RAAS SUPPRESSION Cardio Renal Protection

3. RAAS SUPPRESSION Cardio Renal Protection By Professor Dr Intekhab Alam Department of Medicine Lady Reading Hospital, Peshawar

4. Hypertension • There is a 90% lifetime risk of becoming hypertensive for a person living in a developed country. • BP limits are different in children and pregnancy. • BP goal is different if you have diabetes or CKD. • Primary (“essential”) HTN comprises 95% of cases. • Secondary 5% of cases. • Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg throughout the BP range. • For persons over age 50, SBP is a more important than DBP as CVD risk factor. Question:when did you last check your blood pressure?

5. JNC-7 Classification BP Classification SBP (mmHg) DBP (mmHg) Normal Prehypertension Stage I hypertension Stage II hypertension < 120 120-139 140-159 > 160 and or or or < 80 80-89 90-99 > 100 http://hin.nhlbi.nih.gov/nhbpep_slds/menu.htm

6. The majority of patients are not treated to BP goal *Top-5 EU countries: France, Italy, Spain, Germany and UK †Top-7 countries: US, Japan and Top-5 EU countries; weighted average by population ‡Goal defined as BP<140/90 mmHg • US: NHANES 1999-2002 (NVS Analysis, Dr. Suh, Rutgers University, 2006/03); • France: Thales 2005, Decision Resources DB9; Italy: Thales 2005; Spain: TNS Cardiomonitor 2005, • Germany: Datamonitor, IMS disease analyser; UK: Thales (2006); • Japan: Statistical analysis,CVD basic research, Datamonitor, patient diary

7. Even in clinical trial conditions, many patients do not reach goal with current therapies HOPE SBP DBP PROGRESS mmHg mmHg CAPPP 200 120 INSIGHT NORDIL 190 110 HOT 180 STONE 100 STOP-2 170 ALLHAT 1 160 90 LIFE ALLHAT 2 150 80 ANBP2 140 INVEST SCOPE 130 70 T B T B ASCOT VALUE B = baseline; T = trial Mancia G, Grassi G. J Hypertens 2002

8. Benefits of Lowering BP • Sustaining a 12 mmHg reduction in SBP over 10 years will prevent one death for every 11 patients treated with Stage I HTN with additional CVD risk factors • Why to treat HTN? “The relationship between BP and CVD is positive and continuous.” • 35-40%  in stroke morbidity and mortality • 20-25%  CAD events • 21%  vascular mortality • 52%  in CHF • 35%  in LVH

9. Patients with hypertension have additional co-morbidities, making treatment difficult Men Women 0 0 Obesity Glucose intolerance Hyperinsulinaemia Reduced HDL-C Elevated LDL-C Elevatedtriglycerides 1 1 19% 17% 26% 27% 12% 4+ 4+ 8% 22% 20% 25% 24% 3 3 2 2 >50% have two or more comorbidities Kannel WB, 2000

10. Goals of Therapy • Adopt a holistic approach and abandon ahypertension/ Normotension dichotomy and focus on global risk reduction. • Reduce CVD and renal morbidity and mortality. • Treat to BP <140/90 mmHg or BP <130/80 mmHg in patients with diabetes or chronic kidney disease. • Achieve SBP goal especially in persons >50 years of age. • Maintain QOL and Minimize side effects.

11. Lifestyle Modification • Works best in motivated individuals • Initiate at prehypertension classification • Obesity  risk for HTN and DM • Sodium “restriction” and other diet aids: • Usual salt intake 10 gm/d = 4 gm Na+ • Reduce to 2.4 gm Na+/day • Caution – salt substitutes contain K+ • Discourage excessive consumption of coffee and other caffeine-rich products. • Stop smoking and Alcohol consumption. • Exercise/Activity: • 30-40 minutes 3-4x/wk, optimal 5x/wk • Stress reduction / Meditation.

