Dr. Danny Woo
Normal Glomerulus
Crystal Structure of Renin
Ang I
Aliskerin Binds Prorenin/Renin
Only Direct Renin Inhibition Inhibits the Entire Renin Angiotensin System1-6
Diuretic
ACEI
ARB
Direct Renin Inhibitor (DRI)
Tekturna Suppresses Plasma Renin Activity
Primary study endpoint was reduction in msDBP. DRI, direct renin inhibitor; PRA, plasma renin activity. *The clinical implications of the different effects of TEKTURNA and valsartan on PRA were not known, were not dose related and did not correlate with blood pressure reduction. Data are shown as percentage change in geometric mean PRA (95% confidence interval).
Aliskerin reduces PRA alone or in Combina4on with Valsartan
Oparil S et al. Lancet. 2007;370:221-229.
8-week randomized, double-blind, placebo and active dose escalation study to evaluate the efficacy of aliskiren administered alone and in combination with valsartan in 1797 patients with essential hypertension.
–25
30
60
0
120
-75
-50
-73
180
Ch
ange
fro
m B
asel
ine
at
Wee
k 8
in P
RA
(%)
160
Aliskiren (n=51)
-44 Combined
(n=60)
18
Placebo (n=51)
Valsartan (n=59)
This primary endpoint was reduction in msDBP. DRI, direct renin inhibitor; PRA, plasma renin activity. *The clinical implications of the different effects of TEKTURNA and ramipril on PRA were not known, were not dose related and did not correlate with blood pressure reduction. Data are shown as percentage change in geometric mean PRA (95% confidence interval) for the intent-to-treat population. Data on File. Clinical Study Report 2307, Novartis Pharmaceuticals Corp.
8 wk randomized, double-blind, dose escalation study to evaluate safety and efficacy of aliskiren and ramipril alone and in combination in the treatment of hypertension. C
han
ge F
rom
Bas
elin
e at
W
eek
8 in
PR
A (%
)
–25
25
50
0
110
75
-75
-50
-68 Aliskiren
(n=79)
120
-44 Combined
(n=75)
Ramipril (n=74)
Aliskerin Reduces PRA Alone or In Combina4on with Ramipril
Associa4on Between Baseline Levels of PRA and Risk of Cardiovascular Events
Intermountain Medical Center 1165 male and female patients with severe CAD (>70%
stenosis by angio) Exclusion criteria: no previous MI or CHF, EF <45%, beta
blocker therapy. Maximum follow up 14.6 years, mean follow up 6.4
years. Outcomes included fatal and nonfatal MI, CVA, CHF. Cardiac morbidity/mortality included CHF and MI, but
not CVA.
Intermountain Medical Center
DiaSorin PRA radioimmunoassay Division into PRA tertiles Compared with the low baseline PRA, high baseline
PRA (tertile 3) was independently associated with a significantly increased risk of cardiac morbidity/mortality, MI, all-cause death and all-cause death/CHF.
Impact of Elevated PRA on 3 and 5year Risk of CVE’s in Patients with CAD
Blair TL et. Al. ACC 3/2009 Orlando
Impact of PRA on Hospitalizations for CHF
Blair TL et. Al. ACC 3/2009 Orlando
Sowers, J. R. et. al. Ann Intern Med 2009;150:776-783
Inhibitory actions of aldosterone and angiotensin II on insulin metabolic signaling in skeletal muscle
Sowers, J. R. et. al. Ann Intern Med 2009;150:776-783
Systemic effects of aldosterone on insulin sensitivity and hypertension
Aldosterone Antagonism is Addi4ve to ACE Inhibi4on or AT1 Blockade
RALES – Randomized Aldactone Evaluation Study – additional 25% reduction in CV events in severe heart failure
EPHESUS – Eplerenone Post-MI Heart Failure Efficacy and Survival Study – additional mortality reduction post MI with eplerenone
Aldosterone Breakthrough Aldosterone levels rise in 10-53% of patients treated
with ACE inhibitors or ARB’s Aldosterone breakthrough occurs due to non-ACE
enzymes converting angiotensin I to angiotensin II The suggested treatments for aldosterone
breakthrough are aldosterone receptor blockers or renin inhibitors
Aliskerin and Valsartan – Effects on Aldosterone
2.2
-31
-19
-50
-60
-50
-40
-30
-20
-10
0
10
Median Change from Baseline in Aldosterone
Placebo
Aliskiren
Valsartan
Aliskiren + Valsartan
50 Patients- Treated for 8 weeks- No dietary control
Picomol/L
Aldosterone Excessive aldosterone levels are not necessary to
cause end organ damage A high salt intake enhances the interaction of
aldosterone and endothelial cells to cause endothelial cell stiffening, reduces NO production, increases angiotensinogen, and upregulates AT1 receptors.
