Agir sur la rénine : Efficacité clinique, pour quels patients, quand et comment ? Pr Xavier Girerd Pôle Endocrinologie Unité de Prévention des Maladies Cardiovasculaires Groupe Hospitalier Pitié-Salpêtrière Faculté Pierre et Marie Curie, Paris 6 Paris, 9 octobre 2009 1

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* * * * −5 −10 −15 −20 PAD PAS Biodisponibilité 2,7% L’administration d’aliskiren (150 mg/j ou 300 mg/j) a entraîné des diminutions dose-dépendantes des valeurs de la PAD et de la PAS Aliskiren (mg) Aliskiren (mg) Placebo 150 300 Placebo 150 300 n=163 n=167 n=166 n=163 n=167 n=166 −5 −3.8 −4.9 −10 −10.3 −11.1 * * −13.0 −15 In this double-blind, randomized, placebo-controlled trial, aliskiren significantly lowered mean sitting diastolic and systolic blood pressure (MSDBP, MSSBP; p<0.0001 versus placebo for all aliskiren doses). The magnitude of effect on MSDBP was dose-related – aliskiren 150, 300 and 600 mg reduced DBP (least squares mean ± SEM) by 10.3 ± 0.63, 11.1 ± 0.64 and 12.5 ± 0.64 mmHg, respectively, compared with 4.9 ± 0.64 mmHg with placebo. The magnitude of effect on MSSBP was dose-related – aliskiren 150, 300 and 600 mg reduced SBP (least squares mean ± SEM) by 13.0 ± 1.0, 14.7 ± 1.0 and 15.8 ± 1.0 mmHg, respectively, compared with 3.8 ± 1.0 mmHg for placebo. Abbreviations DBP = diastolic blood pressure MSDBP = mean sitting diastolic blood pressure MSSBP = mean sitting systolic blood pressure SBP = systolic blood pressure Reference Oh B-H, Chung J, Khan M, et al. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in patients with hypertension. J Am Coll Cardiol 2006;47(4 Suppl. A):370A:P1027-191. * −14.7 * −20 PAD PAS Biodisponibilité 2,7% Affinité pour la rénine IC50 = 0.6 nmol/l Oh BH, et al. J Am Coll Cardiol 2007; 49: 1157-1163 *p<0,0001 vs placebo

Effet hypotenseur du doublement de la dose usuelle Efficacité Rare Efficacité Parfois Efficacité Souvent Bêta-bloquant IEC AA2 IDR Inhibiteur calcique Diurétique X Girerd 2009

Comparaison à l’hydrochlorothiazide 12,5 ou 25 mg Les études comparatives avec l’aliskiren en monothérapie ont montré par rapport au ramipril et à l’hydrochlorothiazide (HCTZ) une supériorité de l’aliskiren. Comparaison à l’hydrochlorothiazide 12,5 ou 25 mg Supériorité chez des hypertendus de grade 1 à 2 Supériorité chez des hypertendus de plus de 65 ans Comparaison au Ramipril 5 ou 10 mg Supériorité chez des hypertendus diabétiques

