Role of raas inhibition in management of hypertension

Role of RAAS inhibition Role of RAAS inhibition in the Management of in the Management of

HypertensionHypertension

Dr KyawSoe WinMBBS, M Med Sc (Int Med), MRCPUK, FRCPE, FAsCC, FAPSIC

Asso: Prof / Senoir Consultant CardiologistDepartment of Cardiovascular Medicine

Mandalay General Hospital

Hot Topic In Hypertension 2013

12th January 2013

RAAS: Central Role in the Pathogenesis

of Cardiovascular Disease

Ang II effect in target organ damage

McFarlane SI et al. Am J Cardiol. 2003;91(suppl):30H-7.

Angiotensinogen

Angiotensin I

Angiotensin II

Renin

ACE

Aldosterone(Adrenal/CV tissues)

Stroke HFKidneyfailure

↑BP

VSMC

Fat cells

Reduced baroreceptor sensitivity

RAAS: Sites of intervention with RAAS modulators

Angiotensinogen

Angiotensin I

Renin

ACEinhibitors

Angiotensin-convertingenzyme (ACE)

Angiotensin II

AT1 receptor

Angiotensin receptorblockers

AT2 receptor

Atherosclerosis, hypertension Vascular protection?

Adapted from Nickenig G. Circulation. 2004;110:1013-20.

Direct renin inhibitor

Aldosterone

Aldo antagonist

Atherosclerosis-promoting actions of Ang II and protective effects of bradykinin

↑↑ VasodilationVasodilation↑↑ ProstacyclinProstacyclin↑↑ Nitric oxideNitric oxide

↑↑ tPAtPA

↑↑ Vasoconstriction Vasoconstriction ↑↑ ICAM-1, VCAM-1 ICAM-1, VCAM-1

↑↑ Growth factorsGrowth factors↑ Oxyradical formationOxyradical formation

↑ PAI-1PAI-1↑ Smooth muscle cellSmooth muscle cell

proliferation proliferation↑ Matrix degradationMatrix degradation

Protection against Protection against the effects the effects

of Ang IIof Ang II

↑ Endothelial dysfunctionEndothelial dysfunction↑ Inflammation Inflammation ↑ CoagulationCoagulation

↑ AtherogenesisAtherogenesis

BradykininBradykinin

Ang IIAng II

Inactive peptidesInactive peptides

Ang IAng I

--

--

ACEinhibitor

Ferrari R. Expert Rev Cardiovasc Ther. 2005;3:15-29.

AT1R blockade upregulates both Ang II levels and AT2R expression

Ang I

Strauss MH, Hall AS. Circulation. 2006;114:838-54.

Ang II

AT2

ACE

ARB

AT1 AT4

Ang I

Ang II

AT2

ACE

ARB

AT1 AT4

+

Both physiologic and pathologic effects have been proposed for AT2R stimulation

Vasodilation Hypertrophy Inflammation

ImpairedNO synthase

Ang II and mechanisms of atherosclerosis

Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.

IL-6MCP-1PDGF

LOX-1

PAI-1TF

TGF-β

VCAMICAM

Angiotensin II

Lipid oxidation

Thrombosis

Inflammation

Proliferation fibrosis

Adhesion

EndothelialdysfunctionEndothelialdysfunction

PERTINENT: ACE inhibition ↑ NO via ↑ eNOS activity

Ferrari R et al. www.europa-trial.org

0

1

2

3

4

2.5

3.5

2.4

2.93.3

Controlsn = 45

Placebon = 44

Placebon = 44

Perindopriln = 43

Perindopriln = 43

P < 0.01*P < 0.05†

Baseline 1 Year

eNOSactivity in HUVECs

(pmol/min/mg protein)

Controls CAD patients

* vs baseline† ∆ perindopril vs ∆ placebo

PERindopril – Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial (substudy of EUROPA)

HUVEC = human umbilical vein endothelial cell

Schwartzkopff B et al. Hypertension. 2000;36:220-5.

0

200

400

600

800

Periarteriolar collagen

P = 0.04

53%

558 ± 270

260 ± 173

µm2

0

2

4

6

8

Total interstitial collagen

P = 0.04

22%5.5 ± 3.8

4.3 ± 3.2Vv%

Pretreatment(n = 14)

Post-treatment*(n = 14)

Coronary reserve

+67%

P = 0.001

Baseline 2.1

3.5Perindopril

*Perindopril 4–8 mg for 12 months

ACEI normalizes structure of resistance arteries in CAD patients

At treatment end (12 mo)

AT1 receptor blockade improves flow-mediated vasodilation122 Hypertensive patients treated for 2 months

*P < 0.05 vs baseline and vs placebo Koh KK et al. Am J Cardiol. 2004;93:1432-5.

0.15

1.14

1.66

1.32

0.0

0.5

1.0

1.5

2.0

Placebo(n = 30)

Irbesartan300 mg(n = 30)

Losartan100 mg(n = 31)

Candesartan16 mg

(n = 31)

∆FMD

inbrachialartery(%)

2.5

*

*

*

Inflammation

IL-6MCP-1PDGF

Inflammation



ImpairedNO synthase LOX-1

PAI-1TF

TGF-β

VCAMICAM

Lipid oxidation

Thrombosis


Endothelialdysfunction

Adhesion

Angiotensin II

ACE inhibition reduces oxidative stress and inflammation

20 Patients with type 2 diabetes

Marketou ME et al. J Am Coll Cardiol. 2005;45 (suppl A):396A.

Baseline Perindopril 4 mg x 6 mos

* P < 0.05 vs baseline

TNF-α IL-6Lipid peroxides

3.3

2.0

0

1

2

3

4

2.9

1.8

370

264

0

100

200

300

400

µmol/L pg/mL

** *

LOX-1

VCAMICAM



IL-6MCP-1PDGF

ImpairedNO synthase

PAI-1TF

TGF-β

Thrombosis

Inflammation



Angiotensin II

Lipid oxidationLipid oxidation

AdhesionAdhesion

Ang II upregulates LOX-1 expression via lipoxygenase pathway

* P < 0.0001 vs control† P < 0.0001 vs Ang II‡ P < 0.05 vs Ang II

Bai = baicalein (12-lipoxygenase inhibitor)

Human vascular smooth muscle cells

Limor R et al. Am J Hypertens. 2005;18:299-307.

Ang II10-7 mol/L+

losartan 10-5 mol/L

0

100

200

300

Control Ang II10-7 mol/L

Ang II10-7 mol/L+

Bai 10-5 mol/L

LOX-1mRNA

*† ‡

400

TGF-β



IL-6MCP-1PDGF


PAI-1TF

VCAMICAM

Angiotensin II

Lipid oxidation

Thrombosis

Inflammation


Adhesion

ProliferationProliferation fibrosis

HOPE: Dose-dependent effects of ramipril on LV mass and function

5.31

2.9

–1.9–3

0

2

4

68.21 7.86

–3.53–4

0

5

10

LV end-systolic volumeLV mass

Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.Mean baseline LVEF 58%, all groups

∆(mL)

∆(g)

PTrend = 0.001PTrend = 0.03

N = 446 follow-up, 4 years

Placebo Ramipril 2.5 mg

Ramipril 10 mg

LIFE: Greater reduction in LV mass with angiotensin receptor blockade vs beta-blockade

Devereux RB et al. Circulation. 2004;110:1456-62.

