the benefit of ras inhibition to treat hypertension ... · the benefit of ras inhibition to treat...

SYP.IRB-A.15.04.02

The Benefit of RAS Inhibition to Treat

Hypertension Patient with Renal

Impairment

dr. FX Suharnadi, Sp.PD-KEMD

RS PANTI RAPIH

SYP.IRB-A.16.04.02

SYP.IRB-A.15.04.02

Vessel

Kidney

Hypertension Left Ventricular

Hypertrophy

Chronic Heart Failure

Myocardial Infarction

Congestive Heart

Disease

Arrhythmia Arteriosclerosis

Peripheral Vascular Disease

Coronary Heart Disease

Renal Insufficiency

Heart Brain

Stroke

SYP.IRB-A.15.04.02

The Continuum of Diseases

Increase Risk

Initiation

Progression

End-Stage

Kidney Diseases Cardiovascular Diseases

Diabetes

Hypertension

Hyperlipidemia

Diabetes

Hypertension

Hyperlipidemia

CAD ; LVH Damage ; Proteinuria

GFR CVD events

Heart Failure Dialysis

SYP.IRB-A.15.04.02

Kidney failure Clearance <

60 mL/min

n = 61 (14%)

Microalbuminuria

n = 55 (12%)

2. J Hypertens. 2008;26:427-432.

Renal damage breakdown in 459 non-treated and

non-diabetic hypertensive italian patients

Renal damage = 24%

57 51 4

SYP.IRB-A.15.04.02

BP Control and GFR Decline

•Parving HH et al. Br Med J 1989 Moschio G et al. NEJM 1996 • Viberti GC et al. JAMA 1993

SYP.IRB-A.15.04.02

KIDNEY PROTECTION EFFECT OF

ANGIOTENSIN RECEPTOR BLOCKERS

SYP.IRB-A.15.04.02

GFR

Proteinuria

Aldosterone release

Glomerular sclerosis

A II → AT1

receptor

Atherosclerosis

Vasoconstriction

Vascular hypertrophy

Endothelial dysfunction

LV hypertrophy

Fibrosis

Remodeling

Apoptosis

Stroke

Death

Hypertension

Heart failure

MI

Renal failure

Angiotensin II Plays a Central

Role in Organ Damage

1. Willenheimer R, Dahlof B, Rydberg E, Erhardt L. AT1-receptor blockers in hypertension and heart failure: clinical experience and future directions. Eur Heart J. 1999;20:997–1008.

2. Dahlof B. Effect of angiotensin II blockade on cardiac hypertrophy and remodelling: a review. J Hum Hypertens.1995;9(suppl 5):S37–44. 3. Daugherty A, Manning MW, Cassis LA. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest. 2000;105:1605–12. 4. Fyhrquist F, Metsarinne K, Tikkanen I. Role of angiotensin II in blood pressure regulation and in the pathophysiology of cardiovascular disorders. J Hum Hypertens. 1995;9 (suppl 5):S19–24.

SYP.IRB-A.15.04.02

Role of Angiotensin II

in Chronic Renal Disease

Adhesion molecules Chemotactic factors Cell growth Apoptosis TGF-, CTGF PAI-1

Glomerular capillary

pressure Single nephron GFR

Macrophage infiltration

Angiotensin II

•Mechanical stress •Mesangial changes •Oxidative stress •Proteinuria •NF-B activation

Glomerulosclerosis

& Tubulo-interstitial

fibrosis

Renal disease

Nephron loss

Adapted from Berk B. 2001. www.hypertensiononline.org

SYP.IRB-A.15.04.02

MAP

Renal disease: dilated afferent arteriole allows

transmission of high systemic pressure

leading to glomeular capillary hypertension

ACEI/ARBs dilate the

efferent arteriole – the

downstream pressure

valve – thus controlling

glomerular capillary

hypertension

GCP Anti-hypertensives

reduce MAP

0

2

4

6

8

10

12

14

Optimal Microalbuminuria

≥75

60-74

45-59

15-45

Cardiovascular mortality risk in the

general population Impact of microalbuminuria

1. Adapted from Hallan et al. Archives Internal Medicine 2007 167;22;2490-2496

2. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease Am J Kidney Dis 2002; 39 (2 Suppl 1):S1-246

3. Edinburgh Consensus Conference on Early Chronic Kidney Disease, February 2007

(http://www.rcpe.ac.uk/Whats_New/consensus-statements/final-early-chronic-kidney-disease.pdf; date last accessed 30/04/08)