12. Lifestyle Modification

13. Hot topics – should these be incorporated into the guidelines? • Lower BP targets • First-line combination therapy • β-blockers no longer a first choice treatment for hypertension • The need to consider total CV risk • Acceptance of more measures of organ damage (e.g. intermediate clinical endpoints) • Dual Renin System suppression • New classes of antihypertensives

14. RAAS and CV diseases • While cardiovascular (CV) diseases have long been the leading cause of death in many developed nations, the WHO estimates that it will become the leading cause in the developing world by the year 2010 • The spectrum of CV diseases has been described as a‘CV continuum’ • Renin-angiotensin-aldosterone system (RAAS) activationis pathologically involved throughout the CV continuum • ACEIs and ARBs, originally developed for hypertension, are drugs for which clinical trial evidence has now accumulated throughout the CV continuum ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker

15. RAAS and its inhibitors: Their role along the CV continuum SAVE, AIRE, TRACE OPTIMAAL, VALIANT CONSENSUS SOLVD, Val-HeFT ELITE II Val-HeFT CHARM HOPE, EUROPA, PEACE, LIFE ONTARGET, TRANSCEND Ventricular dilation Remodeling DIRECT Congestive heart failure (HF) Myocardial infarction (MI) End-stage micro-vascular and heart disease Atherosclerosis and LVH DREAM NAVIGATOR RENAAL IDNT IRMA-2 MARVAL Risk factors Diabetes Hypertension VALUE LIFE SCOPE Death LVH = left ventricular hypertrophy Adapted from Dzau, Braunwald. Am Heart J 1991;121:1244–63

16. Where are we now – the best of RAAS suppression? Primary prevention: • In the prevention of CV events in high risk patients Secondary prevention: • In patients with post-MI left ventricular dysfunction/HF Tertiary prevention: • In patients with chronic HF

17. The residual risk • With the best available treatments to suppress the RAAS • 20% of patients at high risk of CV events (HOPE/ONTARGET patients), CV death, non-fatal MI ornon-fatal stroke still occur within a 5-year follow-up period • 22% of patients with post-MI left ventricular dysfunction/failure (VALIANT patients) still die withina 3-year follow-up period • 25% of patients with chronic HF (CHARM/Val-HeFT patients) still die or are admitted for HF within a 3-year follow-up period

18. Dual Blockade of the RAAS What do enthusiasts say?  “Variances in study design and populations, dosing and titration methods, and clinical end points, in addition to inherent differences between agents, limit the ability to reach clinically meaningful conclusions about the value of dual RAS inhibition” Cohn JN, Goldman JN Am J Hypertens 2008; 21: 248 - 256 • More trials needed

19. Can we further improve patient outcomes with more complete block of the RAAS? • Residual risk may be due to the incomplete suppression of the RAAS provided by these agents • ACEIs and ARBs both increase plasma renin activity (PRA), which may limit their organ-protective effects • Aliskiren is the first Direct Renin Inhibitor (DRI), a new class of antihypertensive agents • Aliskiren suppresses the RAAS at its point of activation and therefore may provide more complete control of the RAAS than either ACEIs or ARBs

20. Development of direct Renin inhibitors has been challenging • Numerous renin inhibitors have been synthesized and studied previously, including H142, ditekiren, enalkiren, zankiren and remikiren • However, these agents were not clinically effective due to: • lack of oral availability • low efficacy • short half-life • high cost of synthesis Luther R, et al. 1991; Stanton A. 2003; Wood JM, et al. 2003; Jensen C, et al. 2008

21. Classic understanding of the Renin System Angiotensinogen Renin Ang I ACE Aldosterone Ang II AT1 Receptor Vasoconstriction Hypertension Na+/H2O retention Gibbons GH. 1998; Adapted from: Müller DN & Luft FC. 2006

22. ACEIs and ARBs cause compensatory rises in PRA Kidney • Glomerularvasoconstriction • Inflammation • Fibrosis Angiotensinogen Renin Heart Ang I • Hypertrophy • Fibrosis • Vasoconstriction PRA Non ACE pathways ACE ACEIs Feedback Loop Vessels • Hyperplasia hypertrophy • Inflammation • Oxidation • Fibrosis Ang II ARBs AT1 Receptor Brain • Vasoconstriction Biological effects Adapted from: Müller DN & Luft FC. 2006

