Revue des grandes études en hypertension 1991-2006 Pierre Larochelle, MD, PhD, FRCPC

Déclaration d’intérêts Subventions : Pfizer, Aventis, Servier, BI, Astra-Zeneca, Novartis Comité Aviseur: Pfizer, Servier, BI, Novartis Conférencier: Novartis, Pfizer, Merck, BMS, BI, Abbott, Solvay

Top Five 1991-2006 Mention Honorable- Étude HOPE 2000 Effects of an angiotensin converting enzyme inhibitor,ramipril,on cardiovascular events in high risk patients N Engl J Med 2000;342:145-153

Key Baseline Characteristics (n=9297) Mean age 65.9 Female 26.7% Any CAD 80.6 MI 52.8% Any PVD+AABP 43.4 Any Stroke + TIA 10.8 Any Diabetes 38.3 Hypertension 46.5% High Cholesterol 65.8% GD

Primary Outcome (L) & Primary + Revasc + CHF Hosp Primary Outcome (L) & Primary + Revasc + CHF Hosp. (R): Ramipril vs Placebo SY RR=0.77 (0.68-0.88) RR=0.78 (0.70-0.86) P=0.0001 P=0.000002

SBP vs Primary outcome (CV Death, MI, Stroke) PS 124.5 134 141 158

Traitement de l’hypertension s’accompagnant d’une cardiopathie ischémique 1. Bêta-bloquant 2. Bloquant des canaux calciques à longue durée d’action Angine stable L’emploi d’un inhibiteur de l’ECA est recommandé pour tous les patients chez qui il a été démontré une maladie athéroscléreuse La prudence est de mise en combinant un non BCC non DHP et un bêta-bloquant • Si fonction ventriculaire gauche systolique anormale: éviter un BCC-Non DHP tel que Verapamil ou Diltiazem Nifédipine à action brève

Top Five 1991-2006 5-Prospective Studies Collaboration 2002 Lewington S et al. Age specific relevance of usual blood pressure to vascular mortality: a meta analysis of indivodual data for one million adults in 61 prospective studies. Lancet 2002;360:1903-1913

Ischemic Heart Disease mortality Mortalité par ACV et MCAS (n=122,716/ 958,074) Prospective Studies Collaboration. Lancet 2002;360:1903-1913 Ischemic Heart Disease mortality

Mortalité d’ACV en fonction de l’âge1 TA et mortalité d’ACV Ref 1: P.1903 Col.1 Par.1 S.1; P.1903 Col.2 Par.1 S.5; P.1906 Fig.2 Slide 6: Stroke Mortality Rate by Age: Blood Pressure and Stroke Mortality1 A meta-analysis involving 120,000 deaths among 1 million participants in 61 cohort studies was conducted to determine age-specific relevance of blood pressure to cause-specific mortality. [Ref 1: P.1903 Col.2 Par.1 S.5; P.1903 Col.1 Par.1 S.1] These data are shown as floating absolute risks in which all hazards ratios are related to the absolute death rates in a particular population by some common constant of proportionality. [Ref 1: P.1905 Col.1 Par.2 S.4] As shown in these figures, the relationship between death due to stroke and blood pressure is strong and direct at all ages. [Ref 1: P.1907 Col.1 Par.1 S.1] For every 20 mmHg increase in systolic blood pressure or every 10 mmHg increase in diastolic blood pressure, there is more than a twofold increase in the risk of stroke death. [Ref 1: P.1907 Col.1 Par.1 S.7-8] Reference: 1. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903-1913. Stroke mortality rate in each decade of age vs. usual blood pressure at the start of the decade. A meta-analysis involving 1 million participants in 61 cohort studies to determine the relevance of blood pressure to risk of disease in patients of different ages. 1. Prospective Studies Collaboration. Lancet 2002;360:1903-1913. 10

Top Five 1991-2006 4- Étude LIFE Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Dahloff B et al. Lancet 2002;359:995-1003 5- Prospective Studies Collaboration