*P<0.05

†P<0.01

‡P<0.001

* *

†

‡

‡

Ad

juste

d i

ncid

en

ce

ra

te r

ati

os (

IRR

)

UACR

Category of eGFR,

mL/min/1.73 m2

‡

Corresponding

CKD stage

1 & 22

22

3a3

3b3 & 42

SYP.IRB-A.15.04.02

SYP.IRB-A.15.04.02

Benefit of ARB & ACE-I as

Renoprotective Agent

SYP.IRB-A.15.04.02

IDNT = Irbesartan Diabetic Nephropathy Trial; IRMA 2 = Irbesartan Microalbuminuria Type 2 Diabetes Mellitus in Hypertensive Patients; RENAAL = Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan; MARVAL = Microalbuminuria Reduction with Valsartan. *AHT = other antihypertensive therapy excluding ACE-Is, ARBs, and CCBs; †AHT excluding ACE-Is, ARBs, and DHP CCBs; ‡AHT excluding ACE-Is and ARBs.

Effect of ARBs on Diabetic

Nephropathy Acronym Diagnosis Randomization Primary

End Point Duration

IDNT N = 1715

Type 2 diabetes mellitus (DM) with nephropathy

Irbesartan/ amlodipine/ placebo + AHT*

• ESRD • 2x creatinine • Mortality

2.6 yrs

IRMA 2 N = 590

Type 2 DM with microalbuminuria

Irbesartan (150 mg)/ irbesartan (300 mg)/ placebo + AHT†

Progression to proteinuria

2 yrs

RENAAL

N = 1513 Type 2 DM with nephropathy

Losartan/placebo + AHT‡

• ESRD • 2x creatinine • Mortality

3.4 yrs

MARVAL N = 332

Type 2 DM with microalbuminuria

Valsartan/amlodipine Urinary albumin excretion ratio

6 mths

SYP.IRB-A.15.04.02

IDNT RENAAL

New End Points and Guidelines for Diabetes & Hypertension

Natural History and Progression of

Renal Disease

Preclinical

(0-5 y)

GBM thickening

Mesangial

remodelling

Macroalbuminuria

(15-30 y)

Hypertension

Retinopathy/neuropathy

CV events ++

Microalbuminuria

(5-15 y)

Endothelial dysfunction

HBP

Retinopathy/neuropathy

CV events +

1. Lowering blood pressure 2. Inhibiting RAAS 3. Early intervention

Renal function Death

ESRD Death

IRMA 2 MARVAL

GBM = glomerular basement membrane

SYP.IRB-A.15.04.02

ACEI/ARB & Reduced Risk of Rapid GFR

Decline, Kidney Failure, or Death

-50

-40

-30

-20

-10

0

Co

mp

osit

e R

isk (

%)*

Wright et al for the AASK Study Group. JAMA. 2002;288:2421-2431. [AASK - African American Study of Kidney Disease and Hypertension] Brenner et al for the RENAAL Study Investigators. N Engl J Med. 2001;345:861-869. [RENAAL = Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan] Lewis et al for the Collaborative Study Group. N Engl J Med. 2001;345:851-860. [IDNT = Irbesartan in Diabetic Nephropathy Trial.]

Ramipril vs

Amlodipine

P = 0.004

Ramipril vs

Metoprolol

P = 0.04

Losartan vs

Placebo

P = 0.02

-38

-22

-16

Irbesartan vs Placebo

P = 0.02

-20

Irbesartan vs Amlodipine

P = 0.006

-23

AASK (N=1094) RENAAL (N=1513) IDNT (N=1722)

© 2005 The Johns Hopkins University School of Medicine.

SYP.IRB-A.15.04.02

Comparison among ARBs ARBs Dose

(mg/day)

Other Indications Approved Outside of Hypertension

Losartan 50-100

1-2x/day

Diabetic nephropathy when serum creatinine is increased and

proteinuria present in patients with hypertension and type 2

diabetes; Stroke reduction in patients with hypertension and left

ventricular hypertrophy (non-black only)

Candesartan 16-32

1-2x/day

Treatment of heart failure (NYHA Classes II–IV)

Eprosartan 600-800

1-2x/day

None

Irbesartan 150-300

1x/day

Diabetic nephropathy when serum creatinine is increased and

proteinuria present in patients with hypertension and type 2 diabetes

Telmisartan 40-80

1x/day

Cardiovascular risk reduction in patients unable to take ACE

inhibitors

Valsartan 80-320

1x/day

Treatment of heart failure (NYHA Classes II–IV); Reduction of CV

mortality in clinically stable patients with left ventricular failure or

dysfunction following myocardial infarction.