Patients with hypertension and LVH

Change inLV mass

(g)

–50

–20

Year

–10

0

Losartan 50–100 mg (n = 457)

Atenolol 50–100 mg (n = 459)

–30

–40

1 2 3 4 5Lastvisit

P = 0.009 for all time points

PAI-1TF



IL-6MCP-1PDGF


TGF-β

VCAMICAM

Angiotensin II

Lipid oxidation

Inflammation



AdhesionThrombosisThrombosis

Brown NJ et al. Hypertension. 2002;40:859-65.P = 0.043, drug × time interaction

ACE inhibition (ramipril) AT1 receptor blockade (losartan)

10

0

–10

20

Week 1

–20

∆PAI-1

antigen(ng/mL)

30

Week 3 Week 4

Sustained decrease in PAI-1 antigen over time with ACEI vs ARB

Week 6

Greater decrease in PAI-1 over time with ACEI vs ARB

85 Hypertensive diabetic patients treated for 12 weeks

Fogari R et al. Am J Hypertens. 2002;15:316-20.

10

–10

5

0

–5

Losartan 50 mg

4Perindopril 4 mg

–10

P < 0.01

*P = 0.028 perindopril vs placebo

∆PAI-1ng/dL

*

Change in PAI-1 antigen levels: Differing effects of ARBs

Koh KK et al. Atherosclerosis. 2004;177:155-60.

%Change

–40

20

40

60

Placebo

80

–20

0

Irbesartan 300 mg

Losartan 100 mg

Candesartan 16 mg

P < 0.01

P = 0.012P = 0.163

126 Patients with hypertension

Pretorius M et al. Circulation. 2003;107:579-85.

*P < 0.05 vs baseline†P < 0.05 vs vehicle or baseline

‡P < 0.05 vs enalaprilat + vehicleHOE 140 = bradykinin B2 receptor antagonist

Greater effect in women vs men

Women (n = 7) Men (n = 5)

Baseline

‡

HOE 140 + Enalaprilat

HOE 140

2

1

0

3

Net tPArelease(ng/min/100 mL)

2

1

0Baseline

*†

Vehicle + Enalaprilat

Vehicle

3

ACEI increases tPA release through endogenous bradykinin

tPA release: Differing effects of ACEinhibition vs AT1 receptor blockade

Matsumoto T et al. J Am Coll Cardiol. 2003;41:1373-9.*P < 0.05 vs baseline

20

10

15

5

0.2

0

0 0.6 2.0

tPA antigenin coronary

sinus (ng/mL)

Bradykinin (µg/min)

Perindopril 4 mg(n = 16)

Losartan 50 mg(n = 15)

Control(n = 14)

P < 0.05

*

**

**

* *

25

Antiatherosclerotic effect of RAAS modulation: Clinical and experimental evidence

• Studies in several animal models of atherosclerosis demonstrated reduced lesion progression with ACE inhibitor or AT1 receptor blocker1

• Regression of human carotid plaque demonstrated with ramipril (SECURE2), losartan (LAARS3), and fosinopril (PHYLLIS4)

1Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.2Lonn E et al. Circulation. 2001:103;919-25.

3Ludwig M et al. Clin Ther. 2002;24:1175-93.4Zanchetti A et al. Stroke. 2004;35:2807-12.

Lonn EM et al. Circulation. 2001;103:919-25.

0

0.005

0.010

0.015

0.020

0.025

Ramipril 10 mg

Ramipril 2.5 mg

Placebo

0.022

0.018

0.014

NS

37% Reduction

P = 0.028

Mean maximum IMT slope

(mm/y)

SECURE

ACEI reduces atherosclerosis progression

ARB blunts MMP expression in human carotid plaques: Potential role in plaque stabilization

25.828.2

25.1

22.4

5.8 6.2 7.25.6

0

10

20

30

MMP-2 MMP-9 COX-2 mPGES-1

P < 0.0001 all comparisonsARB = AT1 receptor blockade

MMP = matrix metalloproteinase

% Positive staining

Chlorthalidone Irbesartan

Cipollone F et al. Circulation. 2004;109:1482-8.

Carotid endarterectomy specimens

Role of RAAS Modulation:Evidence from Clinical Trials

• CAD• Heart Failure

ACEIs: Evolution of benefits

BP reduction

Cardioprotection

Improved glycemic control (?)

Vascular protection

Lonn E et al. Eur Heart J Suppl. 2003;5(suppl A):A43-8.DREAM Trial Investigators. N Engl J Med. 2006;355:1551-62.

Renal protection

Benefit of ACE inhibition in CADBenefit of ACE inhibition in CAD

EUROPA

HOPE

All CAD patientsAll CAD patients

Post-MI, HF, LVEF <40%

SOLVDSAVEAIRETRACE

SOLVD(prev)

High risk

Bertrand ME. Curr Med Res Opin. 2004;20:1559-69.

ACEI trials in CAD without HF: Primary outcomes

HOPE Study Investigators. N Engl J Med. 2000;342:145-53.Pitt B et al. Am J Cardiol. 2001;87:1058-63.

PEACECV death/MI/CABG/PCI

HOPECV death/MI/stroke

15

5

10

0

20

0

Placebo

Ramipril 10 mg

Time (years)

%

2 41

22% Risk reductionHR 0.78 (0.70–0.86)

P < 0.001

3Time (years)

12

4

10

0

1 3 4

14

0

Placebo

Perindopril 8 mg

86

2

52

EUROPACV death/MI/cardiac arrest


P = 0.0003

40

20

30

0

50

0

Placebo

Quinapril 20 mg

Time (years)1

4% Risk increaseHR 1.04 (0.89–1.22)

P = 0.6

10

2 3

QUIETAll CV events

Time (years)

Trandolapril4 mg

Placebo30

20

10

15

5

1 2 3 4 5

25

06


P = 0.43

EUROPA Investigators. Lancet. 2003;362:782-8.PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

%

%

%

HOPE EUROPA PEACE QUIET

Antiplatelet agents (%) 76 92 91 73

β-Blockers (%) 40 62 60 26

Lipid-lowering agents (%) 29/49* 58/68† 70 0/14*

Calcium antagonists (%) 47 32 36 0/7*

Diuretics (%) 15 10 13 NA

EUROPA Investigators. Lancet. 2003;362:782-8.HOPE Study Investigators. N Engl J Med. 2000;342:145-53.

PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.Pitt B et al. Am J Cardiol. 2001;87:1058-63.

