1. 1 Item code: 2008.229 Print date: Not applicable 1

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

4. 4 Item code: 2008.229 Print date: Not applicable 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. 5 Item code: 2008.229 Print date: Not applicable 5 JNC-7 Classification NormalPrehypertension Stage I hypertension Stage II hypertension SBP (mmHg) DBP (mmHg) BP Classification < 120 120-139140-159 > 160 < 80 80-8990-99 > 100 andororor http://hin.nhlbi.nih.gov/nhbpep_slds/menu.htm

6. 6 Item code: 2008.229 Print date: Not applicable The majority of patients are not treated to BP goal US Top-5 EU countries * Japan Top-7 countries Hypertension prevalence, in millions (% of population) 65.2 (22%) 72.9 (24%) 36 (28%) 175 (24%) Not diagnosed (%)28%30%49%33% Diagnosed not treated (%)26%16%12%19% Treated not at goal (%) 44%54%74%54% Prevalent patients not at to goal (%) 70%73%88%75% 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 *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

7. 7 Item code: 2008.229 Print date: Not applicable SBP DBP ALLHAT 1 HOPE PROGRESS CAPPP INSIGHT NORDIL HOT STONE STOP-2 LIFE ALLHAT 2 ANBP2 INVEST SCOPE ASCOT VALUE 130 140 150 160 170 180 190 200 mmHg 70 80 90 100 110 120 mmHg Mancia G, Grassi G. J Hypertens 2002 Even in clinical trial conditions, many patients do not reach goal with current therapies B T B T B = baseline; T = trial

8. 8 Item code: 2008.229 Print date: Not applicable 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. 9 Item code: 2008.229 Print date: Not applicable Patients with hypertension have additional co-morbidities, making treatment difficult Obesity Glucose intolerance Hyperinsulinaemia Reduced HDL-C Elevated LDL-C Elevated triglycerides 3 4+ 0 1 2 26% 25% 8% 22% 19% 3 4+ 0 1 2 27% 24% 12% 20% 17% >50% have two or more comorbidities MenWomen Kannel WB, 2000

10. 10 Item code: 2008.229 Print date: Not applicable 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. 11 Item code: 2008.229 Print date: Not applicable 11 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. Lifestyle Modification

12. 12 Item code: 2008.229 Print date: Not applicable 12 Lifestyle Modification Modification Approximate SBP reduction (range) Weight reduction 5 – 20 mmHg/10 kg weight loss Adopt DASH eating plan 8 – 14 mmHg Dietary sodium reduction 2 – 8 mmHg Physical activity 4 – 9 mmHg Stopping alcohol consumption 2 – 4 mmHg

13. 13 Item code: 2008.229 Print date: Not applicable 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. 14 Item code: 2008.229 Print date: Not applicable 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) activation is 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. 15 Item code: 2008.229 Print date: Not applicable Risk factors Diabetes Hypertension Atherosclerosis and LVH Myocardial infarction (MI) Remodeling Ventricular dilation Congestive heart failure (HF) End-stage micro- vascular and heart disease Death Adapted from Dzau, Braunwald. Am Heart J 1991;121:1244–63 CONSENSUS SOLVD, Val-HeFT ELITE II Val-HeFT CHARM DREAM NAVIGATOR RENAAL IDNT IRMA-2 MARVAL HOPE, EUROPA, PEACE, LIFE ONTARGET, TRANSCEND VALUE LIFE SCOPE SAVE, AIRE, TRACE OPTIMAAL, VALIANT DIRECT LVH = left ventricular hypertrophy RAAS and its inhibitors: Their role along the CV continuum

16. 16 Item code: 2008.229 Print date: Not applicable 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. 17 Item code: 2008.229 Print date: Not applicable 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 or non-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 within a 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. 18 Item code: 2008.229 Print date: Not applicable Dual Blockade of the RAAS What do enthusiasts say? More trials needed 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

19. 19 Item code: 2008.229 Print date: Not applicable 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. 20 Item code: 2008.229 Print date: Not applicable 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. 21 Item code: 2008.229 Print date: Not applicable Classic understanding of the Renin System Gibbons GH. 1998; Adapted from: Müller DN & Luft FC. 2006 ACE Na + /H 2 O retention Vasoconstriction Hypertension Aldosterone Renin Angiotensinogen Ang I AT 1 Receptor Ang II

