1. Peut-on aller encore plus loin avec les antagonistes de l’Angiotensine II ? Antoine Sarkis, MD Associate Professor of Cardiology Hotel Dieu de France Hospital

2. RAAS Blockade Angiotensin Converting Enzyme Inhibitors ACE-I Angiotensin Receptor Blockers ARBs

3. Ang II: Influence on structure, function, and atherosclerosis Weir MR, Dzau VJ. Am J Hypertens. 1999;12:205S-213S. Angiotensin II  Growth  Smooth muscle cell growth and migration  Platelet aggregation  Endothelial dysfunction  Thrombosis

4. Ang II effect in target organ damage McFarlane SI et al. Am J Cardiol. 2003;91(suppl):30H-7. Angiotensinogen Angiotensin I Angiotensin II Renin ACE Aldosterone (Adrenal/CV tissues) StrokeHF Kidney failure  BP VSMC Fat cells Reduced baroreceptor sensitivity

5. Angiotensinogen Ang I ACE Bradykinin AT n Renin Inactive peptides Ang II Vasodilator Anti-thrombotic Anti-atherogenic Vasoconstriction Hypertrophy Angiogenesis Apoptosis Endothelium SMC AT 2 AT 1 NO B2B2

6. Angiotensinogen Ang I ACE Bradykinin AT n ACEI Renin Inactive peptides Ang II Vasodilator Anti-thrombotic Anti-atherogenic Vasoconstriction Hypertrophy Angiogenesis Apoptosis Endothelium SMC AT 2 AT 1 NO B2B2

7. Angiotensinogen Ang I ACE Bradykinin AT n ARBs Renin Inactive peptides Ang II Vasodilator Anti-thrombotic Anti-atherogenic Vasoconstriction Hypertrophy Angiogenesis Apoptosis Endothelium SMC AT 2 AT 1 NO B2B2

8. Angiotensin II ReninRenin Converting enzyme AngiotensinreceptorsAngiotensinreceptors Angiotensinogen Angiotensin I Circulating (Liver) Local (Tissue) Non-renin pathways t-PA Cathepsin G Tonin Non-renin pathways t-PA Cathepsin G Tonin Non-ACE pathways Chymase CAGE Cathepsin G Non-ACE pathways Chymase CAGE Cathepsin G Escape phenomena

9. ANGIOTENSIN II VasoconstrictionProliferative Action Vasodilatation Antiproliferative Action AT1 AT2 …. AT1 Receptor Blockers RECEPTORS Angiotensin II Receptor Blockers (ARBs) ATn

10. ARBs more effective than ACE-I due to: - Better RAAS Blockade - Absence of angiotensin II escape - Placebo like side effects Potential advantages of ARBs

11. Effects of A II at AT 1 and AT 2 Receptors Sensitive to blockade by ARBs AT 2 AT 1 Vasoconstriction Aldosterone release Oxidative stress Vasopressin release SNS activation Inhibits renin release Renal Na + & H 2 O reabsorption Cell growth & proliferation Vasodilation Antiproliferation Apoptosis Antidiuresis/antinatriuresis Bradykinin production NO release Siragy H. Am J Cardiol. 1999;84:3S-8S. ?

12. Postulated role of AT 2 R and MMP-1 in plaque destabilization Strauss MH, Hall AS. Circulation. 2006;114:838-54. Destabilization  Rupture  ACS Extracellular matrix Leukocyte activation Vascular smooth muscle cells Ang II ARB AT 1 AT 2  MMP-1 Intracellular inflammation Endothelium

14. ACEIs vs ARBs: Comparative effect on stroke, HF, and CHD Turnbull F. 15th European Meeting on Hypertension. 2005. Adapted by Strauss MH, Hall AS. Circulation. 2006;114:838-54. CHD = MI and CV death Blood Pressure Lowering Treatment Trialists’ Collaboration meta-analysis N = 137,356; 21 randomized clinical trials ACEI ARB Stroke-1% (9% to -10%) HF10% (10% to 0%) CHD9% (14% to 3%) Stroke2% (33% to -3%) HF16% (36% to -5%) CHD-7% (7% to -24%) 30% 0 DecreaseIncrease Stroke P = 0.6 HF P = 0.4 CHD P = 0.001 Risk RRR (95%)

16. Similar  Greater  with amlodipine (2.0/1.6 mm Hg) Losartan vs atenolol Valsartan vs amlodipine Essential HTN N = 9193 (4.8 years) Essential HTN, high CV risk N = 15,245 (4.3 years) LIFE (2002) VALUE (2004) BP BPTreatmentPatients(Follow-up) Trial (year) HTN = hypertension 13%  in primary outcome (CV death, MI, stroke) with ARB (P = 0.021) driven by 25%  in stroke (P = 0.001) No difference in CV death/MI Primary outcome similar at study end Trend favors amlodipine at 3 and 6 months Difficult to interpret due to BP difference Dahlöf B et al. Lancet. 2002;359:995-1003. Julius S et al. Lancet. 2004;363:2022-31. CV outcomes Clinical trials of ARBs in HTN: CV outcomes