*at study end†at 3 yrs

ACEI outcome trials in CAD patients without HF: CV therapies at entry/during study

ACE inhibitor Key inclusion criteria Primary outcome

EUROPA N = 12,218 (4.2 years)

Perindopril 8 mg CAD No heart failure Age ≥18 years

CV death, MI, cardiac arrest

PEACE N = 8290 (4.8 years)

Trandolapril 4 mg CAD LVEF ≥40% Age ≥50 years

CV death, MI, coronary revascularization

QUIET N = 1750 (2.25 years)

Quinapril 20 mg PTCA, atherectomy Normal LVEF

CV death, MI, coronary revasc, cardiac arrest, hosp for angina



ACEI outcome trials in CAD patients without HF

HOPE N = 9297 (4.5 years)

Ramipril 10 mg Vascular disease (80% had CAD) LVEF ≥40%, or No heart failure Age ≥55 years

CV death, MI, stroke

ACEI outcome trials in CAD patients without HF: Totality of trial evidence

MI

Stroke

All-cause death

Event rate (%)

Favors ACEIACEI

Revascularization

Favors placeboPlacebo

7.5

6.4

2.1

15.5

8.9

7.7

2.7

16.3

0.86

0.86

0.77

0.93

0.0004

0.0004

0.0004

0.025

0.5 0.75 1.251Odds ratio

P

Pepine CJ, Probstfield JL. Vasc Bio Clin Pract. CME Monograph; UF College of Medicine. 2004;6(3).

HOPE, EUROPA, PEACE, QUIET

HOPE, EUROPA, PEACE: Benefit of ACEIs across broad spectrum of risk

Dagenais GR et al. Lancet. 2006;368:581-8.

TrialPatients

(n)Annual rates in placebo groups

OR(95% CI) P

-5 20 405 3015 35Odds reduction (%)

25100

PEACE 8290 2.13 7 (-8 to 19) 0.328

HOPE total 9297 3.95 25 (16 to 32) 0.0001HOPE lower risk 3083 2.17 18 (-4 to 35)HOPE med risk 3100 3.58 20 (3 to 33)HOPE high risk 3114 5.98 24 (12 to 34)

EUROPA total 12,218 2.60 19 (8 to 28) 0.0007

EUROPA lower risk 3976 1.40 19 (-5 to 38)EUROPA med risk 3975 2.41 28 (11 to 41)EUROPA high risk 3975 4.00 10 (-4 to 22)

AIRE 1986 22.6 24 (7 to 38) 0.0068

TRACE 1749 17.0 25 (9 to 33) 0.0028

SOLVD-P 4228 7.4 15 (2 to 27) 0.0252SOLVD-T 2569 13.1 23 (10 to 33) 0.0009SAVE 2231 9.8 20 (4 to 33) 0.0168

CV death,* nonfatal MI or strokeACEI worse

ACEI better

*Or total mortality in AIRE, TRACE, SOLVD, SAVE trials

HOPE Study Investigators. N Engl J Med. 2000;342:145-53. EUROPA Investigators. Lancet. 2003;362:782-8.


ACEI outcome trials in CAD patients without HF: Differences in baseline CV risk

HOPE EUROPA PEACE

Annualizedevent rate in placebo group

(%/yr)

CV death Nonfatal MIQUIET

1.8

1.00.8 0.7

2.7

1.5

1.1

2.0

0.0

1.0

2.0

3.0

EUROPA: EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease

EUROPA Investigators. Lancet. 2003;362:782-8.

Objective: Assess effects of the ACEI perindopril on CV risk in a broad-spectrum population with stable CAD and without HF

Design: N = 12,218, age ≥18 years, with CAD/without HF at randomization

Treatment: Perindopril 8 mg or placebo

Follow-up: 4.2 years

Primary outcome: CV death, nonfatal MI, cardiac arrest

EUROPA: Baseline characteristics


Female History of CAD – MI – PCI – CABGDocumented CAD – Angiographic evidence (stenosis >70% )

14.5 100 64.9 29.0 29.3

60.4

14.710064.729.529.4

60.5

– Positive stress test (in men w/chest pain) History of stroke/TIAPVDHypertension DiabetesHypercholesterolemia

22.6

3.4 7.1 27.0 11.8 63.3

23.3

3.3 7.427.212.863.3

Placebo (%)(n = 6108)

Perindopril (%)

(n = 6110)

EUROPA: Concomitant medications

Platelet inhibitors

Beta-blockers

Lipid-lowering agents

Nitrates

Calcium channel blockers

Diuretics

92

62

58

43

32

9

91

63

69

NA

NA

NA


Baseline (%) 3 Years (%)*

*Concomitant medications recorded in 11,547 patients

EUROPA Investigators. Lancet. 2003;362:782-8.Fox KM. Br J Cardiol. 2004;11:195-204.

EUROPA: Primary outcome

12

4

10

0

1 3 4

14

0

Placebo

Perindopril 8 mg8

6

2

52

Primary outcome

(%)

Time (years)

10%

11%

14%

20%


RRR 20% (95% CI: 9%–29%)AR 8.0% vs 9.9%

P = 0.0003

P < 0.05

P = 0.35

AR = absolute risk (perindopril vs placebo)

RRR 24%AR 5.2% vs 6.8%

P < 0.001

EUROPA Investigators. Lancet. 2003;362:782–8.

Fatal and nonfatal MI

RRR 39%AR 1.0% vs 1.7%

P = 0.002

2

4

Events(%)

0

10

6

8

0 1 2 3 4 5

Years

Placebo

Perindopril8 mg

0.5

1.0

0.0

2.0

1.5

0 1 2 3 4 5

Years

Placebo

Perindopril8 mg

HF hospitalization

EUROPA: Effect of ACEI on fatal/nonfatal MI and HF hospitalizations

AR = absolute risk (perindopril vs placebo)


8.0

14.8

7.9

6.1

3.5

5.2

CV mortality, MI, cardiac arrest

Total mortality, MI, UA, cardiac arrest

CV mortality, MI

Total mortality

CV mortality

Fatal/nonfatal MI

Favorsperindopril

Favorsplacebo

Perindopril (%)(n = 6110)

Placebo (%)(n = 6108)

9.9

17.1

9.8

6.9

4.1

6.8

0.5 1.0 2.0

EUROPA: Benefit of ACEI on primary and secondary outcomesN = 12,218


5.6

0.1

1.6

9.4

1.0

Unstable angina

Cardiac arrest

Stroke

Revascularization

HF w/hospital admission

Favorsperindopril

Favorsplacebo

Perindopril (%)(n = 6110)

Placebo (%)(n = 6108)

6.0

0.2

1.7

9.8

1.7

0.5 1.0 2.0

EUROPA: Benefit of ACEI on selected secondary outcomesN = 12,218

EUROPA: Benefit of perindopril was on top of recommended medications


7.0

9.3

7.6

8.7

9.9

7.1

0.5 1.0 2.0

8.3

11.9

10.2

9.4

11.7

9.0

Lipid-lowering drug

No lipid-lowering drug

β-blockers

No β-blockers

Calcium channel blockers

No calcium channel blockers

Favorsperindopril

Favorsplacebo Perindopril

(n = 6110) Placebo

(n = 6108)

Primary events (%)

EUROPA HOPE

Age, mean (yrs) 60 66

BP (mm Hg) 137/82 139/79

Known CAD (%) MI (%) PVD (%) Stroke/TIA (%) Revascularization (%)Diabetes (%)Hypertension (%)Hypercholesterolemia (%)

1006573

58122763

8053431144394766


EUROPA vs HOPE: Study populations

EUROPA vs HOPE: Inclusion criteria

HOPE • Age ≥55 years • Females: 27%• No HF or LV dysfunction • High-risk of CV events

with history of – CAD, stroke, or peripheral

vascular disease– Diabetes + ≥1 CV risk factor

(hypertension, dyslipidemia, smoking, microalbuminuria)

