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Vivencio Barrios University Hospital Ramón y Cajal Madrid, Spain

Olmesartan-based therapies: optimising BP goal achievement and cardiovascular risk reduction in hypertensive patients. Vivencio Barrios University Hospital Ramón y Cajal Madrid, Spain. Relevant disclosure of interest: Consultant to Daiichi Sankyo and the Menarini group.

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Vivencio Barrios University Hospital Ramón y Cajal Madrid, Spain

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  1. Olmesartan-based therapies: optimising BP goal achievement and cardiovascular risk reduction in hypertensive patients Vivencio Barrios University Hospital Ramón y Cajal Madrid, Spain Relevant disclosure of interest: Consultant to Daiichi Sankyo and the Menarini group

  2. Treatment is not based upon BP only; risk factors and organ damage also increase total CV risk Mancia et al. J Hypertens 2007;25(6):1105–1187 OD, organ damage; MS, metabolic syndrome

  3. Treatment is not based upon BP only; risk factors and organ damage also increase total CV risk Mancia et al. J Hypertens 2007;25(6):1105–1187 OD, organ damage; MS, metabolic syndrome

  4. Cardiovascular Risk in hypertensive outpatients in clinical practice (The CONTROLRISK study) High/very high risk is very common in hypertension, even in PC setting Primary Care n=5,169 Specialist Clinics n=5,358 60% PC and 75% SC hypertensive patients are at high or very high CV risk Barrios et al. J Hum Hypertens 2007;21:479-85

  5. ONTARGET: ARB treatment is as effective as ACEI treatment in reducing CV risk Tel Ram Tel + Ram 8542 8576 8502 8177 8214 8133 7778 7832 7738 7420 7472 7375 7051 7093 7022 1687 1703 1718 ARB treatment is non-inferior to ACEI treatment for reducing CV risk Cumulative incidence rates Primary endpoint: CV death, MI, stroke,or hospitalisation for heart failure Years of follow-up Yusuf et al. NEJM 2008;358:1547–59

  6. 0.08 0.95 (0.89-1.00) Clinical relevance of study drug discontinuation in RCT. Post-hoc analysis of the ONTARGET Study Telmi vs Rami RR (95% CI) p-value 1.01 (0.94-1.09) Composite Primary Endpoint 0.83 Primary Endpoint + Discontinuation Favours Telmisartan Favours Ramipril 0.8 0.9 1.0 1.1 1.2 RR (95% CI) Barrios et al. Lancet 2008;372:535-36 [letter]

  7. Treatment choice: Within-class discontinuation rate differences* show that side effects can affect adherence ACEIs ARBs Captopril Moexipril Spirapril Fosinopril Quinapril Benazepril Trandolapril Delapril Cilazapril Lisinopril Enalapril Perindopril Zofenopril Ramipril Losartan Eprosartan Telmisartan Irbesartan Candesartan Valsartan Olmesartan 0 10 20 30 40 0 2 4 6 8 10 12 Standardised discontinuation rate (100 patients/month) Standardised discontinuation rate (100 patients/month) *Discontinuation rates showed significant heterogeneity (p<0.05) for each drug class. For ARBs, the rate was significantly greater for losartan. Mancia et al. J Hypertens 2011;29:1012-1018

  8. Treatment choice: ABPM meta-analysis shows that for ARBs, efficacy depends upon the drug used . Telmisartan Eprosartan Olmesartan Irbesartan Candesartan Placebo Losartan Valsartan 0 -2 -4 Change in ambulatory SBP (mmHg) -6 -8 -10 -12 -14 0 -2 Change in ambulatory DBP (mmHg) -4 -6 -8 -10 Independent meta-analysis of 47 randomised studies of BP changes measured by ABPM Fabia et al. J Hypertension2007;25:1327–1336

  9. ARBs are highly effective in fragile patients: Olmesartan is more effective than ramipril (ESPORT) The ESPORT (Efficacy and Safety in elderly Patients with Olmesartan medoxomil vs. Ramipril Treatment) study • Elderly patients (65–89 years) • Mild-to-moderate hypertension • Treated with olmesartan (OLM) or ramipril (RAM) for 12 weeks Randomisedn=1102 OLM10–40 mg RAM2.5–10 mg Malacco et al. J Hypertens 2010;28:2342–50

  10. Olmesartan10–40 mg (n=542) Ramipril 2.5–10 mg (n=539) Olmesartan provided significantly greater mean reductions in SeSBP and SeDBP than ramipril Week 12 (N=1081) Seated SBP Seated DBP 0.0 –5.0 –7.7 Change in SeBP at Week 12 (mmHg) –10.0 –9.2 p<0.01 –15.0 –15.7 –17.8 –20.0 p<0.01 Malacco et al. J Hypertens 2010;28:2342–50

