How to maximize patient benefit

How to maximize patient benefit
Protecting patients with hypertension How to maximize patient benefit ? Pr Roland Asmar How to maximize patient benefit

Goals of Antihypertensive Treatment ESH/ESC 2007
< 140/90 mmHg Hypertensive patients < 130/80 mmHg Diabetes Patient at high risk How to maximize patient benefit

Worldwide Blood Pressure Control in Treated Hypertensive Patients
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: Chockalingham A, Fodor JG. Treatment of raised blood pressure in the population. The Canadian experience. Am J Hypertens. 1998;11: Colhoun HM, Dong W, Poulter NR. Blood pressure screening, management and control in England: results from the health survey for England J Hypertens. 1998;16: Egypt 33.5 South Africa 47.6 Italy 37.5 How to maximize patient benefit Kearney et al. J Hypertens 2004; 22: 11

HOT: Need for Combination Therapy
How to maximize patient benefit Hansson et al., Lancet 1998, 351:

Percentage of Patients with Combination Treatment in Clinical Trials
% How to maximize patient benefit

ESH/ESC Guidelines

Pharmacological Rationale for Combination Therapy
How to maximize patient benefit

Rationale for Combination Therapy
Increase Efficacy Synergistic & additive effects on BP Effects on several patho-physiological mechanisms of HT Inhibition of the contra-regulation mechanisms Decrease Side effects Inhibition of the contra-regulation Low dose Decrease dose-dependent side effects How to maximize patient benefit

Advantages of Combination Therapy
Efficacy 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

Rationale of Combination Therapy
Pathogenetic Mechanisms in Hypertension Patient A Patient B Patient C Sympathetic nervous system Renin-angiotensin system Total body sodium Waeber B. 2004

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

Efficacy: Up-titration vs Combination
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

Value of combination treatment: analysis of 354 randomised placebo controlled trials How to maximize patient benefit Law MR BMJ 2003

Side Effects 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

Effect of ARB and HCTZ on Serum Potassium
Adjusted mean D from baseline at 8 weeks (mEq/L) 300 100 GLB.IRB 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

Convenience 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 Months Persistence (%) 68.7 57.8 18.8% Lisinopril/HCTZ (1 pill) Lisinopril and HCTZ (2 pills) Dezii CM. Manag Care 2000; 9 : s2

Equal efficacy? 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

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) -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 < 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): Neldam S, et al. AJGC 2006;15:

Neldam S, et al. AJGC 2006;15:

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.

Comparison of Telmisartan HCTZ & Valsartan HCTZ
Change in clinic trough BP from baseline after 8 weeks therapy How to maximize patient benefit White W & al BP Monitoring 2008, 13:21

AIIA + CCB How to maximize patient benefit

Composed end-point comparing a fixed combination of a CCB +ACEI vs a thiazide+ACEI ACCOMPLISH Trial HR: 0,80; IC 95%: 0,72 – 0,90 Incidence of eventos El estudio ACCOMPLISH se realizó para comprobar si la combinación a dosis fijas de amlodipino y un inhibidor del Sistema Renina Angiotensina (SRA) proporciona mayores beneficios en cuanto a reducción de la morbimortalidad por eventos cardiovasculares en una población hipertensa de alto riesgo, en comparación con una combinación tradicional con el mismo inhibidor del SRA Es el primer estudio en comparar dos combinaciones fijas de antihipertensivos en la reducción del riesgo CV. El estudio se interrumpió de forma prematura cuando el efecto positivo del brazo con amlodipino superó los límites de significación estadística marcados previamente: una reducción del riesgo de evento CV de aproximadamente el 20% en comparación con la combinación fija tradicional. Time for events How to maximize patient benefit Jamerson K et al. NEJM; 2008; 359:2417

ASCOT - Summary of all end points
Unadjusted Hazard ratio (95% CI) 0.90 ( ) 0.87 ( ) 0.87 ( ) 0.84 ( ) 0.89 ( ) 0.76 ( ) 0.77 ( ) 0.84 ( ) 1.27 ( ) 0.68 ( ) 0.98 ( ) 0.65 ( ) 1.07 ( ) 0.70 ( ) 0.85 ( ) 0.86 ( ) 0.84 ( ) 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 How to maximize patient benefit

Chemical structures Telmisartan and other angiotensin II antagonists Losartan (active form) Valsartan Irbesartan Candesartan (active form) Olmesartan (active form) O N NH N COOH C OH CH3 H3C NH N CO2H CI NH N O CO2H NH N OCH2CH3 NH COOH Telmisartan N CH3 O OH Telmisartan, a potent and highly selective AT1 receptor antagonist, displays a novel bis-benzimidazole structure. This unique feature of telmisartan accounts for both its high receptor affinity and its excellent pharmacokinetic properties.1 This slide shows the active metabolites of losartan, candesartan and olmesartan. The chemical structures of valsartan, irbesartan and eprosartan are also shown. Ries UJ, et al. 6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: synthesis, biological activity, and structure–activity relationships. J Med Chem 1993;36:4040–4051. Telmisartan是一種強效且具有高度選擇性的AT1受體拮抗劑，具有全新的bis-benzimidazole構造。Telmisartan的這個特徵是其同時具備高的受體親合力與優越的藥物動力學性質的主要原因。1 這張投影片是losartan的活性代謝物candesartan與olmesartan。同時顯示的是valsartan、irbesartan、與eprosartan的化學構造。 How to maximize patient benefit