22. 22 Item code: 2008.229 Print date: Not applicable ACEIs and ARBs cause compensatory rises in PRA Glomerular vasoconstriction Inflammation Fibrosis Kidney Hypertrophy Fibrosis Vasoconstriction Heart Vasoconstriction Brain Hyperplasia hypertrophy Inflammation Oxidation Fibrosis Vessels Feedback Loop AT 1 Receptor Renin Ang I Angiotensinogen Ang II Biological effects ACE Non ACE pathways ARBs ACEIs PRA Adapted from: Müller DN & Luft FC. 2006

23. 23 Item code: 2008.229 Print date: Not applicable Angiotensinogen Aliskiren binds to the active site of renin Aliskiren binds to a pocket in the renin molecule, blocking cleavage of angiotensinogen to angiotensin I Renin Aliskiren Adapted from Wood JM, et al. 2003

24. 24 Item code: 2008.229 Print date: Not applicable Direct renin inhibition acts at the point of activation of the Renin System and neutralizes the PRA rise Feedback Loop AT 1 Receptor Renin Ang I Angiotensinogen Ang II Direct renin inhibitor Biological effects ACE Non ACE pathways PRA Adapted from: Müller DN & Luft FC. 2006 Glomerular vasoconstriction Inflammation Fibrosis Kidney Hypertrophy Fibrosis Vasoconstriction Heart Vasoconstriction Brain Hyperplasia hypertrophy Inflammation Oxidation Fibrosis Vessels

25. 25 Item code: 2008.229 Print date: Not applicable Unlike ACEIs and ARBs, aliskiren reduces Ang I, Ang II and PRA Aliskiren ARB ACEI PRAReninAng IIAng I Feedback Loop AT 1 Receptor Renin Ang I Angiotensinogen Ang II Direct renin inhibitor ARBs ACE Non ACE pathways ACEIs Azizi M et al. 2006; Adapted from: Müller DN & Luft FC. 2006

26. 26 Item code: 2008.229 Print date: Not applicable (Pro)renin receptor may play an important role in cardio vascular disease by local Renin System activation (Pro)renin receptor Vasoconstriction Remodelling Vessels Kidney Heart (Pro)renin receptor actions: Binding of (pro)renin Increased renin catalytic activity Activates VSMC ERK1/2 Increase PAI-1 Aliskiren binds to renin Target cells VSMC Feedback Loop AT 1 Receptor Renin Angiotensinogen Ang II Non ACE pathways Ang I ACE Direct renin inhibitor Nguyen G, et al. 2001 Direct renin inhibitor

27. 27 Item code: 2008.229 Print date: Not applicable 1000 1 0.1 100 10 Aliskiren has a half-life of approximately 40 hours, making it suitable for once-daily dosing Mean (plus SD) plasma aliskiren concentration profiles (n=30) after single oral administration of aliskiren to healthy subjects, semi-logarithmic scale Concentration (ng/mL) 0 Time (hours) 75 mg 150 mg 300 mg 600 mg 10080204060 Vaidyanathan S, et al. 2006 (Study 2205)

28. 28 Item code: 2008.229 Print date: Not applicable Aliskiren monotherapy provides dose-dependent reductions in DBP and SBP 0 15 5 20 10 n=133 n=129n=130n=127n=130 ** * *** p=0.005 p=0.01 Placebo 150 300 600 150 *p<0.02 vs placebo; **p<0.005; ***p<0.0005 vs placeboGradman AH, et al. 2005 (Study 2201) n=133 n=129 n=130n=127n=130 *** Aliskiren (mg) DBP SBP Irbesartan (mg) Aliskiren (mg) Irbesartan (mg) Placebo150300600150 6.3 9.3 11.811.5 8.9 5.3 11.4 15.815.7 12.5 Mean change from baseline in mean sitting BP at Week 8 (mmHg)

29. 29 Item code: 2008.229 Print date: Not applicable 0 10 5 15 20 Aliskiren monotherapy provides dose-dependent reductions in DBP and SBP Mean change from baseline in mean sitting BP at Week 8 (mmHg) ***p<0.0001 vs placebo Placebo150300600 Aliskiren (mg) 150300600Placebo n=166 n=167n=163 *** 4.9 10.3 11.1 12.5 *** n=166 n=167n=163 *** 3.8 13.0 14.7 15.8 *** DBPSBP Aliskiren (mg) Oh BH, et al. 2007 (Study 2308)

