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

Protecting patients with hypertension How to maximize patient benefit ? Pr Roland Asmar. Goals of Antihypertensive Treatment ESH/ESC 2007. < 140/90 mmHg. Hypertensive patients. < 130/80 mmHg. Diabetes Patient at high risk.

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

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  1. Protecting patients with hypertensionHow to maximize patient benefit ?Pr Roland Asmar How to maximize patient benefit

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

  3. 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 Egypt 33.5 South Africa 47.6 Italy 37.5 How to maximize patient benefit Kearney et al. J Hypertens 2004; 22: 11

  4. HOT: Need for Combination Therapy How to maximize patient benefit Hansson et al., Lancet 1998, 351: 1755-62

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

  6. ESH/ESC Guidelines - 2007

  7. Pharmacological Rationalefor Combination Therapy How to maximize patient benefit

  8. 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 Rationale for Combination Therapy How to maximize patient benefit

  9. Advantages of Combination Therapy Efficacy How to maximize patient benefit

  10. 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

  11. How to maximize patient benefit

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

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

  14. Value of combinationtreatment: analysis of 354 randomised placebo controlledtrials How to maximize patient benefit Law MR BMJ 2003

  15. Advantages of Combination Therapy Side Effects How to maximize patient benefit

  16. Effect of ARB and HCTZ on Serum Potassium Adjusted mean Dfrom baseline at 8 weeks (mEq/L) 300 100 ARB dose(mg/d) 37.5 0 0 12.5 6.25 25 HCTZ dose (mg/d) How to maximize patient benefit Kochar M, et al. Am J Hypertens. 1999;12:797

  17. 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

  18. Advantages of Combination Therapy Convenience How to maximize patient benefit

  19. 100 95 90 85 80 75 70 65 60 55 50 Lisinopril/HCTZ (1 pill) Lisinopril and HCTZ (2 pills) Persistence (%) 68.7 18.8% 57.8 0 1 2 3 4 5 6 7 8 9 10 11 12 Months 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 Dezii CM. ManagCare 2000; 9 : s2

  20. Advantages of Combination Therapy Equal efficacy? How to maximize patient benefit

  21. Weber M. Journal of Hypertension 2003; 21 Suppl 6:S37-46 • Weber M.The Telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) programme.Journal of Hypertension 2003; 21 Suppl 6:S37-46 ® Hypertension in special patient populations – ARBs-FDC Blood pressure control with ARBs and in Fixed Dose Combination Protocol Endpoints • 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 last6 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 Neutel JM, et al. Hypertens Res 2005;28:555

  22. 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 -6 -8 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

  23. Weber M. Journal of Hypertension 2003; 21 Suppl 6:S37-46 • Weber M.The Telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) programme. Journal of Hypertension 2003; 21 Suppl 6:S37-46 ® Study of telMisartan On Obese/overweight Type2 diabetics with Hypertension Protocol Endpoints • 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) Sharma AM, et al. Cardiovascular Diabetology. 2007;6:28

  24. Telmisartan + HCTZ vsValsartan+ HCTZPowerful 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

  25. 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

  26. Weber M. Journal of Hypertension 2003; 21 Suppl 6:S37-46 • 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 StudyCirculation 1997; 96(1):308-315 ® A comparison of Telmisartan plusHCTZ with amlodipine plus HCTZ in Olderpatients with predominantly Systolic hypertension Protocol Endpoints • 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 last6 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 Neldam S, et al. AJGC 2006;15:151-60.

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

  28. Telmisartanin combinationHCTZ 25 mg How to maximize patient benefit

  29. Comparison of Telmisartan HCTZ & Valsartan HCTZ Change in clinic trough BP from baseline after 8 weeks therapy Systolic BP Diastolic BP 0 -5 -10 Change from baseline (mmHg) -15 -1.8 (-3.0, - 0.6) p<0.02 -20 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.

