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Assist.Prof.Surapun Sitthisook.

“ Dronedarone : A novel landmark of AF management preventing serious CV events and Hospitalization with New ESC 2010 Guideline ”. Assist.Prof.Surapun Sitthisook. Dronedarone is approved in the US and the EU. AF prevalence is predicted to increase by ≥2.5-fold by 2050 in the US. 15.9. 15.2.

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Assist.Prof.Surapun Sitthisook.

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  1. “Dronedarone: A novel landmark of AF management preventing serious CV events and Hospitalization withNew ESC 2010 Guideline” Assist.Prof.Surapun Sitthisook. Dronedarone is approved in the US and the EU

  2. AF prevalence is predicted to increase by≥2.5-fold by 2050 in the US 15.9 15.2 14.3 13.7 11.7 10.2 12.1 11.7 11.1 8.9 10.3 7.7 9.4 6.7 8.4 5.9 7.5 5.1 6.8 6.1 5.6 5.1 Mayo Clinic data (assuming a continued increasein AF incidence) 16 14 Mayo Clinic data (assuming no further increasein AF incidence) 12 10 Retrospective US database study (Naccarelli) Patients with atrial fibrillation (millions) 8 7.56 6 4 2 3.03 0 1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Year Savelieva I and Camm J Clin Cardiol 2008;31:55–62. Naccarelli GV et al. Am J Cardiol. 2009;104(11):1534-9. 7

  3. AF increases patients’ risk of death and CV outcomes All-cause mortality CV events Fatal or non-fatal stroke Heart failure All-cause mortality CV events Fatal or non-fatal stroke Heart failure Renfrew/Paisley Rate ratio (95% Confidence Interval [CI])* Womenn=8,354 Menn=7,052 -1 0 1 2 3 4 5 6 7 8 * Adjusted for age; follow-up 20 years Stewart S, et al. Am J Med 2002;113:359-64. 8 CV events: death or hospitalisation

  4. AF leads to hospitalisation • AF patients are at a 2-3 times increased risk of hospitalisation1 • Hospitalisation rates for AF have increased dramatically in recent years2-4 Hospitalisation rate X 2 to 3 (US - 1985 to 1999)2 Risk of hospitalisation X 2-31 • Stewart S, et al. Am J Med 2002;113:359-364. • Stewart S, et al. Eur Heart J 2001; 693–701. • Friberg J, et al. Epidemiology 2003;14: 666–672. • Wattigney WA, Circulation 2003;108:711-716. 9

  5. Previously available AADs can have moderate efficacy and serious safety issues Moderate efficacy No previously available AAD has been shown to reduce CV outcomes (unplanned CV hospitalisations, CV mortality) Most AADs have been shown to be 50–65% effective in maintaining normal sinus rhythm over 6 to 12-months1 May have serious adverse events:2 Proarrhythmias (e.g. torsades de pointes) Congestive heart failure Organ toxicity Neurotoxicity Pulmonary toxicity Hepatic toxicity Optic neuropathy Thyroid abnormalities Safety Issues Moderate efficacy • Naccarelli GV, et al. Am J Cardiol 2003;91(suppl):15D-26D. • Camm AJ, Int J Cardiol 2008;127:299-306. 11

  6. Guidelines recommend comprehensive management of AF Improve outcomes of AF "disease" Impactassociated risks Slow ventricular response Prevent AF recurrence CV effects Rhythm control Rate control Treat AF "Arrhythmia" The main selected strategy could be either rhythm or rate control, or their combination The other components optimise the treatment effect and contribute to improve outcomes 12 ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:854-906

  7. Dronedarone’s multiple properties may translate into positive clinical consequences ICaL, b-adrenergic inhibition Reduction in symptoms of AF / AFL Rate control Prevention of cerebrovascular events IKAch, IKr, INa, IKur inhibition Atrial rhythm control ICaL, b-adrenergic, IKr, INa inhibition Ventricular rhythm control Reduced risk of sudden death Reduced risk of acute coronary syndromes b-adrenergic inhibition Anti-adrenergic effects Systemic and coronary vasodilation Reduced risk of stroke and heart failure ICaL inhibition NO liberation Lowering of blood pressure sanofi-aventis. US FDA Cardiovascular & Renal Drugs Advisory Committee: Available from URL: http://www.fda.gov 15

