Adriana Gurghean Sibiu, august 2014 Fibrilatia atriala Adriana Gurghean Sibiu, august 2014

Date epidemiologice 1,5-2% populatia generala 5-15% la varstnici 1/20 AVC acute riscul de aparitie a FiA > 40 ani = 25% mai frecventa la barbati risc de AVC de 5x mai mare; frecvent fatal risc de IC de 3x mai mare !!!

Screening FiA EMBRACE & CRYSTAL-AF - > 1000 pac pac cu AVC criptogenetic monitorizati prelungit: 1luna / monitor implantabil au evidentiat episoade de FiA de 5x mai frecvente fata de martor NEJM, june 2014

Riscul de evenimente cardiovasculare Deces cardiovascular – dublu Insuficienta cardiaca – 30-40% si invers CM tahiaritmica AVC – acelasi risc pentru toate formele de FiA Spitalizari frecvente – 1/3 spitalizarile pentru TR Disfunctie VS asimptomatica Toleranta redusa la effort Scaderea calitatii vietii

Asocieri frecvente cu FiA Varsta Insuficienta cardiaca Valvulopatii – degenerative Cardiomiopatii Boli congenitale – DSA 10-15% Ischemia miocardica – 20% FiA Distiroidii Obezitate – 25% din FiA Diabet – 20% din FiA BPOC – 10-15% din FiA Sleep-apnoea BCR – 10-15% din Fia

Mecanismele de aparitie a FiA anomalii structurale V si A disociatie intre fb mm si conducere electrica circuite mici de reintrare initiere perpetuare stabilitate

Mecanismele electrofiziologice si predispozitia genetica Focare anormale mec celulare: automatism / reintrare v pulm (FiA parox) / dispersate (FiA persist) Unde multiple conducere continua, haotica, independenta Predispozitia genetica - sdr QT lung / scurt; preexcitatie V - CMH - mutatii gene: ANP, hipofct can Na, Hfct can K

Consecintele fiziopatologice ale FiA EF: ↓PRE : primele zile down-reglarea curenti Ca tip L up-reglarea curenti rectificatori de K Mecanic: contractilitate ineficienta: zile down-reglarea curentilor de Ca scaderea eliberarii Ca din depozite modificarea prop energetice miofibrilare

Principalele consecinte clinice Alterarea hemodinamicii pierderea contractiei atriale frecventa V crescuta, neregulata scaderea fluxului miocardic cardiomiopatia A si V Accidentele tromboembolice anomalii ale fluxului: staza AS si US anomalii ale componentelor sg: activare plachetara, hemostaza, inflamatie, factori de ↑

Clasificarea FiA 1. Primul episod de FiA – indiferent de durata / severitatea simptomelor 2. FiA paroxistica – max 48 h 3. FiA persistenta - > 7 zile / necesita cardioversie 4. FiA persistenta lunga - > 1 an 5. FiA permanenta – acceptata de pacient/dr ** FiA asimptomatica – oricare din cele 5 forme/dg ocazional sau printr-o complicatie

Evolutia naturala a FiA AF = atrial fibrillation 12 12

Tipuri de FiA “ Lone AF’’ – fara o boala cardiaca structurala FiA non-valvulara absenta SMi, proteze valvulare, plastie VMi FiA secundara ex. infectii acute

Evaluarea clinica Evaluarea simptomelor (scorul EHRA) Estimarea riscului de AVC Dg conditiilor predispozante pt FiA Evaluarea complicatiilor

Evaluarea clinica initiala Momentul instalarii FiA – tip FiA Semne de IC acuta control urgent AV cardioversie eco – fct VS, PsVD, valve AIT / AVC – CT +/- revascularizare Evaluare risc AVC: ACO Evaluarea cauzelor eco cord fctie tiroida HLG, creat, glicemie teste stress pt ischemie coronarografie (persist disf)

Tratamentul FiA Ameliorarea simptomelor controlul ritmului controlul frecventei Prevenirea complicatiilor tratamentul antitrombotic Tratamentul conditiilor asociate Urgenta !!! SEE sincron

Controlul ritmului in FiA Cardioversia farmacologica sau electrica a FiA persistente sau supresia episoadelor recurente de FiA paroxistica !!! Mentinerea indicatiei de anticoagulare chiar daca optam pentru controlul ritmului Pacientii cu FiA paroxistica = acelasi risc de AVC si embolic ca si cei cu FiA persistenta !