30. 30 Item code: 2008.229 Print date: Not applicable Pooled analyses in >3,500 patients demonstrate that aliskiren provides dose-dependent reductions in BP Dahlöf B, et al. 2007 (Pooled analysis) ***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 Mean change from baseline in mean sitting BP after 8–12 weeks (mmHg) 0 15 5 25 10 20 6.2 *** DBPSBP Placebo150 mg n=1180 n=776 n=1603 10.1 11.8 300 mg Aliskiren Placebo150 mg300 mg Aliskiren n=1180 n=776 n=1603 *** 5.9 *** 12.5 15.2 *** 6.69.3 3.95.6

31. 31 Item code: 2008.229 Print date: Not applicable Aliskiren provides effective DBP-lowering in patients with obesity: pooled analysis ***p<0.001 vs placebo Mean change from baseline in mean sitting DBP after 8–12 weeks (mmHg) Prescott MF, et al. 2007 (Pooled analysis) 0 5 10 15 –6.1 –10.0 –11.1 –6.2 –10.1 –11.8 *** n=275n=434n=630n=776n=1180n=1603 *** Placebo150300 Aliskiren (mg) Placebo150300 Aliskiren (mg) All patientsPatients with obesity

32. 32 Item code: 2008.229 Print date: Not applicable Aliskiren provides effective SBP-lowering in patients with diabetes: pooled analysis Taylor AA, et al. 2007 (Pooled analysis)**p<0.01; ***p<0.001 vs placebo Mean change from baseline in mean sitting SBP after 8–12 weeks (mmHg) 0 15 5 25 10 20 n=1180 n=776 n=1603 5.9 *** 12.5 15.2 *** n=98 n=55 n=393 6.9 ** 13.2 14.8 *** Placebo150300 Aliskiren (mg) Placebo150300 Aliskiren (mg) All patientsPatients with diabetes

33. 33 Item code: 2008.229 Print date: Not applicable Aliskiren provides effective DBP-lowering in patients with metabolic syndrome: pooled analysis p<0.0001 vs placebo Mean change from baseline in mean sitting DBP after 8–12 weeks (mmHg) White WB, et al. 2007 (Pooled analysis) 0 5 10 15 –5.8 –10.4 –11.3 –6.7 –10.4 –11.9 n=189n=365n=387n=299n=531n=640 Placebo150300 Aliskiren (mg) Placebo150300 Aliskiren (mg) Patients with metabolic syndrome Patients without metabolic syndrome UPDATED (ref only)

34. 34 Item code: 2008.229 Print date: Not applicable Aliskiren provides effective BP-lowering in patients with impaired renal function: pooled analysis Mean change from baseline in mean sitting BP after 8 weeks (mmHg) Weir MR, et al. 2007 (Pooled analysis) Aliskiren 300 mgAliskiren 150 mg eGFR <60 –14.9 0 5 10 15 –14.7 –10.4 –9.4 –11.2 –10.1 –11.5 n=25 n=740n=736 n=26n=25 n=740n=736 n=26 –11.4 eGFR <60eGFR 60 DBPSBP eGFR: estimated glomerular filtration rate (assessed in mL/min/1.73 m 2 )

35. 35 Item code: 2008.229 Print date: Not applicable 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. 36 Item code: 2008.229 Print date: Not applicable Aliskiren provides superior BP-lowering compared with ramipril in patients with stage 2 hypertension (post-hoc analysis) Andersen K, et al. 2008 (Study 2306) Stage 2 hypertension defined as SBP 160 mmHg *p<0.05; p=0.0518 for superiority vs ramipril Mean change from baseline in mean sitting BP at Week 12 (mmHg) 0 15 5 25 10 20 n=87 n=88 n=87 n=88 12.7 10.2 18.1 22.3 DBP SBP Aliskiren 150 or 300 mgRamipril 5 or 10 mg n=87 *

37. 37 Item code: 2008.229 Print date: Not applicable Aliskiren monotherapy provides significantly greater reductions in BP compared with HCTZ monotherapy Mean change from baseline in mean sitting BP at Week 12 (mmHg) 0 15 5 25 10 Pairwise comparisons: ***p<0.001 vs HCTZ 20 n=547 n=560 n=547 n=560 12.2 10.3 17.4 14.7 *** DBPSBP Aliskiren 300 mg HCTZ 25 mg Aliskiren 300 mg HCTZ 25 mg Schmieder RE, et al. 2007 (Study 2323)

38. 38 Item code: 2008.229 Print date: Not applicable Aliskiren alone or in combination with ramipril reduces SBP irrespective of the degree of glycaemic control Tschoepe D, et al. 2006 (Study 2307) HbA 1C <7.0%, baseline SBP = 155.7 mmHg HbA 1C 7.0%, baseline SBP = 157.1 mmHg –20 –15 –10 –5 0 p0.001 p0.05 –14.9 n = 133 –14.9 n = 146 –11.8 n = 132 –12.1 n = 142 –15.6 n = 135 –17.8 n = 138 < 7.0% 7.0% HbA 1C level Mean change from baseline in mean sitting SBP at Week 8 (mmHg) AliskirenRamiprilAliskiren/ramipril

