Dronedarona
De los ensayos clínicos a los datos del “mundo real”
Jose L. Merino
Hospital La Paz
Trend in cost of care for atrial fibrillation (AF) hospitalizations.
Patel N J et al. Circulation. 2014;129:2371-2379
2009
Estudio ATHENA
Mortalidad CV o hospitalizaciones
Hohnloser et al. NEJM 2009
Estudio ATHENA
Hohnloser et al. NEJM 2009
Estudio ATHENA
0
2
4
6
8
10
Placebo
Months
Dronedarone
HR=0.84
P=0.176
2301
2290
2274
2250
2240
1629
1593
636
615
7
4
2327...
Estudio ATHENA
Hohnloser et al. NEJM 2009
10
11
PALLAS: Inclusion criteria
1. Permanent AF
– > 6 months
(ECG or medical report)
2. ≥ 65 years
3. CV disease
– CAD, HF, ...
Placebo BID
5400 patients
5400 patients
Variable – Event Driven
Dronedarone 400 mg BID
PALLAS: Study design
On top of Stan...
Nattel NEJM 2011
Px/Ps: 100%
No FA PM
No ICC (Disf VI)
ESC Guidelines 2012
North America
~826,000 patients
Europe
~475,000 patients
Canada
~ 22,000
United States
~796,000
Germany
~245,000
Spain
~ 7...
~1,315,657 patients have received treatment
with dronedarone worldwide since July 2009*
North America
~826,000 patients
Eu...
Estudios mundo real vs Estudios aleatorizados
19
Eficacia
(Clinical trial)
Efectividad
(Real world data)
Objectivo
Funcion...
Registro DoD
(US Department of Defense)
DoD Comparative Effectiveness Study:
Objectives
• To compare the effectiveness of dronedarone and current
established trea...
DoD Study Design: Study duration
• Retrospective (historical) cohort
• Study time period:
• Patients censoring process:
– ...
DoD study design:
propensity score model variables
Demographic variables
• Age*
• Gender (% male)*
• Index date*
• Charlso...
DoD effectiveness study
Poster (Boston AF 2014)
http://www.deggegroup.com/2014-AF_Symposium%20-%20Dronedarone.pdf, accesse...
AADs New initiators Cohorts composition at
baseline
Other AADsa
after PS matching
Total 4,936
Amiodarone, n (%) 2,190 (44....
DoD Effectiveness Study
Baseline demography of new initiators post PS matching
Dronedarone
after PS matching
Other AADs
af...
CV hospitalizations and/or death from any cause
Significant increased risk of CV hospitalization and/or death in the “othe...
CV hospitalizations
Significant increased risk of CV hospitalization in the “other AADs” cohort
compared to dronedarone
Dr...
All-cause mortality
Dronedarone: non-significant lower all-cause mortality compared with “other AADs”
Dronedarone: 2468 19...
Non-hospitalized cardioversion
Dronedarone: significantly higher rate of non-hospitalized cardioversion than “other
AADs”
...
Hospitalization for heart failure
Not different between “other AADs” and the dronedarone group
Dronedarone: 2468 1916 1370...
Treatment Outcomes, N(%)
Other AAD
a
(N = 4936)
Dronedarone
a
(N = 2468)
HR (95% CI) P-Value
CV hospitalization and/or dea...
DoD effectiveness study
Abstract (Boston AF 2014): BAF2014-3004
33
« Real-life comparison of dronedarone with other antiar...
Conclusions
 Consistency of CV hospitalization and mortality results
between this real-life study and the randomized ATHE...
Registro Sueco
Conclusiones
• Ensayos clinicos:
– Dronedarona el FAA mejor y mas estudiado en la FA
– Indicaciones clínicas precisas (No ...
Puerta de Alcalá, Madrid, ES
Limitations
• Dronedarone population represents the population before changes of label
occurred in US and in EU
• Analysis...
El ATHENA de
amiodarona
The AFFIRM trial
N Engl J Med 2002
Amiodarona 63%
AFFIRM
El
ANDROMEDA
de amiodarona
SCD-HeFT
• DAI vs Amiodarona vs. Placebo
• FE-VI ≤35% + NYHA II o III
• Amiodarona vs. Placebo (mortalidad):
– NYHA II -> ...
