How to maximize patient benefit Protection des patients hypertendus Comment mieux les protéger ? Pr Roland Asmar How to maximize patient benefit

Le contrôle tensionnel chez les diabétiques de type 2 1 2

How to maximize patient benefit Contrôle de la Pression Artérielle chez les patients hypertendus traités dans le Monde Turkey 19.8 Canada 41.0 Germany 33.6 Japan 55.7 England 29.2 Greece 49.5 USA 53.1 China 28.8 Spain 38.8 Taiwan 18.0 Mexico 21.8 The BP control rate breakdown, country by country, shows that there is a need for improved BP control, whatever the countries or continents. Several explanations have been proposed, which include limited efficacy and poor compliance, as underlined by Prof P. Sever during the last ESC congress. A very recent paper published in the Journal of Hypertension in June 1998 shows that achievement of a BP level below 140/90 mm Hg can be as low as 6% in England. Data from this survey also provides some explanations for the reasons for the particularly poor control in England. Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VI). Arch Intern Med. 1997;157:2413-2465. Chockalingham A, Fodor JG. Treatment of raised blood pressure in the population. The Canadian experience. Am J Hypertens. 1998;11:747-749. Colhoun HM, Dong W, Poulter NR. Blood pressure screening, management and control in England: results from the health survey for England 1994. J Hypertens. 1998;16:747-752. Egypt 33.5 South Africa 47.6 Italy 37.5 How to maximize patient benefit Kearney et al. J Hypertens 2004; 22: 11

HOT: Besoin en combinaisons thérapeutiques How to maximize patient benefit Hansson et al., Lancet 1998, 351: 1755-62

How to maximize patient benefit Pourcentage de Patients recevant une combinaison thérapeutique dans les essais cliniques % How to maximize patient benefit

Rationel Pharmacologique de la Combinaison Thérapeutique How to maximize patient benefit

Combinaison Thérapeutique : Quel rationnel ? Augmenter l’efficacité Effets Synergique & additifs sur la baisse de PA Actions sur différents mécanismes physio-pathologiques de l’hypertension Inhibition des phénomèmes de contre-régulation Diminuer les effets secondaires Inhibition de la contre-régulation Faible dose Diminuer les effets secondaires dose-dépendants How to maximize patient benefit

Advantages de la Combinaison Thérapeutique Efficacité Certainly, efficacy is one parameter which influences BP control, however in addition to efficacy, compliance can also influence BP control. Therefore an ideal antihypertensive agent which is both effective in BP lowering as well as being convenient in terms of dosing regimen and has a favorable side effect profile may increase the number patients with hypertension getting to goal. How to maximize patient benefit

Combinaison Thérapeutique :Quel Rationnel ? Mécanismes pathogéniques de l’Hypertension Patient A Patient B Patient C Système Nerveux Sympathique SRA (Rénine-Angiotensine) Sodium total Waeber B. 2004

How to maximize patient benefit

Titration vs. Combinaison PAD How to maximize patient benefit Frishman WH et al,Arch Intern Med 1994;154:1461

Efficacité : Up-titration vs Combinaison HCT12.5 V80 HCT12.5 O20 HCT12.5 T40 T80 T40 V80 V160 V80 Ol20 Ol40 Ol20 Change in SBP (mm Hg) How to maximize patient benefit

How to maximize patient benefit Evaluation des valeurs de PA des combinaisons thérapeutiques: analyse de 354 essais randomisés vs placebo How to maximize patient benefit Law MR BMJ 2003

Advantages of Combination Therapy Effets indésirables Certainly, efficacy is one parameter which influences BP control, however in addition to efficacy, compliance can also influence BP control. Therefore an ideal antihypertensive agent which is both effective in BP lowering as well as being convenient in terms of dosing regimen and has a favorable side effect profile may increase the number patients with hypertension getting to goal. How to maximize patient benefit

Adjusted mean D from baseline at 8 weeks (mEq/L) ARB & HCTZ & Kaliémie Adjusted mean D from baseline at 8 weeks (mEq/L) 300 100 GLB.IRB.06.12.01 Irbesartan/HCTZ combination therapy ameliorates the hypokalemic effects of HCTZ.1 In this same trial, HCTZ decreased serum potassium levels in a dose-related manner. However, this effect was less pronounced with the addition of increasing doses of irbesartan. The 300 mg dose of irbesartan appears to provide the most benefit in reversing the hypokalemic effects of HCTZ. No clinically significant occurrences of electrolyte imbalance have been observed in trials with irbesartan/HCTZ combination therapy or with irbesartan monotherapy. Reference Kochar M, et al. Matrix study of irbesartan with hydrochlorothiazide in mild-to-moderate hypertension. Am J Hypertens. 1999;12:797–805 ARB dose (mg/d) 37.5 6.25 12.5 25 HCTZ dose (mg/d) How to maximize patient benefit Kochar M, et al. Am J Hypertens. 1999;12:797

