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Etude KYOTO HEART Effet de Valsartan sur la morbi-mortalité

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1 Etude KYOTO HEART Effet de Valsartan sur la morbi-mortalité
Chez des patients hypertendus non contrôlés à haut risque cardiovasculaire Sawada et al. Eur Heart J 2009; 30:

2 Objectif de l’étude Evaluer l‘effet d’ajouter le Valsartan aux traitements conventionnels (non ARAII) sur la morbi-mortalité chez les patients japonais hypertendus non contrôlés à haut risque CV The KYOTO HEART Study hypothesized that valsartan would improve CV morbidity/mortality when added to conventional (non-ARB) antihypertensive treatment in Japanese patients with hypertension, whose BP was uncontrolled, and at high CV risk. Reference Sawada T, et al; KYOTO HEART Study Group. Rationale and design of the KYOTO HEART study: effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high risk of cardiovascular events. J Hum Hypertens 2009;23(3):188–95. (E-pub 2008). Sawada et al. Eur Heart J 2009; 30: 2

3 Méthodologie - Etude prospective, randomisée, ouverte, en aveugle (PROBE) patients japonais hypertendus non contrôlés à haut risque CV . - Valsartan Vs. Traitement non ARA II pour atteindre la PA cible. - La période de suivi : 3.27 ans Sawada et al. Eur Heart J 2009; 30:

4 Design de l’étude Ajout de Valsartan Traitement conventionnel
Valsartan 160 mg + autres antihypertenseurs (sans IEC/ARAII) Valsartan 160 mg Valsartan 40–80 mg Ajout de Valsartan Patients japonais avec HTA non contrôlée* et risque CV élevé † Pas traitement ou traitement sans ARAII Dose usuelle Traitement conventionnel Dose élévée Dose élevée+ autres antihypertenseurs (sans IEC/ARAII) The KYOTO HEART Study was a multicentre (31 hospitals), prospective, randomized, open-label, blinded endpoints (PROBE), two-arm parallel treatment group comparison with a response-dependent dose-titration scheme. The eligible population consisted of adult Japanese patients with hypertension, BP uncontrolled for at least 4 weeks (mean sitting SBP ≥140 mmHg, and/or a mean sitting DBP ≥90mmHg) and existing CV disease and/or at least one additional risk factor for CV disease (diabetes, lipid abnormalities, current smoker, obesity [body mass index; BMI ≥25 kg/m2] and/or left ventricular hypertrophy defined by electrocardiogram). Patients were randomized to either valsartan add-on or conventional treatment. For the valsartan add-on group, patients received valsartan 80 mg once daily as an initial dose and flexibly adjusted to a dose of 40–80 mg per day, as needed, to control BP. The dose of valsartan was doubled after one month if BP control was not achieved. Additional non-ARB/ACEI therapy was permitted after two months, if necessary. For the conventional therapy group, treatment was with antihypertensive drugs other than ARBs and ACEIs to achieve BP control. Again, doses were elevated at one month and additional non-ARB/ACEI therapy added at Month 2, as necessary. Median follow-up was 3.27 years. Reference Sawada T, et al; KYOTO HEART Study Group. Rationale and design of the KYOTO HEART study: effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high risk of cardiovascular events. J Hum Hypertens 2009;23(3):188–95. (E-pub 2008). –1 Randomisation 0 Titration 1 Titration 2 Fin de l’étude 36 Mois *PAS≥140 mmHg et/ou PAD≥90 mmHg †Histoire de≥1 événement CV, diabète, tabagisme, dyslipidémie, obésité ou HVG Sawada et al. Eur Heart J 2009; 30: 4

