Pitvarfibrilláció kezelése Ritmus vagy frekvencia kontroll?

Az előadások a következő témára: "Pitvarfibrilláció kezelése Ritmus vagy frekvencia kontroll?"— Előadás másolata:

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

2 Silent 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 Symptoms during episodes Frequency of episodes Duration of episodes Prystowsky EN. J Cardiovasc Electrophysiol. 2006;17(suppl 2):S7-S10; Wolf PA et al. Arch Intern Med. 1998;158:

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

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

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 Csökkennek a tünetek Nincs proarrhythmia szükséges
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 AFFIRM: objective Comparing two treatment strategies in AF patients at high-risk for stroke, for preventing mortality Rhythm control Ventricular rate control AFFIRM: Main results and sub-studies References: The AFFIRM Investigators. N Engl J Med 2002;347: Cooper HA, et al. Am J Cardiol ????;93:

17 AFFIRM: study design 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):

18 AFFIRM: inclusion/exclusion criteria
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 AFFIRM: Main results and sub-studies References: The AFFIRM Investigators. N Engl J Med 2002;347: Cooper HA, et al. Am J Cardiol ????;93: * Hypertension, diabetes, CHF, TIA, prior stroke, echocardiographic parameters

19 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 1st qualifying episode in 36% patients Qualifying episode <6 wks: 90% AFFIRM: Main results and sub-studies References: The AFFIRM Investigators. N Engl J Med 2002;347: Cooper HA, et al. Am J Cardiol ????;93: Am Heart J 146(6):

20 AFFIRM: drugs used in the two groups
AFFIRM: Main results and sub-studies References: The AFFIRM Investigators. N Engl J Med 2002;347: Cooper HA, et al. Am J Cardiol ????;93: Warfarin (85.0) (70.0) NEJM 347(23):

21 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 The AFFIRM Investigators. N Eng J Med 2002;347(23):

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

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) The AFFIRM Investigators. N Eng J Med 2002;347(23):

24 Stroke event rates in AFFIRM by AF treatment strategy
Type of stroke All, n=4060 Rate control, n=2027 Rhythm control, n=2033 Ischemic or hemorrhagic (%) 8.2 7.4 8.9 Ischemic (%) 6.3 5.5 7.1 Hemorrhagic (%) 2.0 1.9 2.1 No significant differences between treatment groups Sherman DG et al. Arch Intern Med 2005; 165: 24

25 AFFIRM: subgroups Only sinus rhythm and warfarin use associated with improved survival in AFFIRM Hazard Ratio SR AFFIRM p<0.0001 0.5 1 1.5 2 2.5 Warfarin use Digoxin use p=0.0007 AAD use p=0.0005 Heart failure Stroke/TIA AFFIRM – Subgroups

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

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 AFFIRM: cause-specific mortality (1)
Subanalysis of AFFIRM assessed causes of death within rhythm and rate control groups Percentage P=0.078 310 356 P=0.95 130 129 P=0.82 37 35 P=0.34 32 21 P=0.008 113 169 5 10 15 20 Total Cardiac Vascular Unknown Non-CV Rate (n=2,027) Rhythm (n=2,033) Driven by pulmonary & cancer-related deaths AFFIRM: Cause-specific mortality In the rhythm-control group, 129 patients (9%) died of a cardiac cause, and in the rate-control group, 130 patients (10%) died (P 0.95). Both groups had similar rates of arrhythmic and nonarrhythmic cardiac deaths. The numbers of vascular deaths were similar in the 2 groups: 35 (3%) in the rhythm-control group and 37 (3%) in the rate-control group (P 0.82). There were no differences in the rates of ischemic stroke and central nervous system hemorrhage. In the rhythm-control group, there were 169 noncardiovascular deaths (47.5% of the total number of deaths), whereas in the rate-control arm, there were 113 noncardiovascular deaths (36.5% of the total number of deaths) (P ). Differences in noncardiovascular death rates were due to pulmonary and cancer-related deaths. Nonfatal pulmonary complications requiring drug discontinuation were also more common in the rhythm control group. The absence of severe cardiac disease may allow noncardiac causes of death to emerge in a longitudinal study, when not overwhelmed by cardiac deaths. Reference: Steinberg JS, et al. Circulation 2004;109: Steinberg JS, et al. Circulation 2004;109:

