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Pitvarfibrilláció kezelése Ritmus vagy frekvencia kontroll? Zámolyi Károly Szent Ferenc Kórház, Budapest.

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Az előadások a következő témára: "Pitvarfibrilláció kezelése Ritmus vagy frekvencia kontroll? Zámolyi Károly Szent Ferenc Kórház, Budapest."— Előadás másolata:

1 Pitvarfibrilláció kezelése Ritmus vagy frekvencia kontroll? Zámolyi Károly Szent Ferenc Kórház, Budapest

2 Silent

3 Mi a terápia célja?  Tünetek csökkentése (palpitatio, fáradtság, dyspnoe)  Tromboembolia megelőzése  Tachycardia indukálta myocardialis remodelling és szívelégtelenség megelőzése  Alapbetegség kezelése (hypertonia a legfontosabb)

4 Decreasing Atrial Fibrillation Burden Is an Important Goal As with heart failure or angina, success in managing atrial fibrillation is defined as a decrease in: Decreasing atrial fibrillation burden offers potential to successfully treat atrial fibrillation by: –Decreasing mortality –Decreasing hospitalizations –Increasing QoL Prystowsky EN. J Cardiovasc Electrophysiol. 2006;17(suppl 2):S7-S10; Wolf PA et al. Arch Intern Med. 1998;158: Frequency of episodes Duration of episodes Symptoms during episodes

5 Redefining the therapeutic goals of AF? Comprehensive management of AF should address its multiple impactsComprehensive management of AF should address its multiple impacts AF mindset evolution Reduction in mortality Reduction in morbidity/CV hospitalizations Reduction of AF burden Prevention of thrombo- embolism Short-term: Symptom-driven Long-term: CV outcomes-driven Endpoints in AF management

6 Changing the treatment paradigm for AF in 2009 Old paradigm Rate vs rhythm AF recurrence=failure MD chooses Rx Focus: ECG New paradigm Rate and rhythm AF recurrence only important if symptomatic and severe MD and patient enter into a therapeutic contract Focus: patient NSR = normal sinus rhythm.

7 Tachycardia következményei  Csökken az EF  Diastolés dysfunctio  Megnő a LVEDP, PAP, SVR  Nő az ESV, EDV  Csökkent a CO  Csökken a kontraktilis rezerv  Nő az ANP, epinephrin, norepinephrin, aldosteron  Myocyta vesztés reaktív celluláris hypertrophiával  Tachycardia indukálta cardiomyopathia Scumacher és Luderitz AJC 1998 ; 82:29N

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10 Kezelési stratégia PF - ban Frekvencia kontroll és Sinus ritmus anticoagulálás fenntartás + anticoagulálás Effektivitás Biztonságosság Életminőség (AFFIRM, RACE)

11 Sinus ritmus fenntartás Előny Elektromos és anatómiai remodeling megelőzése Javulnak a tünetek Nő a terhelési kapacitás Javul a haemodynamika Javul az életminőség Visszaáll a pitvari traszport Csökken a tromboembolia? Prognózis?

12 Sinus ritmus fenntartás Hátrány Kamrai proarrhythmia Nő a mortalitás? Gyógyszer okozta bradyarrhythmia Szerv toxicitás PF rekurrálás valószínű Silent PF

13 Frekvencia kontroll Előny Csökkennek a tünetek Nincs proarrhythmia Csökken a tachycardia indukálta CMP Alacsony ár Hátrány Tartós anticoagulálás szükséges Rosszabb haemodynamika Progresszív remodeling PF permanenssé válik

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15 The AFFIRM study First major outcome study to compare long-term clinical benefits of rhythm control versus rate control strategies in AF patients at high– risk for stroke The AFFIRM Investigators. N Eng J Med 2002;347(23):

16 Comparing two treatment strategies in AF patients at high-risk for stroke, for preventing mortality –Rhythm control –Ventricular rate control AFFIRM: objective

17 Multicenter, randomized study N = 4060 patients Mean follow-up: 3.5 years (max 6 years) Both treatment groups received oral anticoagulant therapy (INR 2.0 to 3.0): mandatory for rate control strategy, but only recommended for rhythm control strategy RHYTHM CONTROL  AAD as chosen by physician: amiodarone, disopyramide, flecainide, moricizine, procainamide, propafenone, quinidine, sotalol, dofetilide, or a combination  Cardioversion included as necessary RATE CONTROL  Beta-blockers, calcium-channel blockers (verapamil and diltiazem), digoxin, or a combination  Treatment goal: Heart rate within range bpm during six- minute walk test The AFFIRM Investigators. N Eng J Med 2002;347(23): AFFIRM: study design