EUROPA • Age ≥18 years• Females: 15% • No clinical HF• Documented CAD including

– Previous MI, PCI/CABG– Angiographic evidence of

CAD with/without previous coronary event

– Positive stress test (men)


HOPE patients were at higher risk than EUROPAHOPE patients were at higher risk than EUROPA

EUROPA vs HOPE: Event rates in placebo groups reflect differences in baseline risk

80% higher annual rate of CV and total mortality in HOPE80% higher annual rate of CV and total mortality in HOPE


CV mortality Total mortality

Annualizedevent ratein placebo

groups(%)

HOPEEUROPA

1.8

2.7

1.0

1.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Are all ACEIs the same: Survival post-MI by ACEI at discharge

P < 0.001 log-rank

100

90

80

70121086420

Months

Captopril

Ramipril

Quinapril

Fosinopril

Lisinopril

Enalapril

Perindopril

Unadjusted cumulative

survival(%)

N = 7512

Pilote L et al. Ann Intern Med. 2004;141:102-12.

n = 421

n = 905

n = 276

n = 889

n = 2201

n = 2577

n = 243

Factors that may lead to divergent results in ACEI trials

• Underdosing – Dose-related effects on vascular and myocardial tissue

– Dose for CAD patients can’t be predicted from studies in HF or hypertension

• Differences may exist among ACEIs

• Differences in baseline risk (age, diabetes, HTN, PAD)

• Inclusion of revascularization in primary outcome

• Lack of power

• Poor adherence to assigned treatmentPitt B et al. Am J Cardiol. 2004;87:1058-63.

Yusuf S, Pogue J. N Engl J Med. 2005;352:937-8.Pitt B. N Engl J Med. 2004;351:2115-7.

Pepine CJ, Probstfield JL. Vasc Bio Clin Pract. CME Monograph; UF College of Medicine. 2004;6(3).

• Cumulative evidence supports ACE inhibitors for stable CAD patients with/without clinical signs of HF

• Not all ACE inhibitors can be assumed to have comparable effects for all indications – Dose and individual properties of ACEIs are important

• Benefit may depend on risk level – Benefit may be less in patients with well controlled risk factors

• Randomized clinical trial evidence and guidelines should guide selection of effective ACE inhibitor and dose for CAD patients without HF

Pitt B. N Engl J Med. 2004;351:2115-7.

ACEI outcome trials in CAD patients without HF: Clinical implications

• Totality of clinical trial evidence supports ACEI for treatment of stable CAD patients with/without HF

• Benefits have been shown in patients at all levels of risk

• All ACEIs may not have comparable effects for all indications

• Consider evidence and guidelines in selection of an ACEI and dose.

• Both ramipril and perindopril reduce risk of CV events in stable CAD patients without HF

– Ramipril 10 mg has proven efficacy in CAD patients ≥55 yrs

– Perindopril 8 mg has proven efficacy in CAD patients ≥18 yrs

Pitt B. N Engl J Med. 2004;351:2115-7.EUROPA Investigators. Lancet. 2003;362:782-8.

HOPE Study Investigators. N Engl J Med. 2000;342:145-53.PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

Should all patients with stable CAD without HF receive an ACEI? Interpreting evidence

Evidence-based medicine: Updated guide-lines for ACEI in CAD patients without HF

“ACE inhibitors should be used as routine secondary prevention for patients with known CAD, particularly in diabetics without severe renal disease.” . . . R.J. Gibbons et al.

“The HOPE trial…confirms that the ACE inhibitor ramipril reduced CV death, MI, and stroke in patients who were at high risk for, or had, vascular disease in the absence ofheart failure.” . . . R.J. Gibbons et al.

EUROPA “showed that an ACE inhibitor can have a vasculoprotective effect in patients at lower risk than those enrolled in the HOPE study.” . . . V. Snow et al.

Gibbons RJ et al. 2002 ACC/AHA Practice Guidelines. www.acc.org; July 2005.Snow V et al. Ann Intern Med. 2004;141:562-7.

Role of RAAS Modulation in

CAD Patients with heart failure

ACE inhibition in CAD: Short-term trials in acute MI

Odds ratio (95% CI)

220/3044 (7.23%)

570/9682 (5.89%)

2035/29,028 (7.01%)

676/7460 (9.06%)

CONSENSUS-II*

Test for Heterogeneity: χ2 5.8 (2p = 0.1) df = 3

Deaths (n)/Randomized (n)

GISSI-3

ISIS-4

CCS-1

Total

Control O-E Variance

1.0 1.25 1.50.750.5

727/7489 (9.71%)

650/9712(6.69%)

192/3046(6.30%)

2171/29,022(7.48%)

3501/49,214(7.11%)

3740/49,269(7.59%)

14.07

–39.06

–68.22

–24.14

–117.35

96.05

285.83

975.33

317.85

1675.06

ACEI

ACEI better Control better

Odds reduction (± SD)7 ± 2

Treat Eff: χ2 (2p = 0.004)

ACE Inhibitor MI Collaborative Group. Circulation. 1998;97:2202-12.*IV infusion followed by oral therapy

ACE inhibition in CAD: Long-term trials in post-MI LV dysfunction and HF

AIRE Study Investigators. Lancet. 1993;342:821-8.Køber L et al. N Engl J Med. 1995;333:1670-6.

SOLVD Investigators. N Engl J Med. 1991;325:293-302.SOLVD Investigators. N Engl J Med. 1992;327:685-91.

Pfeffer MA et al. N Engl J Med. 1992;327:669-77.

AIRE

TRACE

SOLVD(Treatment)

SAVE

0.002

0.001

0.0036

0.019

0 5 10 15 20 25

Risk reduction in total mortality (%)

P

30

SOLVD(Prevention)

0.30

27%

22%

8%

16%

19%

Aldosterone blockade and AT1 receptor blockade: Trials in post-MI/LV dysfunction or HF

Pitt B et al. N Eng J Med. 1999;341:709-17.Pitt B et al. N Eng J Med. 2003;348:1309-21.

Pitt B et al. N Eng J Med. 2003;349:1893-906.

VALIANT

Months

CaptoprilValsartan

0.4

0.1

0.2

6 12 24 30 36

0.3

0.0

Probability of event

0% RR V vs CHR 1.00 (0.90–1.11)

P = 0.98

RALES

0.75

0.60

1.00

0

Placebo

Spironolactone

Months

Probability of survival

24 366

30% Risk reductionRR 0.70 (0.60–0.82)

P < 0.001

300.00

12 18

0.90

0.45

180

Valsartan/captopril

22

10

2

6 24 300

Eplerenone

Months

18

14

6

3612

EPHESUS15% Risk reductionRR 0.85 (0.75–0.96)

P = 0.008

Cumulativeincidence

(%)

Placebo

018

2% RR V/C vs CHR 0.98 (0.89–1.09)

P = 0.73)

EPHESUS: New subgroup analysis

Pitt B et al. Am J Cardiol. 2006;97(suppl):26F-33F.

