Antiarytmika vid förmaksflimmer - ett gammalt problem med nya möjligheter

Transkript

1 Antiarytmika vid förmaksflimmer - ett gammalt problem med nya möjligheter Carina Blomström Lundqvist Uppsala University, Sweden CBLundqvist, UAS09

2 Livstidsrisken för förmaksflimmer Livstidsrisk för att utveckla förmaksflimmer är hög för män och kvinnor > 40 års ålder Risken lägre i frånvaro av hjärtsvikt / infarkt; 1:6 2 Lloyd-Jones DM, et al. Circulation 2004;110:

3 Kliniska konsekvenser av FF X 2 Camm et al, ESC Guidelines on Atrial Fibrillation, EHJ 2010.

4 Vilka är behandlings målen? Endast antikoagulantia som visats minska FF relaterad Vi behöver läkemedel mortalitet. som: Antiarytmika vid FF - gammalt problem - nya möjligheter? # # Camm et al, ESC Guidelines on Atrial Fibrillation, EHJ 2010.

5 Frekvens eller Rytm styrd behandling

6 Gradering av symtom

7 Vilken metod for konvertering? DC konvertering - narkos - sängplats Läkemedel - 0 narkos - hem tidigare

8 Recommendationer för farmakologisk konvertering Konvertering frekvens IV Flecainide 67 92% 6 h IV Propafenon 41-91% h IV Amiodarone 80 90% ESC 2010 Guidelines- European Heart Journal h

9 Vilka Antiarytmika har vi för konvertering? Pharmacological cardioversion Cardioversion Pill-in-the-pocket Oral propafenone mg Oral flecainide mg Conversion rate 94%. Alboni P, et al. N Engl J Med Reisinger J et al. Eur Heart J Stambler BS et al. Circulation 1997.

10 Nya möjligheter? Farmakologisk konvertering av FF med kort duration (<48 tim) SR 67-92% at 6 h SR 50% in min SR at 6 h. ESC 2010 Guidelines- EHJ 2010.

11 Vernakalant Multi-ion channel atrial selective blocker Effect on AERP vs VERP in Humans Significantly prolonged atrial, but not ventricular ERP in an open-label EP study in 19 pats T/2 2-5 h Metabolised in lever by CYP2D6 Change From Baseline, msec Paced cycle length: 600 msec (31 ± 14) a (14 ± 14) a (4 ± 15) (0 ± 10) AERP VERP ap<0.05 vs baseline. Dorian P et al. J Cardiovasc Pharmacol. 2007;50: Adapted with permission from Dorian P et al. J Cardiovasc Pharmacol

12 Vernakalant BRINAVESS - Konvertering inom 90 min Conversion from AF to SR within 90 min (%) Vernakalant (N=116) P < Amiodaron(N=116) Camm et al Oral presentation at HRS Denver 2010

13 Vernakalant BRINAVESS P < (Log-Rank test) Median time to conversion for pats responding to Vernakalant : 11 minutes Camm et al Oral presentation HRS Denver 2010

14 Konverterings frekvens relaterat till FF duration innan konverterings försök 70% 60% 62,1% % conversions 50% 40% 30% 20% p< p= ,8% p= 0.09 p< ,6% Vernakalant Placebo 10% 0% Roy D et al. Circulation. 2008;117: ,9% 4,9% 2,6% 0% 0% 3-48 hours 3-7 days 7-45 days Total Duration of Atrial fibrillation

15 Effekt av vernakalant hos pat med FF efter hjärtoperation. Median time to conversion in vernakalant responders was 12.4 min Percentage of Patients With Conversion of AF Vernakalant (N=100) Placebo (N=50) 47% P< % Time to Conversion, min Kowey PR et al. Circ Arrhythm Electrophysiol. 2009;2:

16 Vernakalant för Infusion Snabb konvertering av nydebuterat FF. FF 7 dgr duration Post-op FF 3 dgr duration Kontraindikationer Uttalad aorta stenos, BT systoliskt <100 mm Hg, Hjärtsvikt NYHA III - NYHA IV Förlängt QT tid. Uttalad bradykardi AV block II-III AA droger (class I o class III) 4 tim innan vernakalant Acute coronary syndrome

17 Behandlings prophylax mot FF vilka antiarytmika har vi? ESC 2010 Guidelines- European Heart Journal 2010.

18 Antiarytmika som profylax mot FF Estimates for pats who received amiodarone, sotalol of propafenone. Roy D, Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 2000

19 The SAFE-T study Double-blind, placebo-controlled, N=665 patients No difference in mortality or major side effects. Death rates 4.36 vs 2.84 per 100 person-years of FU drugs vs placebo (P=0.13). (Under-powered for mortality diff.) Singh BN et al. N Engl J Med 2005; 352:

20 AFFIRM On-treatment subanalysis of the AFFIRM study examined relationship between survival, sinus rhythm and treatment Sinus rhythm P< Hazard ratio Currently available antiarrythmic drugs are not associated with improved survival Any survival benefit is offset by their adverse effects. * Amiodarone, sotalol and 6 class I AADs Rhythm control with drug treatment* P= Gammalt problem Proarytmi Ineffektiva AA LM The AFFIRM Investigators. Circulation 2004; 109: CBLundqvist, UAS09

21 Val av Antiarytmika beroende av underliggande hjärtsjk Antiarytmika vid FF - nya möjligheter? Camm et al, ESC Guidelines on Atrial Fibrillation, EHJ 2010.