18 Inclusion criteria: –AF patient at high-risk for stroke [N = 4,060] –Age ≥ 65 or age < 65, plus ≥ 1 clinical risk factor* for stroke –Patient eligible for both rhythm and rate strategies Exclusion criteria: –Lone AF –CHF patients –Absolute contraindication to warfarin * Hypertension, diabetes, CHF, TIA, prior stroke, echocardiographic parameters AFFIRM: inclusion/exclusion criteria

19 Am Heart J 146(6): AFFIRM: baseline characteristics Age ~ 70 years old Women: 39% White: 89% Hypertension: 71% CAD: 38% CHF: 23% LVEF normal in > 2/3 patients AF as 1 st qualifying episode in 36% patients Qualifying episode <6 wks: 90%

20 NEJM 347(23): AFFIRM: drugs used in the two groups Warfarin (85.0) (70.0)

21 The AFFIRM Investigators. N Eng J Med 2002;347(23): AFFIRM: primary endpoint results Greater number of deaths seen in rhythm-control group, although the difference was non-significant –Overall mortality at five years: 23.8% rhythm vs 21.3% rate; HR 1.15 [95% CI ]; p=0.081

22 * Death, disabling stroke, disabling anoxic encephalopathy, major bleeding, or cardiac arrest p=0.33 AFFIRM: composite secondary endpoint The rates of the composite secondary endpoint* were similar –Rate-control: 32.7% –Rhythm-control: 32.0%

23 The AFFIRM Investigators. N Eng J Med 2002;347(23): Adverse events Two adverse events were significantly more frequent in the rhythm-control group: –Torsades de pointes (0.8% vs 0.2%, p=0.007) –All-cause hospitalisation after baseline (80.1% vs 73.0%, p<0.001)

24 Sherman DG et al. Arch Intern Med 2005; 165: Stroke event rates in AFFIRM by AF treatment strategy Type of strokeAll, n=4060 Rate control, n=2027 Rhythm control, n=2033 Ischemic or hemorrhagic (%) Ischemic (%) Hemorrhagic (%) No significant differences between treatment groups

25 Hazard Ratio SR AFFIRM p< Warfarin use p< Digoxin use p= AAD use p= Heart failure p< Stroke/TIA p< AFFIRM: subgroups Only sinus rhythm and warfarin use associated with improved survival in AFFIRM

26 Chung MK, et al. J Am Coll Cardiol 2005;46(10): AFFIRM: increased functional capacity Mean NYHA Functional Class score was significantly better at each visit in patients in sinus rhythm

27 AFFIRM: the stroke problem In AFFIRM and other trials, anticoagulants (e.g. warfarin) used long-term in rate control groups, but discontinued early in rhythm control groups Increasing evidence that anticoagulants must be given long-term as part of rhythm control strategy, even in absence of symptomatic episodes

28 Percentage P= P= P= P= P= TotalCardiacVascularUnknownNon-CV Rate (n=2,027)Rhythm (n=2,033) Steinberg JS, et al. Circulation 2004;109: Driven by pulmonary & cancer-related deaths AFFIRM: cause-specific mortality (1) Subanalysis of AFFIRM assessed causes of death within rhythm and rate control groups

29 AFFIRM compared rate-control and rhythm- control strategies for the treatment of 4060 AF patients at high-risk for stroke Disappointing results: More deaths occurred in the rhythm-control group than in the rate- control group (not statistically significant) AFFIRM: conclusions (1)

30 Conclusion from substudies Maintenance of sinus rhythm is clearly a desired goal in the treatment of AF Currently available antiarrhythmic drugs do not address this need due to their poor tolerability profiles –Of those currently available, amiodarone is the most effective Implication: A rhythm-control strategy based on newer, more tolerable drugs will prove to be superior than simple rate control