N = 6632 with post-MI LVSD, mean follow-up 16 months

Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study

History of hypertensionAll-cause mortalityCV mortality/hospitalizationSudden cardiac death

History of diabetesAll-cause mortalityCV mortality/hospitalizationSudden cardiac death

LVEF ≤30%All-cause mortalityCV mortality/hospitalizationSudden cardiac death

P

0.0010.0020.022

0.1270.03

0.641

0.0120.001

0.010.2 1.0 1.2 1.8

Eplerenone better Placebo better

1.4 1.60.4 0.6 0.8Odds ratio (95% Cl)

Greenberg B et al. Am J Cardiol. 2006;97(suppl):34F-40F.

EMPHASIS-HF: Study design

Eplerenone+ standard therapy

N = 2584 with NYHA class II chronic systolic HF

Results in 2010

Placebo+ standard therapy

Primary end point:CV death, hosp for HF

Follow-up: 4 years

Effect of Eplerenone in Chronic Systolic Heart Failure

EMPHASIS-HF: Major results

EMPHASIS-HF

Outcome Eplerenone (%) Placebo (%) Adjusted hazard ratio (95% CI)

p

Cardiovascular death/heart-failure hospitalization

18.3 25.9 0.63 (0.54–0.74) <0.001

Cardiovascular death 10.8 13.5 0.76 (0.61–0.94) 0.01

Heart-failure hospitalization 12.0 18.4 0.58 (0.47–0.70) <0.001

Hospitalization for hyperkalemia 0.3 0.2 1.15 (0.25–5.31) 0.85

NYHA Class II HF (N=2737)LV EF < 30%

Eplerenone 25-50mg QD vs. Placebo

Greenberg B et al. Am J Cardiol. 2006;97(suppl):34F-40F.

TOPCAT: Study design

Spironolactone

N ≅ 4500 with HF and LVEF >45%

Results anticipated 2011

Placebo

Primary end point:CV death, hosp for HF

Follow-up: ≥2 years

Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist

Enrollment: 3445Study Start Date: August 2006Estimated Study Completion Date: June 2013Estimated Primary Completion Date: June 2013

RAAS Modulation in Patients With Diabetes

Potential role of RAAS activation in metabolic syndrome and diabetes

Adapted from Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9.Paul M et al. Physiol Rev. 2006;86:747-803.

RAAS activation

Skeletal muscle Pancreatic β cells

↑MetS ↑T2DM

MetS = metabolic syndromeT2DM = type 2 diabetes

Obesity

RAAS activation in obesity

Engeli S et al. Hypertension. 2005;45:356-62.

Circulating RAAS, N = 38 menopausal women

*P < 0.05

Renin(ng/l)

ACE(U/l)

Aldosterone (ng/l)

Ang II(nmol/l)

Lean Obese0

3

6

12

9

0

15

30

60

45

0

90

0.00

0.05

0.10

30

60

Lean Obese

Lean Obese Lean Obese

* *

*

Obesity

Volume expansion

Arterial hypertension

Sharma AM. Hypertension. 2004;44:12-19.

↑Leptin Renal medullary compression

↑RAAS activation

Sodium reabsorption

Renal vasodilation ↑SNS activation

SNS = sympathetic nervous system

RAAS activation contributes to obesity-related hypertension

Adipocyte and vasculature interactionsAdipocyte and vasculature interactions

Courtesy of W. Hseuh; 2005.

IL-6

PAI-1TNF-α

AdiponectinLeptin

Insulin sensitivity Insulin resistance

Vascular inflammation Endothelial dysfunction

Angiotensinogen

FFA

Visfatin

Furuhashi M et al. Hypertension. 2003;42:76-81.

• Insulin sensitivity, BMI, and HDL-C independent determinants of adiponectin concentrations

• ACEI and ARB increased insulin sensitivity and adiponectin (P < 0.05)

• Changes in insulin sensitivity correlated with changes in adiponectin (r = 0.59, P < 0.05)

*P < 0.05

N = 16 with essential hypertension and insulin resistance

RAAS blockade increases adiponectin

6

4

10

Adiponectin(µg/mL)

0

8

2

Before After Before After

6

4

10

0

8

2

Temocapril 4 mg(n = 9)

Candesartan 8 mg(n = 7)

*

*

ACEIs: Potential mechanisms of improved glucose metabolism

Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9.

Angiotensin I

ACE/Kininase II

Degradation products

↑Nitric oxide

Angiotensin II

↓Angiotensin II

ACE inhibitors

Bradykinin

↑Bradykinin

↑Skeletal muscleblood flow

↑Glucose metabolism

Effect of ACEIs and ARBs on new-onset diabetes

Abuissa H et al. J Am Coll Cardiol. 2005;46:821-6.

Meta-analysis of 12 randomized controlled trials

CAPPPSTOP-2

HOPELIFE

ALLHATANBP2SCOPEALPINECHARMSOLVDVALUEPEACE

All pooledACEI pooledARB pooled

0.79 (0.67–0.94)0.96 (0.72–1.27)0.66 (0.51–0.85)0.75 (0.63–0.88)0.70 (0.56–0.86)0.66 (0.54–0.85)0.81 (0.61–1.02)0.13 (0.03–0.99)0.78 (0.64–0.96)0.26 (0.13–0.53)0.77 (0.69–0.86)0.83 (0.72–0.96)

0.75 (0.69–0.82)0.73 (0.63–0.84)0.77 (0.71–0.83)

0.125 0.25 0.5 1 2 4 8

Less likely to develop T2DM

Relative risk (95% CI)

More likely to develop T2DM

HOPE, EUROPA, PEACE: Reduction in new-onset diabetes (placebo-controlled trials)

0

2

4

6

8

10

12

14

HOPE EUROPA PEACE Pooled data

New-onset diabetes

(%)

Placebo ACEI

Dagenais GR et al. Lancet. 2006;368:581-8.

n = 23,340 free from diabetes* at baseline

Ramipril 10 mg

Perindopril 8 mg

Trandolapril 4 mg

Overall14% RRRRR 0.86 (0.78–0.95)P = 0.0023

(all trials)

*Not a prespecified end point

PERSUADE: PERindorpil SUbstudy of coronary Artery disease and DiabEtes: The diabetic substudy of EUROPA

Objective: Investigate the effect of long-term treatment with perindopril added to standard therapy on CV

events in diabetic patients with CAD and without heart failure

Population: N = 1502 with known diabetes at randomization

Treatment: Perindopril 8 mg (n = 721) or placebo (n = 781)

Follow-up: 4.2 years

Daly CA et al. Eur Heart J. 2005;26:1369-78.

PERSUADE: Primary outcome

Cumulative frequency

(%)

Perindopril8 mg

Placebo

2 3 4 510

Years from randomization

0

4

8

12

16

20

RRR: 19%95% CI: –7% to 38%

P = 0.13



PERSUADE: Clinical implications

• Perindopril 8 mg once daily reduced CV events in

patients with CAD and diabetes

• Relative risk reduction in primary and secondary

outcomes with perindopril was similar to EUROPA

• Results extend the benefit of ACEI shown in MICRO-

HOPE to a lower-risk population with diabetes and

CAD


HOPE Study Investigators. Lancet. 2000;355:253-9.

