First question: Does CRT Work in AF?

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CRT in AF Does it work and when to ablate AF versus AV node Maurizio Gasparini Chief EP and Pacing Unit Humanitas Research Hospital, Rozzano - Milano, Italy

First question: Does CRT Work in AF? As any machine If optimal working CRT is expected! you need optimal settings and conditions Whitout fuel Even a Ferrari cannot work

Guidelines requires optimal medical therapy in HF, e. the maximum tolerate dosage!! Could you consider OPT the prescription of carvedilol.25 mg ¼ tablet b.i.d.?! In the same way, to cure HF with CRT, we should hieve maximum biventricular pacing (i.e. 100%)!! To achieve 100% BIV pacing 1) in SR pts Would CRT be effective in SR + AV delay of 300 msec?! natural AV conduction! no BIV pacing! no CRT 2) in AF pts?!

AF and CRT (problems for CRT delivery)! intrinsic, irregular spontaneous ventricular rhythm " % of effectively BIV paced captured beats;! during effort, reduced % of BIV pacing;! interference of fusion or pseudo-fusion beats Surface ECG Atrial EGM RV EGM Biventricular pacing! possible negative impact on prognosis of using negative chronotropic therapy.

So does CRT Work in persistent / permanent AF? JACC 2006 JACC 2006 # Due to lack of RCTs, European GL based on several observational studies concerning CRT-AF pts in the last yrs

JACC 2008 1 subgroup of RCT (MUSTIC 2002) 4 prospective cohort studies 1164 pts 797 SR 367 AF SR vs AF

# Finally in 2012 a RCT 1798 patients 229 AF randomized to ICD or CRT-D CRT-D (n =114) ICD (n =115) AF CRT-D AF ICD

# No difference in primary outcome of death or HF hospitalization # Borderline HF hosp in CRT versus ICD # No effect on mortality rate

1) RAFT trial not designed to evaluate CRT effect in AF pts 2) 3) Only 1/3 of AF pt had BIV pacing more than 95% time

Conceptual difference between simply implant a CRT device in AF patients and cure AF patients with CRT. As previously reported BIV pacing % may be compared to OPT! maximized drug therapy! 100% BIV pacing desirable In RAFT, AF pts RECEIVED CRT! NOT ADEQUATE WORKING CONDITIONS and were not cured with CRT

D Hayes Perfect (complete) BIV delivery Ineffective BIV delivery good (acceptable) BIV delivery Less than 5% difference of BIV pacing determine a significative difference in mortality (10% gain) 36000 pts 2yrs f.u.

Circ Arrhythm Electrophysiol June 2014

Circ Arrhythm Electrophysiol June 2014

# After RAFT trial. And considering that 1) DIFFERENCE BETWEEN THE ABSENCE OF POSITIVE TRIAL 2) And DENIED POSSIBILITY OF PERFORMING RCTs back to several observational studies and metanalysis to evaluate CRT in AF pts.

Total pts 1873 AF pts 245 pts AF + CRT + drugs vs AF + CRT + AVJ ablation

AF pts 369 pts

This concept confirmed by.! 7384 pts SR : 6046 pts. AF : 1338 pts AF AVJA! 443 pts AF drugs! 895 pts

person'year 250000 200000 150000 100000 50000 0 person,year mean,fup 48 43 38 33 28 23 18 13 8 3 52 mean'follow.up'(months) COMPANION, CARE,HF REVERSE MADIT,CRT RAFT, NOI CERTIFY : 230.000 person/year: 10-fold higher than all randomized trials of CRT put together!!! JACC HF 2013

Results EF 40% 35% 30% 25% 20% 15% 10% 5% 0% Echo results $ LVEF in $ AF LVEF + AVJA at 6 and months SR higher in all 3 than groups AF + drugs P<0.003 P<0.001 BASE 6M BASE 6M BASE 6M Gasparini et al JACC HF 2013 SR AF+ DRUGS AF+AVJA

