Fibrillazione atriale: la terapia medica Simone Mininni

Atrial Fibrillation Trends in U.S. Deaths and Death Rates* Rate per 100,000 Number of deaths Calendar year: *AF as an underlying or contributing cause; rate per 100,000 ages 45 years+, age-adjusted to 2000 US standard population [Wattigney WA et al. AJE 2002; 155:819-26]

Progetto Cuore – Prevalenza Fibrillazione atriale

Età ed FA (studio Framingham) Range di età (anni) 50-59 60-69 70-79 80-89 Prevalenza di FA % 0.5 1.8 4.8 8.8 Wolf et al, Stroke 1991

PREVALENCE OF HYPERTENSION IN SEVERAL STUDIES ON AF In very recent trials, SPORTIF and ACTIVE > 80% pts treated for hypertension

I farmaci antipertensivi sono tutti uguali per capacità di prevenire la FA ?

From Angiotensin II to Atrial Fibrillation: Possible Mechanisms

Prevention of atrial fibrillation with ACEIs and ARBs. JACC Vol. 45, No. 11, 2005

TRACE New-Onset Atrial Fibrillation by Treatment Group p Trandolapril 1749 pat. 3-7 days after IAM, LVEF < 36% 1577 Sinus rhythm : 790 Trandolapril 787 placebo 2 - 4 years follow-up TRACE p Trandolapril placebo New-Onset AF 22 (2,8 %) 42 (5,3 %) < .05 AF risk reduction with trandolapril (RR ,45 p<0.01) Adjusted for covariates OD Pedersen (TRACE) Circulation1999;100:376

New-Onset Atrial Fibrillation by Treatment Group in the LIFE Study RR: 070 Adj RR:0.72 Proportion of patients with first event (%) atenolol losartan Time (months)

La Proporzione dei pz rimasti in Ritmo Sinusale aumenta con l’associazione ma si correla anche alla dose di irbesartan 1.0 Amiodarone + Irbesartan 300 0.9 0.8 77% Amiodarone + Irbesartan 150 0.7 0.6 65% senza recidive di FA Pz (%) Amiodarone 0.5 52% 0.4 0.3 Studies with ACEIs (such as TRACEa) have suggested that the RAS system is involved in the atrial electrical remodeling by atrial fibrillation (AF). As a result, Madrid et al investigated whether an AIIRA, irbesartan, could play a role in maintaining sinus rhythm after conversion from persistent AF. For the study, 159 patients who had experienced an episode of persistent AF lasting over 7 days were randomized to treatment with amiodarone alone or amiodarone + irbesartan. Electrical cardioversion was scheduled after 3 weeks of treatment. After 2 months of follow-up, fewer patients treated with amiodarone + irbesartan experienced recurrent AF, compared with those treated with amiodarone alone. Among patients who did experience an arrhythmia occurrence, there was also a longer time to first arrhythmia recurrence among patients taking the combination therapy compared with those taking amiodarone alone. 0.2 p = 0.01 amiodarone vs amiodarone + irbesartan 300 mg 0.1 0.0 30 60 90 120 150 180 210 240 270 300 330 360 390 Follow-up dalla CVE (gg) Madrid AH, Moro C et al. JRAAS 2004;5:114–120.

Dan GA et al Circulation 112 (suppl 2) 2005 Do hypertensive patients with paroxysmal atrial fibrillation need a specific therapy? Dan GA et al Circulation 112 (suppl 2) 2005

Materiali e metodi 3 gruppi di pazienti ipertesi trattati con: Telmisartan 80 mg Perindopril 4 mg Verapamil 120 SR Follow up 18+6 mesi

Risultati Nessuna differenza riguardo il controllo pressorio Il periodo libero da eventi è stato maggiore nel gruppo telmisartan Il numero totali di eventi è stato inferiore nel gruppo telmisartan e perindopril rispetto al gruppo verapamil

AHA/ACC/HRS atrial fibrillation guidelines 2014 Classe IIa Un ACE-inibitore o sartano è utile per la prevenzione della FA in pazienti con scompenso e ridotta funzione contrattile Classe IIb La terapia con ACE-inibitore o sartano può essere considerata nella prevenzione della FA nell’iperteso

I problemi Prevenzione e controllo dell’aritmia Controllo della frequenza Prevenzione degli eventi tromboembolici

Prevenzione e controllo dell’aritmia Propafenone Flecainide Dofetilide Amiodarone Dronedarone Sotalolo Chinidina Digossina

Prevenzione e controllo dell’aritmia Propafenone Flecainide Dofetilide Amiodarone Dronedarone Sotalolo Chinidina Digossina