22 Dronedarone A multichannel blocker Electrophysiologic Characteristics of all 4 Vaughan Williams Classes Anti-fibrillatory effects in ventricles and atria in animals2 Reduced transmural dispersion of ventricular repolarisation in dogs. Sicouri et coll. (1997) J Cardiovasc Pharmacol Ther 2: Sicouri (1999) Fund Clin Pharmacol 13:72.

23 Dronedarone significantly decreased risk of unplanned CV hospitalisation or death from any cause by 24% (ATHENA) Cumulative Incidence (%) Placebo (2327) DR 400mg bid (2301) HR=0.76 p<0.001 The number needed to treat (NNT) to prevent one first CV hospitalisation or death is % reduction in relative risk Months PAF / Pers. AF or AFL and additional cardiovascular risk factors eligible. Hohnloser SH, et al. N Engl J Med 2009;360: Any unplanned hospitalisation (i.e., admission with an overnight stay in the hospital) was classified by the investigator as a hospitalisation due to either cardiovascular or non-cardiovascular causes

24 Dronedarone significantly reduced the relative risk of stroke by 34% (ATHENA) Cumulative Incidence (%) Placebo on top of standard therapy DR 400mg bid on top of standard therapy HR=0.66 p= % reduction in relative risk Months Connolly et al; Circulation. 2009;120: Mean follow-up 21 ±5 months.

25 Dronedarone no effect on all cause mortality (ATHENA) Connolly et al; Circulation. 2009;120: Mean follow-up 21 ±5 months.

26 Dronedarone reduced CV mortality (ATHENA) Connolly et al; Circulation. 2009;120: Mean follow-up 21 ±5 months.

27 Only pats in SR at study initiation analyzed for maintenance of SR. 12-lead ECGs at each visit up to 6 mo and every 6 months thereafter. Significant reduction in likelihood of developing AF or AFL with dronedarone (HR 0.749, p = 0.001). Median time to AF recurrence prolonged from 498 days with placebo to 737 days with dronedarone. Page, AJC 2011

28 Time to first electrical cardioversion. Risk for cardioversion significantly reduced in pats receiving dronedarone hazard ratio 0.684, p= Page, AJC 2011

29 Median HR during AF/AFL significantly lower in dronedarone group (ATHENA) Median heart rate during AF/AFL p< bpm 60 Placebo on top of standard therapy Dronedarone on top of standard therapy Page R, et al. AHA Scientific Sessions 2008; Page R, et al. Circulation. 2008;118:S_827.

30 Risk for first cardiovascular hospitalizations or death from any cause in lone AF placebo group after 1 year: 25%! Dronedarone resulted in 44% reduction of cardiovascular hospitalizations or death in lone AF pats. hazard ratio (HR) 0.56; 95%CI , P = Duray, JCE2011

31 First cardiovascular hospitalization in pats with or without lone AF. P: Placebo, D: Dronedarone Duray, JCE2011

32 Dronedaron - praktisk information Indikation Förhindra återfall i FF eller för att sänka kammarfrekvensen Kliniskt stabila pat med icke-permanent FF Förmån Som tillägg till standardbehandling, för pat som har minst en av följande kardiovaskulära riskfaktorer: Tidigare stroke eller TIA Hypertoni Diabetes Hjärtsvikt (ej instabil klass III eller klass IV) Hög ålder, över 75 år

33 Dronedaron - praktisk information Kan initieras och följas polikliniskt Låg risk för proarytmi Varningar och försiktighet Stabil hjärtsvikt NYHA klass III eller LVEF <35%. Kontraindikationer Instabil hemodynamik; Hjärtsvikt i vila eller vid lindrig ansträngning (NYHA klass IV och instabila NYHA klass III).

34 Konklusion Antiarytmika vid FF Nya möjligheter Ökade krav på säkerhet? " " " " Camm et al, ESC Guidelines on Atrial Fibrillation, EHJ 2010.

35 N = 71 pats Followed > 5 yrs after index ablation procedure. telephone encounters cardiac monitoring if available. Am J Cardiol 2009;104: )

36 Carina Blomström Lundqvist, Uppsala University, Uppsala CBLundqvist, UAS09

37 Dronedaron - Interaktioner Skall inte användas tillsammans med: Potenta CYP 3A4-hämmare Läkemedel som kan inducera TdP Klass I eller III antiarytmika Bör undvikas: Grapefruktjuice (CYP 3A4 hämning) Potenta CYP 3A4-inducerare Försiktighet (överväg dosreduktion av): Digoxin, betablockerare, kalciumantagonister Statiner Produktresumé MULTAQ

38 Adjudicated cause of death Outcome Placebo n = 2,327 Dronedarone n = 2,301 Hazard Ratio for dronedarone [95% CI] p value All deaths [ ] 0.18 Non-CV death [ ] 0.65 CV death [ ] 0.03 Cardiac non-arrhythmic death Cardiac arrhythmic death Vascular non-cardiac death [ ] [ ] [ ] 0.57 Hohnloser SH et al. N Engl J Med. 2009;360:668-78