31 Supporting evidence The AFFIRM results are in general agreement with those of three other rhythm vs rate trials: –Pharmacologic Intervention in AF (PIAF) Hohnloser SH, et al. Lancet 2000;356: –Rate Control versus Electrical Cardioversion for Persistent AF (RACE) Van Gelder IC, et al. N Engl J Med 2002;347: –How to Treat Chronic AF (HOT CAFE) Opolski G, et al. Chest 2004;126:

32 RAte Control vs Electrical cardioversion (RACE) Végpont Frekvencia Ritmus kontrol kontrol Kombinált mortalitás és morbiditás 17.2% 22.6% Cardiovascularis mortalitás 7.0% 6.7% NS

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34 Overall conclusions of other rhythm vs rate trials No differences between primary endpoints in two arms All trials showed lower incidence of hospitalizations and adverse drug effects in the rate-control arm PIAF and AFFIRM trials showed slightly better functional capacity in the rhythm control arm Better exercise tolerance was achieved in the rhythm control groups of the PIAF, HOT CAFE, and AFFIRM trials

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36 PF – frekvencia kontroll javasolt BP nagyság > 50 mm PF időtartam > 6 hónap Szívelégtelenség > NYHA II EF < 40% Sinuscsomó betegség Gyógyszer refrakteritás – KV > 3 I, III intolerancia, proarrhythmia Tünetmentesség Proarrhythmia rizikó faktorok Nincs anticoagulálás kontraindikáció Öreg kor Carlsson et al. PACE 2000; 23:891

37 Kezelési stratégia – hogyan döntsünk?  A döntés legyen individuális  A fő szempont a beteg panasza  Befolyásoló tényezők:  alapbetegség  bal kamra funkció  beteg kora, terhelési kapacitása  beteg compliance  ritmuszavar természete (pl. lone típus)  korábbi kezelés eredményessége  kardioverziók száma

38 Ritmus kontroll Egyéni döntés szükséges Újkeletű, vagy a PF első epizódja Fiatalabb betegek (< 65 év) Frekvencia kontrol ellenére fennálló tünetek Alapbetegség pl. HOCM, szívelégtelenség?

39 Ritmus kontroll Gyógyszerek

40 Antiarrhythmiás gyógyszerek Vaughan Williams osztályozás I. Osztály – Na – csatorna blokkolók A. Repolarizációt nyújtók: chinidin, disopyramid, procainamid B. Repolarizációt rövidítők: lidocain, mexiletin, tocainid, phenytoin C. Repolarizációt nem befolyásolják, ingerületvezetést rontják: flecainid, encainid, propafenon, moricizin, lorcainid, ajmalin II. Osztály – Béta – receptor blokkolók III. Osztály – Kálium – csatorna blokkolók: amiodaron, sotalol, bretylium, N-acetyl-procainamid, dofetilid, ibutilid IV. Osztály- Kálcium – csatorna blokkolók: verapamil, diltiazem Digitalis, adenosid

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42 Sicilian Gambit

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47 Új gyógyszerek  Dofetilid – SAFIRE –D trial – SR fenntartás 1 év: 58% vs placebo 25% - 70% -os konverziós ráta  Dronedarone – DAFNE – 800 mg/nap effektív és biztonságos a PF megelőzésében  Ibutilide – csak iv. – mitralis betegségben és nagy pitvar esetében – p.flattern konverzió  Azimilide – ASAP trial – hatásos SV tachycardiában 40% -al csökkenti a tünetmentes PF –t és P.flatternt  Tedisamil – pitvar – szelektív szer  RSD 1235 – Ito, IKur, Ina blockoló – csak pitvarban

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49 Sinus fenntartás PF-PFL-ban

50 I/C szerek proarrhythmiás hatása

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54 Antiarrhythmic Drugs: Efficacy Maintaining NSR ≥6 Months

55 Sinusritmus fenntartás Propafenon 3 hónap - 65 % sinus - UK PPF PSVT study 6 hónap beteg - 67 % sinus - placebo: 35% - Stroobandt,1997) 2 hónap - 5o % sinus - Pritchett, hónap Flec - 49 % sinus Placebo - 36 % sinus (vanGelder, 1989) 12 hónap - 2oo beteg Flec - 77 % sinus Propafenon - 75 % sinus (Chimenti, 1996)