Comparaison Aliskiren 300 mg vs irbesartan 300mg dans l’hypertension métabolique Semaine 8 Semaine 12 PAD PAS PAD PAS n=58 n=66 n=58 n=66 n=66 n=72 n=66 n=72 –2.8 –5 –4.1 –5.8 –6.8 –7.7 –7.1 –10 p=0.009 p=0.001 –13.1 –13.8 –15 This was a double-blind, randomized, placebo and active-controlled 8-week trial in 1797 patients with mild-to-moderate hypertension (defined as mean sitting diastolic blood pressure [MSDBP] ≥95 mmHg and <110 mmHg). Following a washout period of 1–2 weeks, patients underwent a single-blind placebo run-in period lasting 3–4 weeks. Patients with MSDBP ≥95 mmHg and <110 mmHg were randomized to receive aliskiren 150 mg, valsartan 160 mg, aliskiren 150 mg with valsartan 160 mg, or placebo, once daily. After 4 weeks of treatment, the dosages of aliskiren and valsartan were doubled for the final 4 weeks of the study. Ambulatory blood pressure (BP) monitoring (ABPM) was performed in a subset of patients in this study. After 8 weeks of treatment, combination therapy using aliskiren 300 mg and valsartan 320 mg provided significantly greater reductions in 24-hour ambulatory BP compared with either of the component monotherapies (p<0.0001 for both comparisons). In the aliskiren/valsartan combination therapy group, mean 24-hour ambulatory diastolic BP (ADBP) was reduced by 10.3 mmHg and mean 24-hour ambulatory systolic BP (ASBP) was reduced by 14.4 mmHg (both p<0.0001 vs. placebo) compared with baseline values. Abbreviations BP = blood pressure ABPM = ambulatory blood pressure monitoring ADBP = ambulatory diastolic blood pressure ASBP = ambulatory systolic blood pressure MSDBP = mean sitting diastolic blood pressure Reference Oparil S, Yarrows, S, Patel S, et al. The direct renin inhibitor aliskiren in combination with the angiotensin receptor blocker valsartan provides additional blood pressure-lowering effects compared with either agent alone in patients with hypertension. Oral presentation at ACC 2007. p=0.006 p<0.001 –20 Variation moyenne par rapport à l'état basal de la PA (mmHg) Irbesartan 300 mg Aliskiren 300 mg W Krone, et al. For . For the CSPP100A2325 study investigators

Aliskiren vs irbesartan, patients syndrome métabolique Aliskiren vs irbesartan, patients syndrome métabolique. Effets sur l’Activité Rénine Plasmatique Semaine 12 –80 –60 –40 –20 20 40 60 80 100 n=58 +99% p<0.001 n=66 –60% This was a double-blind, randomized, placebo and active-controlled 8-week trial in 1797 patients with mild-to-moderate hypertension (defined as mean sitting diastolic blood pressure [MSDBP] ≥95 mmHg and <110 mmHg). Following a washout period of 1–2 weeks, patients underwent a single-blind placebo run-in period lasting 3–4 weeks. Patients with MSDBP ≥95 mmHg and <110 mmHg were randomized to receive aliskiren 150 mg, valsartan 160 mg, aliskiren 150 mg with valsartan 160 mg, or placebo, once daily. After 4 weeks of treatment, the dosages of aliskiren and valsartan were doubled for the final 4 weeks of the study. Ambulatory blood pressure (BP) monitoring (ABPM) was performed in a subset of patients in this study. After 8 weeks of treatment, combination therapy using aliskiren 300 mg and valsartan 320 mg provided significantly greater reductions in 24-hour ambulatory BP compared with either of the component monotherapies (p<0.0001 for both comparisons). In the aliskiren/valsartan combination therapy group, mean 24-hour ambulatory diastolic BP (ADBP) was reduced by 10.3 mmHg and mean 24-hour ambulatory systolic BP (ASBP) was reduced by 14.4 mmHg (both p<0.0001 vs. placebo) compared with baseline values. Abbreviations BP = blood pressure ABPM = ambulatory blood pressure monitoring ADBP = ambulatory diastolic blood pressure ASBP = ambulatory systolic blood pressure MSDBP = mean sitting diastolic blood pressure Reference Oparil S, Yarrows, S, Patel S, et al. The direct renin inhibitor aliskiren in combination with the angiotensin receptor blocker valsartan provides additional blood pressure-lowering effects compared with either agent alone in patients with hypertension. Oral presentation at ACC 2007. Variation moyenne par rapport à l'état basal de l’Activité Rénine Plasmatique (%) Irbesartan 300 mg Aliskiren 300 mg W Krone, et al. For . For the CSPP100A2325 study investigators