39. 39 Item code: 2008.229 Print date: Not applicable Aliskiren alone or in combination with ramipril reduces BP in patients with microalbuminuria Mean change from baseline in mean sitting BP at Week 8 (mmHg) Aliskiren/ ramipril 300/10 mg Ramipril 10 mg Aliskiren 300 mg 18 6 0 14 DBPSBP 8 10 12 16 *p<0.05 vs ramipril monotherapyGradman AH, et al. 2007 (Study 2307) 20 n=67 n=72n=69 n=67 n=72n=69 13.2 11.1 10.4 16.8 11.8 12.4 * Aliskiren/ ramipril 300/10 mg Ramipril 10 mg Aliskiren 300 mg

40. 40 Item code: 2008.229 Print date: Not applicable Optimal treatment + aliskiren 300 mg n=289 n=287 18 5 0 –5 –10 –15 –20 2 Optimal treatment + placebo Parving H-H, et al. 2007 Parving H-H, et al. 2008 UACR: Urinary Albumin to Creatinine Ratio Mean change from baseline in UACR at Month 6 (%) p<0.001 AVOID Study In patients treated with losartan, adding aliskiren provides significantly greater reductions in UACR compared with placebo

41. 41 Item code: 2008.229 Print date: Not applicable Change in renal plasma flow in response to ACE inhibition, angiotensin receptor blockade and Direct Renin Inhibition 0 50100150200 Change in RPF (ml/min/1.73 m 2 ) 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 Enalapril 5–20 mg 1 Captopril 25 mg 2 Candesartan 16 mg 3 Zankiren 250 mg 4 Enalkiren 0.5 mg/kg 2 Enalkiren* 36 mg 5 Aliskiren 300 mg 6 ACEI ARB DRI *mean dosage based on patient weight UPDATED (ref only)

42. 42 Item code: 2008.229 Print date: Not applicable More obese patients achieve BP control with aliskiren/HCTZ than with other combinations or HCTZ monotherapy * ** 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/m 2 ; class 3 obesity: BMI 40 kg/m 2 80 60 40 20 0 Proportion of patients achieving BP control at Week 12 (%) n=97 n=106 n=102 n=101 n=16 n=10 n=16 n=12 56.7 59.4 53.9 34.7 68.8 43.8 16.7 50.0 Obesity1/231/231/231/23 class Aliskiren/HCTZ 300/25 mg Amlodipine/HCTZ 10/25 mg Irbesartan/HCTZ 300/25 mg HCTZ 25 mg alone Prescott MF, et al. 2007 (Study 2309)

43. 43 Item code: 2008.229 Print date: Not applicable Aliskiren/valsartan combination therapy improves BP control compared with either component monotherapy BP control defined as BP <140/90 mmHg **p<0.0001 vs placebo; p<0.001, p<0.0001 vs aliskiren/valsartan combination BP control rate at Week 8 (%) 0 40 20 50 34 37 16 n=455 n=453 n=438 n=430 60 ** 30 10 49 Oparil S, et al. 2007 (Study 2327) PlaceboAliskiren 300 mg Valsartan 320 mg Aliskiren/ valsartan 300/320 mg UPDATED (BP control rates and ref only)

44. 44 Item code: 2008.229 Print date: Not applicable 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. 45 Item code: 2008.229 Print date: Not applicable Clinical advantages of good 24-hour BP control 24-hour ambulatory BP correlates better than office BP measurements with target organ injury 1 Use of long-acting drugs or preparations providing 24-hour efficacy on a once-daily basis is recommended 2 –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. 46 Item code: 2008.229 Print date: Not applicable Significant reductions in mean ambulatory BP sustained over 24 hours Mitchell J, et al. 2006 (Study 2308) Trough to peak ratio: aliskiren 150 mg 0.64 aliskiren 300 mg 0.98 aliskiren 600 mg 0.86 Mean change from baseline in mean ambulatory DBP (mmHg) Placebo (n=53) Aliskiren 150 mg (n=52) Aliskiren 300 mg (n=56) Aliskiren 600 mg (n=55) Clock hour 5 0 5 10 15 08:00 12:0016:0020:000:0004:00