Aldosterone blockers are effective in drug resistant hypertension
Background
ACE-inhibitors (e.g. ramipril in the HOPE trial) reduces CV death, MI, stroke and HF hosp in those with CVD or DM in the absence of ventricular dysfunction or heart failure
ACE-inhibitors are not tolerated by 15% to 25% of patients
Will an ARB (telmisartan) be as effective and better tolerated?
Is the combination superior?
Study Organization
Study Design: Large Randomized Controlled Clinical Trial, sufficiently powered (15% RRR, 80-90% CI).
Population: subjects at high risk for developing cardiovascular disease. (Approximately 35% diabetics).
Participating Centers: 733 from 40 countries, every inhabited continent globally.
Organization: Coordinated by PHRI/CCC at McMaster University (Hamilton, Ontario) in conjunction with two regional centres (Oxford and Auckland)
Sponsor: Boehringer-Ingelheim, Germany
ONTARGET Questions:
1. Is telmisartan “non-inferior” to ramipril? 2. Is the combination superior to ramipril?
Outcome: 1. Primary: CV death, MI, stroke, CHF hosp 2. Key secondary: CV death, MI, stroke (HOPE trial outcome)
Design: Single blind run-in (n=29,018) Randomized, double blind, double dummy study conducted in 733 centers in 41 countries (n=25,620) 56 months follow-up with 99.8% outcome ascertainment
Time to Primary Outcome # at Risk Yr 1 Yr 2 Yr 3 Yr 4 Yr 4.5
T 8542 8177 7778 7420 7051 4575 R 8576 8214 7832 7472 7093 4562
Ramipril Telmisartan
Years of Follow-up
Cum
ulat
ive
Haz
ard
Rat
es
0.0
0.05
0.10
0.15
0.20
0.25
0 1 2 3 4
Years of Follow-up
Cum
ulat
ive
Haz
ard
Rat
es
0.0
0.05
0.
10
0.15
0.
20
0.25
0 1 2 3 4
Ramipril Tel. & Ram.
# at Risk Yr 1 Yr 2 Yr 3 Yr 4 Yr 4.5
R 8576 8214 7832 7472 7093 4562 T&R 8502 8133 7738 7375 7022 4467
Combination Telmisartan + Ramipril vs Ramipril
Time to Primary Outcome
Renal Dysfunction Dialysis & Related Death
Ram (n=8576)
%
Ram + Tel (n=8502)
%
Ram + Tel v Ram RR (95% CI)
P value
Any renal dysfunction 10.04 13.35 1.33 (1.22-1.45) <0.0001
Creatinine x 2 1.84 2.12 1.15 (0.93-1.42) 0.197
Potassium >5.5 mmol/L 3.32 5.67 1.71 (1.48-1.98) <0.0001
SAE renal failure 0.28 0.64 2.27 (1.40-3.67) 0.0006
Need for dialysis 0.55 0.78 1.42 (0.98-2.06) 0.066
Death after renal dysfunction 1.84 2.21 1.20 (0.97-1.48) 0.087
Combination Telmisartan + Ramipril vs Ramipril
John McMurray1 Bertram Pitt,2 Roberto Latini,3 Aldo Maggioni,4 Scott Solomon,5 Jenny Chung,6 Jessica Ford,7 Beverly Smith6
1Western Infirmary, Glasgow, UK; 2University of Michigan, Ann Arbor, MI, USA; 3Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; 4ANMCO Research Center, Florence, Italy; 5Brigham and
Women’s Hospital, Boston, MA, USA; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 7Novartis Pharma AG, Basel, Switzerland
ALiskiren Observation of heart Failure Treatment
• ClinicalTrials.gov NCT00219011
Brain-Type Natriuretic Peptide (BNP)
Participates in sodium regulation Present in the heart, particularly
the ventricles Both BNP and NT-proBNP
circulate in the plasma
Bhatia V et al. J Postgrad Med. 2003;49(2):182-185.