Une association fixe aliskiren + HCTZ (Rasilez HCT®) a obtenu l’AMM. Les études réalisées avec l’aliskiren utilisé en association ont montré un effet antihypertenseur additif de l’aliskiren en association à l’HCTZ, au ramipril, à l’amlodipine et au valsartan Placebo Aliskiren Association Aliskiren (mg) 150 300 150 300 HCTZ (mg) 12.5 25 n= 192 183 180 184 173 -6.9 –8 -8.9 –10 * -10.3 *** –12 -11.9 p=0,0002 Aliskiren monotherapy yielded dose dependent reductions in mean sitting systolic blood pressure (MSSBP), that were significant versus placebo at doses of 150 and 300 mg. Hydrochlorothiazide (HCTZ) had a similar magnitude of effect to aliskiren 150 and 300 mg, but did not show a dose-response relationship; however, elucidating the effects of HCTZ monotherapy was not an objective of the study, so significance of the effect was not tested. Combinations of aliskiren 75 mg/HCTZ 6.25 mg, aliskiren 150 mg/HCTZ 12.5 mg, and aliskiren 300 mg/HCTZ 25 mg were all associated with significant MSSBP reductions versus placebo (p<0.0001). Most combinations provided significantly greater reductions in MSSBP than the component monotherapy. Abbreviations DBP = diastolic blood pressure HCTZ = hydrochlorothiazide MSSBP = mean sitting systolic blood pressure SBP = systolic blood pressure Reference Villamil A, Chrysant SG, Calhoun D, et al. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens 2007;25:217–226. *** –14 § -14.3 *** § –16 Variation moyenne par rapport à l'état basal de la PAD moyenne en position assise (mmHg) à la semaine 8 Une association fixe aliskiren + HCTZ (Rasilez HCT®) a obtenu l’AMM. J Hypertens 2007; 25: 217-226 10

Les études réalisées avec l’aliskiren utilisé en association ont montré un effet antihypertenseur additif de l’aliskiren en association à l’HCTZ, au ramipril, à l’amlodipine et au valsartan PAD PAS n=81 n=79 n=100 n=94 n=81 n=79 n=100 n=94 –1.1 –1.3 –5 –7.1 –7.1 –10 ** ** –10.3 –9.8 –10.1 ** ** ** 3.2‡ –15 3.2‡ –14.4 This was a double-blind, randomized, placebo and active-controlled 8-week trial in 1797 patients with mild-to-moderate hypertension (defined as mean sitting diastolic blood pressure [MSDBP] ≥95 mmHg and <110 mmHg). Following a washout period of 1–2 weeks, patients underwent a single-blind placebo run-in period lasting 3–4 weeks. Patients with MSDBP ≥95 mmHg and <110 mmHg were randomized to receive aliskiren 150 mg, valsartan 160 mg, aliskiren 150 mg with valsartan 160 mg, or placebo, once daily. After 4 weeks of treatment, the dosages of aliskiren and valsartan were doubled for the final 4 weeks of the study. Ambulatory blood pressure (BP) monitoring (ABPM) was performed in a subset of patients in this study. After 8 weeks of treatment, combination therapy using aliskiren 300 mg and valsartan 320 mg provided significantly greater reductions in 24-hour ambulatory BP compared with either of the component monotherapies (p<0.0001 for both comparisons). In the aliskiren/valsartan combination therapy group, mean 24-hour ambulatory diastolic BP (ADBP) was reduced by 10.3 mmHg and mean 24-hour ambulatory systolic BP (ASBP) was reduced by 14.4 mmHg (both p<0.0001 vs. placebo) compared with baseline values. Abbreviations BP = blood pressure ABPM = ambulatory blood pressure monitoring ADBP = ambulatory diastolic blood pressure ASBP = ambulatory systolic blood pressure MSDBP = mean sitting diastolic blood pressure Reference Oparil S, Yarrows, S, Patel S, et al. The direct renin inhibitor aliskiren in combination with the angiotensin receptor blocker valsartan provides additional blood pressure-lowering effects compared with either agent alone in patients with hypertension. Oral presentation at ACC 2007. ** 4.3‡ 4.7‡ –20 Variation moyenne par rapport à l'état basal de la MAPA sur 24 heures (mmHg) à la semaine 8 Placebo Valsartan 320 mg Aliskiren 300 mg Aliskiren/valsartan 300/320 mg **p<0,0001 vs placebo; ‡p<0,0001 vs association aliskiren/valsartan Oparil S, et al. Lancet 2007; 370:221-29 11