  11. Olmesartan provided significantly greater reductions in ambulatory BP than ramipril All subjects (N=715) Sustained hypertensives (n=582) 0 0 24 hours Daytime Night-time Last 6 hours 24 hours Daytime Night-time Last 6 hours –2 –2 –4 –4 –6 –6 –8 –8 SBP (mmHg) SBP (mmHg) –10 –10 –12 –12 ** ** ** ** * * * * ** ** ** ** ** * * –14 –14 –16 –16 0 0 24 hours Daytime Night-time Last 6 hours 24 hours Daytime Night-time Last 6 hours –2 –2 –4 –4 –6 –6 DBP (mmHg) DBP (mmHg) –8 –8 –10 –10 Omboni et al. J Hypertens 2012;30:1468-77 *p<0.05; **p<0.01 for olmesartan vs. ramipril

  12. Beyond monotherapy: Most patients, especially those at higher risk, need combination therapy • “Evidence has continued to grow that in the vast majority of hypertensive patients, effective BP control can only be achieved by combination of at least two antihypertensive drugs” • “Use of combination therapy has been found to be even more frequently needed in diabetic, renal and high risk patients” • “The combination of two antihypertensive drugs may offer advantages for treatment initiation, particularly in patients at high cardiovascular risk in which early BP control may be desirable” Mancia et al. J Hypertens 2007;25:1105-1187 Mancia et al. J Hypertens 2009;27:2121-2158

  13. Increasing BP goal rate achievement requires greater usage of combination therapy Controlled<140/90 mmHg 1 Drug 2 Drugs 3 Drugs 100 80 60 Patients (%) 40 20 0 6 months 1 year 3 years 5 years Baseline Cushman et al. J Clin Hypertens 2002;4:393-404

  14. Rationale for combination therapy: two drugs are much more effective than doubling the dose of one drug 1.16 1.00 1.04 1.01 0.89 0.37 0.23 0.19 0.20 0.22 Combined therapy increases the probability of control and maximises protection compared with up-titration Doubling dose of same drug (from standard to twice standard dose) Adding a drug from another class 1.4 1.2 1.0 Incremental SBP reduction ratio of observed to expected additive effects 0.8 0.6 0.4 0.2 0 Thiazide Beta blocker ACEI CCB All classes ACEI, angiotensin-converting enzyme inhibitor; CCB, calcium channel blocker Wald et al. Am J Med 2009;122:290-300.

  15. Combination therapy is recommended for higher-risk hypertensive patients at first-line treatment Mild BP elevation Low/moderate CV risk Conventional BP target Choose between Marked BP elevation High/very-high CV risk Lower BP target Single agent at low dose Two-drug combination at low dose If BP goals not achieved Previous agent at full dose Switch to other agentat low dose Previous combination at full dose Add a third agent at low dose If BP goals not achieved Two-to-three drug combination at full dose Full-dose monotherapy Two-to-three drug combination at full dose Mancia et al. J Hypertens 2007;25:1105–1187 2007 ESH/ESC Hypertension Guidelines

  16. Preferred options for combination therapy in the 2007 ESH/ESC guidelines Diuretics -blockers ARBs -blockers CCBs ACEIs Preferred combinations Otherpossible combinations Mancia et al. J Hypertens 2007;25:1105–1187

  17. Preferred options for combination therapy after the 2009 ESH guidelines reappraisal Diuretics RAS-blockers -blockers -blockers CCBs ACEIs Mancia et al. J Hypertens 2009;27:2121-58

  18. Clinical demonstration of increased efficacy after adding a second drug in uncontrolled patients Period I Period II (8 weeks) Washout Weeks 1 - 2 Open-label Week 0 - 8 Double-blind Weeks 9 - 16 OLM 20 mg Non-responders OLM/AML 20/5 mg OLM 20 mg randomised to oneof three arms: OLM/AML 20/10 mg Non-responders to Period I = SeDBP ≥90 mmHg and SeSBP ≥140 mmHg and mean 24-h DBP ≥80 mmHg with ≥30% of daytime readings >85 mmHg Barrios et al. Clin Drug Invest 2007;27:545–558

  19. OLM/AML OLM BP goal rates after 4 and 8 weeks of double-blind treatment BP goal ≤ 140/90 mmHg (<130/80 mmHg for diabetics) Patients reaching BP goal (%) ** * 50 45.8 44.5 ** Week 4 45 39.9 Week 8 40 35 28.5 30 26.5 23.7 25 20 15 10 5 0 20/10 mg (n=177) 20 mg (n=179) 20/5 mg (n=182) Barrios et al. Clin Drug Invest 2007;27:545–558 *p<0.01; **p<0.001 vs. OLM 20 mg monotherapy