NT-proBNP Inactive N-terminal fragment BNP
Active peptide
pro-BNP
Cleavage
Q: If it regulates the heart, why is it called “Brain-type”?
A: It is also found in the brain and was originally cloned from extracts of pig brain.
What Is Its Importance in CHF? Cardiac production and blood levels of BNP and
NT-proBNP increase when the heart is damaged and stressed1
Blood BNP and NT-proBNP levels are a diagnostic test for congestive heart failure (CHF)2
Higher levels of BNP and NT-proBNP correlate with cardiovascular morbidity and mortality in CHF patients1
Reductions in BNP are associated with improved outcomes in CHF patients3
1. Bibbins-Domingo K et al. JAMA. 2007;297(2):169-176. 2. Bhatia V et al. J Postgrad Med. 2003;49(2):182-185. 3. Latini R et al. Am J Med. 2006;119:70.e23-30.
Background to the ALOFT (2313) Study
Despite effective therapies including ACE inhibitors, angiotensin receptor blockers, beta-blockers and aldosterone antagonists, morbidity and mortality remain high and new treatments are needed
The ALOFT study was designed to evaluate the tolerability and safety of the direct renin inhibitor aliskiren, when given in addition to standard therapy in patients with stable heart failure, a history of hypertension and a raised plasma level of B type natriuretic peptide (BNP)
“Efficacy” assessed by measuring change in plasma NT-pro B type natriuretic peptide (NT-pro BNP) between baseline and the end of 3 months’ treatment
ALOFT – Study Design
12-Week Double-blind Treatment
2-Week Run-in
N=280 patients with stable HF/HTN, BNP >150 pg/mL (then lowered to 100 pg/ml) Stratified for systolic dysfunction and preserved systolic function
Placebo Placebo
Aliskiren 150 mg
Standard therapy for heart failure continued throughout study in all patients +
McMurray J, et al. Latebreaker presentation at ESC Congress 2007. CSPP100A2313 protocol
Patient population – inclusion criteria
Consenting men and women ≥ 18 years Stable NYHA class II–IV ≥ 1 month Past or current diagnosis of hypertension Stable dose of an ACE inhibitor (or ARB) and a beta-
blocker (unless intolerant) Plasma BNP > 100 pg/mL (28.9 pmol/L)
302 patients randomized
Study flow diagram
641(100%) patients entered single-blind placebo run in
Placebo, n=146 (100%) patients Aliskiren 150 mg, n=156 (100%) patients
14 (9.0%) discontinued 7 (4.5%) adverse event 5 (3.2%) protocol violation 1 (0.6%) death 0 (0.0%) abnormal laboratory value 1 (0.6%) withdrawal of consent 0 (0.0%) lost to follow-up 0 (0.0%) administrative problems
11 (7.5%) discontinued 4 (2.7%) adverse event 2 (1.4%) protocol violation 2 (1.4%) death 1 (0.7%) abnormal laboratory value 0 (0.0%) withdrawal of consent 1 (0.7%) lost to follow-up 1 (0.7%) administrative problems
142 (91.0%) completed 135 (92.5%) completed