23. Aliskiren binds to the active site of renin Renin Aliskiren Aliskiren binds to a pocket in the renin molecule, blocking cleavage of angiotensinogen to angiotensin I Angiotensinogen Adapted from Wood JM, et al. 2003

24. Direct renin inhibition acts at the point of activation of the Renin System and neutralizes the PRA rise Direct renin inhibitor Kidney • Glomerularvasoconstriction • Inflammation • Fibrosis Angiotensinogen Renin Heart Ang I • Hypertrophy • Fibrosis • Vasoconstriction Non ACE pathways PRA ACE Feedback Loop Vessels • Hyperplasia hypertrophy • Inflammation • Oxidation • Fibrosis Ang II AT1 Receptor Brain • Vasoconstriction Biological effects Adapted from: Müller DN & Luft FC. 2006

25. Non ACE pathways ACE Unlike ACEIs and ARBs, aliskiren reducesAng I, Ang II and PRA Direct renin inhibitor Angiotensinogen Renin Ang I ACEIs Feedback Loop Ang II ARBs AT1 Receptor Ang I Ang II Renin PRA ↑ ↓ ↑ ↑ ACEI ↑ ↑ ↑ ↑ ARB ↓ ↓ ↑ ↓ Aliskiren Azizi M et al. 2006; Adapted from: Müller DN & Luft FC. 2006

26. (Pro)renin receptor may play an important role in cardio vascular disease by local Renin System activation (Pro)renin receptor actions: Binding of (pro)renin Increased renin catalytic activity Activates VSMC ERK1/2 Increase PAI-1 Direct renin inhibitor Angiotensinogen Renin Ang I Non ACE pathways ACE Feedback Loop Ang II Direct renin inhibitor AT1 Receptor Heart Kidney Aliskiren binds to renin Target cells VSMC Vessels • Vasoconstriction • Remodelling (Pro)reninreceptor Nguyen G, et al. 2001

27. 1000 100 10 1 0.1 40 0 20 100 80 60 Aliskiren has a half-life of approximately 40 hours, making it suitable for once-daily dosing Concentration (ng/mL) Mean (plus SD) plasma aliskiren concentration profiles (n=30) after single oral administration of aliskiren to healthy subjects, semi-logarithmic scale 600 mg 300 mg 150 mg 75 mg Time (hours) Vaidyanathan S, et al. 2006 (Study 2205)

28. Aliskiren monotherapyprovides dose-dependent reductions in DBP and SBP Irbesartan(mg) Irbesartan(mg) Aliskiren (mg) Aliskiren (mg) 150 600 Placebo 300 150 Placebo 150 300 600 150 0 n=129 n=130 n=127 n=130 n=133 n=130 n=127 n=130 n=129 n=133 −5 −5.3 −6.3 −10 −8.9 −9.3 ** * −11.4 −11.8 −11.5 −12.5 *** *** *** −15 *** −15.8 −15.7 p=0.01 *** *** p=0.005 −20 DBP SBP Mean change from baseline in mean sitting BP at Week 8 (mmHg) *p<0.02 vs placebo; **p<0.005; ***p<0.0005vs placebo Gradman AH, et al. 2005 (Study 2201)

29. Aliskiren monotherapyprovides dose-dependent reductions in DBP and SBP Aliskiren (mg) Aliskiren (mg) Placebo 150 300 600 Placebo 150 300 600 0 n=163 n=167 n=166 n=166 n=163 n=167 n=166 n=166 −3.8 −5 −4.9 −10 −10.3 −11.1 *** −12.5 *** −13.0 −15 *** *** −14.7 −15.8 *** *** DBP SBP −20 Mean change from baseline in mean sitting BP at Week 8 (mmHg) ***p<0.0001 vs placebo Oh BH, et al. 2007 (Study 2308)

30. Aliskiren Placebo 150 mg 300 mg Pooled analyses in >3,500 patients demonstrate that aliskiren provides dose-dependent reductions in BP Aliskiren Placebo 150 mg 300 mg 0 n=776 n=776 n=1180 n=1603 n=1180 n=1603 −5 3.9 5.6 6.6 9.3 −5.9 −6.2 −10 −10.1 −11.8 *** −15 −12.5 *** *** −15.2 *** −20 DBP SBP −25 Mean change from baseline in mean sitting BP after 8–12 weeks (mmHg) ***p<0.0001 vs placebo Values under bars represent least square mean reductions ± standard error of the mean; values in arrows represent placebo-subtracted reductions Dahlöf B, et al. 2007 (Pooled analysis)