Olmesartan 20-40; 1x/day None

Azilsartan 40-80; 1x/day None

Abraham HMA, et al.Drug Saf.2015;38(1):33-54

SYP.IRB-A.15.04.02

A PRogram for Irbesartan Mortality and

Morbidity Evaluation

SYP.IRB-A.15.04.02

Double-blind Treatment Screening/Enrollment

IRMA-2 Study Design : Irbesartan in

Patients with Early Renal Disease

590 patients (mean age 58 years) with type 2 diabetes,

microalbuminuria (albumin excretion rate 20–200 g/min),

normal renal function, and hypertension

Up to 5 weeks

Irbesartan 150 mg

Follow-up: 2 years

Placebo

Irbesartan 300 mg

Parving H-H et al. N Engl J Med 2001;345: 870–8.

n = 194

n = 201

n = 195

Primary outcome : the time to

the onset of diabetic nephropathy

SYP.IRB-A.15.04.02

0

70

130

160

0 3 6 9 12 15 18 21 24 27 Months

Mean SeSBP

and SeDBP

(mm Hg)

80

90

100

110

120

140

150

Control SeDBP

Irbesartan 150 mg SeDBP

Irbesartan 300 mg SeDBP

Control SeSBP

Irbesartan 150 mg SeSBP

Irbesartan 300 mg SeSBP

IRMA-2 Results: Consistent Blood

Pressure Response

Concomitant antihypertensive agents received by 56% of patients in

the control group, 45% in the irbesartan 150 mg group, and 43% in the

irbesartan 300 mg group.


SYP.IRB-A.15.04.02

95

100

105

110

Placebo

Irbesartan 150 mg

Irbesartan 300 mg

Cre

ati

nin

e

cle

ara

nce

(ml/m

in/1

.73 m

2)

3 6 12 18 24

Months of follow-up

Parving HH et al. N Engl J Med 2001;345:870-8

IRMA: Creatinine clearance

NS

SYP.IRB-A.15.04.02

-50

-40

-30

-20

-10

0

10

20

3 6 12 18 24

Months of follow-up

Parving HH et al. N Engl J Med 2001;345:870-8

IRMA: Change in urinary albumin excretion C

han

ge

in

uri

nary

Alb

um

in

excre

tio

n

(%)

Placebo

Irbesartan 150 mg

Irbesartan 300 mg

p<0.001

p<0.001

SYP.IRB-A.15.04.02

IRMA-2 Results: Irbesartan Significantly Delays

Progression To Diabetic Nephropathy

Incidence of Progression to Diabetic Nephropathy


0

5

10

15

20

0 3 6 12 18 22 24 Follow-up (months)

Subjects

(%)

Control

Irbesartan 150 mg

Irbesartan 300 mg n = 194

n = 201

n = 195

P=0.08

P<0.001

SYP.IRB-A.15.04.02

Summary IRMA-2 Study: Use of Irbesartan in

Hypertensive Type 2 Diabetes Patients with

Microalbuminuria

• Irbesartan is renoprotective in

hypertensive patients with type 2 diabetes

and microalbuminuria,

– Regression to normoalbuminuria was more

frequent with irbesartan 300 mg

• The renoprotective effect of irbesartan is

independent of its blood pressure-lowering

effect


SYP.IRB-A.15.04.02

Angiotensin II Receptor Blockers in Type 2

Diabetics Progression of Microalbuminuria†

Primary Outcome:

Development of

clinical proteinuria‡

Duration

IRMA II

(n=590)

Irbesartan 150mg

vs placebo* 39% (P=0.080)

2 yrs

Irbesartan 300mg

vs placebo* 70% (P<0.001)

†Albumin excretion rate of 20 to 200 g per minute in 2 of 3 consecutive, sterile, overnight urine

samples

‡Urinary albumin excretion rate >200 g per minute and at least 30% higher than baseline in at

least 2 consecutive measurements

*In combination with conventional antihypertensive therapy (excluding ACE inhibitors)

IRMA II=The Irbesartan Microalbuminuria Type 2 Diabetes in Hypertensive Patients Study


SYP.IRB-A.15.04.02

Double-blind Treatment

Screening/Enrollment

1,715 patients (mean age 59 years) with type 2 diabetes,

nephropathy (proteinuria 900 mg/d), and hypertension

Up to 5 weeks

Placebo*

Irbesartan*

Amlodipine*

Minimum follow-up:

approximately 2 years

(average 3 years)

* Adjunctive antihypertensive therapies (excluding ACE

inhibitors, angiotensin II receptor antagonists, and

calcium channel blockers) added to each arm to

achieve equal blood pressure reduction

Lewis EJ et al. N Engl J Med 2001; 345: 851–860.

