1. Resistant hypertension increases patients’ cardiovascular risk 30% of all treated patients develop resistant hypertension [1-5]. Resistant hypertension is defined as a failure to achieve blood pressure targets in spite of the concurrent use of three antihypertensive agents of different classes (at maximal doses), including diuretics [2,6]. Patients with resistant hypertension are at a higher risk of cardiovascular morbidity and mortality compared with those who have more easily controlled hypertension [2,6,7]. 1 1. Sarafidis PA et al. J Am Coll Cardiol. 2008;52:1749–1757. 2. Chobanian AV et al. The JNC 7 report. JAMA. 2003;289:2560–2572. 3. Cushman WC et al. J Clin Hypertens (Greenwich). 2002;4:393–404. 4. Hyman DJ et al. N Engl J Med. 2001;345:479–486. 5. Pepine CJ et al. JAMA. 2003;290:2805–2816. 6. Calhoun DA et al. Circulation. 2008;117:e510–e526. 7. Cuspidi C et al. J Hypertens. 2001;19:2063–2070.

2. 2 Gupta AK et al. J Hypertens. 2011;29:2004-2013. ASCOT-BPLA: the analysis of baseline determinants of resistant hypertension OBJECTIVE: To study the baseline determinants of resistant hypertension among hypertensive patients and to develop a risk score to identify those at high risk of developing resistant hypertension. METHOD: A multivariate Cox model.  Primary analysis was done using data from previously untreated hypertensive patients at randomization (“untreated” population; n=3666).  Secondary analysis was done using data from all randomized patients (“total” population; n=19 257), the majority (n=15 591, 81%) of whom were previously treated. 2011

3. Adapted from Gupta AK et al. J Hypertens. 2011;29:2004-2013. The earlier patients are switched to amlodipine/perindopril, the less therapeutic escape on long term is observed Atenolol/thiazide Amlodipine/perindopri l HR 0.57 (0.50-0.60), P<0.001 N= 3666 untreated patients RRR 43% Cox regression analysis of development of resistant hypertension, % “Potential mechanisms for this protection include a greater reduction in brachial BP, central aortic BP, BP variability, and possibly arterial stiffness, compared with the atenolol/thiazide treatment strategy.” 2011 3 NEW

4. Amlodipine/perindopril regimen is highly protective against the risk of resistant hypertension (n=3666) Baseline characteristics of “untreated” population (n=3666) Hazard ratio (95% CI)P Randomization to amlodipine/perindopril (versus atenolol/thiazide) 0.57 (0.50–0.64)<0.001 Baseline SBP (per category versus < 150 mm Hg) 151–160 mm Hg 161–170 mm Hg 171–180 mm Hg >180 mm Hg 1.24 (0.81–1.88) 1.50 (1.03–2.20) 2.15 (1.47–3.16) 4.43 (3.04–6.45) 0.322 0.035 <0.001 Diabetes (vs no) BMI (kg/m²) 1.69 (1.40–2.04) 1.04 (1.02–1.05) <0.001 Male sex (vs female)1.56 (1.33–1.83)<0.001 Alcohol consumption (per category)1.14 (1.07–1.23)<0.001 Presence of LVH (versus no)1.27 (1.11–1.46)0.001 Fasting glucose (per mmol/L)1.05 (1.01–1.09)0.013 Previous use of aspirin (vs no)0.78 (0.62–0.98)0.036 Randomization to atorvastatin (vs placebo)0.87 (0.76–1.00)0.043 4 Gupta AK et al. J Hypertens. 2011;29:2004-2013.

5. Amlodipine/perindopril regimen is highly protective against the risk of resistant hypertension (n=19 257) Baseline characteristics of “total” population (n=19 257) Hazard ratio (95% CI)P Randomization to amlodipine/perindopril (versus atenolol/thiazide) 0.53 (0.51–0.55)<0.001 Baseline SBP (per category versus <150 mm Hg) 151–160 mm Hg 161–170 mm Hg 171–180 mm Hg >180 mm Hg 1.67 (1.55–1.79) 2.15 (2.00–2.31) 2.85 (2.64–3.08) 4.47 (4.13–4.84) <0.001 History of antihypertensive treatment 1 agent >2 agents 1.69 (1.57–1.81) 3.92 (3.65–4.20) <0.001 Diabetes (vs no) BMI (kg/m²) 1.52 (1.43–1.61) 1.02 (1.02–1.03) <0.001 Male sex (vs female)1.44 (1.36–1.52)<0.001 Alcohol consumption (per category)1.09 (1.07–1.12)<0.001 Presence of LVH (versus no)1.22 (1.16–1.28)0.001 Randomization to atorvastatin (vs placebo)0.94 (0.89–0.99)0.011 5 Gupta AK et al. J Hypertens. 2011;29:2004-2013.

6. ASCOT-BPLA: the analysis of determinants of resistant hypertension This is the most comprehensive evaluation of the determinants of resistant hypertension to date. Among 3666 patients, “untreated” at study entry, the risk of resistant hypertension was higher in those with higher baseline systolic BP, with diabetes, increased body weight, alcohol consumption, and with LVH. Among the “total” ASCOT population (n=19 257), a history of prior use of one or more antihypertensive agents was associated with increased risk of developing resistant hypertension (1.7-fold and 3.9-fold, respectively), compared with previously untreated patients. 6 INVESTIGATORS’ CONCLUSION 2011 Gupta AK et al. J Hypertens. 2011;29:2004-2013.

7. Amlodipine/perindopril protects against the risk of developing resistant hypertension: risk was reduced among “untreated” as well as among “total” population by 43% and 47%, respectively. “Potential mechanisms for this protection include a greater reduction in brachial BP, central aortic BP, BP variability, and possibly arterial stiffness, compared with the atenolol-based treatment strategy”. “The optimal selection of combinations of antihypertensive agents can reduce the risk of developing resistant hypertension among all patients regardless of associated comorbidities or baseline risk”. 7 INVESTIGATORS’ CONCLUSION 2011 ASCOT-BPLA: the analysis of determinants of resistant hypertension Gupta AK et al. J Hypertens. 2011;29:2004-2013.