1	Direct Renin Inhibition Yoram Yagil, MD, FAHA Professor of Medicine Faculty of Health Sciences, Ben-Gurion University Nephrology and Hypertension, Barzilai Med Ctr, Ashkelon
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4	Blockade of RAAS …a thousand ways…
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17	History of Direct Renin Inhibitors
18	History of Direct Renin Inhibitors
19	Major problems with DRI
20	History of Direct Renin Inhibitors
21	History of Direct Renin Inhibitors
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29	The ASPIRE HIGHER clinical study program
30	The ASPIRE HIGHER clinical study program
31	The ASPIRE HIGHER clinical study program The AVOID study results The ALOFT study results The ALLAY study results The ALTITUDE study design
32	The ASPIRE HIGHER clinical study program Overview
33	Aliskiren in the eValuation of prOteinuria In Diabetes (AVOID) study
34	Population and objectives Study population: Patients with mild-to-moderate HTN, type 2 DM and DN (UACR 200–3500 mg/g) Primary objective: Change in UACR from baseline to study end with Aliskiren when added to losartan 100 mg once daily + optimal antihypertensive therapy, compared with placebo Secondary objectives included: Proportion of patients with ≥50% reduction in UACR Effect of treatment on BP Safety and tolerability
35	Study design overview All patients continued to receive open-label losartan 100 mg and optimal antihypertensive therapy during the double-blind period Patients force-titrated after 3 months All treatments administered once daily
36	Baseline laboratory variables
37	Reduction in UACR: Aliskerin vs Placebo
38	Patients with ≥50% reduction in UACR from baseline: Aliskiren vs Placebo
39	BP: Aliskiren vs Placebo
40	Tolerability: Aliskiren vs Placebo
41	Effect of study laboratory values
42	AVOID Summary In patients with HTN, type 2 DM and DN receiving losartan 100 mg daily + optimal antihypertensive therapy, Aliskiren 300 mg reduced UACR by 20% more than Placebo. The effect of aliskiren on UACR was independent of the level of BP control In these patients, Aliskiren has tolerability comparable to placebo
43	The ASPIRE HIGHER clinical study programme Overview
44	ALiskiren Observation of congestive heart Failure Treatment (ALOFT)
45	Population and objectives Study population: Patients with stable CHF, prior or current HTN, BNP>100 pg/mL, and receiving a β-blocker with either ACEI or ARB Primary objective: Safety and tolerability of Aliskiren 150 mg when given in addition to standard therapy in patients with HTN and stable CHF Secondary objectives: Effect of Aliskiren on BNP, N-terminal proBNP (NT-proBNP), aldosterone levels, echocardiographic measures of LV function, signs and symptoms of CHF, and BP
46	Study design overview
47	Baseline characteristics and concomitant CHF Rx
48	Echocardiographic assessments of LV function: Aliskiren vs Placebo
49	BNP: Aliskiren vs Placebo
50	Tolerability: Aliskiren vs Placebo
51	ALOFT Summary In patients receiving standard therapy for CHF: Aliskiren provides significant improvements in some echocardiographic assessments of LV function Aliskiren significantly reduces BNP, Aldosterone and PRA levels compared with placebo Aliskiren has a placebo-like tolerability profile
52	The ASPIRE HIGHER clinical study programme Overview
53	ALiskiren in Left ventriculAr hypertrophY (ALLAY)
54	Population and objectives Study population: Patients with a history of or newly diagnosed HTN (140 <SBP<180 mmHg; 90< DBP<110 mmHg), body mass index (BMI) >25 kg/m² and LV wall thickness ≥1.3 cm^† Primary objective: To evaluate whether Aliskiren/Losartan combination therapy was superior to Losartan monotherapy in reducing LVH, by measuring the change in LVMI using CMR Key secondary objectives included: Evaluation whether Aliskiren monotherapy was non-inferior to Losartan monotherapy in reducing LVMI; safety and tolerability
55	Study design overview
56	LVH: Effect of Aliskiren/Losartan combination therapy vs monotherapy
57	BP: Effect of Aliskiren/Losartan combination therapy vs monotherapy
58	LVMI: Aliskiren/Losartan combination vs monotherapy
59	Association of SBP with reduction in LVMI
60	ALLAY Summary Aliskiren was as effective as Losartan in reducing LVMI, a measure of end-organ damage, in overweight patients with HTN, over 36 weeks of treatment The combination of Aliskiren and Losartan did not provide a greater reduction in LVMI The overall degree of LVMI reduction was related to the degree of BP lowering This study demonstrates that Aliskiren is an effective treatment option in patients with LVH
61	The ASPIRE HIGHER clinical study program Overview
62	ALiskiren Trial In Type 2 diabetes Using cardio-renal Disease Endpoints (ALTITUDE)
63	Objectives Primary objective: Determine whether Aliskiren, when added to conventional treatment, delays the occurrence of CV and renal complications in patients with type 2 diabetes at high risk for CV and renal events (CV death, resuscitated sudden death; non-fatal MI; non-fatal stroke; hospitalization for CHF; onset of ESRD or renal death; doubling of baseline serum creatinine concentration) Secondary objectives: Determine whether Aliskiren, when added to conventional treatment, delays the occurrence of CV complications and the occurrence of renal complications
64	Patient population
65	Design overview
66	The ASPIRE HIGHER clinical study programme Overview
67	Other clinical studies assessing the renoprotective properties of aliskiren Time course of the antiproteinuric and antihypertensive effect of direct renin inhibition with aliskiren in patients with type 2 diabetes and albuminuria – Study 2242 Antiproteinuric effect of aliskiren compared, and in combination, with irbesartan in patients with type 2 diabetes, hypertension and albuminuria – Study 2243 Effect of aliskerin on renal plasma flow in normotensive patinets – Study 2318
68	Future prospects with DRI