3.0

2.5

2.0

1.5

1.0

0.5

0 1 2 3 4.5

Placebo

Ramipril 10 mg

Mean albumin-creatinine ratio

Years

P = 0.001

P = 0.02

0

10

20

30

40

Overtnephro-pathy

CV deathStrokeMI

Riskreduction

(%)P = 0.027

P = 0.0001

P = 0.007

P = 0.01

22

3337

24

N = 3577 (32% with microalbuminuria)

MICRO-HOPE: ACEI improves renal and CV outcomes in type 2 diabetes

HOPE Study Investigators. Lancet. 2000;355:253-9.Daly CA et al. Eur Heart J. 2005. In press.

PERSUADE(N = 1502)

CV death/MI/cardiac arrest

MICRO-HOPE(N = 3577)

CV death/MI/stroke

MICRO-HOPE, PERSUADE: Primary outcome

Placebo

Ramipril10 mg

25

20

15

10

5

0

%

Follow-up (years)

0 1 2 3 4 5

25% Risk reductionRR 0.75 (0.64–0.88)

P = 0.000420

15

10

5

00 1 2 3 4 5

Follow-up (years)

Placebo

Perindopril8 mg

19% Risk reductionP = 0.131

25

MICRO-HOPE, PERSUADE: Consistency of benefit

HOPE Study Investigators. Lancet. 2000;355:253-9.Daly CA et al. Eur Heart J. 2005. In press.

Primary outcome

Total mortality

CV mortality

All MI

Stroke

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

Favors ACEI Favors placebo

Relative risk (95% CI)

MICRO-HOPE(N = 3577)

PERSUADE(N = 1502)

Effects of ACEI on endothelial function: EUROPA substudies

• PERTINENT: PERindopril Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial

– Determined the mechanisms by which the ACEI perindopril improved outcomes in patients with stable coronary artery disease

• PERFECT: PERindopril-Function of the Endothelium in Coronary artery disease Trial

– Evaluated whether long-term administration of perindopril improves endothelial dysfunction

Ferrari R. ESC 2004; Munich.Bots ML et al. Cardiovasc Drugs Ther. 2002;16:227-36.

PERTINENT: Study design

Endothelial cell (EC) studiesEndothelial cell (EC) studiesECs incubated with serum from CAD ECs incubated with serum from CAD patients at baseline and at 1 year* patients at baseline and at 1 year*

Plasma studiesPlasma studiesMeasure substances in plasma that Measure substances in plasma that

modulate ecNOS and apoptosismodulate ecNOS and apoptosis

Ang IIAng IIBradykininBradykinin

TNF-TNF-ααvon Willebrand factorvon Willebrand factor

ecNOSecNOSEC apoptosis rateEC apoptosis rate

*Human umbilical vein ECsecNOS = EC nitric oxide synthase Ferrari R. ESC 2004; Munich.

Levels measured at baseline vs 1 year

Objective: Objective: Evaluate effects of perindopril on endothelial function and markers of Evaluate effects of perindopril on endothelial function and markers of inflammation and thrombosis in EUROPA subgroup of CAD patientsinflammation and thrombosis in EUROPA subgroup of CAD patients

EUROPA substudy

↑ ecNOS activity

↓ Endothelial cell apoptosis

↓ Ang II

↑ Bradykinin

↓ TNF-α↓ von Willebrand factor

Ferrari R. ESC 2004; Munich.*Incubated with patients’ serum

Endothelial cells* Patients’ plasma

EUROPA substudy

• The only significant correlation was between bradykinin and ecNOS

• Results suggest perindopril modifies inflammation and thrombosis and endothelial function through bradykinin-dependent mechanisms

PERTINENT: Effects of treatment with perindopril for 1 year

PERFECT: Study design

Objective: Determine effect of perindopril on brachial artery endothelial function in patients with stable CAD and without clinical HF

Design: Double-blind randomized controlled trial

Population: N = 333 at 20 centers

Treatment: Perindopril 8 mg or placebo

Follow-up: 3 years

Primary outcome: Change in flow-mediated vasodilation of

brachial artery assessed over 36 months

EUROPA substudy

Bots ML et al. J Am Coll Cardiol. 2005;45A(suppl):409A.Bots ML et al. Cardiovasc Drugs Ther. 2002;16:227-36.

• Mean FMD* increased (baseline vs 36 months) Perindopril 2.7% to 3.3% (+37%)Placebo 2.8% to 3.0% (+7%)

• Endothelial function (rate of change per 6 months) Perindopril 0.14% (P < 0.05 vs baseline) Placebo 0.02% (P = 0.74 vs baseline) (P = 0.07 for perindopril vs placebo)

• Conclusion: Part of the beneficial effect of perindopril on CV morbidity and mortality in the EUROPA study may be explained by improvement in endothelial function

*Brachial artery vasodilation in response to reactive hyperemia Bots ML et al. J Am Coll Cardiol. 2005;45A(suppl A):409A.

PERFECT: ACEI and endothelial functionEUROPA substudy

Effects of ARBs in type 2 diabetes: Renal and CV outcomes

Lewis EJ et al. N Engl J Med. 2001;345:851-60.Brenner BM et al. N Engl J Med. 2001;345:861-9.Parving HH et al. N Engl J Med. 2001;345:870-8.

*Doubling of baseline serum creatinine, end-stage renal disease (IDNT, RENAAL): progression to

diabetic nephropathy (IRMA-2)

Study(N) ARB

Primary outcome: Renal disease progression*

Secondaryoutcomes

(CV)

Average duration(years)

IDNT (N = 1715)

Irbesartan 300 mg/d vs amlodipine 10 mg

↓20% vs placebo, (P = 0.02) and ↓23% vs amlodipine (P = 0.006)

Combined CV outcomes: NS

2.6

RENAAL(N = 1514)

Losartan 100 mg/d vs placebo†

↓16% (P = 0.02) CV morbidity and mortality: NS HF hospitalization ↓32%

3.4

IRMA-2(N = 590)

Irbesartan 150–300 mg vs placebo

↓39% with 150 mg (P = 0.08)↓70% with 300 mg (P < 0.001)

Nonfatal CV events: NS

2

Clinical trials of ARBs: CV outcomes

Similar ↓

Greater ↓ with amlodipine (2.0/1.6 mm Hg)

Losartan vs atenolol

Valsartan vs amlodipine

Essential HTN

N = 9193

(4.8 years)

Essential HTN, high CV risk

N = 15,245

(4.3 years)

LIFE (2002)

VALUE (2004)

BPTreatment

Patients

(Follow-up)Trial (year)

HTN = hypertension

13% ↓ in primary outcome (CV death, MI, stroke) with ARB (P = 0.021) driven by 25% ↓ in stroke (P = 0.001)

No difference in CV death/MI

CV outcomes

Primary outcome similar at study end

Trend favors amlodipine at 3 and 6 months

Difficult to interpret due to BP difference

Dahlöf B et al. Lancet. 2002;359:995-1003. Julius S et al. Lancet. 2004;363:2022-31.

LIFE: Effects of ARB vs β-blockade on primary outcome and components

Dahlöf B et al. Lancet. 2002;359:995-1003.