Raccomandazioni per la cardioversione farmacologica

Raccomandazioni per la cardioversione farmacologica

Farmaci per il controllo del ritmo Classe Livello Amiodarone I A Dronedarone Flecainide Propafenone Sotalolo ACC 2014

Farmaci e riduzione recidive FA NNT Amiodarone 3 Dronedarone 4 Flecainide Propafenone 5 Sotalolo 8 ESC Guidelines 2010

NB Alla luce della sua potenziale tossicità l’uso dell’amiodarone deve essere fatto quando altri farmaci hanno fallito o sono controindicati AHA/ACC/HRS Guidelines 2014

Utilità dei farmaci a lento rilascio Flecainide RP e migliore stabilità a livello cardiaco rispetto alla flecainide IR La somministrazione della Flecainide RP riduce le variazioni circadiane della durata del QRS rispetto alla flecainide IR. La flecainide RP neutralizzando gli aumenti delle variazioni del QRS dimostrati durante l’attività diurna dei pazienti, può ridurre potenziali problemi di tolleranza.

New England Journal of Medicine 2004;351:2384 Aim of the study: To evaluate the safety and efficacy of self-administered oral loading of flecainide or propafenone in terminating AF of recent onset outside the hospital

Pill in the pocket Time to conversion Time from onset of symptoms and drug ingestion: 36+93 min Time from drug ingestion ad symptoms termination: 113+84 min (median 98 min) Efficacy: Flecainide 94% Propafenone 94%

Pill in the pocket Emergency room access 210 patients enrolled Year before Year after p Arrhythmic episodes 59.8/mo 54.5/mo ns Calls for emergency room 45.6/mo 4.9/mo P<0.001 Hospitalization 15.0/mo 1.6/mo

Pill in the pocket Conclusions In a selected risk-stratified population of patients with recurrent AF, pill in the pocket treatment is feasible and safe, with a low rate of adverse events and a marked reduction in emergency room vistis and hospital admssions.

Controllo della frequenza Beta-bloccanti Calcio-antagonisti (verapamil e diltiazem) Digitale Amiodarone (IIa)

…….. Ma è meglio il controllo del ritmo od il controllo della frequenza???

AFFIRM: Atrial Fibrillation Follow-up Investigation of Rhythm Management Purpose To compare the effects of rhythm control and rate control on mortality in patients with atrial fibrillation and high risk of stroke or death Reference The AFFIRM Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–33.

AFFIRM: Atrial Fibrillation Follow-up Investigation of Rhythm Management - RESULTS continued - All-cause mortality Cumulative 30 mortality (%) 25 20 15 10 P=0.08 5 Rhythm control Rate control 1 2 3 4 5 Years after randomization AFFIRM Investigators. N Engl J Med 2002; 347 :1825 – 33.

AFFIRM: Atrial Fibrillation Follow-up Investigation of Rhythm Management - RESULTS - No significant difference between rate control and rhythm control groups in: all-cause mortality (25.9 vs. 26.7%, P=0.08) composite secondary endpoint (death, disabling stroke or anoxic encephalopathy, major bleeding, and cardiac arrest) total number of central nervous system events (stroke or hemorrhage) Nonsignificant trends were towards reduction of all-cause mortality and CNS events with rate control, compared with rhythm control Significantly reduced hospitalization in rate control group compared with rhythm control Fewer patients initially assigned to rate control crossed over to rhythm control than crossed from rhythm to rate control (15 vs. 38% at 5 years; P<0.001) NOTE ON LAST POINT: paper shows crossover at 1, 3 and 5 years; have included only the latter here

RACE II RAte Control Efficacy in Permanent Atrial Fibrillation A Randomized Comparison of Lenient Rate Control versus Strict Rate Control Concerning Morbidity and Mortality Isabelle C Van Gelder, Hessel F Groenveld, Harry J Crijns, Jan G Tijssen, Hans H Hillege, Ype Tuininga, Marco Alings, Hans Bosker, Jan Cornel, Raymond Tukkie, Otto Kamp, Dirk J Van Veldhuisen, Maarten P Van den Berg, on behalf of the RACE II Investigators Mr chairmen ladies and gentlemen It is my pleasure to present to you the results of the RACE II study, that is Rate control efficacy in permanent atrial fibrillation, a randomized comparison of lenient versus strict rate control concerning morbidity and mortality, carrying the acronym RACE II 10 marzo 2010

ACC/AHA/ESC Guidelines Strict rate control At rest: 60 - 80 During moderate exercise: 90-115 The present guidelines advocate a strict rate control approach with control of heart rate at rest between 60 and 80 and at moderate exercise between 90 and 115 beats per minute However, these guidelines are not evidence based Fuster et al. Guidelines J Am Coll Cardiol 2006