Conversia electrica a FiA SEE sincron 200-360 J Sedare / midazolam In urgenta : simpt severe / degradare hemodinamica / WPW Electiva : stabili ACO – 3 sapt ant FiA< 48 h - control TEE si conversie +/- pretratament AA

DC cardioversion for AF aClass of recommendation. bLevel of evidence. AF = atrial fibrillation; DCC = direct current cardioversion. 20 20

Drugs and doses for pharmacological conversion of (recent-onset) AF ACS = acute coronary syndrome; AF = atrial fibrillation; DCC = direct current cardioversion; i.v. = intravenous; N/A = not applicable; NYHA, New York Heart Association; p.o. = per os; QRS = QRS duration; QT = QT interval; T-U = abnormal repolarization (T-U) waves. 21 21

Cardioversia farmacologica Vernakalant FiA < 7 zile / < 3 zile postinterv cardiace Actiune: atrial Prelungeste PRA si scade conducerea A Instalare efect: rapida T1/2 = 3-5 ore

Vernakalant - studii Superior Amiodarona Eficient la: HTA Ischemie postoperator +/-: IC Ineficient in: FiA > 7 zile/ FlA tipic

Vernakalant – reactii adverse si contraindicatii Hipotensiune arteriala 5-7% (16% in IC) Bradicardie 0,5% TR-V – in IC 7,3% TVNS Alungirea QT si QRS Contraindicatii TAs < 100 mmHg SCA < 30 zile IC NYHA III-IV SAO severa QT > 440msec FE < 35 %

Terapia antiaritmica orala I: preventia FiA recurenta (persistenta / paroxistica) !!Eficienta vs reactii adverse si Mo crescute Controlul simptomelor persistente date de recurenta FiA

Antiaritmicele orale – pe ce durata ? Flec-SL (Flecainide Short Long) 635 pts, (B 64%, 64 ani, HFPEF, 6 luni) 3 brate: fara AA; short (4sapt); long Short: protectie 80% long la 6 l Amiodarona Long (t1/2 lung) Short (episodic) daca: r adv sint mici sau recurentele sint rare Dronedarona

Dronedarona in mentinerea RS Structura asemanatoare A Blocant multiplu: canale Na si K antiadrenergic prop asemanatoare Ca blocantelor Eficienta: superior placebo/ inferior A

Dronedarona - studii

Dronedarona – I si CI I: CI: FiA paroxistica / persistenta post conv. IC NYHA I –II cu FE pastrata CI: FiA permanenta (PALLAS) IC NYHA III-IV (ANDROMEDA) Instabilitate hemodinamica Disfunctie sistolica VS

Choice of an antiarrhythmic drug for AF control aClass of recommendation. bLevel of evidence. AF = atrial fibrillation; AV = atrioventricular; LoE = level of evidence; NYHA = New York Heart Association. 32 32

Concluzii – terapia AA orala pt controlul ritmului

Recurenta FiA la pacientii cu AAD

77% - RFCA vs 19% - 52% - AAD ! Yun-Yu Chen, BS. 2013

Limite / complicatii ale ablatiei Limite ale eficacitatii FiA persistenta lunga (>1 an) AS dilatat (>55 mm) Age > 70 years Patologie structurala cardiaca Recurente mai frecvente pe termen lung Complicatii TC, pericardita, fistula A-E, stenoza VP Vasculare periferice Infarct cerebral silentios (MRI) – 4-35% 39

Ablatia in FiA cu IC Eficienta neclara in IC cu disfunctie VS Amiodarona e I indicatie I: simptome legate de FiA sub amiodarona ACO = obligatorie Rata mentinerii RS e mica Riscurile procedurale mult mai mari Ameliorarea functiei VS ?

Ablatia pe cateter vs ablatia chirurgicala Studiul FAST A chirurgicala – eficienta > in controlul ritm A chirurgicala - complicatii > Dificultati tehnice

Ablatia chirurgicala ‘’maze procedure’’ Succes 75-95% la 15 ani Complic si Mo crescute FiA + BMi

Evaluarea preablatie Holter ECG Eco cord: afectare structurala MRI, CT: fibroza A TEE: excludere tromb AS, US ACO preablatie

Controlul Frecventei in Fibrilatia Atriala

Efectele functionale ale FiA Pierderea pompei atriale In caz de HVS reducerea volumului bataie cu peste 25 % Scurtarea diastolei – umplere deficitara Tahicardia de efort – simptome de efort Miocardiopatia tahicardica Insuficienta cardiaca

Cind trebuie redusa frecventa ? Terapia initiala Pina la deciderea conversiei Prevenirea frecventei inalte in FA paroxistica si persistenta recurenta FA cronica

Cum alegem intre controlul frecventei si controlul ritmului in FiA persistenta ?