LIFE: Blood Pressure Results – Follow-up 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 Atenolol Losartan Atenolol 145.4 mmHg Systolic Losartan 144.1 mmHg mmHg Mean Arterial Losartan 81.3 mmHg Diastolic Atenolol 80.9 mmHg 6 12 18 24 30 36 42 48 54 Study Month B Dahlof et al. Lancet 2002;359:995-1003

LIFE: Primary Composite Endpoint 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 0.16 Intention-to-Treat Atenolol Losartan Endpoint Rate Adjusted Risk Reduction 13·0%, p=0·021 Unadjusted Risk Reduction 14·6%, p=0·009 Study Day 180 360 540 720 900 1080 1260 1440 1620 1800 1980 Study Month 6 12 18 24 30 36 42 48 54 60 66 Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876 13 B Dahlof et al. Lancet 2002;359:995-1003

LIFE: Fatal/Nonfatal Stroke Intention-to-Treat Losartan Atenolol Adjusted Risk Reduction 24·9%, p=0·001 Unadjusted Risk Reduction 25·8%, p=0.0006 Study Day Endpoint Rate 180 360 540 720 900 1080 1260 1440 1620 1800 1980 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 14 B Dahlof et al. Lancet 2002;359:995-1003

Résumé: Traitement d’association pour l'hypertension systolo-diastolique sans autre indication formelle CIBLE <140/90 mmHg Modification du mode de vie Diurétique thiazidique BCC à longue durée d’action Béta- bloquant * IECA ARA * non recommandé comme traitement de première ligne pour patient de 60 ans et plus ENVISAGER Inobservance? Hypertension secondaire? Médicaments ou habitudes de vie pouvant entraver le traitement? Effet «sarrau blanc»? Association de deux médicaments Trithérapie ou quadrithérapie

Kaplan-Meier curves of stroke 10 Atenolol Losartan 8 6 Relative risk: 0.60 95% CI: 0.38 - 0.92 p = 0.02 Patients (%) 4 2 6 12 18 24 30 36 42 48 54 60 66 Study month No. at risk Atenolol Losartan 666 660 650 651 630 640 621 628 606 618 593 605 579 595 568 581 562 577 536 551 245 266 99 108 JAMA. 2002;288:1491-1498.

Algorithme de traitement de l’hypertension systolique isolée sans indication formelle: Résumé CIBLE <140 mmHg PA systolique Modications du mode de vie Diurétique thiazidique ARA BCC-DHP-LA ENVISAGER Inobservance? Hypertension secondaire? Médicaments ou habitudes de vie pouvant entraver le traitement? Effet «sarrau blanc»? Association de deux médicaments Si la pression artérielle n'est toujours pas maîtrisée, ou s'il y a des effets secondaires indésirables, d'autres classes d'antihypertenseurs peuvent être associées. (tel que alpha-bloquants, agents du système nerveux central ou bloquants des canaux calciques non dihydropyridiniques). Trithérapie ou quadrithérapie

Top Five 1991-2006 3- Étude HOT Effects of intensive blood pressure lowering and low dose aspirin in patients with hypertension; Principal results of the Hypertension Optimal Treatment (HOT) randomised trial Hansson L et al Lancet 1998;351:1755-176 4- Étude LIFE 5- Prospective Studies Collaboration

Randomisation to target blood pressure and ASA in the HOT Study £ 90 mm Hg placebo ASA £ 85 mm Hg placebo ASA £ 80 mm Hg placebo

Risk of a major cardiovascular event reduced by 30% in the HOT Study Achieved DBP mm Hg 105 100 95 90 85 80 5 Optimal DBP reduction in the HOT Study 10 15 20 25 30 % risk reduction

Major CV events in patients with diabetes at randomisation in relation to target blood pressure groups Major CV events/ 1000 patient years p=0.005 for trend 25 20 15 10 5 £ 90 £ 85 £ 80 Target DBP mm Hg

II. But de la thérapie Valeurs cibles de la pression artérielle pour le traitement de l’hypertension Condition But SPA / DPA mmHg Hypertension systolique isolée <140 Hypertension systolique/diastolique • Pression artérielle systolique • Pression artérielle diastolique <90 Diabète • Systolique • Diastolique <130 <80 Maladie rénale chronique

