Dr. Danny Woo - Nephrology Associates of Kentuckiananephky.com/woo/Aldosterone, Renin, and...

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

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120

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-73

180

Ch

ange

fro

m B

asel

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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

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W

eek

8 in

PR

A (%

)

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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

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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

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Years of Follow-up

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0.

10

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20

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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

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Cha

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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

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g/m

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－500

－250

n=127

n=137

p=0.0106 761.7

－243.6

mean±SEM

ALOFT findings: significant reduction in PRA

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－4

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－1

0

Cha

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－6

n=137 n=145

p<0.0001

－0.97

－7 －5.71

mean±SEM

ALOFT findings: change in plasma aldosterone

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0

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n=134 n=145

p=NS

－30.9

－48.6

－70

mean±SEM

AloF-‐ significant reduc4on in urinary aldosterone

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－4

－2

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－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

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NP

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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.

Dr. Danny Woo - Nephrology Associates of Kentuckiananephky.com/woo/Aldosterone, Renin, and...

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