Quality of life Morbidity Mortality

Controlul ritmului vs controlul frecventei Impactul FiA cronice asupra evolutiei Probabilitatea de mentinere a RS Severitatea simptomatologiei legate de FiA Factori ce pot influenta mentinerea RS

Factori ce influenteaza negativ mentinerea RS Istoric indelungat de FiA Virsta Boala cardiovasculara severa coexistenta Comorbiditati AS dilatat

Cine ar beneficia cel mai mult de controlul frecventei ?

Controlul frecventei pe termen lung

Controlul frecventei pe termen lung

Care este frecventa optima ? AFFIRM (60-80bpm rep; 90-115bpm effort moderat) <110bpm, rep

Controlul nefarmacologic al frecventei Ablatia nodului AV paliativa, ireversibila esecul terapiei farmacologice Modificarea NAV – radiofrecventa mai putin eficienta Implantare PM fctie de tipul FiA (VVI, DDD, CRT)

Tratamentul antitrombotic in FiA

Factorii de risc tromboembolic in FiA Antecedente de accidente TE Varsta Diabet zaharat HTA Boli structurale cardiace Disfunctia sistolica VS moderat-severa (TTE) Tromb prezent in AS (TEE) Placi complexe Ao (TEE) Contrast spontan, viteze mici US (TEE)

Riscul tromboembolic in FiA (scor CHADS2) 2 = istoric AVC / AIT 1 = varsta > 75 ani HTA IC DZ Scor 0 = risc mic Scor 1-2 = risc moderat Scor > 2 = risc crescut >2 = ACO cronic

Limitele scorului CHADS2 Categoriile de risc – mai degraba artificiale Beneficii ACO vs aspirina si la cei cu risc moderat Nu include multi alti FR-TE Majoritatea schemelor de risc cu VPP mica pt AVC

Scorul CHA2DS2 - VASc

Aprecierea riscului hemoragic HEMORR2 HAGES Hepatic or renal disease, Ethanol abuse, Malignancy, Older (>75), reduced platelet count/function, Rebleeding risk, Hypertension, Anemia, Genetic factors, Excessive fall risk, Stroke HAS-BLED Hypertension, Abnormal liver/renal function, Stroke, Bleeding history, Labile INR, Elderly, Drugs/alcohol ATRIA AnTicoagulation and Risk factors In Atrial fibrillation

Terapia antitrombotica in FiA Aspirina Clopidogrel Antivitamina K Antitromboticele noi

Aspirina in FiA Metaanaliza 8 studii (4876 pts) reducerea RA cu 0,8%/an – prev I reducerea RA cu 2,5%/an – prev II Se prefera dozele mici (<100mg) FiA izolata – beneficiu mic / risc hemoragic mare (1,6% vs 0,4% placebo)

Aspirina + Clopidogrel in FiA ACTIVE-W: CLO+ASA vs WAR WAR superioara (reducere RR AVC isch cu 40%) WAR – acelasi risc hemoragic ACTIVE-A: CLO+ASA vs ASA CLO+ASA superior / risc hemoragic mare Concluzii: CLO+ASA doar daca ACO e CI

Antivitamine K in FiA Reducerea RR AVC ischemic cu 67% INR terapeutic Rezultate similare pentru preventia I si II Reducere Mo generala cu 26% Indicatie: orice FiA + cel putin 1 FR AVC

Current Trial-Associated Outcomes With Warfarin in Prevention of Stroke in Patients With Nonvalvular Atrial FibrillationA Meta-analysis  S. Agarwal et al, Arch. Intern. Med, 2012

Recomandarile pentru profilaxie

Anticoagularea pericardioversie

Anticoagularea pericardioversie

Anticoagularea, FiA si AVC acut

Anticoagularea, FiA si interventiile chirurgicale

Anticoagularea, FiA si stenturile

Anticoagularea periablatie Previne TES indiferent de FR Nu se intrerupe/se scade daca e nevoie E recomandata postablatie pe termen lung la scor > 2. ACO noi – nu exista experienta

Anticoagulantele noi Inhibitori directi ai trombinei – dabigatran (RE-LY) Inhibitori directi ai factorului Xa – rivaroxaban (ROCKET-AF) / apixaban (ARISTOTLE)

Dabigatran versus Warfarin in Patients with Atrial Fibrillation (RE-LY) In a large, randomized trial, two doses of the direct thrombin inhibitor dabigatran were compared with warfarin in patients who had atrial fibrillation and were at risk for stroke

Efficacy Outcomes, According to Treatment Group Table 2. Efficacy Outcomes, According to Treatment Group. Connolly SJ et al. N Engl J Med 2009;361:1139-1151

Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group Figure 1. Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group. Connolly SJ et al. N Engl J Med 2009;361:1139-1151

Rata accidentelor hemoragice

Conclusion In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage

Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation (ROCKET-AF) In this trial, 14,264 patients with atrial fibrillation were randomly assigned to receive either rivaroxaban or warfarin.