IDNT Study: Irbesartan in Patients with Late

Renal Disease Study Design

n = 579

n = 569

n = 567

SYP.IRB-A.15.04.02

IDNT: Irbesartan Produces A Consistent

Blood Pressure Response

0 6 12 18 24 30 36 42 48 54

Follow-up visit (mo)

BP

(mm Hg)

Irbesartan

Amlodipine

Control

80

100

120

140

160

SBP

Mean

DBP

Patients received 3.0 concomitant

antihypertensive agents in the

irbesartan and amlodipine groups, and

3.3 concomitant agents in the control

group.


SYP.IRB-A.15.04.02

Subjects

(%)

Follow-up (mo)

0 6 12 18 24 30 36 42 48 54 60

0

10

20

30

40

50

60

70

Irbesartan

Amlodipine

Control

RRR 20%

p=0.02 p=NS

RRR 23%

p=0.006

IDNT primary endpoint: Time to doubling of serum creatinine, ESRD, or death

IDNT Results: Irbesartan Reduces the Progression

of Diabetic Nephropathy (Combined Endpoint)


n = 579

n = 569

n = 567

SYP.IRB-A.15.04.02

Irbesartan

Amlodipine

Placebo

RRR = 34% p = 0.0002 RRR = 26%

p = 0.011 RRR = -12% p = 0.32


Patients

reaching

Scr

doubling

or ESRD

(fraction)

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 6 12 18 24 30 36 42 48 54 60 66 72 78

Follow-up time (months)

n = 579

n = 569

n = 567

IDNT: Time to renal endpoint (Doubling of serum creatinine or ESRD)

SYP.IRB-A.15.04.02

Summary of IDNT: Use of Irbesartan in

hypertensive patients with type 2 DM with

nephropathy

• Irbesartan reduced the incidence of the primary composite

endpoint of a doubling of serum creatinine, end stage renal

disease, or death by 23% vs amlodipine (P=0.006) and

20% vs placebo (P=0.02)

• Risk of a doubling of the serum creatinine concentration

was reduced 33% in the irbesartan group compared to

10% with placebo (37% vs amlodipine)

• These benefits were above and beyond those

attributable to blood pressure reduction alone


SYP.IRB-A.15.04.02

Angiotensin II Receptor Blockers

in Type 2 Diabetics With Nephropathy

Progression of Renal Insufficiency

Primary Endpoint:

Composite of doubling of

serum creatinine, end

stage renal disease, or

death

Average

Duration

RENAAL

(n=1,514)

Losartan 50-100 mg

vs placebo* 16% (p=0.02) 3.4 yrs

IDNT

(n=1,715)

Irbesartan 150-300mg vs

placebo* 20% (p=0.02)

2.6 yrs

Irbesartan 150-300 mg

vs Amlodipine*

23% (p=0.006)

*In combination with conventional antihypertensive therapy (excluding ACE inhibitors)

RENAAL=The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study

IDNT=The Irbesartan in Diabetic Nephropathy Trial

Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.

Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860. www.hypertensiononline.org

SYP.IRB-A.15.04.02

THE RECOMMENDATION

SYP.IRB-A.15.04.02

JNC 8. James et al, 2014; JAMA 2014; DOI:10.1001/jama.2013.284427.

Available at: http://jama.jamanetwork.com/journal.aspx

Guideline JNC 8

SYP.IRB-A.15.04.02

Guidelines Recommendation – Initial Treatment for Adult Hypertension (JNC 8)

James et al, 2014

SYP.IRB-A.15.04.02

Goals

• Most patients with diabetes and hypertension should be treated to a systolic blood pressure goal of ,140 mmHg and a diastolic blood pressure goal of ,90 mmHg (A)

• Lower systolic and diastolic blood pressure targets, such as 130/80 mmHg, may be appropriate for individuals at high risk of cardiovascular disease, if they can be achieved without undue treatment burden (C)

• Treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes (ACE inhibitors, angiotensin receptor blockers, thiazide- like diuretics, or dihydropyridine calcium channel blockers).(A)

ADA Recommendations: Hypertension/Blood Pressure Control

ADA. IX. Cardiovascular Disease and Risk Management. Diabetes Care 2017;40(Suppl. 1):S75–S87 | DOI: 10.2337/dc17-S012

SYP.IRB-A.15.04.02

Specific Treatment

• An ACE inhibitor or angiotensin receptor blocker, at the maximum tolerated dose indicated for blood pressure treatment, is the recommended first-line treatment for hypertension in patients with diabetes and urinary albumin–to–creatinine ratio ≥ 300 mg/g creatinine (A) or 30–299 mg/g creatinine (B).