Un ejemplo: Dronedarona, de los ensayos clínicos a los datos del "mundo real"
Un ejemplo: Dronedarona, de los ensayos clínicos a los datos del "mundo real"
Un ejemplo: Dronedarona, de los ensayos clínicos a los datos del "mundo real"
Un ejemplo: Dronedarona, de los ensayos clínicos a los datos del "mundo real"
Un ejemplo: Dronedarona, de los ensayos clínicos a los datos del "mundo real"
Un ejemplo: Dronedarona, de los ensayos clínicos a los datos del "mundo real"
Un ejemplo: Dronedarona, de los ensayos clínicos a los datos del "mundo real"
Un ejemplo: Dronedarona, de los ensayos clínicos a los datos del "mundo real"
Un ejemplo: Dronedarona, de los ensayos clínicos a los datos del "mundo real"
Un ejemplo: Dronedarona, de los ensayos clínicos a los datos del "mundo real"
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Un ejemplo: Dronedarona, de los ensayos clínicos a los datos del "mundo real"

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Actualización en Fibrilación Auricular: de la evidencia a la práctica clínica.
10 de Junio de 2014, 16:30h
http://www.secardiologia.es/directos/actualizacionFA.html

Un ejemplo: Dronedarona, de los ensayos clínicos a los datos del "mundo real"
Dr. José Luis Merino Llorens
Hospital Universitario La Paz (Madrid)

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Un ejemplo: Dronedarona, de los ensayos clínicos a los datos del "mundo real"

  1. 1. Dronedarona De los ensayos clínicos a los datos del “mundo real” Jose L. Merino Hospital La Paz
  2. 2. Trend in cost of care for atrial fibrillation (AF) hospitalizations. Patel N J et al. Circulation. 2014;129:2371-2379
  3. 3. 2009
  4. 4. Estudio ATHENA Mortalidad CV o hospitalizaciones Hohnloser et al. NEJM 2009
  5. 5. Estudio ATHENA Hohnloser et al. NEJM 2009
  6. 6. Estudio ATHENA 0 2 4 6 8 10 Placebo Months Dronedarone HR=0.84 P=0.176 2301 2290 2274 2250 2240 1629 1593 636 615 7 4 2327Placebo Dronedarone Patients at risk 0 6 12 18 24 30 CummulativeIncidence(%) All-cause Mortality Hohnloser et al. NEJM 2009
  7. 7. Estudio ATHENA Hohnloser et al. NEJM 2009
  8. 8. 10
  9. 9. 11 PALLAS: Inclusion criteria 1. Permanent AF – > 6 months (ECG or medical report) 2. ≥ 65 years 3. CV disease – CAD, HF, LV EF ≤40% – Stroke – Peripheral vascular disease – ≥ 75 yo + HT + DBM
  10. 10. Placebo BID 5400 patients 5400 patients Variable – Event Driven Dronedarone 400 mg BID PALLAS: Study design On top of Standard of CareR
  11. 11. Nattel NEJM 2011 Px/Ps: 100% No FA PM No ICC (Disf VI)
  12. 12. ESC Guidelines 2012
  13. 13. North America ~826,000 patients Europe ~475,000 patients Canada ~ 22,000 United States ~796,000 Germany ~245,000 Spain ~ 70,000 Italy ~ 53,000 United Kingdom ~ 24,000 ~1,315,657 patients* treated since launch WORLDWIDE Over 1,3 million patients exposed to dronedarone throughout 40 countries up to 31 March 2014* France ~ 27,000 * Cumulative number of patients. Estimated. IMS/MIDAS Worldwide Monthly Database, Standard Units Sold up until 31 March 2014.