Events in relation to ASA or placebo Events/ 1000 patient years 12 p=0.03 ASA 10 Placebo 8 6 p=0.002 4 2 Major CV events All MI All stroke

Considérer ASA à faible dose Protection vasculaire des patients hypertendus: Utilisation de l’ ASA Considérer ASA à faible dose La prudence est recommandée lorsque la pression artérielle n’est pas maîtrisée

Top Five 1991-2006 2- Étude ALLHAT Major outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blockers vs Diuretics JAMA 2000;283:1967-1975 (Doxazosin) JAMA 2002;288:2981-2997 Arch Intern Med 2005;165: 1401-1409 (Diabétiques) 3- Étude HOT 4- Étude LIFE 5- Prospective Studies Collaboration

Nbre de patients à risque : Taux cumulatif d‘incidence quant au paramètre principal (coronaropathie mortelle ou IM non mortel), par groupe de traitement Nombre d’années avant la manifestation coronarienne 1 2 3 4 5 6 7 Taux cumul. de manifestations coronar. 0,04 0,08 0,12 0,16 0,2 RR (IC à 95 %) p A/C 0,98 (0,90-1,07) 0,65 L/C 0,99 (0,91-1,08) 0,81 Chlorthalidone Amlodipine Lisinopril ____________________________________________________________ Nbre de patients à risque : Chlorthalidone 15 255 14 477 13 820 13 102 11 362 6340 2956 209 Amlodipine 9048 8576 8218 7843 6824 3870 1878 215 Lisinopril 9054 8535 8123 7711 6662 3832 1770 195 ALLHAT Collaborative Research Group. JAMA 2002;288:2981-97. SLIDE 26

Résumé: Traitement d’association pour l'hypertension systolo-diastolique sans autre indication formelle CIBLE <140/90 mmHg Modification du mode de vie Diurétique thiazidique BCC à longue durée d’action Béta- bloquant * IECA ARA * non recommandé comme traitement de première ligne pour patient de 60 ans et plus ENVISAGER Inobservance? Hypertension secondaire? Médicaments ou habitudes de vie pouvant entraver le traitement? Effet «sarrau blanc»? Association de deux médicaments Trithérapie ou quadrithérapie

Whelton PK et al. Arch Intern Med 2005; 165: 1401-1409

Résumé: Traitement de l’hypertension s’accompagnant de diabète Seuil égal ou supérieur à 130/80 mmHg et Cible < 130/80 mmHg IECA ou ARA avec néphropathie Diabète IECA ou ARA ou Diurétique thiazidique ou BCC-DHP Traitement d’association Association efficace de 2 médicaments sans néphropathie L’atteinte des taux cibles chez les diabétiques peut nécessiter l’administration de plus de 3 médicaments Si la créatininémie est supérieure à 150 µmol/L, le thiazide peut être substitué par un diurétique de l'anse.

Top Five 1991-2006 1- Étude SHEP. 2- Étude ALLHAT 3- Étude HOT Prevention of stroke by Antihypertensive Drug Treatment in Older Persons with Isolated Systolic Hypertension.Final Resulsts of the Systolic Hypertension in the Elderly Program JAMA 1991;265:3255-3264 2- Étude ALLHAT 3- Étude HOT 4- Étude LIFE 5- Prospective Studies Collaboration

SYSTOLIC HYPERTENSION IN THE ELDERLY PROGRAM (SHEP) Baseline values (n=4736) Age yrs 727 Systolic BP mmHg 1709 Diastolic BP mmHg 7710 Total cholesterol mmol/l 6.11.1 HDL cholesterol mmol/l 1.40.4 Current smokers % 13 ECG Abnormality % 61 Diabetes % 10 SHEP Investigators JAMA 1991;265:3255