17. Algorithm for Treatment of Hypertension (JNC 7) JAMA, May 2003 Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices Drug(s) for the compelling indications With Compelling Indications Lifestyle Modifications Stage 2 Hypertension 2-drug combination for most Stage 1 Hypertension Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination Without Compelling Indications

18. 2003 ESH/ESC Hypertension Guidelines Consider: Untreated BP level Presence or absence of TOD and risk factors Choose between Single agent at low dose Two-drug combination at low-dose Previous agent at full dose Switch to different agent at low dose Previous combination at full dose Add a third drug at low dose Two-to three drug combination Full dose monotherapy Three drug combination at effective doses If goal BP not achieved

19. Choosing drugs for patients newly diagnosed with hypertension BHS Guidelines (June 2006) Younger than 55 years 55 years or older Or black patients of any age AC or D A+C or A+D A+C+D Add further diuretic therapy Or alpha blocker Or Beta Blocker Consider seeking specialist advice Abbreviations: A: ACE-I (or ARB if ACE intolerant) C: CCB D: thiazide type diuretic Step 1 Step 2 Step 3 Step 4

20. Hypertension and Diabetes Recommendations of the American Diabetic Association Treat to BP <130/80 mmHg All patients with diabetes and hypertension should be treated with a regimen that includes either an ACEi or an ARB. If needed to achieve blood pressure targets, a thiazide diuretic should be added. American Diabetes Association. Diabetes Care. 2005; 28 (Suppl 1): S10 – S17.

21. Conditions favoring the use of ARBs Type 2 diabetic nephropathy Type 2 diabetic nephropathy Diabetic microalbuminuria Diabetic microalbuminuria Proteinuria Proteinuria Left ventricular hypertrpphy Left ventricular hypertrpphy ACE-I induced cough ACE-I induced cough

22. Specific considerations about Candesartan Pharmacological properties Pharmacological properties Delaying new onset of hypertension in pre- hypertensive patients Delaying new onset of hypertension in pre- hypertensive patients Preventing diabetes Preventing diabetes End Organ protective effects (CHF) End Organ protective effects (CHF)

23. Pharmacological properties 1. Candesartan binds unsurmountably to AT1 receptor 2. Longest lasting AT1-receptor binding ► T/ P Ratio almost 100% In the latest JNC 7: Candesartan 8-32 mg Once daily Losartan 25-100 mg Once to Twice daily Valsartan 80-320 mg Once to Twice daily JNC 7, Hypertension, 2003

24. Use in pre-hypertensive patients? TROPHY hypothesis The TRial Of Preventing HYpertension (TROPHY) is an investigator-initiated trial. Aim: To examine whether early treatment of high-normal blood pressure values (according to JNC VI) with 16 mg Candesartan would prevent or postpone the development of stage 1 hypertension. Julius et al, Hypertension 2004

25. TROPHY – study design Two Years Qualifying period * Placebo Non-pharmacological treatment Candesartan cilexetil 16 mg n  400 Placebo * Clinic BP reading of 130-139/  89 mm Hg or  139/85-89 mm Hg Julius et al, Hypertension 2004

26. TROPHY: Reduction in new-onset hypertension  66%*  16%* Candesartan vs PlaceboPlacebo only *Relative risk reduction † P < 0.001; ‡ P = 0.007 Julius S et al. N Engl J Med. 2006;354:1685-97. † ‡ N = 772

27. Adipocyte and vasculature interactions Courtesy of W. Hseuh; 2005. IL-6 PAI-1 TNF-  Adiponectin Leptin Insulin sensitivityInsulin resistance Vascular inflammationEndothelial dysfunction Angiotensinogen FFA Visfatin

28. Furuhashi M et al. Hypertension. 2003;42:76-81. Insulin sensitivity, BMI, and HDL-C independent determinants of adiponectin concentrations ACEI and ARB increased insulin sensitivity and adiponectin (P < 0.05) Changes in insulin sensitivity correlated with changes in adiponectin (r = 0.59, P < 0.05) *P < 0.05 N = 16 with essential hypertension and insulin resistance RAAS blockade increases adiponectin 6 4 10 Adiponectin (µg/mL) 0 8 2 BeforeAfter BeforeAfter 6 4 10 0 8 2 Temocapril 4 mg (n = 9) Candesartan 8 mg (n = 7) * *