  14. 14. ~1,315,657 patients have received treatment with dronedarone worldwide since July 2009* North America ~826,000 patients Europe ~475,000 patients USA ~796,000 Germany ~245,000 Spain ~70,000 Italy ~53,000
  15. 15. Estudios mundo real vs Estudios aleatorizados 19 Eficacia (Clinical trial) Efectividad (Real world data) Objectivo Funciona en condiciones ideales? Funciona en condiciones usuales? Diseño Ensayo controlado Practica en el mundo real Objetivo Aprobación regulatoria Comportamiento del fármaco Intervención/Tratamie nto Fijo Flexible Comparador Activo Practica habitual Población Homogenea / Muy seleccionada Heterogenea / cualquiera Compliance Alta Variable Validez interna Alta Baja Validez externa (generalizable a otras poblaciones) Baja-Media Media-Alta Patsopoulos, Dialogues Clin Neurosci. 2011;13:217-224
  16. 16. Registro DoD (US Department of Defense)
  17. 17. DoD Comparative Effectiveness Study: Objectives • To compare the effectiveness of dronedarone and current established treatments for AF/AFL, as measured by the occurrence of health outcomes • Specific objectives associated with the use of either dronedarone or comparators include: – Identification of the demographic and clinical characteristics of patients treated for AF/AFL – Assessment of health outcomes including • Hospitalization of patients for at least 1 night (CV and non-CV) • Death (all-cause or CV) 21 21 http://www.deggegroup.com/2014-AF_Symposium%20-%20Dronedarone.pdf, accessed online on 24 March 2014 http://onlinelibrary.wiley.com/doi/10.1111/jce.12390/pdf, Journal of Cardiovascular Electrophysiology, access online on 24 March 2014
  18. 18. DoD Study Design: Study duration • Retrospective (historical) cohort • Study time period: • Patients censoring process: – Discontinuation of the index drug (+ 60 days to take into account various half-life) – Switch or addition of another study drug – Loss of eligibility for health care in the DoD database – End of study period (July 2011) – Death • Patient’s follow-up: 22 July 2009 July 2011 http://www.deggegroup.com/2014-AF_Symposium%20-%20Dronedarone.pdf, accessed online on 24 March 2014 http://onlinelibrary.wiley.com/doi/10.1111/jce.12390/pdf, Journal of Cardiovascular Electrophysiology, access online on 24 March 2014 Max 24 months of follow-up
  19. 19. DoD study design: propensity score model variables Demographic variables • Age* • Gender (% male)* • Index date* • Charlson score* • AF without other CV disease – Y/N • COPD – Y/N History of comorbid conditions – Y/N • Hypertension* • Diabetes* • TIA or stroke* • Structural heart disease* • Coronary heart disease* • Valvular heart disease* • Non-ischaemic cardiomyopathy • Congestive heart failure* History of comorbid procedures – Y/N • Ablation • Cardiac surgery* • Pacemaker evaluation • Pacemaker insertion* • Stent placement • Valve placement* • Valvular surgery* • Major open heart surgery* History of concomitant medication use – Y/N • ACE inhibitors or ARBs* • Statins* • Beta blockers* • Anticoagulants* • Warfarin • Dabigatran* • Aspirin, prescribed by physician* Medical encounters • Hospitalization in prior year – Y/N* • Number of office visits in prior year • Skilled nursing facility visit in prior year – Y/N* • Number of other study medications in prior year – Y/N* • Number of other nonstudy medications in prior year Prior event occurrence – Y/N* • Prior acute myocardial infarction • Prior stable angina pectoris • Prior arrhythmia • Prior cerebrovascular accident • Prior deep vein thrombosis • Prior hospitalized bleeding • Prior pulmonary embolism • Prior systemic arterial embolism • Prior syncope • Prior stroke 23  To control for potential confounding and bias, propensity score (PS) matching used • Ratio 1:2 (dronedarone, other AADs respectively)
  20. 20. DoD effectiveness study Poster (Boston AF 2014) http://www.deggegroup.com/2014-AF_Symposium%20-%20Dronedarone.pdf, accessed online on 24 March 2014 24