  8. A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter (AF/AFL)

  9. ACT2401 2a DAFNE EURIDIS/ADONIS 2b ERATO 2c ANDROMEDA 2d ATHENA 3a ATHENA Post-hoc Analysis 3b Dronedarone Clinical Trial Programme LV Dysfunction Atrial Fibrillation

  10. Before ATHENA, AF Trials Adoptedan "ECG focused" Approach • Time to first recurrence of AF • Percentage of patients remaining in sinus rhythm at a given point of time Identified by: • Routine ECGs/symptomatic ECGs • Prolonged monitoring: event recorders, automated recorders Rhythm Control • Ventricular rate in AF • ECG, Holter, graded exercise test(GXT) Rate Control Camm AJ, et al. EHJ 2008;10 (suppl. H) H55-H78.

  11. For the first time in AF, ATHENA adopted an "outcomes focused" approach The largest single antiarrhythmic drug trial ever conducted in AF >4,600 patients with a history of atrial fibrillation or atrial flutter More than 550 investigational sites in 37 countries ATHENA’s objective: Evaluate the efficacy and safety of dronedarone 400mg bid vs placebo on top of standard therapy* in the prevention of CV hospitalisation or death from any cause over a minimum treatment and follow-up duration of 12 months in patients with paroxysmal or persistent AF/AFL * 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 CV agents such as ACEIs/ARBs and statins 21 Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73.

  12. Study Endpoints • Primary endpoint • Combined endpoint of cardiovascular hospitalisation and death from any cause • Secondary endpoints • Death from any cause • Cardiovascular death • Hospitalisation for cardiovascular reasons • Safety endpoint • Incidence of treatment emergent adverse events including all adverse events, serious adverse events, and adverse events leading to study drug discontinuation Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73.

  13. Inclusion and Exclusion Criteria • 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.

  14. Study Flow Patients randomised n=4628 Placebo n=2327 Dronedarone n=2301 Completed studyn=2301 Not treatedn=10 Lost to follow upn=0 Completed studyn=2325 Not treatedn=14 Lost to follow upn=2 Permanentstudy drug discontinuation n=716 (30.8%) Completedstudy drugas per protocol n=1611 (69.2%) Permanentstudy drug discontinuation n=696 (30.2%) Completedstudy drugas per protocol n=1605 (69.8%) Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  15. Baseline Patient Characteristics Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73.

  16. Concomitant Medications Rate Control Agents Anti-thrombotics Hohnloser SH, et al. J Cardiovasc Electrophysiol 2008;19:69-73.

  17. 50 40 30 20 24% reduction in relativerisk 10 Placebo on top of standard therapy* DR 400mg bid on top of standard therapy* 0 Dronedarone Significantly Decreased Riskof CV Hospitalisation or Death by 24% Cumulative Incidence (%) HR=0.76 p<0.001 Months 0 6 12 18 24 30 Patients at risk: * 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. Mean follow-up 21 ±5 months. Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  18. 16% reduction in relativerisk Placebo on top of standard therapy DR 400mg bid on top of standard therapy Dronedarone Reduced Risk of All-causeDeath by 16% 10 8 6 Cumulative Incidence (%) 4 HR=0.84 p=0.18 2 Months 0 0 6 12 18 24 30 Patients at risk: Mean follow-up 21 ±5 months. Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  19. 7.5 5.0 2.5 29% reduction in relativerisk Placebo on top of standard therapy DR 400mg bid on top of standard therapy 0 Dronedarone Significantly DecreasedRisk of Cardiovascular Death by 29% Cumulative Incidence (%) HR=0.71 p=0.03 Months 0 6 12 18 24 30 Patients at risk: Mean follow-up 21 ±5 months. Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  20. Dronedarone Significantly Decreased Risk of Arrhythmic Death by 45% and CV death by 29% Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  21. 0.1 1.0 10.0 Dronedarone Better Placebo Better Dronedarone Reduced CV Hospitalisation or All-cause Death Across Important Subgroups Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  22. Dronedarone Significantly Decreased Hospitalisations Related to AF by 37% Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  23. Adverse Event Rates were Not Significantly Different Between Dronedarone and Placebo Groups TEAE=Treatment Emergent Adverse Events. Adapted from Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  24. Post-hoc analysis Effect of Dronedarone on Cardiovascular Outcomes and Stroke in patients with atrial fibrillation