29. Candesartan in preventing Diabetes development…

30. ALPINE Study Design Time-40 12m 12m4w8w12w6m No other antihypertensive drugs allowed Goal BP: <135/<85; 65+ <140/<90 mm Hg HCTZ 25 mg HCTZ 25 mg + Atenolol 50 mg HCTZ 25 mg + Atenolol 100 mg Candesartan 16 mg Candesartan 16 mg + Felodipine 2.5 mg Candesartan 16 mg + Felodipine 5 mg R Placebo Lindholm et al 2003

31. ALPINE study…New onset of diabetes 0 1 2 3 4 5 6 7 8 9 p < 0.05 No of patients HCTZ ِCandesartan Lindholm LH J Hypertens 2003

32. Development of new diabetes – CHARM study 0 10 20 30 40 50 60 70 80 No. of cases developing new Diabetes Control candesartan 40% p=0.005 Lancet, 2003

33. Possible mechanisms involved in the prevention of diabetes GLUCOSE ABSORPTION MUSCLE PANCREAS ADIPOSE TISSUE LIVER INTESTINE HYPERGLYCEMIA DECREASED PERIPHERAL GLUCOSE UPTAKE INCREASED GLUCOSE PRODUCTION DECREASED INSULIN SECRETION “Candesartan improved insulin sensitivity and hence reduce the development of DM in hypertensive patients”

34. Circulation, July 2005

35. End Organ Protective effects of Candesartan Congestive Heart failure

36. Renin-Angiotensin-Aldosterone System in CHF RAAS is activated early in the course of heart failure and plays an important role in the progression of the syndrome RAAS is activated early in the course of heart failure and plays an important role in the progression of the syndrome

37. ACE-I Indications Symptomatic heart failure (stage C) Symptomatic heart failure (stage C) Asymptomatic ventricular dysfunction with LVEF <35-40 % (stage B) Asymptomatic ventricular dysfunction with LVEF <35-40 % (stage B) Patients with recent or remote history of MI regardless of EF or presence of HF Patients with recent or remote history of MI regardless of EF or presence of HF Class I recommendation (therapy is recommended) Level of evidence A AHA / ACC HF guidelines 2005 ESC HF guidelines 2005

38. However: 4-year mortality remains ~40% 1.Davies MK et al. BMJ. 2000;320:428-431 (meta-analysis: 32 trials, N = 7105). 2.Gibbs CR et al. BMJ. 2000;320:495-498 (meta-analysis: 18 trials, N = 3023). HF: Mortality Remains High ACEI ACEI Risk reduction 35% (mortality and hospitalizations) 1 Risk reduction 35% (mortality and hospitalizations) 1 ß-blockers ß-blockers Risk reduction 38% (mortality and hospitalizations) 2 Risk reduction 38% (mortality and hospitalizations) 2 Spironolactone Spironolactone Mortality reduction 23% Mortality reduction 23%

39. Substitute or adjunctive therapy to ACE inhibitors ? Angiotensin Receptor Blockers (ARBs) in Heart Failure

40. Pitt B, et al. Lancet. 2000;355:1582-1587. All-cause mortality Probability of Survival 1.0 0.8 0.6 0.4 0.2 0.0 All-cause mortality or hospital admission Event-free Probability Sudden death or resuscitated arrest Event-free Probability 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 0100200400300500600700 Follow-up (days) P =.16 P =.08 P =.18 Losartan Captopril Comparative trial: ELITE II

41. 1.0 0.9 0.8 0.6 13% risk reduction p= 0.009 0 Event-free probability Placebo Valsartan 369122118152427 Time since randomisation (months) 0.7 1.0 0.9 0.8 0.7 Time since randomisation (months) p = 0.80 Survival probability (%) 0 369122118152427 All-cause mortality and morbidity All-cause mortality Cohn et al. NEJM 2001;345:1667 Add-on trial: Val-HeFT. Valsartan 160 mg Bid vs placebo on top of standard therapy

42. CHARM Added CHARM Preserved CHARM Program Candesartan vs placebo in patients with symptomatic heart failure CHARM Alternative n=2028 LVEF  40% ACE inhibitor intolerant n=2548 LVEF  40% ACE inhibitor treated n=3025 LVEF >40% ACE inhibitor treated/not treated Primary outcome for Overall Programme: All-cause death Primary outcome for each trial: CV death or CHF hospitalisation

43. Granger CB et al. Lancet. 2003;362:772-777 012 3 Years 50 HR 0.77 p=0.0004 0 40 30 20 10 Candesartan Placebo CV Death of Hospitalization for HF 2,028 patients with symptomatic HF, LVSD (EF <40%), and intolerance to ACE-I randomized to candesartan (32 mg) or placebo over 34 months CHARM Alternative trial

