1 / 93

Relevance of AT 1 blockade

Relevance of AT 1 blockade. Angiotensin II effects at the AT 1 and AT 2 receptors. Angiotensin II. -sartan. AT 1 Receptor. AT 2 Receptor. Vasoconstriction Activate sympathetic activity Increase sodium retention Increase vasopressin release

garron
Download Presentation

Relevance of AT 1 blockade

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Relevance of AT1 blockade

  2. Angiotensin II effects at the AT1 and AT2 receptors AngiotensinII -sartan AT1 Receptor AT2 Receptor Vasoconstriction Activate sympathetic activity Increase sodium retention Increase vasopressin release Promote myocyte hypertrophy and proliferation Stimulate vascular and cardiac fibrosis Stimulate plasminogen activator inhibitor 1 Stimulate superoxide formation Antiproliferation Apotosis Endothelial cell growth Vasodilation (NO mediated?) Stimulate renal bradykinin and NO Adapted from McConnaughey et al. J Clin Phamacol 1999;39: 547–59.

  3. The Renin-Angiotensin Systemshowing ACE and non-ACE pathways ACE PATHWAY (< 30%) NON-ACE PATHWAY (> 70%) Angiotensinogen ChymaseToninCathepsinKallikrein Renin Angiotensin I ACE Angiotensin McConnaughey et al. J Clin Phamacol 1999;39: 547–59.

  4. Angiotensin II, endothelial dysfunction and atherosclerosis Angiotensin II  NADH/NADPH oxidases  Free radicals  NO Endothelial dysfunction Leucocyte adhesion SMC proliferation Atherosclerosis

  5. Angiotensin II induces endothelial dysfunction and superoxide production Superoxide production from NADH/NADPH oxidases Endothelial dysfunction Relaxation (%) (nmol/min) 50 0 Control AII 40 20 30 40 60 20 Control AII 80 10 AII+SOD 100 0 NADPH NADH -9 -8 -7 -6 Concentration of Ach (log M) Griendling et al. Circ Res 1994;74:11–48. Rajagopalan and Harrison. JCI 1996;97:1916–23.

  6. AT1 blockade with irbesartan

  7. Responses to Ang I and [Pro11D-Ala12] Ang I Angiotensin I [Pro-11D-Ala12] Angiotensin I 80 70 p = 0.002 p = 0.0007 60 50 Veno- Constriction (%) 40 30 20 10 0 Pre Post Pre Post Pre Post Pre Post Irbesartan Placebo Captopril Placebo Captopril McDonald et al. Circulation 2001;104:1805–8.

  8. Superior inhibition of SBP to exogenous Ang II with irbesartan SBP response to exogenous Ang II (%) 100 Placebo Losartan 50 mg Valsartan 80 mg Irbesartan 150 mg 80 * * † * 60 * * * ‡ 40 * p < 0.01 vs. placebo † p < 0.05 vs. placebo ‡ p < 0.05 vs. other antagonists 20 * ‡ Values are mean ± SEM 0 0 5 10 15 20 25 30 35 Time (hours) Mazzolai L et al. Hypertension 1999;33:850–5.

  9. Relative potency of AT1 blockers 25 Day 1 Day 8 20 Plasma renin activity (ng/ml•h) 15 10 5 0 0 h 4 h 24 h 0 h 4 h 24 h Valsartan 80 mg Valsartan 160 mg Valsartan 320 mg Losartan 50 mg Irbesartan 150 mg Candesartan 8 mg Increases in PRA reflect AT1 receptor blockade Maillard MP et al. Clin Pharmacol Ther 2002;71:68–76.

  10. Blood pressure lowering

  11. Irbesartan vs. losartanFixed dose mean change from baseline in trough SeDBP  SeDBP from baseline (mmHg) 0 Placebo (n = 138) -2 Losartan 100 mg (n = 131) -4 -6 * p < 0.01 vs. losartan †p < 0.02 vs. losartan Irbesartan 150 mg (n = 129) -8 Irbesartan 300 mg (n = 134) -10 * † -12 * N shown is at Week 8 8 0 1 4 Time (weeks) Kassler-Taub K et al. Am J Hypertens 1998;11:445–53.