Dissociation Half-Lives of ARB’s from Human AT1 Receptors
Telmisartan min min min 60-83 min 73-91 min 60-77 min Olmesartan Candesartan Valsartan Losartan Telmisartan : the strongest binding affinity to human AT1 receptors of all ARBs EXP3174 50 100 150 200 250 Dissociation half-life (min) How to maximize patient benefit Kakuta et al. Int J Clin Pharmacol Res. 2005;25:41-6.

Selective Nuclear Hormone Receptor Modulation
Peroxisome Proliferator-Activated Receptor Gamma (PPAR g) interaction Pioglitazone Full Agonists Telmisartan Rosiglitazone Selective Modulation Selective Peroxisome Proliferator-Activated Receptor Gamma Modulators (SPPARMS) PPAR g Insulin Sensitivity NO Weight Gain NO Oedema Insulin Sensitivity Weight Gain Oedema How to maximize patient benefit

Difference between Thiazolodinediones & ARBs
in the Interaction with PPARg Receptor 150 100 50 Full Agonists Fold Activation Partial Agonist PPARg activation was evaluated in a heterologous transactivation assay in CV1 cell lines (eliminating interference from endogenous nuclear receptors). Cells treated with thiazolodinediones & ARB’s at a concentration of 40 mmol/l rosiglitazone pioglitazone telmisartan irbesartan eprosartan How to maximize patient benefit Benson et al. Hypertension. 2004;43:993

Activation of PPARg by ARB’s
25 20 Telmisartan was the only ARB that activated PPARg at concentrations (1-5 mmol/l) attained in plasma with conventional oral dosing 15 Fold Activation 10 PPARg activation was evaluated in a heterologous transactivation assay in CV1 cell lines (eliminating interference from endogenous nuclear receptors). Cells were treated with ARB’s added at a concentration of 10 mmol/l 5 Telmisartan Candesartan Olmesartan EXP 3174 Irbesartan Valsartan Eprosartan How to maximize patient benefit Benson et al. Hypertension. 2004;43:993.

Effects of Telmisartan & Losartan in Patients with metabolic syndrome
FPG FPI HOMA IR HbA1c -10 -20 -30 P<0.05 P<0.05 P<0.06 Change from baseline (%) Double-Blind Parallel Group Comparison of 3 Months Therapy with Telmisartan 80mg and Losartan 50mg Daytime ABPM Reductions Telmisartan 13.5 / 8.9 mmHg Losartan 10.0 / 5.6 mmHg Night-time ABPM Reductions Telmisartan 8.7 / 7.8 mmHg Losartan 7.8 / 4.7 mmHg Telmisartan (n=20) Losartan (n=20) P<0.05 How to maximize patient benefit Vitale et al. Cardiovasc Diabetol. 2005;15:6.

Effects of Telmisartan and Amlodipine on Metabolic Parameters in Type 2 Diabetic Hypertensives FPG HbA1c TG HOMA IR Adiponectin FPI * -16 -14 -12 -10 -8 -6 -4 -2 -60 -40 -20 20 40 60 80 100 120 Telmisartan Amlodipine % change from baseline % change from baseline 40 diabetic hypertensive subjects were randomly assigned to 4 months treatment 4mg + Amlodipine 10mg. All patients were already treated with metformin, but not with antihypertensive drugs with either rosiglitazone 4mg + Telmisartan 80mg or rosiglitazone n.s. n.s. * ** * * p<0.05 & ** p<0.01 vs amlodipine How to maximize patient benefit Negro et al. JRAA 2006:243-6.