5 Critères d’inclusion et d’exclusion
Patients japonais hypertendus(homme et femme, ≥20 ans) PA non contrôlée pour ≥4 semaines (≥140/90 mmHg) Non traitée avec ARA dans les 4 semaines avant la randomisation Histoire de ≥1 événement CV (coronaropathie, maladie cérébro-vasculaire ou maladie artérielle périphérique) et/ou ≥1 facteur de risque CV (diabète, tabagisme, dyslipidémie, obésité ou HVG) Critères d’exclusion Hypertension maligne ou secondaire Histoire de l’aggravation de l’IC, SCA, intervention coronarienne percutanée, pontage coronaire ou événement cérébro-vasculaire dans les 6 mois Arythmie nécessitant un traitement ou accompagnée de symptômes Insuffisance rénale ou hépatique Inclusion criteria: Japanese hypertensive patients (men and women, ≥20 years old) whose blood pressures have been uncontrolled for at least 4 weeks. Uncontrolled hypertension was defined as a mean sitting systolic blood pressure ≥140 mmHg, and/or a mean sitting diastolic blood pressure ≥90 mmHg. Patients had at least one of sign of CAD (angina pectoris/history of MI), cerebrovascular disease (history of stroke/TIA) or PAD (previous limb bypass surgery/angioplasty, limb ulcer/gangrene or intermittent claudication with ankle/brachial blood pressure index <0.8), and/or one or more of the following cardiovascular risk factors: Type II diabetes mellitus Current smoking Lipid metabolism abnormality Obesity Left ventricular hypertrophy In patients already treated for hypertension, anti-hypertensive drugs other than ARB were administered for the first 4 weeks and then if still uncontrolled they were considered as candidates for the study. Uncontrolled hypertensive patients treated with ACE inhibitors before randomisation could also participate in this study. Uncontrolled hypertensive patients who had been treated with ARB, but were not treated with ARB within 4 weeks before randomisation, could participate in this study. Exclusion criteria: Malignant or secondary hypertension Pregnant women or women of childbearing potential History of worsening heart failure, unstable angina, myocardial infarction, PCI, or CABG within the preceding 6 months Arrhythmia needing to be treated or accompanied with symptoms including second or third degree atrioventricular block Renal impairment (serum creatinine level 43.0 mg per 100 ml) Hepatic impairment (hepatic failure, cirrhosis, etc.) History of cerebral infarction, cerebral haemorrhage or transient ischaemic attack within the past 6 months Allergy of potential clinical concern Electrolyte abnormality (remarkable change in sodium or potassium) History of malignant tumour including leukaemia and lymphoma Patients who were unwilling or unable to comply with the trial protocol. Reference Sawada T, et al; KYOTO HEART Study Group. Rationale and design of the KYOTO HEART study: effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high risk of cardiovascular events. J Hum Hypertens 2009;23(3):188–95. (E-pub 2008). Sawada et al. Eur Heart J 2009; 30:

6 Critères d’évaluation primaires : Critère composé des événements CV et Cérébro-vasculaires
Apparition et/ou Aggravation des événements cardio et cérébro-vasculaires: - AVC - Nouvelle apparition ou récurrence des AIT - Nouvelle apparition ou récurrence d’IDM aigu - Hospitalisation à cause d’une insuffisance cardiaque - Hospitalisation à cause d'une angine de poitrine - PCI ou pontage coronarien - Anévrisme disséquant de l'aorte - Obstruction artérielle des membres inférieurs - Passage à la dialyse, doublement du taux plasmatique de Créatinine - Thrombose d'urgence The primary endpoint was a composite of cardio- and cerebro-vascular events, including: Stroke Transient ischaemic attack Myocardial infarction New or exacerbated HF New or exacerbated angina Aortic aneurysm Lower limb arterial obstruction Emergency thrombosis Transition to dialysis or doubling of serum creatinine levels Endpoints were adjudicated by an independent committee. Reference Sawada T, et al; KYOTO HEART Study Group. Rationale and design of the KYOTO HEART study: effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high risk of cardiovascular events. J Hum Hypertens 2009;23:188–95. (E-pub 2008). Sawada et al. Eur Heart J 2009; 30: 6

7 Critères d’évaluation secondaires
Mortalité de toutes causes Détérioration de la fonction cardiaque Nouvelle apparition ou aggravation des arythmies Nouvelle apparition ou aggravation de diabètes ou IGT Pression artérielle non contrôlée Secondary endpoints included: All-cause mortality Worsening cardiac function New or exacerbated arrhythmias New or exacerbated diabetes mellitus Impaired glucose tolerance Uncontrolled BP Reference Sawada T, et al; KYOTO HEART Study Group. Rationale and design of the KYOTO HEART study: effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high risk of cardiovascular events. J Hum Hypertens 2009;23:188–95. (E-pub 2008). Sawada et al. Eur Heart J 2009; 30: 7

8 Caractéristiques des patients à l’inclusion
Valsartan N=1517 Non ARAII N=1514 Age (ans) 66 Tabagisme actuel 22% Obésité (IMC≥ 25) 39% Maladie artérielle coronaire 23% Maladie cérébrovasculaire 4% IC 6% 7% Diabète 26% 27% Dyslipidémie 70% 71% HVG par ECG 8% 9% PAS (mmHg) 157 PAD (mmHg) 88 All patients enrolled in the study were Japanese. Patients were well matched for baseline characteristics, with no significant differences between treatment groups. Reference Sawada T, Yamada H, Dahlöf B, Matsubara H, for the KYOTO HEART Study Group. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009;30:2461–69. Sawada et al. Eur Heart J 2009; 30: 8