29 AFFIRM: conclusions (1)
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: Main results and sub-studies References: The AFFIRM Investigators. N Engl J Med 2002;347: Cooper HA, et al. Am J Cardiol ????;93:

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 % % Cardiovascularis mortalitás % % 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, 1991 12 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 : % Krónikus PF visszatérés: placebo: 70% sotalol: 50% Q/V: % 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 – enalapril 78 GISSI- lisinopril 33 TRACE – trandolapril 48 CAPP – captopril 13 ns STOP-H2 – enalapril 12 ns CHARM – candesartan ns ValHeFT – valsartan 33 LIFE – losartan 28

66 Irbesartan significantly increased probability of maintaining sinus rhythm
100 p = vs. amiodarone 80 85% Probability of maintaining sinus rhythm (%) 60 63% 40 20 By intention-to-treat analysis, the recurrence rate was lower in the amiodarone + irbesartan group. Kaplan-Meier analysis demonstrated a 2-month probability for maintaining sinus rhythm of 85% for irbesartan + amiodarone-treated patients compared with 63% for those taking amiodarone alone (p=0.008).20 Irbesartan + amiodarone Amiodarone 159 patients with persistent atrial fibrillation were randomized to either amiodarone or amiodarone + irbesartan Results are taken at 2-month follow-up visit Madrid A et al. Circulation 2002;106:331–6.

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 LVH = left ventricular hypertrophy. Healey JS, et al. J Am Coll Cardiol. 2005;45: 67

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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 p < 0.001 32.6 32.8 25.1 Prevalence of AF, % 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. 69

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
(CH2)3CH3 CH3SO2HN (CH2)3CH3 O(CH2)3N (CH2)3CH3 sulfonamid O O Dronedarone is a benzofuran derivative structurally related to amiodarone but without the iodine on the benzene ring and with a sulfonamide group added to the benzofuran ring Dronedarone was originally developed with the aim of leveraging amiodarone’s antiarrhythmic efficacy and cardiac safety but with improved organ toxicity The electrophysiological properties of dronedarone are similar to those of amiodarone and their structural differences may be responsible for the improved clinical profile of dronedarone compared to amiodarone The most significant structural changes are the removal of iodine and the addition of a methane sulfonyl group. The removal of iodine should result in freedom of amiodarone’s iodine-related organ toxicity, and the second molecular change is thought to decrease lipophilicity, thus shortening the half-life and reducing tissue accumulation A consequence of this toxicity is that amiodarone administration requires dose titration to determine the minimum effective dose, as adverse effects are often dose-related. On the other hand, due to its amended profile, dronedarone is administered as a fixed dosing regimen with no loading dose or need for titration. Reference Kathofer et al. Cardiovasc Drug Rev 2005;23(3): Wegener F et al. J Cardiovasc Electrophysiol. 2006;17(S2):S17-S20 (CH2)3CH3 I CH2CH3 O(CH2)2N CH2CH3 O Amiodarone I Kathofer, et al. Cardiovasc Drug Rev. 2005;23(3): 76 76

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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 EURIDIS and ADONIS studies
EURIDIS ADONIS Dronedarone showed a significant reduction in first AF recurrence in combined analysis EURIDIS and ADONIS studies Placebo + standard therapy 60 120 180 240 360 Time (days) Relative risk 0.7 0.6 0.5 0.4 0.3 0.2 0.1 300 0.8 Hazard ratio 0.75 (95% CI 0.65–0.87) p < 0.001 25% reduction in relative risk Dronedarone 400 mg b.i.d. + standard therapy Dronedarone showed a significant reduction in first AF recurrence in the combined trials Together EURIDIS and ADONIS show a consistent efficacy of dronedarone in the prevention of AF recurrence Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonists and/or digoxin) and/or anti-thrombotic therapy (oral anticoagulation and/or long-term antiplatelet therapy) and/or other cardiovascular therapy such as ACE inhibitors and statins. Reference Singh BN et al. N Engl J Med 2007;357:987–99 Singh BN, et al. N Engl J Med. 2007;357: 79 79