Cumulative incidence primary outcome Strict 14.9% 12.9% Lenient Cumulative Incidence (%) This slide shows the KM curves in the strict and lenient group over 3 years of follow up. The 2 Kaplan-Meijer curves were superimposible with a slight trend favoring lenient control with a cumulative incidence of the primary outcome of 12.9% for the lenient and 14.9% for the strict group. months No. At Risk Strict 303 282 273 262 246 212 131 Lenient 311 298 290 285 255 218 138

L’ablazione “ utile per pazienti con forme parossistiche refrattarie o intolleranti ad almeno 1 farmaco della classe I o III” ACC 2014

I risultati dell’ablazione Casistica Necessità di reintervento Successo 30-245 pazienti 1.8-26% 56-89%

Il rischio tromboembolico

Incidence of Stroke in Hypertensive Subjects in Relation to Atrial Fibrillation Incidence of stroke (x 100 person-years) No AF Paroxismal AF (n=41) Chronic AF (n=20) Verdecchia P, Angeli F et al. Hypertension 2003;41:218-223

Ictus, età ed FA (studio Framingham) 50-59 60-69 70-79 80-89 Rischio di ictus correlato alla FA % 1.5 2.8 9.9 23.5 Wolf et al, Stroke 1991

STROKE RISK IN AF PATIENTS

The left-atrial appendage is the most common site of intracardiac thrombus formation. The LAA is the most common site of intracardiac thrombus formation in patients with AF.

Left atrial appendage occlusion: Watchman

Event-free probability Left atrial appendage occlusion: Watchman WATCHMAN Control Event-free probability 900 patient-year analysis Days 244 147 52 12 463 270 92 22

Come individuare i pazienti ad elevato rischio?

Predittori clinici di stroke nella fibrillazione atriale CHADS’2 SCORE Età > 75 anni Ipertensione Diabete Scompenso di cuore Precedente stroke o TIA o IMA

CHA2DS2VASc score Congestive heart failure Hypertension Age> 75 Diabetes mellitus Stroke/TIA/thrombo-embolism Vascular disease Age 65-74 Female sex

CHA2DS2VASc score Congestive heart failure 1 Hypertension Age> 75 2 Diabetes mellitus Stroke/TIA/thrombo-embolism Vascular disease Age 65-74 Female sex

Anticoagulante……. Sì ma quale?

Il Warfarin?

I NAO!!!!! Rivaroxaban Apixaban LY517717 YM150 Via orale Via parenterale TF/VIIa TFPI (tifacogin) TTP889 X IX APC (drotrecogin alfa) sTM (ART-123) IXa Rivaroxaban Apixaban LY517717 YM150 DU-176b PRT-054021 VIIIa Va AT Xa Fondaparinux Idraparinux There are many targets for novel anticoagulants in the coagulation pathway: Tissue factor pathway inhibitor (TFPI) bound to Factor Xa inactivates the tissue factor (TF)–Factor VIIa complex, preventing initiation of coagulation Activated protein C (APC) degrades Factors Va and VIIIa, and thrombomodulin (soluble; sTM) converts thrombin (Factor IIa) from a procoagulant to a potent activator of protein C Fondaparinux and idraparinux indirectly inhibit Factor Xa, requiring antithrombin (AT) as a cofactor Direct (AT-independent) inhibitors of Factor Xa include rivaroxaban (BAY 59­7939), LY517717, YM150 and DU-176b (all orally available), and DX-9065a (intravenous) Oral, direct thrombin inhibitors include ximelagatran (now withdrawn) and dabigatran Weitz JI & Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843–1853 II DX-9065a Otamixaban Ximelagatran Dabigatran IIa Fibrinogeno Fibrina Weitz & Bates, J Thromb Haemost 2005

Grazie per l’attenzione

CHADS Interpretation Interpretation CHADS Score >2 (CVA risk >5% per year): Warfarin with goal INR 2.0 to 3.0 CHADS Score >1 (CVA risk >4% per year): Warfarin or Aspirin CHADS Score 0: Aspirin 81 to 325 mg daily

Symptoms baseline end of study % Symptoms Palpitations Fatigue Dyspnea No differences were observed in symptoms associated with AF between both groups, at baseline and end of study. At end of study the was a small decline in both group, predominantly due to a reduction of palpitations from 20 and 27% in the lenient and strict group at baseline to 11% and 10% at end of study Palpitations Fatigue Dyspnea Lenient Strict Lenient Strict

