortening in animal models (Carnes et al. Circ Res 2004) Treatment with anti-oxidant/anti-inflammatory agents prevents atrial ERP shortening and AF in a dog model of atrial tachypacing (Carnes et al. Circ Res 2001, Shiroshita-Takeshita et al. Circ Res 2004)
AF: one arrhythmia, different substrates Focal activity Lone /Paroxysmal AF Electrical Remodelling AERP shortening icontractility Inflammation & Oxidative stress LV dysfunction/lvh Atrial Structural Remodelling Fibrosis Metabolic changes Atrial Structural Remodelling Sustained Atrial Fibrillation
AF: one arrhythmia, different substrates Focal activity Statins LV dysfunction/lvh Lone /Paroxysmal AF Electrical Remodelling AERP shortening icontractility Atrial Structural Remodelling Fibrosis Metabolic changes Atrial Structural Remodelling Sustained Atrial Fibrillation
Statins and AF Treatment with simvastatin prevents atrial ERP shortening and AF in the dog model of fast atrial pacing (Shiroshita-Takeshita et al. Circ Res 2004) Atrial pacing + simvastatin Atrial pacing
57% vs. 35%; OR 0.39 95% CI [0.18-0.85] P=0.003
Effect of statins on post-operative AF Chen et al. J Thorac Cardiovasc Surg. 2010 Statins should be considered for prevention of new-onset AF after coronary artery bypass grafting, isolated or in combination with valvular interventions IIa B
Atrial Fibrillation: statin vs. control Long-term 'hypothesis-testing' trials (published + unpublished) Study Statin No. (%) events Control Odds ratio (OR), statin vs control, and 99% or 95% confidence interval (CI) WOSCOPS 12 (0.4%) 21 (0.6%) AFCAPS/TexCAPS 20 (0.6%) 26 (0.8%) GISSI-P 16 (0.7%) 12 (0.6%) ALLHAT-LLT 85 (2.0%) 82 (1.9%) HPS 193 (1.9%) 177 (1.7%) LIPS 23 (2.7%) 16 (1.9%) PROSPER 283 (9.8%) 264 (9.1%) ASCOT-LLA 2 (0.0%) 3 (0.1%) ALLIANCE 29 (2.4%) 31 (2.5%) CARDS 27 (1.9%) 32 (2.3%) PREVEND IT 8 (1.8%) 8 (1.9%) PCAB 2 (1.2%) 0 (0.0%) 4D 38 (6.1%) 50 (7.9%) MEGA 36 (0.9%) 33 (0.8%) ASPEN 38 (3.1%) 45 (3.8%) Sola et al. 6 (11.1%) 5 (9.3%) GISSI-HF 258 (13.9%) 294 (16.0%) ATAHEB 3 (5.8%) 10 (18.5%) Vrtovec et al. 7 (12.7%) 10 (18.2%) METEOR 4 (0.6%) 0 (0.0%) JUPITER 145 (1.6%) 171 (1.9%) Subtotal: 21 trials 1235 (2.3%) 1290 (2.5%) 0.95 (0.88, 1.03) p = 0.24 Heterogeneity test: c = 21.9 (p=0.35) 20 99% or 95% CI Courtesy of Rahimi, Emberson et al Statin better 0.5 1 2 3 Control better
Summary Perioperative treatment with statins decreases the incidence of post-operative AF in statin-naïve patients undergoing cardiac surgery Will this beneficial effect be seen in patients on chronic statin treatment? Are these findings applicable to all patients with raised inflammatory markers?
Upstream treatment of AF: Controversial or work in progress? AF has many different aetiologies upstream treatment may target specific substrates Majority of available evidence is hypothesis generating rather than conclusive several RCTs will report in the next few years Added value vs. Added Hazard : upstream treatment of AF may improve patients outcome, independently of its effect on heart rhythm.
Atrial Fibrillation: statin vs. control Short-term trials (published only) Study Statin No. (%) events Control Odds ratio (OR), statin vs control, and 99% or 95% confidence interval (CI) Tveit et al. 18 (35.3%) 17 (33.3%) MIRACL 93 (6.0%) 96 (6.2%) Dernellis et al. 14 (35.0%) 36 (90.0%) ARMYDA-3 35 (34.7%) 56 (56.6%) Chello et al. 2 (10.0%) 5 (25.0%) Ozaydin et al. 3 (12.5%) 11 (45.8%) Garcia-Fernandez et al. 15 (55.6%) 10 (40.0%) Song et al. 8 (12.9%) 17 (27.4%) Mannacio et al. 18 (18.0%) 35 (35.0%) Tamayo et al. 0 (0.0%) 1 (4.5%) Almroth et al. 54 (48.6%) 64 (57.7%) Subtotal: 11 trials 260 (12.4%) 348 (16.6%) 0.65 (0.53, 0.79) p < 0.0001 Heterogeneity test: c = 39.3 (p<0.0001) 10 99% or 95% CI 0.5 1 2 3 Statin Control better better