  21. 21. AADs New initiators Cohorts composition at baseline Other AADsa after PS matching Total 4,936 Amiodarone, n (%) 2,190 (44.4) Sotalol, n (%) 987 (20.0) Dofetilide, n (%) 111 (2.2) Class IC, n (%) 1,285 (26.0) Propafenone, n (%) 553 (11.2) Flecainide, n (%) 732 (14.8) Mexiletine, n (%) 11 (0.2) Other, n (%) 352 (7.1) a Class IC/III. Data on file, Sanofi 2014
  22. 22. DoD Effectiveness Study Baseline demography of new initiators post PS matching Dronedarone after PS matching Other AADs after PS matching All patients, n (%) 2,468 (100.0) 4,936 (100.0) Mean age (years) 72.1 70.7 Male, n (%) 1,444 (58.5) 2,997 (60.7) History of disease, n (%) AF/AFL 2,468 (100.0) 4,936 (100.0) AF without CV disease 927 (37.6) 1,812 (36.7) CV hospitalization 928 (37.6) 1,928 (39.1) Hypertension 2,038 (82.6) 4,045 (81.9) Diabetes 733 (29.7) 1,421 (28.8) TIA/stroke 306 (12.4) 568 (11.5) Structural heart disease 630 (25.5) 1,360 (27.6) Coronary heart disease 1,269 (51.4) 2,579 (52.2) Valvular heart disease 991 (40.2) 1,936 (39.2) CHF 693 (28.1) 1,328 (26.9)
  23. 23. CV hospitalizations and/or death from any cause Significant increased risk of CV hospitalization and/or death in the “other AADs” cohort compared to dronedarone Dronedarone: 2468 1875 1309 929 713 523 397 279 171 106 43 11 0 Other AAD: 4936 3818 2305 1587 1132 820 581 428 279 159 98 56 0 Months After Index Date PatientsRemaining Event-Free(%) HR (95% CI), 1.24 (1.05-1.47) Dronedarone Other AAD; P = 0.011
  24. 24. CV hospitalizations Significant increased risk of CV hospitalization in the “other AADs” cohort compared to dronedarone Dronedarone: 2468 1875 1309 929 713 523 397 279 171 106 43 11 0 Other AAD: 4936 3818 2305 1587 1132 820 581 428 279 159 98 56 0 Months After Index Date PatientsRemaining Event-Free(%) HR (95% CI), 1.21 (1.02-1.44) Dronedarone Other AAD; P = 0.026
  25. 25. All-cause mortality Dronedarone: non-significant lower all-cause mortality compared with “other AADs” Dronedarone: 2468 1925 1381 986 761 567 434 301 189 115 50 12 0 Other AAD: 4936 3976 2493 1740 1262 928 663 492 320 184 113 63 0 Months After Index Date PatientsRemaining Event-Free(%) HR (95% CI), 1.83 (0.84-4.02) Dronedarone Other AAD; P = 0.131 29
  26. 26. Non-hospitalized cardioversion Dronedarone: significantly higher rate of non-hospitalized cardioversion than “other AADs” Dronedarone: 2468 1693 1202 854 665 495 374 260 158 95 39 10 0 Other AAD: 4936 3561 2164 1481 1063 782 557 417 271 157 96 52 0 Months After Index Date PatientsRemaining Event-Free(%) HR (95% CI), 0.81 (0.71-0.92) Dronedarone Other AAD; P = 0.001 30
  27. 27. Hospitalization for heart failure Not different between “other AADs” and the dronedarone group Dronedarone: 2468 1916 1370 975 754 561 429 297 184 113 48 12 0 Other AAD: 4936 3950 2466 1715 1236 899 642 478 314 181 113 63 0 Months After Index Date PatientsRemaining Event-Free(%) HR (95% CI), 1.21 (0.82-1.78) Dronedarone Other AAD; P = 0.343
  28. 28. Treatment Outcomes, N(%) Other AAD a (N = 4936) Dronedarone a (N = 2468) HR (95% CI) P-Value CV hospitalization and/or death (all-cause) 453 (9.2) 196 (7.9) 1.24 [1.05, 1.47] 0.011 All-cause death 28 (0.6) 8 (0.3) 1.83 [0.84, 4.02] 0.131 CV hospitalization 429 (8.7) 190 (7.7) 1.21 [1.02, 1.44] 0.026 CV-related death 3 (0.1) 2 (0.1) 0.77 [0.13, 4.61] 0.774 Non-CV hospitalization 678 (13.7) 286 (11.6) 1.29 [1.12,1.48] < 0.001 Hospitalization for AF 166 (3.4) 87 (3.5) 1.01 [0.78,1.31] 0.951 Hospitalized cardioversion 14 (0.3) 8 (0.3) 0.91 [0.38, 2.18] 0.840 Nonhospitalized cardioversion 596 (12.1) 369 (15.0) 0.81 [0.71, 0.92] 0.001 Hospitalization for arrhythmia 54(1.1) 14 (0.6) 2.01 [1.11, 3.61] 0.020 Hospitalization for bleeding 50 (1.0) 30 (1.2) 0.88 [0.56, 1.38] 0.579 Hospitalization for CVA 20 (0.4) 9 (0.4) 1.20 [0.55, 2.64] 0.647 Hospitalization for TIA 10 (0.2) 5 (0.2) 1.11 [0.38, 3.24] 0.855 Hospitalization for heart failure 84 (1.7) 37 (1.5) 1.21 [0.82, 1.78] 0.343 Hospitalization for CV surgery 172 (3.5) 68 (2.8) 1.34 [1.02,1.78] 0.039 CV hospitalization and/or death (any cause) b 176 (8.7) 152 (7.6) 1.26 [1.01, 1.57] 0.037 CV hospitalization and/or death (any cause) c 308 (8.9) 131 (7.6) 1.29 [1.05, 1.59] 0.014 Overview of CV Outcomes Other AAD versus dronedarone on CV outcomes (post-PS-matching). Less Favorable to Other AAD 0 21 3 4 5 32