Change in the Visceral Fat Area (VFA) Change in waist circumference
Effects of telmisartan on fat distribution in individuals with metabolic syndrome Change in the Visceral Fat Area (VFA) Change in waist circumference 300 100 +10% p=0.046 -12% p=0.008 -5% +3% 250 98 200 96 VFA cm² Waist circumference (cm) 150 94 100 BACKGROUND: Visceral fat obesity plays an essential role in the clustering of atherosclerotic multiple risk factors in the metabolic syndrome. Telmisartan, an angiotensin II type 1 receptor blocker, has partial agonistic properties for peroxisome proliferator-activated receptor gamma, which is a key regulator of adipocyte differentiation and function. METHODS: This study aimed to clarify the impact of telmisartan on fat distribution and insulin sensitivity in the metabolic syndrome. In this open-label, prospective, randomized study, patients with the metabolic syndrome (waist circumference: men >or= 85 cm, women >or= 90 cm) were treated either with amlodipine (n = 26) or with telmisartan (n = 27) for 24 weeks, and fat distribution and insulin sensitivity were determined. RESULTS: Systolic and diastolic blood pressure were decreased in both groups to a comparable level. However, insulin and glucose levels during an oral 75 g glucose loading were decreased only in the telmisartan group. The visceral fat area, determined by abdominal computed tomography scan, was reduced in the telmisartan group after 24 weeks' treatment, but the subcutaneous fat area did not change in either group. CONCLUSION: The results imply that telmisartan could treat both the hemodynamic and metabolic aberrations seen in patients with the metabolic syndrome, improving insulin resistance and glucose intolerance at least partly through visceral fat remodeling. 92 50 90 Amlodipine Telmisartan Amlodipine Telmisartan Baseline 24 wks treatment How to maximize patient benefit Shimabukuro, J Hypertens 2007;25:841 41

Comparative Cardio-Metabolic Studies with Telmisartan
Trial Patients N Duration (weeks) Comparator Agent(s) BP differential Improved Insulin Sensitivity Improved Lipid Profile Anti-oxidant/ Inflammatory Action Derosa 2004a HT, T2DM 119 52 Eprosartan/Placebo No (P yes) No Yes - Derosa 2004b 116 Nifedipine GITS Vitale 2005 HT, MS 40 12 Losartan Yes? Miura 2005 18 Candesartan/Valsartan Koulouris 2005 NT, T2DM Ramipril Honjo 2005 38 Candesartan Benndorf 2006 HT 37 6 Nisoldipine No? Negro 2006a 16 Amlodipine Negro 2006b HT, obese,IR 46 26 Irbesaratn Bahadir 2007 HT, MS 42 10 Derosa 2007 188 Irbesartan Sharma 2007 HT, obese 840 Valsartan HCTZ How to maximize patient benefit

Conclusions Use of more than one agent is necessary to achieve target BP in the majority of patients. Combination therapy is related with a higher BP reduction and CV protection Fixed combinations of two drugs can simplify treatment schedule and improve compliance and tolerability. A combination of two drugs should be preferred as first step treatment when initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very high Are all the combination therapies equipotent

Backup How to maximize patient benefit

Combination Therapy Study / Drugs BP Mo- Mort STOP 2 Old/Recent ≡ BACRI ARB + HCTZ / ACEI + Verap NA INVEST BB + HCTZ / Verap + ACEI EXFORGE ARB + CCB / ACEI + HCTZ ≡ ou ≥ ASCOT ACEI + CCB LIFE ARB + HCTZ ≥ ACCOMPLISH ACEI + HCTZ / ONTARGET ACEI + ARB / ACEI Side effects ++ How to maximize patient benefit

CV Risk Reduction in Diabetics
The HOT Study: CV Risk Reduction in Diabetics 25 p < for trend (n = 1501) 20 15 major CV events/1000 patient.y 10 5 Target Achieved < 90 mmHg 85 mmHg < 85 mmHg 83 mmHg < 80 mmHg 81 mmHg How to maximize patient benefit Hansson L, et al. Lancet 1998;351:1755–62.

Management of BP for adults- JNC VII
BP classification SBP* mmHg DBP mmHg Lifestyle modification Initial drug therapy Without compelling indication With compelling indications Normal <120 and <80 Encourage Prehypertension 120–139 or 80–89 Yes No antihypertensive drug indicated. Drug(s) for compelling indications. ‡ Stage 1 Hypertension 140–159 or 90–99 Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Drug(s) for the compelling indications.‡ Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Stage 2 Hypertension >160 or >100 Two-drug combination for most† (usually thiazide-type diuretic and ACEI or ARB or BB or CCB). †Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. ‡Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg. How to maximize patient benefit

Adverse Events: HCTZ 25 mg vs ARB + HCTZ 25 mg
Potassium Insulin Glucose Lipids Uric Acid Adverse events Impotence How to maximize patient benefit

Effect of Telmisartan HCTZ 25 mg
Change in clinic trough BP from baseline after 8 weeks therapy How to maximize patient benefit Neldam & al J Clin Hypertens 2008; 10:612

INVEST: Primary Composite Endpoint by Treatment Group
Calcium Antagonist Strategy (CAS) (Verap + ACEI) Non-Calcium Antagonist Strategy (NCAS) (BB + HCTZ) RR = 0.98 (0.90 – 1.06) Cumulative % Log-Rank P=.57 During follow-up evaluations over 60 months, the time to first primary composite endpoint (all-cause mortality, nonfatal MI, or nonfatal stroke) was the same for the CAS and NCAS treatment groups. 6 12 18 24 36 48 54 42 60 30 No. at Risk CAS NCAS Time, mo 35 33 Pepine CJ, et al. JAMA. 2003;290:2805

ONTARGET – Combination ACEI + ARB vs ACE
How to maximize patient benefit The ONTARGET Investigators N EJM 2008;358:1547

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