  30. 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

  31. AIIA + CCB How to maximize patient benefit

  32. 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 Time for events How to maximize patient benefit Jamerson K et al. NEJM; 2008; 359:2417

  33. 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) ASCOT - Summary of all end points PrimaryNon-fatal MI (incl silent) + fatal CHD SecondaryNon-fatal MI (exc. Silent) +fatal CHD Total coronary end pointTotal CV event and proceduresAll-cause mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal heart failure Tertiary Silent MI Unstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset diabetes mellitusNew-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + stroke 1.00 1.45 2.00 0.50 0.70 Atenolol thiazide better Amlodipine perindopril better The area of the blue square is proportional to the amount of statistical information How to maximize patient benefit

  34. H3C CH3 CI N C N N O OH N CO2H N O N N CO2H COOH N N N N N N N N N N N N N N N NH NH NH NH NH N N OCH2CH3 COOH CH3 CH3 N N N OH O N CH3 Chemical structures Telmisartan and other angiotensin II antagonists Losartan (active form) Valsartan Irbesartan Candesartan(active form) Olmesartan (active form) Telmisartan How to maximize patient benefit

  35. 202-226 min 151-184 min 121-149 min 60-83 min 60-77 min 73-91 min Dissociation Half-Lives of ARB’sfrom Human AT1 Receptors 95% CI Telmisartan Olmesartan Candesartan Valsartan Losartan EXP3174 250 100 150 200 50 0 Dissociation half-life (min) How to maximize patient benefit Kakuta et al.Int J Clin Pharmacol Res. 2005;25:41-6.

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

  37. Difference between Thiazolodinediones & ARBs in the Interaction with PPARg Receptor 150 100 50 0 Full Agonists Fold Activation PartialAgonist rosiglitazone pioglitazone telmisartan irbesartan eprosartan How to maximize patient benefit Benson et al.Hypertension. 2004;43:993

  38. Activation of PPARg by ARB’s 25 Telmisartan was the only ARB that activated PPARg at concentrations (1-5 mmol/l) attained in plasma with conventional oral dosing 20 15 Fold Activation 10 5 0 Telmisartan Candesartan Olmesartan EXP 3174 Irbesartan Valsartan Eprosartan How to maximize patient benefit Benson et al.Hypertension. 2004;43:993.

  39. 0 -10 -20 -30 Effects of Telmisartan & Losartan in Patients with metabolic syndrome FPG FPI HOMA IR HbA1c P<0.05 P<0.05 P<0.06 Change from baseline (%) Telmisartan (n=20) Losartan (n=20) P<0.05 How to maximize patient benefit Vitale et al. Cardiovasc Diabetol. 2005;15:6.

  40. 0 120 100 -2 80 -4 60 -6 40 -8 20 -10 0 -12 -20 -40 -14 -60 -16 Effects of Telmisartan and Amlodipineon Metabolic Parameters in Type 2 Diabetic Hypertensives FPG HbA1c TG HOMA IR Adiponectin FPI * Telmisartan Amlodipine % change from baseline % change from baseline n.s. * n.s. ** * * p<0.05 & ** p<0.01 vs amlodipine How to maximize patient benefit Negro et al.JRAA 2006:243-6.

  41. Effects of telmisartan on fat distribution in individuals with metabolic syndrome Baseline 24 wks treatment Change in the Visceral Fat Area (VFA) Change in waist circumference 300 100 -5% +10% p=0.046 -12% p=0.008 +3% 250 98 200 96 Waist circumference (cm) VFA cm² 150 94 100 92 50 90 Amlodipine Telmisartan Amlodipine Telmisartan How to maximize patient benefit Shimabukuro, J Hypertens 2007;25:841

  42. ComparativeCardio-Metabolic Studies with Telmisartan How to maximize patient benefit

  43. 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

  44. Backup How to maximize patient benefit

  45. CombinationTherapy How to maximize patient benefit

  46. The HOT Study: CV Risk Reduction in Diabetics 25 p < 0.005 for trend (n = 1501) 20 15 major CV events/1000 patient.y 10 5 0 TargetAchieved < 90 mmHg85 mmHg < 85 mmHg83 mmHg < 80 mmHg81 mmHg How to maximize patient benefit Hansson L, et al. Lancet 1998;351:1755–62.

  47. Management of BP for adults- JNC VII †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

  48. Adverse Events: HCTZ 25 mg vs ARB + HCTZ 25 mg How to maximize patient benefit

  49. 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 ClinHypertens 2008; 10:612

  50. 0 6 12 18 24 30 36 42 48 54 60 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 No. at RiskCAS NCAS Time, mo 1126711309 1092110991 1071610785 1051210536 1000810048 66126604 37383706 15681563 974960 393390 3533 Pepine CJ, et al. JAMA. 2003;290:2805

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