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61 Sinus ritmus fenntartás

62 PAFAC Prevention of Atrial Fibrillation After Cardioversion Sotalol és Quinidin+ verapamil összehasonlítás KV után A rekurráló epizódok 70% - a tünetmentes 1 év után > 30 sec PF nélküli betegek: placebo: 12% sotalol: 30% Q/V : 27% Krónikus PF visszatérés: placebo: 70% sotalol: 50% Q/V: 38% Mortalitás: 0, 1.6 és 1.4% Sotalol= Quinidin+verapamil Circulation 2001, 104:E

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64 Renin-angiotensin –aldosterone rendszer - pitvarfibrillatio  Csökkenti az intracavitalis stresst pitvari refrakteritás kedvező változása korai utódepolarisatio csökken  Gátolja a myocardialis fibrosist szubsztrát változás impulzus propagatio  Megelőzi az apoptosist  Csökkenti a gyulladást  Csökkenti a hypertrophiát

65 ACE – gátlók és ARB-k- PF megelőzés Vizsgálat PF – RRR (%)  SOLVD – enalapril78  GISSI- lisinopril33  TRACE – trandolapril48  CAPP – captopril13 ns  STOP-H2 – enalapril12 ns  CHARM – candesartan 18 ns  ValHeFT – valsartan33  LIFE – losartan28

66 Irbesartan significantly increased probability of maintaining sinus rhythm Probability of maintaining sinus rhythm (%) Probability of maintaining sinus rhythm (%) Irbesartan + amiodarone Irbesartan + amiodarone Madrid A et al. Circulation 2002;106:331–6. p = vs. amiodarone Amiodarone 85% 63% 159 patients with persistent atrial fibrillation were randomized to either amiodarone or amiodarone + irbesartan Results are taken at 2-month follow-up visit 159 patients with persistent atrial fibrillation were randomized to either amiodarone or amiodarone + irbesartan Results are taken at 2-month follow-up visit

67 ACEIs and ARBs reduce the risk of AF especially in patients with HF 11 studies including 56,308 patients –4 heart failure –3 hypertension –2 after cardioversion for AF –2 after MI ACEIs and ARBs reduced risk of AF by 28% No difference between the two drug classes Risk reduction greatest in patients with HF (44%) No significant risk reduction in hypertension, except for one trial with 29% reduction when LVH present Healey JS, et al. J Am Coll Cardiol. 2005;45: LVH = left ventricular hypertrophy.

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69 Lipid-lowering drugs significantly reduced prevalence of AF in patients with decreased LVEF ADVANCENT Registry –25,268 patients, LVEF ≤ 40% –71.3% with hyperlipidaemia –66.8% on lipid-lowering drugs Prevalence of AF, % p < Multivariable analysis: OR 0.69, 95% CI 0.64–0.74 Effect larger than ACE inhibitors (OR 0.85, 95% CI 0.79–0.92) or beta-blockers (OR 0.95, 95% CI 0.88–1.02) Hanna IR, et al. Heart Rhythm. 2006;3:881-6.

70 „Upstream” kezelés – primer prevenció ACEi és ARB újkeletű PF prevenciójára szívelégtelenségben és csökkent EF esetén – IIaB ACEi és ARB – prevenció – hypertonia, főleg BKH - IIaB Statin – prevenció- CABG műtét után -IIaB Statin- prevenció – szívbetegség, főleg szívelégtelenség- IIbB ACEi, ARB és statin primer prevencióra nem ajánlott KV betegség nélkül – IIIC Eur Heart J 2010; 31:

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72 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation:

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76 Dronedarone has key structural differences to amiodarone Dronedarone CH 3 SO 2 HN O(CH 2 ) 3 N O O (CH 2 ) 3 CH 3 Amiodarone O(CH 2 ) 2 N O O CH 2 CH 3 (CH 2 ) 3 CH 3 I I Kathofer, et al. Cardiovasc Drug Rev. 2005;23(3): sulfonamid

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78 Dronedarone Nincs reverse-use dependens hatása az AP-ra Csökkenti a kamrai repolarizáció transmurális disperzióját III-as osztályú szerek okozta korai utódepolarizáció ellen véd Nem indukál torsades de pointes kamrai arrhythmiát Nincs szerv-toxikus hatása