Rénine IDR A ll PA ARA II Récepteur AT1 N.GIRERD 12

Compte tenu de l’absence de données de morbi-mortalité, la commission de la transparence considère que l’aliskiren n’est pas un médicament de première intention dans le traitement de l’hypertension artérielle. 9 SAVE Captopril CONSENSUS Enalapril 4 6 GISSI 3 Lisinopril 14 PROGRESS Périndopril 12 AIRE HOPE Ramipril 5 AIPRI Bénazépril TRACE Trandolapril 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 2001 13

Compte tenu de l’absence de données de morbi-mortalité, la commission de la transparence considère que l’aliskiren n’est pas un médicament de première intention dans le traitement de l’hypertension artérielle. 2008 2009 2010 2011 2012 2013 2014 2015 ALTITUDE : 8600 diabétiques de type 2 avec néphropathie, aliskiren vs placebo + traitement conventionnel ATMOSPHERE : 6600 Insuffisants cardiaques à FEVG<35%, aliskiren vs IEC vs association ASTRONAUT : 1800 patients insuffisants cardiaques et BNP>400mg, aliskiren vs placebo APPOLO : 12500 patients âgés avec PAS entre 130 et 159 mmHg, aliskiren vs placebo 14

Dans les études disponibles, les effets indésirables n’ont pas été globalement plus fréquents sous aliskiren que sous placebo.

Médicament - ARA2 Coût du traitement journalier Aprovel ® 150 ; 300 0,79 € ; 1,06 € Olmetec® 10 ; 20 ; 40 0,51 €, 0,81 € ; 0,82 € Tareg® 80 ;160 0,81 € ; 1,02 € Atacand® 4 ; 8 ; 16 0,59 €; 0,78 €; 0,84 € Cozaar ® 50 ; 100 0,75 € ; 1,26 € Médicament - IEC Coût du traitement journalier Coversyl ® 2,5 ; 5 ; 10 0,65 € ; 0,91 € ; 1,43 € Ramipril 2,5 ; 5 ; 10 0,32 €, 0,39 € ; 0,58 €

Place du Rasilez® pour le traitement des hypertendus Un bloqueur du SRA, plus puissant qu’un IEC, que l’HCTZ et chez certains patients qu’un AA2, ayant la tolérance du placebo. Utilisable en monothérapie et en association. X Girerd 2009 17

Le choix d’une monothérapie en 2009 HTA métabolique ARA2 IEC 1 IDR Rasilez® 300 2 X Girerd 2009 18

Le choix d’une monothérapie en 2009 HTA vasculaire Antagoniste Calcique Diurétique Thiazidique 1 IDR Rasilez® 150 2 X Girerd 2009 19

Le choix d’une monothérapie en 2009 HTA familiale IEC ARA2 Bêta- Bloquant 1 IDR Rasilez® 300 2 X Girerd 2009 20

Le choix d’une association en 2009 HTA métabolique - HTA familiale ARA2 ou IEC + HCTZ ARA2 ou IEC + Ant Calcique 1 Thiazidique 2 Rasilez®300 + Antagoniste Calcique X Girerd 2009 21

Le choix d’une association en 2009 HTA vasculaire Antagoniste Calcique ARA2 ou IEC 1 + Antagoniste Calcique IDR Rasilez® 300 + 2 X Girerd 2009 22

Optimiser la trithérapie en 2009 « Le triangle de la réussite » IDR ARA2 IEC Diurétique Thiazidique Antagoniste Calcique X Girerd 2009

Au delà de la trithérapie ? Bêta- Bloquant ARA2 IEC IDR Antagoniste Calcique Diurétique Thiazidique Spironolactone 25 mg Centraux alpha- Bloquant X Girerd 2009