N = 9193 with hypertension and ECG-LVH

LIFE = Losartan Intervention for Endpoint Reduction in Hypertension

16

Proportionof patientswith first

event (%)

12

8

4

0

60 18 30 5442 66

AtenololLosartan

Primary composite endpoint(CV death/MI/stroke)

Adjusted RR 13.0%P = 0.021

(losartan vs atenolol)

Time (months)

5

10Risk

increase(%)

0

5

10

15

20

25

Primary outcome components

(Losartan vs atenolol)

Riskreduction

(%)

P = 0.206

CV death

P = 0.491

Stroke

MI

P = 0.001

LIFE: Comparison of treatment effects in overall population vs with diabetes

Patients with hypertension and LVH

Dahlöf B et al. Lancet. 2002;359:995-1003. Lindholm LH et al. Lancet. 2002;359:1004-10.

0.5 1.0 1.5

Overall (n = 9193)

Diabetes (n = 1195)0.206

0.028

0.001

0.204

0.491

0.373

Favors losartan50–100 mg

Favors atenolol50–100 mg

P

CV death

Stroke

MI

Hazard ratio

VALUE: Similar treatment effectson primary outcome at study end

14

4

2

0

Proportionof patientswith first

event (%)

0 12 3018 24 54 60 66

Time (months)

6

8

10

12

6 36 42 48

HR = 1.03; 95% CI 0.94–1.14; P = 0.49

Valsartan-based regimen

Amlodipine-based regimen

Julius S et al. Lancet. 2004;363:2049-51

Timeinterval(mos)

∆ SBP(mm Hg)

Odds ratio Odds ratio

Favorsvalsartan

Favorsamlodipine

Favorsvalsartan

Favorsamlodipine

Primary outcome Myocardial infarction

0.5 1.0 2.0 4.0 0.5 1.0 2.0 4.0

All study 2.20–3 3.83–6 2.36–12 2.012–24 1.824–36 1.6

Study end 1.736–48 1.4

Julius S et al. Lancet. 2004;363:2022-31.

VALUE: SBP and outcome differences during consecutive time periods

VALUE = Valsartan Antihypertensive Long-Term Use Evaluation

Direct Renin InhibitorAliskerin

pre-clinical data

Aliskerin preclinical dataSummary

• Aliskerin demonstrates organ protective effects in animal models

• Renoprotection comparable with ACEIs and ARBs

• LVH reductions comparable with ARBs• Suppresses markers of renal damage in

diabetic nephropathy• Atherogenesis prevention


Clinical data


Outcome data

EFFECT OF THE DIRECT RENIN INHIBITOR ALISKIREN ON LEFT VENTRICULAR

REMODELING FOLLOWING MYOCARDIAL INFARCTION WITH LEFT VENTRICULAR

DYSFUNCTION

ASPIRE TrialScott D. Solomon, MD, FACC, Sung Hee Shin, MD, Amil Shah, MD, Lars Kober, MD, Aldo P.

Maggioni, MD, Jean Rouleau, MD, FACC, John J. V. McMurray, MD, FACC, Roxzana Kelly, Allen Hester, Marc A. Pfeffer, MD, PhD, FACC for the Aliskiren Study in Post-MI Patients to Reduce

Remodeling (ASPIRE) investigators

Brigham and Women’s Hospital, Boston, MA; Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; ANMCO Research Center, Firenze, Italy; University of Montreal, Montreal,

Canada; Western Infirmary, Glasgow, Scotland; Novartis Pharmaceuticals, East Hanover, NJ

Cardiovascular Outcomes ASPIRE Trial

EndpointPlacebo

n=397n (%)

Aliskiren n=423n (%)

CV Death 6 (1.5) 13 (3.1)

Resuscitated Sudden Death 4 (1.0) 1 (0.2)

HF Hospitalization 17 (4.3) 12 (2.8)

Myocardial Infarction 16 (4.0) 11 (2.6)

Stroke 2 (0.5) 7 (1.7)

Any of the above 34 (8.6) 39 (9.2)

No Significant between group differences

Conclusions ASPIRE Trial

• In high risk post-MI patients with LV systolic dysfunction, the addition of aliskiren to a standard optimal medical regimen, including an ACE-I or an ARB, did not result in benefit with respect to ventricular remodeling compared to placebo and was associated with more adverse events

• Although ASPIRE utilized a surrogate endpoint, and was not powered to assess hard clinical outcomes, these results do not provide support for testing the use of aliskiren in a morbidity and mortality trial in the high-risk post-MI population

• Ongoing outcomes trials with aliskiren in patients with heart failure and diabetic kidney disease are well underway and will further assess the role for direct renin inhibition in these populations

Evidence of Dual RAA inhibition

RAAS: Pathways of ACE inhibition and angiotensin receptor blockade

Dzau V. J Hypertens. 2005;23(suppl 1):S9-S17.

ACE inhibitor

Bradykinin/NO

Inactivefragments

Chymase,tPA,

cathepsin

‘Angiotensin IIescape’

ARB

AT1 receptor AT2 receptor

Angiotensin I

Angiotensin II

ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

ONTARGET: Study design

Ramipril 10 mg Telmisartan 80 mg

N = 25,620≥55 years with coronary, cerebrovascular, or peripheral vascular disease,

or diabetes + end-organ damage

Results in 2007

Ramipril 10 mg + telmisartan 80 mg

Primary end point:CV death, MI, stroke, hosp for HF

Secondary end point:Newly diagnosed diabetes

ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial

ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

TRANSCEND: Study design

Telmisartan 80 mg

N = 5776 ACEI-intolerant≥55 years with coronary, cerebrovascular, or peripheral vascular disease,

or diabetes + end-organ damage

Results in 2007

Placebo

Primary end point:CV death, MI, stroke, hosp for HF

Secondary end point:Newly diagnosed diabetes

Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease

Yusuf S et al. N Engl J Med 2008: 358:1547-1559.

ONTARGET: Key results Outcome Ramipril,

n=8576 (%)Telmisartan, n=8542 (%)

Combination, n=8502 (%)

CV death/MI/stroke/ CHF hospitalizationa

16.5 16.7 16.3

CV death/MI/strokeb 14.1 13.9 14.1

MI 4.8 5.2 5.2

Stroke 4.7 4.3 4.4

CHF hospitalization 4.1 4.6 3.9

CV death 7.0 7.0 7.3

Any death 11.8 11.6 12.5

Renal impairment 10.2 10.6 13.5

a. Primary end pointb. Primary end point in the HOPE trial


ONTARGET: Key results Outcome Risk ratio (95% CI),

telmisartan vs ramipril Risk ratio (95% CI), combination therapy vs ramipril

CV death/MI/stroke/ CHF hospitalizationa

1.01 (0.94–1.09) 0.99 (0.92–1.07)

CV death/MI/strokeb 0.99 (0.91–1.07) 1.00 (0.93–1.09)

MI 1.07 (0.94–1.22) 1.08 (0.94–1.23)

Stroke 0.91 (0.79–1.05) 0.93 (0.81–1.07)

CHF hospitalization 1.12 (0.97–1.29) 0.95 (0.82–1.10)

CV death 1.00 (0.89–1.12) 1.04 (0.93–1.17)

Any death 0.98 (0.90–1.07) 1.07 (0.98–1.16)

Renal impairment 1.04 (0.96–1.14) 1.33 (1.22–1.44)

a. Primary end pointb. Primary end point in the HOPE trial

ONTARGET: Reasons for permanent discontinuations


Outcome Ramipril (%)

Telmisartan (%)

Combination (%)

p, telmisartan vs ramipril

p, combination therapy vs ramipril

Hypotensive symptoms

1.7 2.7 4.8 <0.001 <0.001

Syncope 0.2 0.2 0.3 0.49 0.03

Cough 4.2 1.1 4.6 <0.001 0.19

Diarrhea 0.1 0.2 0.5 0.20 <0.001

Angioedema 0.3 0.1 0.2 0.01 0.30

Renal impairment

0.7 0.8 1.1 0.46 <0.001

Conclusions: Telmisartan vs. Ramipril

1. Telmisartan is clearly “non-inferior” to ramipril,with most ( 95-100%) of the benefits preserved

2. Consistent results on a range of:• Secondary outcomes• Subgroups

3. Telmisartan exhibits slightly superior overall tolerability:

• Less cough and angioneurotic edema• More mild hypotensive symptoms, but no

difference in severe hypotensive symptoms, such as syncope

Conclusions: Telmisartan plus Ramipril vs. Ramipril

1. Combination therapy does not reduce the primary outcome to a greater extent compared to ramipril alone and has higher adverse events.