31. Aliskiren provides effective DBP-lowering in patients with obesity: pooled analysis Aliskiren (mg) Aliskiren (mg) Placebo 150 300 Placebo 150 300 0 n=275 n=434 n=630 n=776 n=1180 n=1603 5 –6.1 –6.2 10 –10.0 –10.1 *** –11.1 *** –11.8 *** *** Patients with obesity All patients 15 Mean change from baseline in mean sitting DBP after 8–12 weeks (mmHg) ***p<0.001 vs placebo Prescott MF, et al. 2007 (Pooled analysis)

32. Aliskiren provides effective SBP-lowering in patients with diabetes: pooled analysis Aliskiren (mg) Aliskiren (mg) Placebo 150 300 Placebo 150 300 0 n=776 n=1180 n=1603 n=55 n=98 n=393 −5 −5.9 −6.9 −10 −12.5 −13.2 −15 *** −14.8 ** −15.2 *** *** −20 Patients with diabetes All patients −25 Mean change from baseline in mean sitting SBP after 8–12 weeks (mmHg) **p<0.01; ***p<0.001 vs placebo Taylor AA, et al. 2007 (Pooled analysis)

33. Aliskiren provides effective DBP-loweringin patients with metabolic syndrome: pooled analysis UPDATED (ref only) Aliskiren (mg) Aliskiren (mg) Placebo 150 300 Placebo 150 300 0 n=189 n=365 n=387 n=299 n=531 n=640 5 –5.8 –6.7 10 –10.4 –10.4 –11.3 –11.9 † † † † 15 Patients with metabolic syndrome Patients without metabolic syndrome Mean change from baseline in mean sitting DBP after 8–12 weeks (mmHg) †p<0.0001 vs placebo White WB, et al. 2007 (Pooled analysis)

34. Aliskiren provides effective BP-lowering in patients with impaired renal function: pooled analysis DBP SBP eGFR <60 eGFR ≥60 eGFR <60 eGFR ≥60 0 n=26 n=25 n=740 n=736 n=26 n=25 n=740 n=736 5 –9.4 10 –10.1 –10.4 –11.2 –11.4 –11.5 15 –14.7 Mean change from baseline in mean sitting BP after 8 weeks (mmHg) –14.9 Aliskiren 150 mg Aliskiren 300 mg eGFR: estimated glomerular filtration rate (assessed in mL/min/1.73 m2) Weir MR, et al. 2007 (Pooled analysis)

35. Summary- Efficacy in monotherapy • Aliskiren 150 mg is the recommended starting dose • Titration to 300 mg may provide additional benefit • Aliskiren 600 mg does not provide additional benefit compared with 300 mg and is not recommended for clinical use • Aliskiren demonstrates antihypertensive efficacy regardless of age or gender • Aliskiren demonstrates antihypertensive efficacy in patients with obesity, diabetes, impaired renal function and metabolic syndrome

36. Aliskiren provides superior BP-lowering compared with ramipril in patients with stage 2 hypertension (post-hoc analysis) SBP DBP 0 n=87 n=87 n=87 n=88 n=88 n=87 n=87 −5 −10 −10.2 −12.7 −15 * −18.1 −20 −22.3 −25 † Mean change from baseline in mean sitting BP at Week 12 (mmHg) Aliskiren 150 or 300 mg Ramipril 5 or 10 mg Stage 2 hypertension defined as SBP ≥160 mmHg *p<0.05; †p=0.0518 for superiority vs ramipril Andersen K, et al. 2008 (Study 2306)