80 Dronedarone decreased ventricular rate at rest by 11.7 bpm
ERATO Dronedarone decreased ventricular rate at rest by 11.7 bpm 24-hour Holter assessment Placebo + standard therapy Dronedarone 400 mg b.i.d. + standard therapy 60 70 80 90 100 -15 -10 -5 5 Heart rate (bpm) Change from baseline (bpm) Dronedarone significantly reduced 24-hour heart beat by 11.7 beats per minute at day 14 vs baseline compared to placebo There was no significant change in the placebo group vs baseline Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonist and/or digoxin) and/or anti-thrombotic therapy (Vit. K antagonists and /or aspirin and other antiplatelets therapy) and/or other cardiovascular agents such as ACEIs/ARBs and statins. Reference Davy et al. Am Heart J 2008;156:527.e1-527.e9 p < -11.7 bpm Baseline (B) D14 D14-B Davy, et al. Am Heart J. 2008;156:527.e1-527.e9. 80 80

81 Change from baseline (bpm)
Reductions in ventricular rate with dronedarone were of greater absolute magnitude during exercise ERATO 25.6 bpm reduction Placebo + standard therapy Dronedarone 400 mg b.i.d. + standard therapy 170 -35 -15 -5 5 160 150 140 -10 130 Heart rate (bpm) Change from baseline (bpm) 120 -20 Dronedarone significantly reduced 24-hour heart beat by 11.7 beats per minute at day 14 vs baseline compared to placebo There was no significant change in the placebo group vs baseline Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonist and/or digoxin) and/or anti-thrombotic therapy (Vit. K antagonists and /or aspirin and other antiplatelets therapy) and/or other cardiovascular agents such as ACEIs/ARBs and statins. Reference Davy et al. Am Heart J 2008;156:527.e1-527.e9 110 -25 100 -30 90 p < 80 Baseline (B) D14 D14-B Davy, et al. Am Heart J. 2008;156:527.e1-527.e9. 81 81

82 Increase in all-cause mortality in compromised CHF patients
ANDROMEDA Increase in all-cause mortality in compromised CHF patients Placebo n = 317 Dronedarone 800 mg n = 310 Number of patients who died 12 25 Hazard ratio 2.13 95% CI 1.07–4.25 Log rank p value 0.03 0.8 0.7 0.6 0.5 Cumulative incidence (%) 0.4 Placebo 0.3 Dronedarone 400 mg b.i.d. 0.2 0.1 A total of 37 patients, 25 in the dronedarone group and 12 in the placebo group, died during the study This imbalance in mortality rates was observed in the early course of the study and led the independent Data Safety Monitoring Board to recommend an early trial discontinuation The number of deaths attributed to arrhythmia or sudden death did not differ significantly between the two groups (10 in dronedarone group and 6 in the placebo group) 10 patients in the dronedarone group had worsening heart failure when they died compared with 2 patients in the placebo group Subgroup analyses showed that the risk of death associated with dronedarone was increased among patients who had a lower wall-motion index as compared with those who had a higher wall-motion index After an additional 6 months without study treatment, 42 patients in the dronedarone group (13.5%) and 39 patients in the placebo group (12.3%) had died (hazard ratio, 1.13; 95% CI, 0.73 to 1.74; p=0.60). This safety board was also monitoring the EURIDIS and ADONIS trials and did not recommend discontinuation of these trials, despite the ANDROMEDA findings Reference Køber L et al. N Engl J Med. 2008;358: 0.0 30 60 90 120 150 180 210 Time (days) Patients at risk Placebo 317 256 181 103 50 18 6 1 Dronedarone 400 mg b.i.d. 310 257 174 104 59 22 5 Køber L, et al. N Engl J Med. 2008;358: 82 82