  29. 29. DoD effectiveness study Abstract (Boston AF 2014): BAF2014-3004 33 « Real-life comparison of dronedarone with other antiarrhythmic drugs on cardiovascular outcomes in atrial fibrillation: an updated analysis of a large US population Table 1: Other AAD Versus Dronedarone on CV Outcomes Key outcomes (n, %) Other AAD (N =4936) Dronedarone (N=2468) HR [95% CI] P-value CV hospitalization and/or death (all-cause) 453 (9.2) 196 (7.9) 1.24 [1.05, 1.47]* 0.011 All-cause mortality 28 (0.6) 8 (0.3) 1.83 [0.84, 4.02] 0.131 CV-related mortality 3 (0.1) 2 (0.1) 0.77 [0.13, 4.61] 0.774 CV hospitalization 429 (8.7) 190 (7.7) 1.21 [1.02, 1.44] 0.026 Non-CV hospitalization 678 (13.7) 286 (11.6) 1.29 [1.12, 1.48] <0.001 Non-hospitalized cardioversion 596 (12.1) 369 (15.0) 0.81 [0.71, 0.92] 0.001 Hospitalization for arrhythmia 54 (1.1) 14 (0.6) 2.01 [1.11, 3.61] 0.020 Hospitalization for CV surgery 172 (3.5) 68 (2.8) 1.34 [1.02, 1.78] 0.039 * Sensitivity analyses: HR=1.26 [95% CI: 1.01, 1.57]; P=0.037 (ratio 1:1, caliper 0.001) and HR=1.29 [95% CI: 1.05; 1.59]; P=0.012 (ratio 2:1, caliper 0.001).
  30. 30. Conclusions  Consistency of CV hospitalization and mortality results between this real-life study and the randomized ATHENA clinical trial:  Dronedarone showed significantly lower risk of CV hospitalization and/or death from any cause than “other AADs” and  Numerically lower all-cause mortality (not significant)  Consistency of rhythm / cardioversion results between this study and the randomized DIONYSOS clinical trial:  Dronedarone showed a significantly higher rate of non-hospitalized cardioversion than “other AADs”  In the DIONYSOS clinical trial, dronedarone was less effective in the maintenance of normal sinus rhythm than amiodarone 1. Hohnloser SH et al. N Engl J Med 2009;360:668-78. 2. Le Heuzey JY et al. J Cardiovasc Electrophysiol. 2010;21(6):597-605. 34
  31. 31. Registro Sueco
  32. 32. Conclusiones • Ensayos clinicos: – Dronedarona el FAA mejor y mas estudiado en la FA – Indicaciones clínicas precisas (No ICC, No FA PM) • Gran experiencia clínica actual (USA, Alemania, España) • Registros del mundo real han valido los resultados de los ensayos clínicos en: – Eficacia (hospitalizaciones, mortalidad CV) – Seguridad
  33. 33. Puerta de Alcalá, Madrid, ES
  34. 34. Limitations • Dronedarone population represents the population before changes of label occurred in US and in EU • Analysis not worldwide, concerns a US sub-population • Type of AF unknown – Not possible to describe the proportion of paroxysmal, persistent and permanent patients – Not included in PS • Severity of heart failure not taken into consideration (NYHA level) – Not possible to use the type of AF in the PS • No 12-Lead ECG results available – Need to approximate recurrence of AF using cardioversion which is an issue especially in patients treated with a rate control strategy • Insufficient max FUP of 24 months to see events taking time to occur http://www.deggegroup.com/2014-AF_Symposium%20-%20Dronedarone.pdf, accessed online on 24 March 2014 43
  35. 35. El ATHENA de amiodarona
  36. 36. The AFFIRM trial N Engl J Med 2002 Amiodarona 63%
  37. 37. AFFIRM
  38. 38. El ANDROMEDA de amiodarona
  39. 39. SCD-HeFT • DAI vs Amiodarona vs. Placebo • FE-VI ≤35% + NYHA II o III • Amiodarona vs. Placebo (mortalidad): – NYHA II -> Neutro (disminución, P=0.17) – NYHA III-> Aumento 44% mortalidad (P<0.01) Bardy GH, et al. N Engl J Med 2005;352:225–37. Months of follow up

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