37. Aliskiren monotherapy provides significantly greater reductions in BP compared with HCTZ monotherapy Aliskiren 300 mg HCTZ 25 mg Aliskiren 300 mg HCTZ 25 mg 0 n=560 n=560 n=547 n=547 −5 −10 −10.3 −12.2 −15 −14.7 *** −17.4 −20 *** DBP SBP −25 Mean change from baseline in mean sitting BP at Week 12 (mmHg) Pairwise comparisons: ***p<0.001 vs HCTZ Schmieder RE, et al. 2007 (Study 2323)

38. Aliskiren alone or in combination with ramipril reduces SBP irrespective of the degree of glycaemic control HbA1C level < 7.0% ≥ 7.0% < 7.0% ≥ 7.0% < 7.0% ≥ 7.0% 0 n = 133 n = 146 n = 132 n = 142 n = 135 n = 138 –5 –10 –11.8 –12.1 –15 –14.9 –14.9 –15.6 –20 –17.8 Mean change from baseline inmean sitting SBP at Week 8 (mmHg)  p≤0.05 p≤0.001 Aliskiren Ramipril Aliskiren/ramipril HbA1C <7.0%, baseline SBP = 155.7 mmHg HbA1C ≥7.0%, baseline SBP = 157.1 mmHg Tschoepe D, et al. 2006 (Study 2307)

39. Aliskiren alone or in combination with ramipril reduces BPin patients with microalbuminuria Aliskiren/ramipril300/10 mg Aliskiren/ramipril300/10 mg Ramipril10 mg Aliskiren300 mg Ramipril10 mg Aliskiren300 mg 0 n=69 n=72 n=67 n=69 n=72 n=67 −6 −8 −10 −10.4 −11.1 −12 −11.8 −12.4 −13.2 −14 −16 −16.8 −18 * DBP SBP −20 Mean change from baseline in mean sitting BP at Week 8 (mmHg)  *p<0.05 vs ramipril monotherapy Gradman AH, et al. 2007 (Study 2307)

40. AVOID StudyIn patients treated with losartan, adding aliskiren provides significantly greater reductions in UACR compared with placebo 5 0 –5 –10 –15 –20 2 n=289 n=287 Optimal treatment+ placebo Mean change from baseline in UACR at Month 6 (%) −18 Optimal treatment + aliskiren 300 mg p<0.001 Parving H-H, et al. 2007 Parving H-H, et al. 2008 UACR: Urinary Albumin to Creatinine Ratio

41. Enalapril 5–20 mg1 ACEI Captopril 25 mg2 ARB Candesartan 16 mg3 Zankiren 250 mg4 Enalkiren 0.5 mg/kg2 DRI Enalkiren* 36 mg5 Aliskiren 300 mg6 Change in renal plasma flow in response to ACE inhibition, angiotensin receptor blockade and Direct Renin Inhibition UPDATED (ref only) 0 50 100 150 200 Change in RPF (ml/min/1.73 m2) *mean dosage based on patient weight 1. Hollenberg et al. 2000; 2. Fisher et al. 1994; 3. Lansang et al. 2000; 4. Fisher & Hollenberg 1995; 5. Cordero et al. 1991; 6. Fisher & Hollenberg. 2007

42. More obese patients achieve BP control with aliskiren/HCTZ than with other combinations or HCTZ monotherapy Proportion of patients achieving BP control at Week 12 (%) Aliskiren/HCTZ 300/25 mg 80 60 40 20 0 Irbesartan/HCTZ 300/25 mg 68.8 Amlodipine/HCTZ 10/25 mg n=16 59.4 56.7 53.9 HCTZ 25 mg alone n=106 50.0 * n=97 n=102 43.8 n=10 ** n=16 34.7 n=101 ** 16.7 n=12 Obesity 1/2 3 1/2 3 1/2 3 1/2 3 class BP control defined as BP <140/90 mmHg *p<0.05, **p<0.01 vs aliskiren/HCTZ Class 1/2 obesity: BMI of 30–39.9 kg/m2; class 3 obesity: BMI ≥40 kg/m2 Prescott MF, et al. 2007 (Study 2309)