79 Dronedarone showed a significant reduction in first AF recurrence in combined analysis Singh BN, et al. N Engl J Med. 2007;357: Placebo + standard therapy Dronedarone 400 mg b.i.d. + standard therapy Time (days) Relative risk Hazard ratio 0.75 (95% CI 0.65–0.87) p < % reduction in relative risk EURIDIS and ADONIS studies EURIDIS ADONIS

80 Dronedarone decreased ventricular rate at rest by 11.7 bpm 24-hour Holter assessment Davy, et al. Am Heart J. 2008;156:527.e1-527.e9. ERATO Baseline (B)D14D14-B Heart rate (bpm) p < bpm Placebo + standard therapy Dronedarone 400 mg b.i.d. + standard therapy Change from baseline (bpm)

81 Reductions in ventricular rate with dronedarone were of greater absolute magnitude during exercise 25.6 bpm reduction Davy, et al. Am Heart J. 2008;156:527.e1-527.e9. ERATO Baseline (B)D14D14-B Heart rate (bpm) Placebo + standard therapy Dronedarone 400 mg b.i.d. + standard therapy p < Change from baseline (bpm)

82 Placebo Dronedarone 400 mg b.i.d Increase in all-cause mortality in compromised CHF patients Time (days) Cumulative incidence (%) Placebo Dronedarone 400 mg b.i.d. Køber L, et al. N Engl J Med. 2008;358: Placebo n = 317 Dronedarone 800 mg n = 310 Number of patients who died 1225 Hazard ratio % CI1.07–4.25 Log rank p value0.03 Patients at risk ANDROMEDA

83 Post-hoc analysis: dronedarone reduced hospitalization from all causes or death by 27% Singh BN, et al. N Engl J Med. 2007;357: Survival function Placebo Dronedarone 400 mg b.i.d 360 Hazard ratio 0.73 (95% CI 0.57–0.93) p = % reduction in relative risk Time (days) Patients at risk EURIDIS ADONIS Placebo Dronedarone 400 mg b.i.d

84 ATHENA trial design Prospective double-blind trial to assess the efficacy of dronedarone in preventing cardiovascular hospitalization or death from any cause in AF and AFL patients with additional risk factors* AFL = atrial flutter; TIA = transient ischaemic attack. Hohnloser S, et al. N Engl J Med. 2009;360: * Age ≥ 75 years or ≤ 75 years with hypertension, diabetes, prior stroke/TIA, LAD > 50 mm, or LVEF ≤ 0.40 Dronedarone 400 mg b.i.d. (n = 2,301) Placebo (n = 2,327) 12–30 months AF and AFL patients with additional risk factors* Double-blind All patients treated with standard of care treatment. R ATHENA

85 Study end-points Primary end-point –First cardiovascular hospitalization or death Secondary end-points –Death –Cardiovascular death –Cardiovascular hospitalization Hohnloser S, et al. N Engl J Med. 2009;360:

86 Inclusion and Exclusion Criteria Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19: Inclusion criteriaExclusion criteria High-risk patients with a history of paroxysmal or persistent AF/AFL Aged ≥75 years with or without additional risk factors Aged ≥70 years and ≥1 risk factor (hypertension; diabetes; prior stroke/TIA; LA ≥50 mm; LVEF <0.40) Permanent AF Unstable hemodynamic situation (i.e. recently decompensated CHF) CHF NYHA class IV Bradycardia 0.28 sec Sick sinus syndrome Calculated GFR at baseline <10 ml/min Potassium <3.5 mmol/L Concomitant antiarrhythmic drug Rx Severe illness limiting life expectancy Pregnancy or breastfeeding Refusal or inability to give informed consent Originally the protocol had allowed patients <70 years of age with additional risk factors into the study The protocol was subsequently amended to include only patients ≥70 years of age ATHENA

87 Baseline characteristics Placebo n = 2,327 Dronedarone n = 2,301 All patients n = 4,628 Mean age ± SD, years72 ± ± ± 9.0 Female gender1,038 (45%)1,131 (49%)2,169 (47%) AF/AFL at baseline586 (25%)569 (25%)1,155 (25%) Structural heart disease1,402 (61%)1,330 (58%)2,732 (60%) Coronary heart disease737 (32%)668 (29%)1,405 (30%) Valvular heart disease380 (16%)379 (17%)759 (16%) Non-ischaemic cardiomyopathy 131 (6%)123 (5%)254 (6%) History of CHF NYHA II or III515 (22%)464 (20%)979 (21%) LVEF < /2,281 (13%)255/2,263 (11%)540/4,544 (12%) LVEF < /2,281 (4%)92/2,263 (4%)179/4,544 (4%) Hohnloser S, et al. N Engl J Med. 2009;360: ATHENA