339 (52.9%) discontinued 264 (41.2%) abnormal test result 33 (5.1%) abnormal laboratory value 17 (2.7%) protocol violation 11 (1.7%) adverse event 11 (1.7%) withdrawal of consent 1 (0.2%) lost to follow-up 1 (0.2%) administrative problems 1 (0.2%) death
776 patients screened
Baseline treatment
Placebo (n=146)
Aliskiren 150 mg (n=156)
ACE inhibitor, n (%) 123 (84) 130 (83)
ARB, n (%) 21 (14) 25 (16)
Aldosterone antagonist, n (%) 49 (34) 52 (33)
Beta-blocker, n (%) 138 (95) 147 (94)
ACE, angiotensin converting enzyme ARB, angiotensin receptor blocker
AloF – Significant Reduc4on in BNP
-70
-60
-50
-40
-30
-20
-10
0
Cha
nge
from
bas
elin
e (p
g/m
L)
Optimal HF therapy + placebo
Optimal HF therapy + aliskiren 150 mg
-90
-80
n=137 n=148
p=0.0160
-12.2
-61
mean±SEM
AloF – Significant Reduc4on in NT-‐pro BNP
0
250
500
750
1000
1250
1500
Cha
nge
from
bas
elin
e (p
g/m
L)
Optimal HF therapy + placebo
Optimal HF therapy + aliskiren 150 mg
-500
-250
n=127
n=137
p=0.0106 761.7
-243.6
mean±SEM
ALOFT findings: significant reduction in PRA
-5
-4
-3
-2
-1
0
Cha
nge
from
bas
elin
e (n
g/m
L/h)
Optimal HF therapy + placebo
Optimal HF therapy + aliskiren 150 mg
-8
-6
n=137 n=145
p<0.0001
-0.97
-7 -5.71
mean±SEM
ALOFT findings: change in plasma aldosterone
-50
-40
-30
-20
-10
0
Cha
nge
from
bas
elin
e (p
mol
/L)
Optimal HF therapy + placebo
Optimal HF therapy + aliskiren 150 mg
-80
-60
n=134 n=145
p=NS
-30.9
-48.6
-70
mean±SEM
AloF-‐ significant reduc4on in urinary aldosterone
-10
-8
-6
-4
-2
0
Cha
nge
from
bas
elin
e (n
mol
/day
)
Optimal HF therapy + placebo
Optimal HF therapy + aliskiren 150 mg
-14
-12
n=128 n=141
p=0.015
-7.0
-9.2
mean±SEM
Patients (%)
7
4
0
5
6
8
Renal dysfunction
3
2
1
Symptomatic hypotension
Hyperkalaemia
1.9% 1.4%
3.2%
1.4 %
4.8%
6.4%
p=1.0000
p=0.4495
p=0.4989
Aliskiren 150 mg (n=156)
Placebo (n=146)
No Significant increase in renal dysfunction, symptomatic hypotension or hyperkalemia compared to placebo
McMurray J, et al. Latebreaker presentation at ESC Congress 2007
ALOFT: Pre-specified safety assessments
Perspectives from other Outcome Studies
-70
-60
-50
-40
-30
-20
-10
0
10
Cha
nge
in B
NP
(pg/
mL)
n=137 n=148 n=1850
n=51 n=50 n=340 n=343
ALOFT 3 months
A-HeFT 6 months
Val-HeFT 4 months
RALES 3 months
-12
-61
-34
+2 n=1890
- 6
-15 -8
-39
Placebo Aliskiren Valsartan
Spironolactone Hydralazine-isosorbide dinitrate
Baseline BNP concentration (pg/mL)
p=0.016
p<0.0001
p=0.02
p=0.05
291 181 ~70 ~300
Summary
The RAAS system is an important system contributing to hypertension.
New insights reveal that aldosterone is a major cause of resistant hypertension and metabolic syndrome.
Agents vary in their ability to antagonize aldosterone, eg aldosterone blockers and renin inhibitors.
Multiple RAAS blockers are complementary in their ability to lower blood pressure and prevent target organ damage.