44. 0123 0 10 20 30 40 50 3.5 HR 0.85, p=0.011 Candesartan Placebo CV Death of Hospitalization for HF Years McMurray JJ et al. Lancet. 2003;362:767-71 2,548 patients with symptomatic HF and LVSD (EF <40%) randomized to candesartan (32 mg) or placebo in addition to an ACE-I over 34 months CHARM Added Trial

45. CHARM Program Mortality and morbidity 0.70.80.91.01.11.20.60.70.80.91.01.11.2 All Cause Mortality CV Death or CHF Hospitalisation Hazard ratio p heterogeneity=0.43 Alternative Added Preserved Overall p heterogeneity=0.37 p=0.0004 p=0.055 p=0.011 p=0.118 p<0.0001 0.77 0.85 0.89 0.84 0.91

46. CHARM LVEF  40% (CHARM-Alternative and CHARM-Added ) All-cause death 0.88 0.79-0.98 0.018 CV death 0.84 0.75-0.95 0.005 HRCI p-value Pfeffer et al, Lancet 2003 12% Reduction 16%

47. FDA approved candesartan cilexetil on top of ACE inhibitor for HF NYHA class II-IV heart failure NYHA class II-IV heart failure Dose: initial dose of 4 mg once daily to a target dose of 32 mg once daily, achieved by doubling the dose at approximately two-week intervals, as tolerated Dose: initial dose of 4 mg once daily to a target dose of 32 mg once daily, achieved by doubling the dose at approximately two-week intervals, as tolerated May 19, 2005

48. ARB Indications in CHF Patients intolerant to ACE-Inhibitors: (Class I recommendation in stage C, class IIa in stage B, class I in stage B post MI) Use of ARB instead of ACE-I in stage C heart failure: Class IIa recommendation (reasonable, should be considered) On top of ACE I and B Blockers in patients who remain symptomatic: optional, because of discrepancy in guidelines: Class I (ESC, CCS), IIa (HFSA), and IIb (ACC/AHA)

49. CHARM-Overall Non-fatal MI 3803352132062163744 3796341331012088722 0 1 3 4 5 6 7 2 01233.5yrs Hazard ratio 0.77 (95% CI 0.60 – 0.98), p=0.032 placebo candesartan Number at risk Candesartan Placebo Cumulative events % 23 % reduction of Non Fatal MI Demers C et al. JAMA 2005; 294: 1794-1798.

50. Clinical trials continue with ARBs…

51. ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61. ONTARGET: Study design Ramipril 10 mgTelmisartan 80 mg N = 25,620 ≥55 years with coronary, cerebrovascular, or peripheral vascular disease, or diabetes + end-organ damage Results anticipated in 2007 Ramipril 10 mg + telmisartan 80 mg Primary end point: CV death, MI, stroke, hosp for HF Secondary end point: Newly diagnosed diabetes ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial

52. Diabetic retinopathy is the most common cause of blindness in people aged 30-69 in developed countries Diabetic retinopathy is the most common cause of blindness in people aged 30-69 in developed countries Laser photocoagulation reduces the risk of blindness, but is performed only when advanced vascular damage is present Laser photocoagulation reduces the risk of blindness, but is performed only when advanced vascular damage is present Only current established treatment involves careful glycaemic control Only current established treatment involves careful glycaemic control strict glycaemic control reduces both onset and progression of retinopathy strict glycaemic control reduces both onset and progression of retinopathy Diabetic retinopathy

53. Beneficial effect of ACE-inhibition 3 small studies, non-significant results, positive tendency (Larsen et al 1990, Chase et al 1993, Ravid et al 1993). EUCLID, n = 354, Lisinopril 10-20 mg or placebo, 2 year follow-up Progression reduced by 50% (p=0.02) Incidence reduced by 31%(n.s.) (Chaturvedi et al 1998)

54. Study question Does blockade of the RAS system with Candesartan cilexetil prevent incidence and progression of retinopathy in type 1 and type 2 diabetes?

55. DIRECT programme The Diabetic REtinopathy Candesartan Trials  3 separate studies - each sufficiently powered to establish treatment effects on retinopathy in the respective study population  Pooling of the three populations to detect effects on microalbuminuria  Results expected in 2007 JRAAS 2002;3:255-261

56. DIRECT Design I. Type 1 diabetic patients without diabetic retinopathy Endpoint: Development of retinopathy II. Type 1 diabetic patients with diabetic retinopathy Endpoint: Progression of retinopathy III.Type 2 diabetic patients with diabetic retinopathy Endpoint: Progression of retinopathy Pooled populations of all three studies Endpoint: Incidence of microalbuminuria

57. In conclusion The controversial dilemma between ACE-I and ARBs is not settled ARBs have suffered from their introduction late after ACE-I were well established However a placebo-like tolerability has extended their indications in daily practice irrespective of guidelines Candesartan is a potent ARB with solid data in end organ protection Need for earlier intervention in the natural history of HTN? (targeting subclinical organ damage)