ADA Recommendations: Hypertension/Blood Pressure Control

ADA. IX. Cardiovascular Disease and Risk Management. Diabetes Care 2017;40(Suppl. 1):S75–S87 | DOI: 10.2337/dc17-S012

SYP.IRB-A.15.04.02

Health Economic Benefits of

Irbesartan in Hypertensive

Patients with Type 2 Diabetes

and Microalbuminuria

PRIME MODEL

Palmer AJ, Annemans L, Roze S, et al.Diabetes Care.2004;27:1897-903.

PRIME = Program for Irbesartan Mortality and Morbidity Evaluations

SYP.IRB-A.15.04.02

DESIGN AND METHOD

SYP.IRB-A.15.04.02

Irbesartan delays onset of ERSD

SYP.IRB-A.15.04.02

RESULT

• Early irbesartan treatment was projected to improve life expectancy and reduce costs in hypertensive patients with type 2 diabetes and microalbuminuria.

• Late given irbesartan is also cost effective but at a lower extent.

SYP.IRB-A.15.04.02

Summary

• Hypertension is a major contributor of end organ disease

including kidney damage and Angiotensin II plays a role in the

organ damage.

• Proteinuria is one of the established CV risk factors that indicate

organ damage and hence need proper management.

• RENAAL, IDNT and IRMA II present strong evidence to date for

the efficacy of specific types of treatment (ARB) to slow the

progression of nephropathy in type 2 diabetes.

• ARB (irbesartan) in long term treatment and given at early stage

of diabetic nephropathy is showing cost-effective.

SYP.IRB-A.15.04.02

Irbesartan delays progression of nephropathy as measured by

estimated glomerular filtration rate: post hoc analysis of the

Irbesartan Diabetic Nephropathy Trial (IDNT) Evans M, Bain SC, Hogan S, et al.Nephrol Dial Transplant.2012;27:2255-63.

Irbesartan initially decreased

ΔeGFR vs placebo

The first 3 months

In long-term, irbesartan

significantly slowed the rate of

ΔeGFR decline vs amlodipine

and placebo :

• from 6 to 21 months

(P=0.0048)

• and 24 to 48 months (P <

0.0001)

eGFR : estimated glomerular filtration rate

Irbesartan

Amlodipine Placebo

SAID.IRB.17.10.0377

SYP.IRB-A.15.04.02




The first 3 months

The longer patients

remained on irbesartan, the

greater the benefit :

ΔeGFR decline : (mL/min/m2/year)

o Irbesartan : - 2.34

o Amlodipine : - 3.76

o Placebo : - 3.52

Irbesartan

Amlodipine Placebo

SAID.IRB.17.10.0377

SYP.IRB-A.15.04.02




Irbesartan significantly

slowed the rate of

deterioration in ΔeGFR in all

3 baseline CKD stages (vs

placebo) :

o stages 1-2 : p=0.022

o stage 3 : p=0.006

o stages 3-4 : p=0.018

The rate of decline in ΔeGFR was greater in

those with earlier CKD stages

SAID.IRB.17.10.0377

SYP.IRB-A.15.04.02




DISCUSSION :

• Irbesartan produced a rapid and sustained proteinuria reduction

• The long-term efficacy of irbesartan was independent of changes in

blood pressure

• Irbesartan has been shown to reduce endothelial dysfunction, oxidative

stress and inflammation. In addition, RAAS blockade decreases

collagen formation and improves kidney oxygenation.

Irbesartan significantly slowed the long-term rate of decline in eGFR

compared to non-RAAS-based therapies, resulting in delayed

progression towards ESRD by at least 33%.

RAAS : renin-angiotensin-aldosterone system; ESRD : end-stage renal disease

SAID.IRB.17.10.0377

the benefit of ras inhibition to treat hypertension ... · the benefit of ras inhibition to treat...

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