  12. Irbesartan vs. losartanFixed dose mean change from baseline in trough SeSBP  SeSBP from baseline (mmHg) 0 -2 Placebo (n = 138) -4 Losartan 100 mg (n = 131) -6 * p < 0.01 vs. losartan -8 Irbesartan 150 mg (n = 129) -10 -12 -14 Irbesartan 300 mg (n = 134) -16 * -18 N shown is at Week 8 8 0 1 4 Time (weeks) Kassler-Taub K et al. Am J Hypertens 1998;11:445–53.

  13. Irbesartan vs. valsartan Superior reduction in trough 24-h Ambulatory BP ADBP ASBP 0 -2 -4  Trough ABP from baseline (mmHg) (p = 0.035) -6 -8 (p < 0.01) N = 426 -10 -12 Irbesartan 150 mg Valsartan 80 mg Mancia G. Blood Pressure Monitoring 2002;7(2):135–42.

  14. Irbesartan vs. valsartan Superior reduction in mean 24-h Ambulatory BP ADBP ASBP 0 -2 -4  Mean ABP from baseline (mmHg) (p = 0.023) -6 -8 (p < 0.01) -10 -12 Irbesartan 150 mg Valsartan 80 mg Mancia G. Blood Pressure Monitoring 2002;7(2):135–42.

  15. Irbesartan vs. losartan and valsartanOverall Summary • Irbesartan provides more complete and sustained blockade of Ang II effects than losartan or valsartan • Irbesartan 300 mg provides superior efficacy compared with the highest dose of losartan (100 mg) • Elective titration of irbesartan provides superior antihypertensive effect compared with elective titration of losartan • The starting and usual maintenance dose of irbesartan results in statistically superior reductions in blood pressure vs. the starting dose of valsartan Kassler-Taub K et al. Am J Hypertens 1998;11:445–53. Oparil S et al. Clin Ther 1998;20: 398–409. Mancia G. Blood Pressure Monitoring 2002;7(2):135–42.

  16. Irbesartan and enalapril equally lower mean ambulatory BP over 24-h SBP DBP 0 -2 -4 -6 Mean reduction in BP (mmHg) -8.8 -8 -9.4 -10 -12.6 -12 Irbesartan -14.7 Enalapril -14 -16 Multicentre, randomized, double-blind, 12-week, comparative trial. Patients received either 150–300 mg/day of irbesartan (n = 111) or 10–20 mg/day of enalapril (n = 116) Coca A et al. Clinical Therapeutics 2002;1:12–38.

  17. Irbesartan vs. enalapril in severe hypertension Change in trough SeSBP Change in trough SeDBP 0 0 -5 -5 -10 -10 Change from baseline (mmHg) Change from baseline (mmHg) -15 -15 -20 -20 -25 -25 -30 -30 -35 -35 -40 -40 -45 -45 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Time (weeks) Time (weeks) Irbesartan 75–300 mg* (n = 95) Enalapril 10–40 mg* (n = 97) * Titrated at week 1 for SeDBP  106 mmHg or at week 2 or thereafter for SeDBP  90 mmHg; additional antihypertensive therapies added after week 4 for SeDBP  90 mmHg Larochelle P et al. Am J Cardiol 1997;80:1613–15.

  18. Dose response with irbesartan/HCTZ combination therapy and components HCTZ 12.5 mg Irbesartan 300 mg Irbesartan 300 mg HCTZ 12.5 mg Placebo 0 -2 -4 -3.5 -6 -6.2 SeDBP (mmHg) -8 -10 -10.2 -12 -14 n = 40 patients per group -15.0 -16 Kochar M et al. Am J Hypertens 1999;12:797–805.

  19. Long-term efficacy withirbesartan/HCTZ-based regimens Month 2 6 12 0 -5 -10  BP (mmHg) -15 -14.2 -15.6 -15.7 -20 -19.1 -20.6 -20.7 N = 1,098 -25 SeDBP SeSBP Raskin P et al. J Hum Hypertens 1999;13:68–7.