  25. Baseline Risk Factors for Stroke CHADS2 Score: Congestive heart failure, Hypertension, Age >75 years, Diabetes, Stroke or TIA. Connolly et al; Circulation. 2009;120:1174-1180

  26. 5 4 3 2 34% reduction in relativerisk 1 Placebo on top of standard therapy DR 400mg bid on top of standard therapy 0 Dronedarone Reduced the Relative Riskof Stroke by 34% Cumulative Incidence (%) HR=0.66 p=0.027 Months 0 6 12 18 24 30 Patients at risk: Mean follow-up 21 ±5 months. Connolly et al; Circulation. 2009;120:1174-1180

  27. Post-hoc analysis Effect of Dronedarone on Hospitalisation in Patients with AF

  28. 26% reduction in relativerisk Placebo on top of standard therapy DR 400mg bid on top of standard therapy Dronedarone Significantly Decreased Cardiovascular Hospitalisation by 26% 7.5 5.0 Cumulative Incidence (%) 2.5 HR=0.74 p<0.001 0 Months 0 6 12 18 24 30 Patients at risk: Mean follow-up 21 ±5 months. Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  29. Dronedarone Significantly Decreased CV Hospitalisations by 26% On study analysis.Hohnloser SH et al. N Engl J Med 2009;360:668-78.

  30. 14% reductionin relativerisk Placebo on top of standard therapy DR 400mg bid on top of standard therapy Dronedarone Significantly Decreased the Rate of Non-AF Related CV Hospitalisations by 14% 30 20 Cumulative Incidence (%) 10 HR=0.86 p=0.016 0 Months 0 6 12 18 24 30 Patients at risk: Mean follow-up 21 ±5 months. On study analysis. Torp-Pedersen, et al. AHA Scientific Sessions 2008

  31. 50 40 30 20 10 Placebo on top of standard therapy DR 400mg bid on top of standard therapy 0 The Two Treatment Groups had Similar Ratesof First Non-CV Hospitalisation Cumulative Incidence (%) HR=0.98 p=0.769 Months 0 6 12 18 24 30 Patients at risk: Mean follow-up 21 ±5 months. On study analysis. Torp-Pedersen, et al. AHA Scientific Sessions 2008

  32. Dronedarone led to a decrease of 1.02 CV hospitalisation days/patient/year For every 1000 patients treated with dronedarone for one year, the healthcare system would save 1020 CV hospitalisation days Dronedarone Significantly Decreasedthe Total CV Hospitalisation Days by 35% On treatment analysis. Torp-Pedersen, et al. AHA Scientific Sessions 2008

  33. Dronedarone led to a decrease of 1.26 hospitalisation days/patient/year For every 1000 patients treated with dronedarone for one year, the healthcare system would save 1260 hospitalisation days Dronedarone Significantly Decreasedthe Total Hospitalisation Burden by 28% Data on file. On treatment analysis. Torp-Pedersen et al. AHA Scientific Sessions 2008.

  34. Dronedarone reduced hospitalisation for CV reasons Summary of nights of hospitalisation for CV reasons in patients with a first recurrence of AF and with at least one CV hospitalisation In ICU In ICU In medium care unit 9% 19% 18% 17% 64% In medium care unit 73% In ward In ward Dronedarone (n=195) Placebo (n=288) ICU: intensive care unit Hohnloser S, et al. Scientific sessions HRS 2010. Hohnloser S, et al. Heart Rhythm 2010 7:5 (S215-S216). 54

  35. Conclusion

  36. Meta-analysis of 5 trials in 6157 patients confirms the principle results of ATHENA Dronedarone decreased the risk of Unplanned CV Hospitalisation or death by 24% a Efficacy population bRandomized and treated patients bRandomized and treated patients bRandomized and treated patients 66 Hohnloser S, et al. J Am Coll Cardiol. 2009;53(10, Suppl 1):A113-A114.