Primary End Point of Stroke or Systemic Embolism. Table 2 Primary End Point of Stroke or Systemic Embolism. Patel MR et al. N Engl J Med 2011;365:883-891

Cumulative Rates of the Primary End Point (Stroke or Systemic Embolism) in the Per-Protocol Population and in the Intention-to-Treat Population. Figure 1 Cumulative Rates of the Primary End Point (Stroke or Systemic Embolism) in the Per-Protocol Population and in the Intention-to-Treat Population. Patel MR et al. N Engl J Med 2011;365:883-891

Rates of Bleeding Events. Table 3 Rates of Bleeding Events. Patel MR et al. N Engl J Med 2011;365:883-891

Conclusions In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group.

Original Article Apixaban versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) The oral direct factor Xa inhibitor, apixaban, was compared with warfarin in atrial fibrillation. Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and lowered mortality. N Engl J Med Volume 365(11):981-992 September 15, 2011

Kaplan–Meier Curves for the Primary Efficacy and Safety Outcomes. Figure 1 Kaplan–Meier Curves for the Primary Efficacy and Safety Outcomes. The primary efficacy outcome (Panel A) was stroke or systemic embolism. The primary safety outcome (Panel B) was major bleeding, as defined according to the criteria of the International Society on Thrombosis and Haemostasis. The inset in each panel shows the same data on an enlarged segment of the y axis. Granger CB et al. N Engl J Med 2011;365:981-992

Efficacy Outcomes. Table 2 Efficacy Outcomes. Granger CB et al. N Engl J Med 2011;365:981-992

Bleeding Outcomes and Net Clinical Outcomes. Table 3 Bleeding Outcomes and Net Clinical Outcomes. Granger CB et al. N Engl J Med 2011;365:981-992

Conclusions In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.

rata NOAc rata WAR CI AVC/TES 3,11% 3,79% 0,81(0,73-0,91) AVC hemor 0,44% 0,90% 0,49(0,38-0,64) Hemor maj 5,26% 6,17% 0,86(0,73-1) HIC 0,70% 1,45% 0,48(0,39-0,59) Mo generala 6,90% 7,68% 0,90(0,85-0,95) J.Udell, Metaanaliza NOAC vs WAR, 2014

Excizia / inchiderea US Tehnici Chirurgical: in cursul interv cardiace Minimal invazive: epicardice / trans SIA WATCHMAN / AMPLATZER CARDIAC PLUG Ratiuni: alternativa la ACO cronic Limite: Studii mici, putine, in curs Nu toate AVC sint legate de FiA Alte localizari posibile ale trombilor Nu exista comparatii intre tehnicile neinvazive

Studii PROTECT-AF: WATCHMAN vs ACO (707 PTS) Complicatii precoce postinterventionale PREVAIL: WATCHMAN vs WARFARINA CR (in curs)

Terapia antiremodelare miocardica si fibrilatia atriala

Terapia antiremodelare intirzierea remodelarii Preventie I FiA Preventie II FiA: ↓ratei recurentelor/ progresiei FiA Droguri cu valente antiremodelare IEC / ARB antialdosteronice statine AG polinesaturati (PUFA)

IEC/ARB in preventia I FiA In IC: ↓riscului FiA cu 30-48% in HFREF Nu exista evidente in HFPEF In HTA – rezultate neclare: Studii HTA: LIFE (Lo), VALUE (Val) = (+) Studii HTA + FR: HOPE (Ram), TRANSCEND (Telmi) = (-)

IEC / ARB in preventia II FiA 1 metaanaliza: ↓risc recurenta cu 45-50% in asociere cu AA CAPRAF (Candesartan in preventia FiA recurente: (-) NB! fara AA GISSI-AF: FiA paroxistica/perrsistenta recurenta: Valsartan + AA + IEC: (-)

Antialdosteronicele in preventia FiA Haldosteronismul primar – risc x12 FiA FiA se asociaza cu nivel crescut aldost sg. Antialdosteronicele – rol neclar Spironolactona: pare a ↓recurenta FiA postcardioversie la HTA & disfunctie VS

Statinele in preventia FiA Mecanisme posibile: ameliorarea metabolism lipidic antiaterosclerotic antiinflamator & antioxidant ameliorarea disfunctiei endoteliale ameliorarea activarii NH

Statinele in preventia FiA Preventia I: doar studii obs, retrospective (+): in disfunctia VS si IC (-): in HTA, ischemie Preventia II: fara efecte certe Postoperator: 3 studii - 17643 pac ↓incid I episod FiA (p<0,001) efect dependent de doza