9 Histoire Médical des patients à l’inclusion
Maladies concomitantes Bras Valsartan (n=1,517) Bras non-ARAII (n=1,514) Maladie coronarienne, n (%) 355 (23) 352 (23) Maladie cérébrovasculaire, n (%) 58 (4) 65 (4) Insuffisance cardiaque, n (%) 84 (6) 109 (7) Diabète type 2, n (%) 401 (26) 406 (27) Dyslipidémie, n (%) 1,065 (70) 1,079 (71) HVG (ECG), n (%) 122 (8) 129 (9) There were no significant differences between the two treatment groups in terms of medical history at baseline. Reference Sawada T, Yamada H, Dahlöf B, Matsubara H, for the KYOTO HEART Study Group. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009;30:2461–69. Sawada et al. Eur Heart J 2009; 30: 9

10 Les traitements de début de l’étude
Valsartan N=1517 Non ARAII N=1514 IEC 19% 20% ICa 54% 55% Alpha-bloquants 3% Bétabloquants 17% 18% Anti-aldostérone 2% Thiazidiques Autres diurétiques 5% 6% Statines 32% 33% Fibrate ADO 14% 13% Anti-coagulants 7% Anti-plaquettaires 26% 28% At baseline, half of all patients were receiving a CCB (54–55%), while approximately 20% were receiving a RAAS blocker with an ACE inhibitor. Other medications at baseline included β-blockers (17–18%), diuretics (8–9%) and statins (32–33%). Reference Sawada T, Yamada H, Dahlöf B, Matsubara H, for the KYOTO HEART Study Group. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009;30:2461–69. ACE = angiotensin converting-enzyme; CCB = calcium channel blocker Sawada et al. Eur Heart J 2009; 30: 10

11 The KYOTO HEART Study Résultats

12 Réductions comparables de la PA >20mmHg avec Valsartan et traitement non-ARAII
200 180 160 140 120 100 80 60 40 20 Valsartan Non-ARAII Moyenne ± ET mmHg Baseline Fin de l’étude Valsartan Non-ARAII SBP 157 ± 14 133 ± 14 DBP 88 ± 11 76 ± 11 76 ± 10 BP was similarly lowered in both therapy groups (from 157/88 mmHg at baseline to 133/76 mmHg at study end for both valsartan- and non-ARB- based groups). Reference Sawada T, Yamada H, Dahlöf B, Matsubara H, for the KYOTO HEART Study Group. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009;30:2461–69. ET : Ecart Type Mois Sawada et al. Eur Heart J 2009; 30: 12

13 Probabilité des événements (%)
Valsartan réduit le risque CV lorsqu'il est ajouté au traitement conventionnel 20 15 10 5 Critère primaire HR = 0.55 (95% CI 0.42–0.72) p = –45%* Probabilité des événements (%) Valsartan (83 événements) Non-ARAII (155 événements) The primary endpoint (a composite of CV and cerebrovascular events) was recorded in fewer patients who received valsartan-based add-on therapy (n=83, 5.5%) than in those given additional non-ARB treatment (n=155, 10.2%). The HR between treatment regimens was 0.55, (representing a 45% decrease) in favour of valsartan-based therapy (p= ). Reference Sawada T, Yamada H, Dahlöf B, Matsubara H, for the KYOTO HEART Study Group. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009;30:2461–69. Temps (mois) Number at risk Valsartan Non-ARB * Réduction du risque relatif Sawada et al. Eur Heart J 2009; 30: 13

14 Probabilité des événements (%)
Valsartan réduit le risque d’incidence des AVC lorsqu'il est ajouté au traitement conventionnel 10 8 6 4 2 HR = 0.55 (95% CI 0.79–1.28) p = Valsartan (25 événements) Non-ARB (46 événements) Probabilité des événements (%) –45%* In patients receiving valsartan-based therapy, the incidence of stroke was reduced by 45% when compared with non-ARB-based treatment (n=25, 1.6% vs n=46, 3.0%, respectively; HR 055 [95% CI 0.3–0.9], p=0.0149). Reference Sawada T, Yamada H, Dahlöf B, Matsubara H, for the KYOTO HEART Study Group. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009;30:2461–69. Time (mois) Number at risk Valsartan Non-ARB * Réduction du risque relatif Sawada et al. Eur Heart J 2009; 30:

15 Réduction de risque de l’incidence d’Angor
10 8 6 4 2 HR = 0.51 (95% CI 0.30–0.90) p = Valsartan (22 événements) Non-ARB (44 événements) Probabilité des événements (%) –49%* In patients receiving valsartan-based therapy, the incidence of angina pectoris was reduced by almost half (49%) when compared with non-ARB-based treatment (n=22, 1.5% vs n=44, 2.9%, respectively; HR 0.51 [95% CI 0.3–0.9], p=0.0106). Reference Sawada T, Yamada H, Dahlöf B, Matsubara H, for the KYOTO HEART Study Group. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009;30:2461–69. Temps (mois) Number at risk Valsartan Non-ARB * Réduction du risque relatif Sawada et al. Eur Heart J 2009; 30:

16 Nouvelle apparition du diabète Réduction du risque avec valsartan* (%)
L’ajout du Valsartan a montré un bénéfice significatif dans les AVC, l'angor et la Nouvelle apparition du diabète AVC/AIT Nouvelle apparition du diabète Morbidité CV Angor 20 40 60 80 45%* 45%* 49%* 33%* Réduction du risque avec valsartan* (%) p=0.0282 p= p=0.0149 p=0.0106 The primary endpoint (a composite of CV and cerebrovascular events) was recorded in fewer patients who received valsartan-based add-on therapy (n=83, 5.5%) than in those given additional non-ARB treatment (n=155, 10.2%). The HR between treatment regimens was 0.55, (representing a 45% decrease) in favour of valsartan-based therapy (p= ). The difference in the number of primary endpoints was mainly attributable to reduced frequency of stroke and transient ischaemic attack (HR 0.55, p=0.0149), and angina pectoris (HR 0.51, p=0.0106). There were also fewer episodes of new-onset diabetes in the valsartan-based treatment group (n=58, 5.2%) compared with the non-ARB treatment group (5.2% vs 7.7%, respectively; HR 0.67, p=0.0282). The ongoing NAVIGATOR study should build upon these data demonstrating reductions in new-onset diabetes by examining whether valsartan will reduce new-onset diabetes in patients with impaired glucose tolerance. Reference Sawada T, Yamada H, Dahlöf B, Matsubara H, for the KYOTO HEART Study Group. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009;30:2461–69. AIT = Accident ischémique transitoire *Réduction du risque relatif vs traitement non ARAII Sawada et al. Eur Heart J 2009; 30: 16

17 Incidence des effets indésirables était faible et similaire entre les 2 bras
Effets indésirables (n ≥ 2) Bras Valsartan Bras non-ARAII Cancer ou métastase, n (%) 12 (0.8) 14 (0.9) Malaise à l’estomac, n (%) 9 (0.6) 11 (0.7) Vertige, n (%) 8 (0.5) Hémoptysie, n (%) 5 (0.3) 7 (0.5) Rashes, n (%) 4 (0.3) 6 (0.4) Maux de tête, n (%) 2 (0.1) Hémorragie gastro-intestinale, n (%) 3 (0.2) Dysfonction hépatique, n (%) Toux sèche, n (%) Potassium sérique élevé, n (%) Cellulite, n (%) 1 (0.1) Palpitations, n (%) Fracture, n (%) Autres EI, n (%) 41 (2.7) 39 (2.6) TOTAL 97 (3.2) 114 (3.8) Throughout the study there were no significant differences in adverse events between the two treatment groups. Reference Sawada T, Yamada H, Dahlöf B, Matsubara H, for the KYOTO HEART Study Group. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009;30:2461–69. Sawada et al. Eur Heart J 2009; 30:

18 Etude The KYOTO HEART Analyse secondaire
Sawada et al. Eur Heart J 2009; 30:

19 Objectif L’analyse secondaire de l’étude Kyoto Heart a pour objectif :
Examiner l’effet de Valsartan sur la prévention primaire et secondaire, Examiner l’effet de la combinaison Valsartan+ Inhibiteur calcique. Sawada et al. Eur Heart J 2009; 30:

20 Effet de Valsartan sur la prévention primaire et secondaire
Etude KYOTO Heart n=3031 Maladie coronaire (n=707) Maladie cérébrovasculaire (n=123) Insuffisance cardiaque (n=193) Absence de maladie CV n= 2116 Présence de maladie CV n= 915 Valsartan n=1065 Non ARB n= 1051 Valsartan n=452 Non ARB n= 463 Sawada et al. Eur Heart J 2009; 30:

21 Caractéristiques des patients
Groupe prévention primaire Groupe prévention secondaire Valsartan (n=1065) Non ARAII (n=1051) Valsartan (n=452) (n=463) Age (ans) 64 ± 11 70 ± 10 71 ± 9 PAS (mmHg) 157 ± 14 157 ± 15 PAD (mmHg) 90 ± 11 89 ± 11 86 ± 11 85 ± 11 IMC (kg/m2) 25 ± 4 24 ± 3 Tabagisme 243 (23%) 237 (23%) 98 (22%) 95 (21%) Diabète 285 (27%) 272 (26%) 116 (26%) 134 (29%) Dyslipidémie 770 (72%) 762 (73%) 296 (65%) 316 (68%) Obésité 453 (43%) 432 (41%) 140 (31%) 152 (33%) HVG 280 (27%) 127 (27%) 124 (28%) Maladies cérébroVasculaires 0 (0%) 58 (13%) 65 (14%) Maladie coronaires 355 (79%) 352 (78%) IC 84 (19%) 109 (24%) Facteurs de risque Sawada et al. Eur Heart J 2009; 30:

22 Médicaments à l’inclusion
Groupe prévention primaire Groupe prévention secondaire Valsartan (n=1065) Non ARAII (n=1051) Valsartan (n=452) (n=463) Ica 554 (52%) 550 (52%) 271 (60%) 282 (57%) IEC 155 (15%) 168 (16%) 134 (30%) 137 (28%) Bétabloquants 126 (12%) 136 (13%) 138 (31%) 141 (29%) Diurétiques thiazidiques 40 (4%) 33 (3%) 12 (3%) 12 (2%) Autres diurétiques 26 (2%) 18 (2%) 50 (11%) 68 (14%) Statine 308 (29%) 290 (28%) 183 (40%) 213 (43%) ADO 100 (9%) 89 (8%) 41 (9%) 54 (11%) Insuline 24 (2%) 20 (2%) 14 (3%) 24 (5%) Sawada et al. Eur Heart J 2009; 30:

23 Réductions comparables avec Valsartan et traitement non-ARAII
Pas de différence significative entre les 2 bras de traitement Sawada et al. Eur Heart J 2009; 30:

24 Effet du valsartan sur la prévention primaire et secondaire
Probabilité des événements Mois Sawada et al. Eur Heart J 2009; 30:

25 Effet de la combinaison valsartan +ICa
Etude KYOTO Heart n=3031 Avec ICa est définie comme l'utilisation des inhibiteurs calciques plus de 12 mois Avec ICa n= 1807 Sans ICa n= 1224 Val+ICa n=773 Non-Val+ICa n= 1034 Val+non-ICa n=744 Non Val+non ICa n= 480 Sawada et al. Eur Heart J 2009; 30:

26 Caractéristiques des patients
Valsartan+ ICa (n=773) Valsartan+ autres (n=744) Non ARAII+ ICa (n=1034) Non ARAII+ autres (n=480) Age (ans) 67 ± 11 65 ± 12 PAS (mmHg) 156 ± 14 159 ± 15 158 ± 14 PAD (mmHg) 87 ± 11 90 ± 12 IMC (kg/m2) 25 ± 4 24 ± 4 Tabagisme 154 (20%) 187 (25%) 219 (21%) 113 (24%) Diabète 210 (27%) 191 (26%) 282 (27%) 124 (26%) Dyslipidémie 556 (72%) 509 (68%) 734 (71%) 345(72%) Obésité 327 (42%) 266 (36%) 415 (40%) 169 (35%) Maladie cérébroVasculaires 32 (4%) 26 (3%) 50 (5%) 15 (3%) Maladies coronaires 201 (26%) 154 (21%) 255 (25%) 97 (20%) IC 37 (5%) 47 (6%) 79 (8%) 30 (6%) Facteurs de risque Sawada et al. Eur Heart J 2009; 30:

27 Réductions comparables avec Valsartan et traitement non-ARAII
Sawada et al. Eur Heart J 2009; 30:

28 Comparaison entre le bras « avec ICa » et le bras « sans Ica »
Probabilité des événements Sawada et al. Eur Heart J 2009; 30:

29 Réduction des événements cardio et cérébro-vasculaires de 50%
Probabilité des événements Sawada et al. Eur Heart J 2009; 30:

30 Conclusion Etude KYOTO HEART confirme que Valsartan a un effet cardiovasculaire protecteur chez les patients japonais à haut risque CV et notamment il prévient l’AVC et L’angor. Sawada et al. Eur Heart J 2009; 30:


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