Gasparini et al JACC HF 2013 Results Echo results - Reverse remodelling 180 160 3 groups : " LVESV at 6 months (all p<0.001) no further " after 6 months in AF+ drugs! ESV ml 140 120 100 80 Continuous " LVESV 0 6 12 18 24 30 36 months SR AF+drugs AF+AVJA

Results 6.8%/yrs 6.1%/yrs 11.3%/yrs Gasparini et al JACC HF 2013

Results 6.8%/yrs 4.2%/yrs 6.1%/yrs 4.0%/yrs 11.3%/yrs 8.1%/yrs Gasparini et al JACC HF 2013

Multivariable analysis Gasparini et al JACC HF 2013 HR 1.52 HR 0.93 HR 1.57 HR 0.88

Back to 1 st question: does CRT Work in AF? YES, IT DOES!!!! if 100% BIV achieved! usually possible with AVNJ ablation only Pre abl Post abl VP 100%

Second question: when to ablate AF versus AV node Could CRT pts be ideal candidates for PV isolation?! pts with LV recovery and parallel LA remodelling?! paroxysmal AF after CRT usually well controlled...! Even in persistent and permanent AF! CRT may allow SINUS RHYTHM RESUMPTION

CRT & AF: sinus rhythm resumption 330 pts permanent AF + CRT! 34 (10%) SRR at a median 4 mos f.u. At the multivariate analysis SRR was associated to! post CRT QRS < 150 ms! baseline EDD < 65 mm! LA diameter < 50 mm! AV junction ablation Pts with HF and permanent AF may restore SR

And back to clinical experience After SR resumption, stable SR (usually no need for PV isolation) SR Resumption Stable SR

Concerning AV node ablation.. Do not forget Not only 100% BIV warrented. Abolition of inappropriate shocks on rapid AF Risk of AF recurrences with PV isolation and inappropriate shocks

HF + AF: Is the correct 2 nd question PV ablation or CRT+ AVJ ablation??? Upstream decision..

Ablation for AF in patients with HF Or? Which has to be treated first? How to evaluate an AF + HF pt? Different scenarios are possible Which came first? The chicken / egg dilemma AF or HF?

AF driving HF! Usually not very enlarged LA! Moderately depressed LVEF (40-45%)! Paroxysmal AF/ Persistent AF! ~ EF in SR! "" EF during AF TACHICARDIOMIOPATHY - FIRST CHOICE AF ABLATION AF and HF Upstream decision.. HF driving AF! Usually enlarged LA- LV (complex substrate-fibrosis)! depressed LVEF (< 30-35%)! Persistent AF/Permanent AF! Previous failed RF attempts Failed Electr CV! LV vol! secondary MVR LA volume! permanent AF CARDIOMIOPATHY - FIRST CHOICE CRT-D

% Randomized trial on AF pts with CHF: PV Antrum Isolation vs AVJ abl + CRT 41 pts PVI and 40 pts CRT+ AVJ ablation Mean follow up : 6 months

PABA CHF HF pts are not the conventional CRT pts! it is not possible to extend these results to all HF pts 1) PVI may be indicated in pts with PAROXYSMAL AF with MILD HF probably due to tachycardiomyopathy 2)...since in patients with refractory HF despite OPT and PERMANENT AF, CRT is now recommended (class IIa)

Second question: when to ablate AF versus AV node In clinical practice pts with CRT-D are prone to peristent/permanent AF more than Paroxysmal Indications to AV nodal ablation if inadequate BIV pacing

Conclusions! 1 st question: does CRT in AF works?,! Yes, it works!! only if 100% BIV pacing is obtained! in permanent AF usually possible by AVJ ablation only! After CRT + AVJ ablation, sinus rhythm resumption is possible in up to 10-15% of pts! 2 nd question : The choice between PV isolation and AV node ablation (after CRT) should be an UPSTREAM DECISION (not after CRT )