Drug related symptoms: comparison between monotherapy & combination 50 trials testing drugs of two different categories separately and in combination, How to maximize patient benefit BMJ 2003;326:1427

Advantages of Combination Therapy Observance Certainly, efficacy is one parameter which influences BP control, however in addition to efficacy, compliance can also influence BP control. Therefore an ideal antihypertensive agent which is both effective in BP lowering as well as being convenient in terms of dosing regimen and has a favorable side effect profile may increase the number patients with hypertension getting to goal. How to maximize patient benefit

Fixed-dose Combination Therapy Increases Compliance to Treatment Persistence rates of one pill of lisinopril/HCTZ in fixed-combination vs two separate pills of lisinopril and HCTZ 100 95 90 85 80 75 70 65 60 55 50 0 1 2 3 4 5 6 7 8 9 10 11 12 Months Persistence (%) 68.7 57.8 18.8% Lisinopril/HCTZ (1 pill) Lisinopril and HCTZ (2 pills) Dezii CM. Manag Care 2000; 9 : s2

Advantages of Combination Therapy Efficacité égale? Certainly, efficacy is one parameter which influences BP control, however in addition to efficacy, compliance can also influence BP control. Therefore an ideal antihypertensive agent which is both effective in BP lowering as well as being convenient in terms of dosing regimen and has a favorable side effect profile may increase the number patients with hypertension getting to goal. How to maximize patient benefit

How to maximize patient benefit AIIA + CCB How to maximize patient benefit 20 20

ASCOT - Summary of all end points Unadjusted Hazard ratio (95% CI) 0.90 (0.79-1.02) 0.87 (0.76-1.00) 0.87 (0.79-0.96) 0.84 (0.78-0.90) 0.89 (0.81-0.99) 0.76 (0.65-0.90) 0.77 (0.66-0.89) 0.84 (0.66-1.05) 1.27 (0.80-2.00) 0.68 (0.51-0.92) 0.98 (0.81-1.19) 0.65 (0.52-0.81) 1.07 (0.62-1.85) 0.70 (0.63-.078) 0.85 (0.75-0.97) 0.86 (0.77-0.96) 0.84 (0.76-0.92) Primary Non-fatal MI (incl silent) + fatal CHD Secondary Non-fatal MI (exc. Silent) +fatal CHD Total coronary end point Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure Tertiary Silent MI Unstable angina Chronic stable angina Peripheral arterial disease Life-threatening arrhythmias New-onset diabetes mellitus New-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + stroke 0.50 0.70 1.00 1.45 2.00 Amlodipine  perindopril better Atenolol  thiazide better The area of the blue square is proportional to the amount of statistical information 21 How to maximize patient benefit 21

Hypertension in special patient populations – ARBs-FDC ® Hypertension in special patient populations – ARBs-FDC Blood pressure control with ARBs and in Fixed Dose Combination Protocol Endpoints Weber M. Journal of Hypertension 2003; 21 Suppl 6:S37-46 Primary endpoint Changes from baseline in SBP during last 6 hours of dosing interval using ABPM Secondary endpoints Changes from: Baseline in DBP during the last 6 hours of dosing interval Baseline in pulse pressure during the last 6 hours of dosing interval Baseline in the 24-hour mean SBP and DBP n=294 n=160 n=297 Patients are randomised to starting dose Telmisartan (40 mg/day) or Losartan (50 mg/day), respectively or to high dose Telmisartan (80 mg/day), all in a fixed-dose combination with 12.5 mg/day Hydrochlorothiazide. The endpoints focus on parameters of blood pressure control derived from 24-hour ambulatory blood pressure measurements. Secondary Endpoints in detail: Reductions in blood pressure and responder rates for patients treated with Telmisartan combined with Hydrochlorothiazide compared to patients treated with Losartan combined with Hydrochlorothiazide at the end of a 6-week treatment phase as measured by: Change from baseline in the ABPM mean SBP during the last 6 hours of the 24-hour dosing interval. Changes from baseline in the 24-hour ABPM mean DBP and SBP. Changes from baseline in the ABPM mean DBP and SBP during other periods (i.e. morning, daytime,and nighttime) of the 24-hour dosing interval. Changes from baseline in mean seated trough DBP and SBP using manual cuff sphygmomanometer. Percentage of patients responding as determined by both ABPM and manual in-clinic blood pressures. Weber M. The Telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) programme. Journal of Hypertension 2003; 21 Suppl 6:S37-46 Neutel JM, et al. Hypertens Res 2005;28:555

Telmisartan HCTZ & Losartan HCTZ ABPM Comparison of Telmisartan HCTZ & Losartan HCTZ Parallel Group Comparison after 6 weeks Therapy Time after dosing (h) Time after dosing (h) 2 6 10 14 18 22 2 6 10 14 18 22 -8 -6 Systolic BP Diastolic BP Telmisartan 80mg + HCTZ 12.5mg -8 Telmisartan 40mg + HCTZ 12.5mg -12 Losartan 50mg + HCTZ 12.5mg -10 Change from baseline (mmHg) -16 -12 -20 -14 -24 -16 How to maximize patient benefit Neutel et al. Hypertens Res. 2005;28:555