43. Aliskiren/valsartan combination therapy improves BP control compared with either component monotherapy UPDATED (BP control rates and ref only) BP control rate at Week 8 (%) 60 ** 49 50 † n=438 ** ‡ ** 37 40 34 n=430 n=453 30 20 16 n=455 10 0 Placebo Aliskiren 300 mg Valsartan 320 mg Aliskiren/ valsartan 300/320 mg BP control defined as BP <140/90 mmHg **p<0.0001 vs placebo; †p<0.001, ‡p<0.0001 vs aliskiren/valsartan combination Oparil S, et al. 2007 (Study 2327)

44. Summary- Efficacy in comparative and add-on studies • Aliskiren 300 mg monotherapy is more effective at reducing BP than ramipril 10 mg or HCTZ 25 mg monotherapy • Aliskiren 300 mg combined with ramipril 10 mg provides significantly greater reductions in BP than component monotherapies • Aliskiren 300 mg combined with ramipril 10 mg provides significantly greater reductions in SBP than ramipril 10 mg monotherapy in patients with microalbuminuria • Aliskiren 75–300 mg provides additional BP lowering when combined with HCTZ 6.25–25 mg • Aliskiren 300 mg combined with valsartan 320 mg provides significantly greater reductions in BP than component monotherapies • For patients with hypertension and obesity who fail to respond to diuretic monotherapy, adding aliskiren provides BP reductions and improved BP control rates • Addition of aliskiren 150 mg to amlodipine 5 mg in patients not responding adequately to amlodipine 5 mg monotherapy provides additional BP reductions and improves responder and control rates

45. Clinical advantages of good 24-hour BP control • 24-hour ambulatory BP correlates better than office BP measurements with target organ injury1 • Use of long-acting drugs or preparations providing 24-hour efficacy on a once-daily basis is recommended2 • minimization of BP variability, possibly providing greater protection against the risk of major CV events and the development of target-organ damage 1. Chobanian AV, et al. 2003;2. Mancia G, et al. 2007

46. Placebo (n=53) Aliskiren 150 mg (n=52) Aliskiren 300 mg (n=56) Aliskiren 600 mg (n=55) Significant reductions in mean ambulatory BP sustained over 24 hours Mean change from baseline in mean ambulatory DBP (mmHg) 5 0 −5 −10 −15 08:00 12:00 16:00 20:00 0:00 04:00 Clock hour Trough to peak ratio: aliskiren 150 mg 0.64 aliskiren 300 mg 0.98 aliskiren 600 mg 0.86 Mitchell J, et al. 2006 (Study 2308)

47. Summary-Sustained >24-hour BP control • Aliskiren once daily provides persistent and smooth 24-hour BP reduction • Aliskiren once daily demonstrates >24-hour blood pressure control, with a trough-to-peak ratio of 98% with the 300 mg dose • Adding aliskiren to valsartan provides significantly greater reductions in mean 24-hour ambulatory BP compared with either component monotherapy • Even during the early morning BP surge, aliskiren maintains sustained BP reductions • With a half-life of 40 hours, aliskiren demonstrates sustained BP reductions at every time point over 24 hours

48. Aliskiren combined with valsartan provides long-term BP-lowering efficacy – interim analysis after 6 months NEW SLIDE DBP SBP 0 n=87 n=87 n=87 n=386 n=386 n=182 n=182 −5 −10 −15 −13.9 −15.9 −20 −25 −23.8 −24.6 Mean change from baseline in mean sitting BP at Week 28 (mmHg)* Aliskiren/valsartan 300/320 mg Aliskiren/valsartan/HCTZ 300/320/25 mg *patients completing 6 months’ treatment Chrysant SG, et al. 2008 (Study 2301)

49. Long-term efficacy • Long-term treatment with aliskiren, alone or in combination with HCTZ, provides sustained BP reductions over a 12-month period • Long-term treatment with aliskiren in combination with valsartan provides sustained BP reductions over a 6-month period

50. Aliskiren provides prolonged BP-lowering Mean change in sitting diastolic blood pressure (mmHg) 0 −5 −10 −15 Drug discontinuation −20 0 1 2 3 4 5 6 7 8 9 10 Week Aliskiren 300 mg (n=166) Placebo (n=163) Aliskiren 600 mg (n=166) Aliskiren 150 mg (n=167) Herron J, et al. 2006 (Study 2308)