47. 47 Item code: 2008.229 Print date: Not applicable 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. 48 Item code: 2008.229 Print date: Not applicable Aliskiren combined with valsartan provides long-term BP-lowering efficacy – interim analysis after 6 months Mean change from baseline in mean sitting BP at Week 28 (mmHg)* 0 15 5 25 10 20 n=182 n=386 n=87 n=386 15.9 23.8 DBP SBP Aliskiren/valsartan 300/320 mgAliskiren/valsartan/HCTZ 300/320/25 mg n=87 n=182 24.6 13.9 Chrysant SG, et al. 2008 (Study 2301)*patients completing 6 months treatment NEW SLIDE

49. 49 Item code: 2008.229 Print date: Not applicable 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. 50 Item code: 2008.229 Print date: Not applicable Aliskiren provides prolonged BP-lowering Placebo (n=163) Aliskiren 150 mg (n=167) Aliskiren 300 mg (n=166) Aliskiren 600 mg (n=166) 0 20 5 10 15 Mean change in sitting diastolic blood pressure (mmHg) Drug discontinuation 100123456789 Week Herron J, et al. 2006 (Study 2308)

51. 51 Item code: 2008.229 Print date: Not applicable SBP returns to baseline levels more rapidly after discontinuation of ramipril compared with aliskiren BaselineWeek 1Week 2Week 3Week 4 12 10 8 6 4 2 0 –2 Mean change in mean sitting SBP during the 4-week withdrawal period (mmHg) *Following 26-weeks treatment, patients randomized to discontinuation received placebo for 4 weeks; Patients continuing active treatment could be receiving aliskiren 150 or 300 mg, or ramipril 5 or 10 mg, with or without optional HCTZ (12.5 mg or 25 mg). Aliskiren regimen discontinued (n=163)* Aliskiren regimen continued (n=170) Ramipril regimen discontinued (n=177)* Ramipril regimen continued (n=165) Andersen K, et al. 2008 (Study 2306)

52. 52 Item code: 2008.229 Print date: Not applicable Aliskiren maintained BP reductions after a missed dose with significantly greater efficacy than irbesartan or ramipril (post-hoc analysis) Missed dose on Day 42 or Day 49, 48 hours after the last dose ***p<0.0001 vs ramipril; § p<0.005 vs irbesartan Data are shown as least squares mean change ± SE for the ABPM completer population Change in mean 24-hour ambulatory BP from start to end of missed dose period (mmHg) 0 1 2 3 4 1.0 n=171 3.6 n=152 4.0 n=155 0.7 n=171 2.2 n=152 2.6 5 n=155 DBP SBP Ramipril 10 mgIrbesartan 300 mgAliskiren 300 mg Palatini P, et al. 2008 (Study 2351) § ***

53. 53 Item code: 2008.229 Print date: Not applicable Persistence of effect Aliskiren demonstrates persistence of effect after drug discontinuation Return to baseline BP occurs more slowly after discontinuation of aliskiren than after discontinuation of ramipril Aliskiren provides superior maintenance of BP-lowering effect compared with ramipril and irbesartan after a missed dose Aliskiren maintains BP reductions after a missed dose with significantly greater efficacy than ramipril or irbesartan

54. 54 Item code: 2008.229 Print date: Not applicable Blood Pressure Goals Must be Less than 140/90 Ideally 120/80 or less Less than 130/80 if have diabetes Lifestyle Changes when over 135/85

55. 55 Item code: 2008.229 Print date: Not applicable 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

56. 56 Item code: 2008.229 Print date: Not applicable Take home message stress the importance of compliance Many people still believe that hypertension is a disease that can be cured and that the treatment can be stopped or reduced when the BP levels fall. Physicians need to convey the message that Hypertension is the first and easily measurable, usually irreversible sign that many organs in the body are under attack and that many catastrophes can be prevented by controlling the Blood Pressure.

57. 57 Item code: 2008.229 Print date: Not applicable Questions?

58. 58 Item code: 2008.229 Print date: Not applicable THANK YOU

59. 59 Item code: 2008.229 Print date: Not applicable

60. 60 Item code: 2008.229 Print date: Not applicable Rationale for selective angiotensin type 1 receptor blockade Bradykinin/NO Inactive fragments ANGIOTENSIN I ANGIOTENSIN II ARB AT 1 RECEPTOR Vasoconstriction Sodium retention SNS activation Inflammation Growth-promoting effects AT 2 RECEPTOR Vasodilation Natriuresis Tissue regeneration Inhibition of inappropriate cell growth Chymase, tPA, Cathepsin Angiotensin II escape ACE inhibitor