  20. Some patients need more than two drugs to get to goal Patients on ≥3 drugs in large clinical studies ALLHAT = 23.0% INVEST = 33.6% ESH guidelines reappraisal: “…in no less than 15–20% of hypertensive patients, BP control cannot be achieved by a two-drug combination.” “When three drugs are required, the most rational combination appears to be a blocker of the RAS, a CCB and a low-dose thiazide diuretic.” Cushman et al. J Clin Hypertens 2002;4:393-404 Pepine et al. JAMA 2003;290:2805-16 Mancia et al. J Hypertens 2009;27:2121-58

  21. Comparing high-dose OLM/AML/HCTZ with dual combination therapy in the TRINITY study Double-blind randomised treatment Triple combination therapy OR continuation of dual combination therapy: Dual combination therapy: OLM/AML 40/10 mg OR OLM/HCTZ 40/25 mg OR AML/HCTZ 10/25 mg 4 weeks 8 weeks Run-In OLM/AML/HCTZ 40/10/25 mg OR OLM/AML 40/10 mg OR OLM/HCTZ 40/25 mg OR AML/HCTZ 10/25 mg Oparil et al. Clin Ther 2010;32:1252–69

  22. Baseline 2 4 6 8 10 12 TRINITY: Reductions in SBP are faster with OLM/AML/HCTZ than with dual combination therapy Randomisation Dual combination ONLY Triple combination therapy OR continuation of dual combination 170 160 Mean SeSBP (mmHg) 150 AML/HCTZ (n=593)* 140 OLM/AML (n=624)* OLM/HCTZ (n=627)* 130 OLM/AML/HCTZ (n=614)* Time (weeks) Oparil et al. Clin Ther 2010;32:1252–69 *Number of patients in each treatment group at Week 12

  23. TRINITY: OLM/AML/HCTZ significantly increased SBP reductions in patients with mod-severe hypertension OLM/AML 40/10 mg AML/HCTZ 10/25 mg OLM/HCTZ 40/25 mg OLM/AML/HCTZ 40/10/25 mg n=168 n=408 n=160 n=453 n=160 n=452 n=136 n=463 Least squares mean changein systolic blood pressure (mmHg) *† Severe Moderate *† *p<0.0001 vs. baseline; †p<0.0001 vs. each dual combination Severe, SeSBP/SeDBP ≥180/≥110 mmHg, moderate, <180/<110 mmHg Oparil et al. Clin Ther 2010;32:1252–69

  24. Assessing long-term efficacy and tolerability in the TRINITY OLE (Weeks 12–52) Responders O/A/H 40/5/12.5 mg All treatment decisions at investigator’s discretion after re-randomisation Responders O/A/H 40/5/25 mg Non-responders Non-responders O/A/H 40/10/25 mg O/A/H 40/5/12.5 mg Non-responders Non-responders O/A/H 40/10/12.5 mg Responders Re-randomisation Week 12 Week 14 Week 52 Period III Kereiakes et al. J Clin Hypertens 2012;14(3):149-57

  25. Long-term OLM/AML/HCTZ effectively controls BP in patients with high CV risk due to diabetes Diabetic and non-diabetic patients with BP <140/90 mmHg at any time by final regimen Diabetic Non diabetic Patients with BP <140/90 mmHg (%) 40/5/12.5 mg 40/5/25 mg 40/10/12.5 mg 40/10/25 mg 40/5/12.5 mg 40/5/25 mg 40/10/12.5 mg 40/10/25 mg Oparil et al. J Clin Hypertens 2011;13 (Suppl 1):A75 (ASH 2011 poster PO-150)

  26. Long-term OLM/AML/HCTZ effectively controls BP in patients with high CV risk due to obesity Obese and non-obese patients with BP <140/90 mmHg at any time by final regimen BMI ≥30 kg/m2 BMI <30 kg/m2 Patients with BP <140/90 mmHg (%) 40/5/12.5 mg 40/5/25 mg 40/10/12.5 mg 40/10/25 mg 40/5/12.5 mg 40/5/25 mg 40/10/12.5 mg 40/10/25 mg Oparil et al. J Clin Hypertens 2011;13 (Suppl 1):A75 (ASH 2011 poster PO-150)

  27. Adding HCTZ to a range of OLM/AML doses in patients with moderate-to-severe hypertension OLM/AML 20/5 mg n=337 OLM/AML 20/5 mg n=652 OLM/AML/HCTZ 20/5/12.5 mg n=335 OLM/AML 40/5 mg n=337 OLM/AML 40/5 mg n=989 Randomisation N=2690 OLM/AML/HCTZ 40/5/12.5 mg n=336 OLM/AML/HCTZ 40/5/25 mg n=336 OLM/AML 40/10 mg n=336 OLM/AML 40/10 mg n=988 OLM/AML/HCTZ 40/10/12.5 mg n=336 OLM/AML/HCTZ 40/10/25 mg n=336 Week 2 Week 10 Week 0 *Placebo groups in Period I tested regression to the mean Volpe et al. Clin Drug Invest 2012;32(10):649–664