83 EURIDIS ADONIS Post-hoc analysis: dronedarone reduced hospitalization from all causes or death by 27% 1.0 0.9 0.8 Placebo 0.7 Dronedarone 400 mg b.i.d 0.6 Hazard ratio 0.73 (95% CI 0.57–0.93) p = 0.01 Survival function 0.5 0.4 0.3 27% reduction in relative risk 0.2 0.1 In a post-hoc analysis of time from randomisation to first event within 12 months, dronedarone significantly reduced the relative risk of all-cause hospitalization or death by 27% compared with placebo. This endpoint formed the basis for the hypothesis explored in the ATHENA trial. Reference Singh BN et al. N Engl J Med 2007;357:987–99 0.0 60 120 180 270 360 Patients at risk Time (days) Placebo 409 320 272 241 205 179 Dronedarone 400 mg b.i.d. 828 668 597 559 494 440 Singh BN, et al. N Engl J Med. 2007;357: 83 83

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

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

86 Inclusion and Exclusion Criteria
ATHENA Inclusion and Exclusion Criteria Inclusion criteria Exclusion 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 <50 bpm and/or PR >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 Patients were either ≥75 years (with or without cardiovascular risk factors) or ≥ 70 years and ≥ 1 risk factor (hypertension; diabetes; prior stroke/TIA; LA ≥ 50 mm; LVEF < 0.40) The protocol originally allowed patients <70 years of age with additional risk factors into the study but was amended to include only patients ≥70 years of age as described above. This means that the study population contains a large proportion of patients under 70 Reference Hohnloser SH et al. J Cardiovasc Electrophysiol 2008;19:69-73. 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 Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73. 86 86

87 Baseline characteristics
ATHENA Baseline characteristics Placebo n = 2,327 Dronedarone n = 2,301 All patients n = 4,628 Mean age ± SD, years 72 ± 9.0 72 ± 8.9 Female gender 1,038 (45%) 1,131 (49%) 2,169 (47%) AF/AFL at baseline 586 (25%) 569 (25%) 1,155 (25%) Structural heart disease 1,402 (61%) 1,330 (58%) 2,732 (60%) Coronary heart disease 737 (32%) 668 (29%) 1,405 (30%) Valvular heart disease 380 (16%) 379 (17%) 759 (16%) Non-ischaemic cardiomyopathy 131 (6%) 123 (5%) 254 (6%) History of CHF NYHA II or III 515 (22%) 464 (20%) 979 (21%) LVEF < 0.45 285/2,281 (13%) 255/2,263 (11%) 540/4,544 (12%) LVEF < 0.35 87/2,281 (4%) 92/2,263 (4%) 179/4,544 (4%) Hohnloser S, et al. N Engl J Med. 2009;360: 87

88 Primary Outcome: Cardiovascular hospitalization or death
ATHENA Primary Outcome: Cardiovascular hospitalization or death Placebo on top of standard therapy 50 Dronedarone 400 mg b.i.d. on top of standard therapy 24% reduction in relative risk 40 Hazard ratio = 0.76 p < 0.001 30 Cumulative incidence (%) 20 Mean follow-up 21 ± 5 months 10 Patients at risk 6 12 18 24 30 Follow-up time, months Placebo 2,327 1,858 1,625 1,072 385 3 Dronedarone 400 mg b.i.d. 2,301 1,963 1,776 1,177 403 2 Hohnloser S, et al. N Engl J Med. 2009;360: 88

89 Secondary Outcome: Total mortality
ATHENA Secondary Outcome: Total mortality Placebo on top of standard therapy 10.0 Dronedarone 400 mg b.i.d. on top of standard therapy 16% reduction in relative risk 7.5 Hazard ratio = 0.84 p = 0.176 Cumulative incidence (%) 5.0 Mean follow-up 21 ± 5 months 2.5 0.0 6 12 18 24 30 Follow-up time, months Patients at risk Placebo 2,327 2,290 2,250 1,629 636 7 Dronedarone 400 mg b.i.d. 2,301 2,274 2,240 1,593 615 4 Hohnloser S, et al. N Engl J Med. 2009;360: 89