  20. Long-term therapeutic response with irbesartanand irbesartan/HCTZ-based regimens 100 90 87 87 83 81 80 80 60 Patients (%) 40 20 0 6 24 12 Time (months) Normalized* Responder† *Trough SeDBP < 90 mmHg †Normalized or reduction from baseline of  10 mmHg N = 1,006 Littlejohn T III et al. Clin Exp Hypertens 1999;21:1273–95.

  21. Renoprotective effects

  22. Definitions of abnormalities in albumin excretion Spot collection (µg/mg creatinine) 24h collection (mg/24h) Time collection (µg/min) Normal Microalbuminuria Clinical albuminuria < 30 30 -299 300 < 30 30 -299  300 < 20 20 -199  200 Diabetes Care 2003;26 (Supp 1):594–598.

  23. Time 0 Placebo Irbesartan Irbesartan reduces microalbuminuria in type 2 diabetic patients A randomized double-blind placebo-controlled crossover study Normotensive diabetic subjects Hypertensive diabetic subjects AER 5 (µg/min) AER 5 (µg/min) 180 180 160 160 140 140 * * 120 120 * * 100 100 80 80 60 60 40 40 20 20 0 0 Subgroup 1 Subgroup 2 Subgroup 1 Subgroup 2 *p < 0.01 Sasso FC et al. Diabetes Care 2002;25:NR II.

  24. Relative prognostic value of microalbuminuriain type 2 Diabetes 10.02 10 8 6.52 6 Mortality from CHD (odds ratio) 4 3.20 2.32 2 0 Microalbuminuria Smoking Diastolic BP Cholesterol Eastman RC, Keen H. Lancet 1997;350(Suppl 1):29–32.

  25. Microalbuminuria predicts future coronary events in patients with type 2 diabetes Remaining event free (%) Remaining event free (%) 100 100 90 90 80 80 70 60 70 Neither SMI nor microalbuminuria SMI, but no microalbuminuria Microalbuminuria, but no SMI Both SMI and microalbuminuria 50 60 40 No microalbuminuria Microalbuminuria 50 30 40 20 0 1 2 3 4 5 0 1 2 3 4 5 Follow-up (years) Follow-up (years) 86 pts with type 2 diabetes No history of coronary artery disease - 43 with microalbuminuria (AER > 200 g/min) - 43 with normoalbuminuria SMI = Silent myocardial ischemia (> 1 mm ST depression on treadmill exercise) Follow-up: 2.8 years; 23 coronary events Rutter MK et al. J Am Coll Cardiol 2002;40:56–61.

  26. Prognostic value of microalbuminuria in initially untreated hypertensive (n = 99) and normotensive (n = 21)non-diabetic subjects followed for 10 years 20 18 p = 0.015 Baseline urinary albumin excretion (median, mg/24-h) 16 14 12 10 0 No CV events (n = 101) Developed CVD (n = 19) Ljungman S et al. Am J Hypertens 1996;9:770–8.

  27. Microalbuminuria predicts coronary events in subjects with essential hypertension 100 95 90 Proportion without ischemic heart disease (%) 85 80 Normoalbuminuria Microalbuminuria (UA/Cr ratio > 1.07 mg/mmol) 75 70 0 1 2 3 4 5 6 7 8 9 10 Time (years) 204 hypertensive subjects drawn from 2,085 general population subjects No previous CV events, no diabetes, no renal or urinary disease Follow-up from 1983–84 till 1993 18 coronary events Jensen JS et al. Hypertension 2000;35:898–903.

  28. PRIMETime course of type 2 diabetic renal disease PRIME Prevention Protection IRMA 2 IDNT Microalbuminuria Proteinuria ESRD Cardiovascular morbidity and mortality Early Stage Late Stage End Stage PRIME: PRogram for Irbesartan Mortality and Morbidity Evaluations IRMA 2: IRbesartan in Patients with Type 2 Diabetes and Microalbuminuria IDNT: Irbesartan Diabetic Nephropathy Trial ESRD: End-stage renal disease

  29. IRMA 2Study design 590 patients with type 2 diabetes, microalbuminuria (albumin excretion rate 20 – 200 g/min), normal renal function, and hypertension Screening/Enrollment Double-blind treatment Placebo Irbesartan 150 mg Irbesartan 300 mg Up to 5 weeks Follow-up: 2 years Parving H-H et al. N Engl J Med 2001;345:870–8.