  37. Dronedarone significantly reduced the risk of all-cause mortality following first AF recurrence HR 0.56 (95% CI, 0.34-0.91; p=0.018) 75 51 (35 CV deaths) 50 Mortality in patients with a first Recurrence of AF (no. patients) 23 (15 CV deaths) 25 0 Placebo + standard therapy Dronedarone + standard therapy Hohnloser S, et al. Scientific sessions HRS 2010. Hohnloser S, et al. Heart Rhythm 2010 7:5 (S215-S216). 67

  38. Was dronedarone an effective AAD in ATHENA? Number of Patients 350 p<0.001 30 90 295 (12.7%) HR=0.69 HR=0.75 300 80 p<0.001 p<0.001 250 70 20 60 178 (7.7%) 200 50 150 40 100 10 30 20 50 n=2313 n=2291 10 0 0 0 Placebo Dronedarone 0 6 12 18 24 30 0 6 12 18 24 30 on top of standard therapy Months Months No patients in "Permanent AF" Time to 1st DCV Time to 1st AF/AFL Cumulative Incidence (%) Cumulative incidence of AF/AFL (%) Placebo Placebo Dronedarone Dronedarone All AF related hospitalisation: HR = 0.626; 95% CI = [.54; .73] First AF related hospitalisation: HR = 0.63; 95% CI = [.55; .72] DCV=Direct cardioversion Hohnloser SH, et al. N Engl J Med 2009;360:668-78 Page R, et al. AHA Scientific Sessions 2008 Page R, et al. Circulation. 2008;118:S_827 68

  39. Indirect comparison suggests that dronedarone has a significant mortality reduction vs. amiodarone and sotalol Compared with placebo dronedarone N=3378 0.85 (0.67 to 1.09) p=0.165 amiodarone N=653 2.73 (1.00 to 7.41) p=0.049 sotalol N=873 4.32 (1.59 to 11.70) p=0.013 0.5 1 2 5 10 100 MTC • No evidence of an increase in mortality associated with the use of dronedarone in AF population • Dronedarone showed a statistically significant mortality reduction vs. amiodarone (p=0.032) and sotalol (p=0.009) 69 Freemantle N et al. Circulation. 2009;120:S691-S692

  40. Landmark ATHENA study results compare favourably with other CV morbi-mortality studies 37 (%) 40 35 25 24 30 22 20 20 25 16 20 13.2 11 15 8 10 5 0 ATHENA ACCLAIM FIELD Val-HeFT CHARM EUROPA CURE HOPE LIPID CARDS 7.5 (%) 8 7 6 4.3 5 3.8 3.3 3.2 3 4 2.1 1.9 1.9 3 2 1 1 0 ATHENA FIELD EUROPA LIPID CURE ACCLAIM CARDS Val-HeFT HOPE CHARM (%) 40 30 24.7 23.9 30 14.6 20 10 7 FIELD 0 10 ACCLAIM 0 JIKEIHEART CURE CHARM EUROPA LIPID HOPE ATHENA -10 -9.8 -20 -20 -30 2.3 (%) 2 2 2.5 2 1.13 1.5 0.6 1 0.4 FIELD 0 0.5 ACCLAIM 0 ATHENA JIKEIHEART CURE EUROPA CHARM HOPE LIPID -0.5 -0.5 -1 -1 -1.5 RelativeRisk Reduction Morbi- Mortality annualised Absolute Risk Reduction RelativeRisk Reduction CV Mortality annualised Absolute Risk Reduction 70 See notes page for references

  41. Dronedarone and hospitalisation – key points Dronedarone significantly decreased unplanned CV hospitalisation by 26% and hospitalisations related to AF by 37%, which is a sign of its AAD efficacy Dronedarone significantly decreased the rate of unplanned non-AF related CV hospitalisations by 14% The reduction in unplanned AF-related hospitalisation is not simply a result of reduced admission for electrical cardioversion which was mainly performed out of hospital Only 27% of unplanned AF-related hospitalisations were related to electrical cardioversion Dronedarone significantly decreased the total CV hospitalisation days by 35% and the total AF related CV hospitalisation days by 32% 72

  42. MULTAQ Packshot • Dronedarone 400 mg • Film-coated tablet • 60 tablets/ box • Blister pack

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