90 Dronedarone reduces cardiovascular death by 29%
ATHENA Dronedarone reduces cardiovascular death by 29% Placebo on top of standard therapy 7.5 Dronedarone 400 mg b.i.d. on top of standard therapy 29% reduction in relative risk 5.0 Hazard ratio = 0.71 p = 0.034 Cumulative incidence (%) 2.5 Mean follow-up 21 ± 5 months 0.0 6 12 18 24 30 Patients at risk Follow-up time, months Placebo 2,327 2,290 2,250 1,629 636 7 Dronedarone 400 mg b.i.d. 2,301 2,274 2,240 1,593 615 4 Hohnloser S, et al. N Engl J Med. 2009;360: 90

91 ATHENA Dronedarone also significantly reduces the incidence of arrhythmic death Outcome Placebo n = 2,327 Dronedarone n = 2,301 Hazard ratio (95% CI) p value All deaths 139 116 0.84 0.66–1.08 0.18 Non-cardiovascular death 49 53 1.10 0.74–1.62 0.65 Cardiovascular death 90 63 0.71 0.51–0.98 0.03 Cardiac non-arrhythmic death 18 17 0.95 0.49–1.85 0.89 Cardiac arrhythmic death 48 26 0.55 0.34–0.88 0.01 Vascular non-cardiac death 24 20 0.47–1.52 0.57 Hohnloser S, et al. N Engl J Med. 2009;360: 91

92 ATHENA Post-hoc Analysis
Dronedarone significantly decreases both first and recurrent AF-related CV hospitalization First AF-related CV hospitalization1 All AF-related CV hospitalization2 30 HR = %CI = [0.55; 0.72] 0.5 HR = %CI = [0.536; 0.730] Placebo Placebo p < 0.001 829 25 510 p < 0.001 0.4 20 335 0.3 514 Cumulative incidence (%) Dronedarone 15 Mean recurrence number Dronedarone 0.2 10 0.1 5 Months Months 0.0 6 12 18 24 30 6 12 18 24 30 Patients at risk: Patients at risk: Placebo 2,327 2,290 2,250 1,629 636 7 DR 400 mg b.i.d. 2,301 2,274 2,240 1,593 615 4 Placebo 2,327 2,290 2,250 1,629 636 7 DR 400 mg b.i.d. 2,301 2,274 2,240 1,593 615 4 1. Hohnloser SH, et al. N Engl J Med. 2009;360:

93 Dronedarone reduces the risk of stroke
5 Placebo on top of standard therapy Dronedarone 400 mg b.i.d. on top of standard therapy 4 34% reduction in relative risk 3 Cumulative incidence (%) Hazard ratio = 0.66 p = 0.027 2 1 Mean follow-up 21 ± 5 months 6 12 18 24 30 Follow-up time, months Patients at risk Placebo 295 244 224 151 60 Dronedarone 400 mg b.i.d. 178 160 150 110 47 1 Connolly SJ, et al. Circulation. 2009;120: 93

94 TEAE = treatment-emergent adverse event.
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-intestinal 508 (22%) 600 (26%) < 0.001 Respiratory 337 (15%) 332 (15%) 0.97 Skin 176 (8%) 237 (10%) 0.001 Creatinine increase 31 (1%) 108 (4.7%) Patients with any serious TEAE 489 (2%) 456 (20%) 0.31 68 (3%) 81 (4%) 0.28 45 (2%) 41 (2%) 0.74 6 (0.3%) 7 (0.3%) 0.79 1 (< 0.1%) 5 (0.2%) 0.12 TEAE = treatment-emergent adverse event. Hohnloser S, et al. N Engl J Med. 2009;360: 94

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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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