88 Primary Outcome: Cardiovascular hospitalization or death Hohnloser S, et al. N Engl J Med. 2009;360: Patients at risk Placebo2,3271,8581,6251, Dronedarone 400 mg b.i.d. 2,3011,9631,7761, ATHENA Mean follow-up 21 ± 5 months Hazard ratio = 0.76 p < Follow-up time, months Cumulative incidence (%) 24% reduction in relative risk Placebo on top of standard therapy Dronedarone 400 mg b.i.d. on top of standard therapy

89 Secondary Outcome: Total mortality Hohnloser S, et al. N Engl J Med. 2009;360: Patients at risk Placebo2,3272,2902,2501, Dronedarone 400 mg b.i.d. 2,3012,2742,2401, ATHENA Hazard ratio = 0.84 p = Cumulative incidence (%) Mean follow-up 21 ± 5 months Follow-up time, months 16% reduction in relative risk Placebo on top of standard therapy Dronedarone 400 mg b.i.d. on top of standard therapy

90 Dronedarone reduces cardiovascular death by 29% Hohnloser S, et al. N Engl J Med. 2009;360: Patients at risk ATHENA 29% reduction in relative risk Hazard ratio = 0.71 p = Cumulative incidence (%) Mean follow-up 21 ± 5 months Follow-up time, months Placebo on top of standard therapy Dronedarone 400 mg b.i.d. on top of standard therapy Placebo2,3272,2902,2501, Dronedarone 400 mg b.i.d. 2,3012,2742,2401,

91 Dronedarone also significantly reduces the incidence of arrhythmic death Outcome Placebo n = 2,327 Dronedaron e n = 2,301 Hazard ratio (95% CI) p value All deaths – Non-cardiovascular death – Cardiovascular death – Cardiac non-arrhythmic death – Cardiac arrhythmic death – Vascular non-cardiac death – Hohnloser S, et al. N Engl J Med. 2009;360: ATHENA

92 Dronedarone significantly decreases both first and recurrent AF-related CV hospitalization 1. Hohnloser SH, et al. N Engl J Med. 2009;360: ATHENA Post-hoc Analysis p < HR = %CI = [0.55; 0.72] Cumulative incidence (%) Months Placebo Dronedarone Patients at risk: Months p < HR = %CI = [0.536; 0.730] Placebo Dronedarone Patients at risk: Mean recurrence number All AF-related CV hospitalization 2 First AF-related CV hospitalization 1 Placeb o 2,32 7 2,29 0 2,25 0 1, DR 400 mg b.i.d. 2,30 1 2,27 4 2,24 0 1, Placeb o 2,3272,2902,2501, DR 400 mg b.i.d. 2,3012,2742,2401,

93 Dronedarone reduces the risk of stroke Patients at risk Connolly SJ, et al. Circulation. 2009;120: Placebo Dronedarone 400 mg b.i.d Hazard ratio = 0.66 p = Cumulative incidence (%) Mean follow-up 21 ± 5 months Follow-up time, months 34% reduction in relative risk Placebo on top of standard therapy Dronedarone 400 mg b.i.d. on top of standard therapy

94 Adverse events Outcome Placebo n = 2,313 Dronedarone n = 2,291 p value Patients with any TEAE 1,603 (69%)1,649 (72%)0.048 Gastro-intestinal508 (22%)600 (26%)< Respiratory337 (15%)332 (15%)0.97 Skin176 (8%)237 (10%)0.001 Creatinine increase31 (1%)108 (4.7%)< Patients with any serious TEAE 489 (2%)456 (20%)0.31 Gastro-intestinal68 (3%)81 (4%)0.28 Respiratory45 (2%)41 (2%)0.74 Skin6 (0.3%)7 (0.3%)0.79 Creatinine increase1 (< 0.1%)5 (0.2%)0.12 TEAE = treatment-emergent adverse event. Hohnloser S, et al. N Engl J Med. 2009;360:

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108 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation:

109 Köszönöm a megtisztelő figyelmet !

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