  30. IRMA 2Blood pressure response 160 150 SeSBP 140 130 Mean SeSBP and SeDBP(mmHg) 120 Control Irbesartan 150 mg Irbesartan 300 mg 110 100 90 SeDBP 80 70 0 0 3 6 9 12 15 18 21 24 27 Time (months) Concomitant antihypertensive agents received by 56% of patients in the control group, 45% in the irbesartan 150 mg group, and 43% in the irbesartan 300 mg group Parving H-H et al. N Engl J Med 2001;345:870–8.

  31. IRMA 2 Primary endpoint: Time to overt proteinuria 20 Control Irbesartan 150 mg Irbesartan 300 mg 15 70% RRR p < 0.001 Subjects (%) 10 5 0 0 3 6 12 18 22 24 Follow-up (months) Parving H-H et al. N Engl J Med 2001;345:870–8.

  32. IRMA 2Normalization of urinary albumin excretion rate 45 p = 0.006 40 35 34% 30 24% 25 Subjects (%) 21% 20 15 10 5 0 Control(n = 201) 150 mg(n = 195) 300 mg(n = 194) Irbesartan Parving H-H et al. N Engl J Med 2001;345:870–8.

  33. IRMA 2Adverse outcomes No. of adverse outcomes (%) Irbesartan (150 mg) Irbesartan (300 mg) Control Cardiovascular events Serious adverse events Discontinuations due to adverse events 18 47 19 (8.7) (22.8) (9.2) 14 32 18 (6.9) (15.8) (8.9) 9 30 11 (4.5) (15.0) (5.5) Parving H-H et al. N Engl J Med 2001;345:870–78.

  34. Proteinuria levels predict stroke and CHD events in type 2 diabetes Survival curves(CV mortality) Incidence (%) 40 1.0 p < 0.001 < 150 0.9 30 0.8 150-300 20 0.7 0.6 10 > 300 Overall: p < 0.001 0.5 0 0 Stroke CHD events 0 10 20 30 40 50 60 70 80 90 Time (months) U-Prot < 150 mg/L U-Prot 150-300 mg/L U-Prot > 300 mg/L U-Prot = Urinary protein concentration Miettinen H et al. Stroke 1996;27:2033–9.

  35. Course of diabetic renal disease Micro- albuminuria Pre-clinical Diabetic Renal Disease Overt Proteinuria 160 4 140 120 3 100 Protein excretion (g/day) GFR (ml/min) 80 2 60 Proteinuria 40 1 Persistent Microalbuminuria 20 0 0 20 Time (yrs 10) Adapted from Mogensen CE. Kidney Int 1982;21:673. and Friedman EA. Kidney Int 1982;21:780.

  36. Screening for microalbuminuria: ADA guidelines Test for microalbuminuria + for albumin Yes Condition that may invalidate urine albumin excretion? Yes No Treat and/or wait until resolved. Repeat test. + for protein? Yes Repeat microalbuminuria test twice within 3–6 month period No Rescreen in one year 2 of 3 test positive? Yes Microalbuminuria, begin treatment Diabetes Care 2003;26 (Supp 1):594–598.

  37. IDNTStudy design 1,715 patients with type 2 diabetes, proteinuria  900 mg/d, and hypertension Screening/Enrollment Double-blind treatment Irbesartan* Placebo* Amlodipine* Minimum follow-up: approximately 2 years (average 3 years) Up to 5 weeks * Adjunctive antihypertensive therapies (excluding ACE inhibitors, angiotensin II receptor antagonists, and calcium channel blockers) added to each arm to achieve equal blood pressure reduction Collaborative Study Group. Rodby RA et al. Nephrol Dial Transplant 2000;15:487–97.

  38. IDNTSystolic, mean, and diastolic BP response 160 SBP 140 Irbesartan Amlodipine Control 120 BP (mmHg) Mean 100 DBP 80 0 6 12 18 24 30 36 42 48 54 Follow-up visit (months) Lewis EJ et al. N Engl J Med 2001;345(12):851–60.