® Study of telMisartan On Obese/overweight Type2 diabetics with Hypertension Protocol Endpoints Weber M. Journal of Hypertension 2003; 21 Suppl 6:S37-46 Primary endpoint Changes from baseline in SBP during last 6 hours of dosing interval using ABPM Secondary endpoints Changes in other ABPM-derived parameters Changes in trough cuff SBP and DBP Metabolic blood markers (e.g.cholesterol) Urine markers (e.g. proteinuria) Objective To compare telmisartan with valsartan in a fixed-dose combination with a thiazide type diuretic in obese type 2 diabetics with hypertension. Patients receive Telmisartan (80 mg/day) and Valsartan (160 mg/day) as antihypertensive treatment in fixed-dose combination with Hydrochlorothiazide. The study is not powered to detect differences in prognosis but focuses on parameters of blood pressure control derived from ABPM and surrogate endpoints like changes in metabolic and urinary parameters. Secondary Endpoints in detail:  Statistically greater reductions in ambulatory blood pressure for patients treated with Telmisartan/HCT compared to patients treated with Valsartan/HCT at the end of the 10-week study as measured by: Changes from baseline in the last 6 hours of the 24-hour dosing interval for pulse pressure Changes from baseline in the 24-hour ABPM mean (relative to dosetime) for SBP, DBP, and pulse pressure Changes from baseline in the ABPM mean SBP, DBP, and pulse pressure (relative to clocktime) during other periods (i.e. morning, daytime, nighttime) of the 24-hour dosing interval Change from baseline in systolic and diastolic blood pressure load during the 24-hour dosing interval Percentage of patients responding to treatment based on the 24-hour ABPM mean SBP and DBP (relative to dosetime). Changes from baseline in metabolic markers using laboratory assay for serum: triglycerides, low density lipoprotein cholesterol, high density lipoprotein cholesterol, total cholesterol, potassium, fasting glucose and HbA1c, and for urine: sodium, potassium, chloride, proteinuria (as measured by spot urine for protein:creatinine ratio). Weber M. The Telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) programme. Journal of Hypertension 2003; 21 Suppl 6:S37-46 Sharma AM, et al. Cardiovascular Diabetology. 2007;6:28

Telmisartan + HCTZ vsValsartan + HCTZ Powerful 24 hr SBP reductions *** SBP change from baseline (mmHg) ***p < 0.001 T + H vs V + H 24-hour and last 6-hour mean SBP How to maximize patient benefit Sharma et al. Hypertension 2005;46:898

Telmisartan 80mg/HCTZ 12.5 mg vs Olmesartan 20mg/HCTZ12.5 mg Systolic BP Diastolic BP How to maximize patient benefit Fogari & al Current Therapeutic Research; 2008; 69

® A comparison of Telmisartan plus HCTZ with amlodipine plus HCTZ in Older patients with predominantly Systolic hypertension Protocol Endpoints Weber M. Journal of Hypertension 2003; 21 Suppl 6:S37-46 Primary endpoint Changes from baseline in SBP during last 6 hours of dosing interval using ABPM Secondary endpoints Changes from: Baseline in DBP during the last 6 hours of dosing interval Baseline in pulse pressure during the last 6 hours of dosing interval Baseline in the 24-hour mean SBP and DBP n=497 n=503 Objective To compare the effect of telmisartan with the calcium channel blocker amlodipine in a fixed dose combination with HCTZ in elderly patients with ISH Weber M. The Telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) programme. Journal of Hypertension 2003; 21 Suppl 6:S37-46 Franklin SS et al. Hemodynamic Patterns of Age-Related Changes in Blood Pressure: The Framingham Heart Study Circulation 1997; 96(1):308-315 Neldam S, et al. AJGC 2006;15:151-60.

How to maximize patient benefit Neldam S, et al. AJGC 2006;15:151-60.

Telmisartan in combination HCTZ 25 mg How to maximize patient benefit

Comparison of Telmisartan HCTZ & Valsartan HCTZ Change in clinic trough BP from baseline after 8 weeks therapy Systolic BP Diastolic BP -5 -10 Change from baseline (mmHg) -15 -20 -1.8 (-3.0, - 0.6) p<0.02 Telmisartan-HCTZ 80/25mg (n=467) Valsartan-HCTZ 160/25mg (n=479) -25 Placebo (n=120) -2.8 (-4.6, -1.0) p<0.004 How to maximize patient benefit White et al. J Hypertens Suppl. 2003;21:S9-15.

Conclusions Le recours a une plurithérapie est souvent nécessaire chez le patient à haut risque. Les Combinaisons thérapeutiques permettent une réduction tensionnelle importante associées à une protection CV. Amélioration de l’observance thérapeutique . Les combinaisons thérapeutiques peuvent être utilisées en première intention chez les patients à haut risque. Les combinaisons thérapeutiques sont-elles toutes équivalentes ?