SHEP Change in Blood Pressure Systolic BP Diastolic BP Placebo (n=2,371) Placebo (n=2,371) Change in BP (mmHg) Active Rx (n=2,365) The Systolic Hypertension in the Elderly Program, 1991 The Systolic Hypertension in the Elderly Program (SHEP) was a clinical trial launched at a time when it was not known if treating older patients with isolated systolic hypertension (ISH) would be beneficial, harmful, or make no difference. The objective was to assess the ability of antihypertensive drug treatment to reduce the risk of nonfatal and fatal (total) stroke in ISH. Multicenter, randomized, double-blind, placebo-controlled. Community-based ambulatory population in tertiary care centers. The study cohort consisted of 4736 men and women 60 years old (mean age = 72) with stage 2 or higher ISH. Active therapy began with the diuretic chlorthalidone; other drugs (or their placebo controls) could be added later as dictated by the blood pressure response to treatment. SHEP Change in Blood Pressure In the SHEP cohort, the mean blood pressure (BP) was 170/76 mmHg in both treatment arms at baseline. The systolic and diastolic BPs during follow-up are shown on this slide. For the actively treated group, the 5-year average systolic BP was 143 mmHg and the 5-year average diastolic BP was 68 mmHg. Blood pressure also declined in the placebo group, largely due to "drop in," which refers to patients who were assigned to placebo but were started on open label active therapy by their personal physicians. In the placebo group, the 5-year average systolic and diastolic BPs were 155 mmHg and 72 mmHg, respectively. Primary outcome----nonfatal and fatal (total) stroke Secondary---cardiovascular and coronary morbidity and mortality, all-cause mortality, and quality of life measures Reference: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991; 265 (24):3255-64. Active Rx (n=2,365) 1 2 3 4 5 1 2 3 4 5 Years Years SHEP=Systolic Hypertension in the Elderly Program BP=blood pressure SHEP Research Group. JAMA. 1991;265:3255-3264. Copyright ©1991, American Medical Association.

SHEP Cardiovascular Disease Endpoints Active Therapy vs. Placebo 0.87 Relative risk (95% CI) 0.63 0.68 0.75 SHEP Study Cardiovascular Disease Endpoints Reduced the incidence of total stroke by 36%, with 5-year absolute benefit of 30 events per 1000 participants. Major CV events were reduced, with 5-year absolute benefit of 55 events per 1000. In SHEP, not only was stroke risk reduced in those receiving active therapy, but risk for coronary heart disease (-25%), congestive heart failure (-54%), and cardiovascular disease (-32%) also were reduced. While the trend was in a favorable direction for deaths from any cause, the results for this endpoint were not statistically significant. Reference: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991; 265 (24):3255-64. 0.46 Stroke CHD CHF CVD Death CHD=coronary heart disease; CHF=congestive heart failure; CVD=cardiovascular disease SHEP=Systolic Hypertension in the Elderly Program SHEP Research Group. JAMA. 1991;265:3255-3264.

Difference in Event Rate (Active Treatment vs. Placebo) Mortality Treatment better Placebo better Nondiabetic Patients SHEP SYST-EUR -15 -18 -34 -30 -38 -39 -19 -22 -26 -64 -68 -86 -56 -58 Tuomilehto et al. NEJM 1999;340:677-84 -100% -50% 0 +50% Diabetic Patients Stroke Cardiovascular events Coronary events

Algorithme de traitement de l’hypertension systolique isolée sans indication formelle: Résumé CIBLE <140 mmHg PA systolique Modications du mode de vie Diurétique thiazidique ARA BCC-DHP-LA ENVISAGER Inobservance? Hypertension secondaire? Médicaments ou habitudes de vie pouvant entraver le traitement? Effet «sarrau blanc»? Association de deux médicaments Si la pression artérielle n'est toujours pas maîtrisée, ou s'il y a des effets secondaires indésirables, d'autres classes d'antihypertenseurs peuvent être associées. (tel que alpha-bloquants, agents du système nerveux central ou bloquants des canaux calciques non dihydropyridiniques). Trithérapie ou quadrithérapie

Top Five 1991-2006 1- Étude SHEP 2- Étude ALLHAT 3- Étude HOT 4- Étude LIFE 5- Prospective Studies Collaboration MENTION HONORABLE: Etude HOPE