  28. Primary endpoint: Adding HCTZ to OLM/AML significantly improved SeDBP changes O/A 20/5 mg n=337 O/A/H 20/5/12.5 mg n=334 O/A 40/5 mg n=334 O/A/H 40/5/12.5 mg n=336 O/A/H 40/5/25 mg n=335 O/A 40/10 mg n=335 O/A/H 40/10/12.5 mg n=336 O/A/H 40/10/25 mg n=332 LS mean change in SeDBP from baseline to Week 10 (mmHg) ** * ** ** ** *p<0.05; **p≤0.01 for triple vs. dual combination All changes significant vs. baseline (p<0.0001) Volpe et al. Clin Drug Invest 2012;32(10):649–664

  29. An open-label extension period assessed long-term efficacy, with dose titration for non-responders Primary endpoint Responders (begin open-label titration at start of Period IV) OLM/AML/HCTZ (mg) OL titration Non-responders uptitrated to 40/5/12.5 Non-responders 20/5/12.5 (Control) 20/5/0 20/5/0 20/5/12.5 Open-label wash-out Responders 20/5/12.5 40/5/0 OL titration 20/5/12.5 40/5/12.5 40/5/0 OL titration Non-responders 40/5/25 40/5/25 40/10/0 Non-responders 40/5/12.5 (Control) Non-responders 40/5/12.5 40/10/12.5 40/10/0 OL titration 40/10/25 Responders 20/5/12.5 OL titration 8 weeks 8 weeks 2 weeks 1-2 weeks Randomised to Double-Blind Period I-II Treatment Sequence 4 weeks 4 weeks Open-Label Single-Blind Double-Blind Double-Blind Volpe et al. ESC 2012 poster presentation

  30. Long-term treatment with OLM/AML/HCTZ reduced SBP to <140 mmHg in each group -36.5 -42.8 -40.1 -39.9 -39.4 Mean SBP (mmHg) Final treatment group Patients with BP goal <130/80 mmHg 29.1% 46.0% 53.3% 58.9% 56.1% Volpe et al. ESC 2012 poster presentation

  31. Long-term OLM/AML/HCTZ effectively reduced SBP even in patients with severe hypertension at baseline *p<0.0001 for Week 54 vs. baseline -59.4* Mean SBP (mmHg) -51.9* -45.5* -39.0* -34.3* Mean BP level in each group remained above 120 mmHg Baseline SBP category (mmHg) Volpe et al. J Hypertens. 2012;30 (e-Suppl A):e278

  32. BP goal achievement with a stepwise OLM/AML/HCTZ algorithm: The BP-CRUSH study Assessing BP control in patients uncontrolled on monotherapy Primary endpoint Start of active treatment Extension period OLM/AML20/5 mg OLM/AML40/5 mg OLM/AML40/10 mg OLM/AML/HCTZ40/10/12.5 mg OLM/AML/HCTZ40/10/25 mg Day 0 Week 4 Week 8 Week 12 Week 16 Week 20 Up titration if SeSBP/SeDBP ≥120/70 mmHg(OLM/AML) ≥125/75 mmHg(OLM/AML/HCTZ) Weir et al. J Clin Hypertens 2011;13:404–12

  33. BP-CRUSH: Treating to BP target, nearly all patients achieved BP <140/90 mmHg Dual combination Triple combination 100 90.3 86.7 77.1 80 63.8 60 49.5 Patients* with BP <140/90 mmHg at Week 20 (%) 40 20 0 OLM/AML 20/5 mg OLM/AML 40/5 mg OLM/AML 40/10 mg OLM/AML/HCTZ 40/10/12.5 mg OLM/AML/HCTZ 40/10/25 mg *Cumulative proportion of patients Weir et al. J Clin Hypertens 2011;13:404–12

  34. Summary • Treatment must take level of BP and total CV risk into account • ARBs like olmesartan are effective and well tolerated antihypertensive agents especially in higher-risk groups • Combining drugs increases efficacy and is recommended for patients with increased CV risk • high-risk patients are harder to control and often need combination therapy • early BP control is important for high risk patients • OLM/AML/HCTZ triple combination therapy is effective and well tolerated in a wide range of patients, including higher-risk patients • When dual combinations are not enough, adding HCTZ significantly increases the efficacy of OLM/AML (add-on label) • The availability of a range of effective, well tolerated dual and triple combinations based upon agents like OLM, AML and HCTZ offers significant benefits for higher-risk patients

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