Cardiovascular death 3.9% tabel 2.9% Lenient control Strict control % Endpoint Lenient control Strict control

CHADS Score Congestive Heart Failure (1 point) Relative risk of Stroke or TIA: 1.4 Hypertension (1 point) Relative risk of Stroke or TIA: 1.6 Age over 75 years (1 point) Diabetes Mellitus (1 point) Relative risk of Stroke or TIA: 1.7 Stroke or TIA history (2 points) Mitral Stenosis or prosthetic heart valve carry similar risk and also indicate Warfarin Relative risk of Stroke or TIA: 2.5 Survival after stroke - The impact of CHADS(2) score and atrial fibrillation. Henriksson KM, Farahmand B, Johansson S, Asberg S, Terént A, Edvardsson N. Department of Laboratory Medicine, Lund University, Lund, Sweden; AstraZeneca, Epidemiology R&D, Sweden. OBJECTIVE: This study examined all-cause mortality in stroke patients with and without documented atrial fibrillation (AF), and the impact of CHADS(2) score. DESIGN: A cohort of 105,074 patients, 31,821 (30.3%) with and 73,253 (69.7%) without documented AF, was studied. These patients were registered in the Swedish Stroke Registry during the years 2001-2005. Mortality data were retrieved from the Swedish Cause of Death Register. CHADS(2) score prior to stroke were assessed using the Swedish National Discharge Register. RESULTS: The age and sex adjusted relative risk (RR) of death was 1.46 (1.43-1.49) for AF vs non-AF patients. High age (>/=75 years) tripled the risk of death and was the single most important predictor, followed by congestive heart failure, previous stroke and diabetes. Less than half of the AF patients with a CHADS(2) score of 1-6 survived more than 5 years, whereas AF patients with a CHADS(2) score of 0 had a 73% chance of survival. In patients with AF, the relative risk of death was 6.05 (CI: 2.26-6.95); in subjects with the highest vs the lowest CHADS(2) score; the corresponding RR for non-AF patients was 7.93 (CI: 7.01-8.97). CONCLUSIONS: The CHADS(2) score seems to have an impact on all-cause mortality after stroke. The CHADS(2) score can give valuable insight for other outcome variables apart from having had an ischemic stroke and can be applied to patients with different risk factor profiles, e.g. with a previous known cardiovascular disease but without known AF.

Risk Stratification and Anticoagulation Stroke Reduction with Warfarin Instead of Aspirin CHADS2 Score ~ 3 2 1 0 Number of patients Needed-to-treat to prevent 1 stroke/year 13 42 83 250 EAFT Study Group. Lancet 1993; 324:1255. Zabalgoitia M, et al. J Am Coll Cardiol 1998; 31:1622.

Stroke Risk Score for Atrial Fibrillation The CHADS2 Index Stroke Risk Score for Atrial Fibrillation Score (points) Risk of Stroke (%/year) 0 1.9 1 2.8 2 4.0 3 5.9 4 8.5 5 12.5 6 18.2 Approximate Risk threshold for Anticoagulation 3%/year Van Walraven C, et al. Arch Intern Med 2003; 163:936. Go A, et al. JAMA 2003; 290: 2685. Gage BF, et al. Circulation 2004; 110: 2287.

Figure 1 Adjusted stroke rate stratified by CHADS2 score in patients with nonvalvular atrial fibrillation not taking warfarin13 Syed TM and Halperin JL (2007) Left atrial appendage closure for stroke prevention in atrial fibrillation: state of the art and current challenges Nat Clin Pract Cardiovasc Med 4: 428–435 doi:10.1038/ncpcardio0933

Left Atrial Thrombus : 91% Localized in the LAA Location of Thrombus in Non-Rheumatic Atrial Fibrillation Patients Setting N Appendage Percent LA Body Reference TEE 317 66 21 1 0.3 Stoddard; JACC, 1995 233 34 15 0.4 Manning; Circ, 1994 Autopsy 506 35 7 12 2.4 Aberg; Acta Med Scan, 1969 52 2 4 3.8 Tsai; JFMA, 1990 48 25 2.1 Klein; Int J Card Image, 1993 TEE & Operation 171 8 5 3 1.8 SPAF III TEE 359 19 Klein; Circ, 1994 272 0.0 Leung; JACC, 1994 60 6 10 Hart; Stroke, 1994 Total Thrombus 2018 201 1.0 Blackshear and Odell concluded based upon a comprehensive literature review that 91% of left atrial thrombus are localized to the LAA in patients with non-rheumatic AF. The PLAATO device occludes this known source of thrombus. Blackshear and Odell, Ann Thoracic Surgery 1996