  39. IDNT primary endpointTime to doubling of serum creatinine, ESRD, or death 70 Irbesartan Amlodipine Control RRR = 23% p = 0.006 60 RRR = 20% p = 0.02 50 p = NS 40 Subjects (%) 30 20 10 RRR: Relative Risk Reduction 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up (months) Lewis EJ et al. N Engl J Med 2001;345(12):851–60.

  40. IDNTTime to doubling of serum creatinine 70 Irbesartan Amlodipine Control RRR = 37% p < 0.001 60 RRR = 33% p = 0.003 50 p = NS 40 Subjects (%) 30 20 10 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up (months) Lewis EJ et al. N Engl J Med 2001;345(12):851–60.

  41. IDNTTime to ESRD 40 Irbesartan Control + amlodipine RRR = 23% p = 0.004 30 Subjects (%) 20 10 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up (months) Lewis EJ et al. N Engl J Med 2001;345(12):851–60. Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.

  42. The role of irbesartan in the treatment of diabetic kidney disease Time to renal endpoint by treatment assignment (Doubling of serum creatinine or ESRD) Irbesartan Amlodipine Placebo RRR = 34% p = 0.0002 0.6 RRR = 26% p = 0.011 RRR = -12% p = 0.32 0.5 Patients reaching Scr doubling or ESRD (fraction) 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Follow-up time (months) Lewis EJ et al. N Engl J Med 2001;345(12):851–60. Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.

  43. Time to the development of ESRD after doubling serum creatinine 1.0 Type 1 diabetic nephropathy 0.9 0.8 0.7 0.6 Proportion with event 0.5 0.4 0.3 0.2 0.1 0 0.0 0.5 1.0 1.5 Time after creatinine doubling (years) n at risk: 68 37 17 5 Lewis EJ et al. N Engl J Med 1993;329(20):1456–62.

  44. IDNTAdverse outcomes No. of adverse outcomes (%) Irbesartan Amlodipine Control Early serum creatinine rise D/C due to hyperkalemia Stopped study medicine SAEs/1000 days on drug 0 11 134 2.0 (1.9) (23) 0 3 133 2.5 (0.5) (23) 1 2 140 2.3 (0.4) (25) Lewis EJ et al. N Engl J Med 2001;345:851–60.

  45. Cardiovascular and renal disease continuum ESRD End-Stage CHF Chronic renal insufficiency ( GFR) Arteriosclerotic cardiovascular disease events Progression Albuminuria Proteinuria Coronary artery disease Left ventricular hypertrophy Initiation Elderly,DM,  BP Elderly,DM,  BP “At Risk” Chronic Renaldisease Cardiovasculardisease Adapted from Sarnak and Levey, Am J Kidney Dis 2000;35:S117–31.

  46. Markers of cardiovascular risk

  47. Irbesartan decreases inflammatory marker levels in CAD patients 0 -10 -20 Level decrease (%) -30 -36% -40 -52% -50 -54% -60 VCAM-1 Serum TNF-RII Superoxide 33 normotensive patients with stable CAD treated with irbesartan (75 to 150 mg/day) for 24 weeks Navalkar S et al. J Am Coll Cardiol 2001;37(2):440–4.

  48. Irbesartan improves endothelial functionin vasculature of CAD patients 100 * p < 0.05 vs. placebo Placebo Irbesartan 80 Monocyte binding to receptor CD11 (%) 60 40 * * 20 0 4 12 0 Time (weeks) 47 patients with documented coronary artery disease, previous CABG or PTCA Randomized, placebo-controlled Irbesartan (150 mg/d) or placebo for 12-week Khan BV et al. J Am Coll Cardiol 2001;38(6):1662–7.

  49. Irbesartan reduces oxidative stress in CAD patients 10 * p < 0.05 vs. placebo 8 Thiobarbituric acid reactive substances (µmol/L) * * 6 4 2 0 4 12 0 Time (weeks) Irbesartan Placebo Khan BV et al. J Am Coll Cardiol 2001;38(6):1662–7.

  50. Cardiovascular structure

More Related