Implications• Telmisartan is as effective as ramipril, with a slightly

better tolerability.

• Combination therapy is not superior to ramipril, and has increased side effects.

•The combination of aliskiren (Rasilez) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has been associated with serious adverse cardiovascular and renal outcomes in a recent large clinical trial (ALTITUDE). •This combination is now contraindicated in: diabetic patients (type I or type II); and non-diabetic patients with an estimated glomerular filtration rate (eGFR) <60 mL/min per 1•73 m2

•In all other patient groups, aliskiren in combination with an ACE inhibitor or an ARB is not recommended•Any use of aliskiren (either as monotherapy or in combination with other medicines) is no longer recommended in any patient with severe renal impairment: eGFR <30 mL/min per 1•73 m2

RAA inhibition

? ACEI? ARB? DRI

Evidences from Recent Analysis

Aliskiren in HypertensionClinical summary

•Aliskerin provides long- term suppression of PRA

•Aliskerin effectively reduces PRA from baseline as monotherapy, and blocks the rise in PRA seen during treatment with other antihypertensives such as ARB

•Aliskerin monotherapy provides dose-dependent reductions in DBP and SBP

•Additional BP lowering when combined with other antihypertensives but more side effects

Meta-analyses show consistency of ACEI benefit in preventing CV events

No. of trials N

Relative risk reduction (%)

CV death MI

Danchin, 2006 7 33,960 19 18

Al-Mallah, 2006 6 33,500 17 16

Dagenais, 2006 3 29,805 18 18

Danchin N et al. Arch Intern Med. 2006.Al-Mallah MH et al. J Am Coll Cardiol. 2006.

Dagenais GR et al. Lancet. 2006.

Randomized, placebo-controlled trials in patients with CAD without HF or LV dysfunction

Meta-analysis of trials comparing ARB vs placebo, non-ACEI comparators, or ACEI

Strauss MH, Hall AS. Circulation. 2006;114:838-54.

9 of 11 trials show excess MI for ARB

TrialARB

n/N (MI)Controln/N (MI)

ELITE 3/352 4/370

DETAIL 9/120 6/130

ELITE II 31/1578 28/1574

IDNT 39/579 66/1136

CHARM-Alt 75/1013 48/1015

SCOPE 70/2477 63/2460

RENAAL 50/751 68/762

LIFE 198/4605 188/4588

VALUE 369/7649 313/7596

OPTIMAAL 384/2744 379/2733

VALIANT 587/4909 559/4909

Total 26,777 27,273

0.5 1.0 1.5 2.0Odds ratio (95% Cl)

Favors ARB

Favors control

1.08 (1.01–1.16)

Meta-analyses of ACEI and ARB trials

StraussStrauss TsuyukiTsuyuki VolpeVolpe VerdecchiaVerdecchia

NACEIACEI

150,943150,943ARBARB

55,05055,050ARBARB

68,71168,711ARBARB

56,25456,254ARBARB

64,38164,381

MIMI ↓↓14%14%(P < 0.00001)(P < 0.00001)

Event Rate 5.8%Event Rate 5.8%

↑8%(P = 0.03)(P = 0.03)


↑3%(P = ns)

↑4%(P = ns)

↑2% (P = ns)

CV deathCV death ↓↓12%12%(P < 0.0005)(P < 0.0005)


↑↑1%(P = ns)


NA NA ↓1%

Strauss MH, Hall AS. Circulation. 2006.Tsuyuki RT, McDonald MA. Circulation. 2006.

Volpe M et al. J Hypertension. 2005.Verdecchia P et al. Eur Heart J. 2005.

Relative risk

ACEIs vs ARBs: Comparative effect on stroke, HF, and CHD

Turnbull F. 15th European Meeting on Hypertension. 2005.Adapted by Strauss MH, Hall AS. Circulation. 2006;114:838-54.CHD = MI and CV death

Blood Pressure Lowering Treatment Trialists’ Collaboration meta-analysisN = 137,356; 21 randomized clinical trials

ACEI

ARB

Stroke -1% (9% to -10%)

HF 10% (10% to 0%)

CHD 9% (14% to 3%)

Stroke 2% (33% to -3%)

HF 16% (36% to -5%)

CHD -7% (7% to -24%)

30% 0 30%Decrease Increase

StrokeP = 0.6

HFP = 0.4

CHDP = 0.001

Risk

RRR (95%)

Eur Heart J 2012

Van Vark LC, Bertrand M, Fox K, Mourad JJ, Boersma E, et al. Eur Heart J 2012; published online April 17.

All-cause mortality: effect of ACE inhibitors

ASCOT-BPLA

ADVANCE

HYVET

Overall

1.03 (0.90-1.15)

0.90 (0.75-1.09)

0.99 (0.62-1.58)

1.32 (0.61-2.86)

0.89 (0.81-0.99)

0.86 (0.75-0.98)

0.79 (0.65-0.95)

0.90 (0.84-0.97)

ACE inhibitor better Control better

Random effects model HR (95% CI) P

N= 76 6150.50 0.75 1.33 2.01HR (log scale)

0.03

0.03

0.02

0.87(0.81-0.93)

0.004

<0.001

ALLHAT (lisinopril)

ANBP-2 (enalapril)

pilot HYVET (lisinopril)

JMIC-B (lisinopril, enalapril)

(perindopril)


All-cause mortality: effect of ARBs

RENAAL (losartan)

IDNT (irbesartan)

LIFE (losartan)

SCOPE (candesartan)

VALUE (valsartan)

MOSES (eprosartan)

JIKEI HEART (valsartan)

PRoFESS (telmisartan)

TRANSCEND (telmisartan)CASE-J (candesartan)

HIJ-CREATE (candesartan)

KYOTO HEART (valsartan)

NAVIGATOR (valsartan)

Overall

HR (log scale) Control betterARB better0.50 0.75 1.33 2.01

1.03 (0.83-1.29)

0.92 (0.69-1.23)

0.88 (0.77-1.01)

0.96 (0.81-1.14)

1.04 (0.94-1.14)

1.07 (0.73-1.57)

1.09 (0.64-1.85)

1.03 (0.93-1.14)

1.05 (0.91-1.22)

0.85 (0.62-1.16)

1.18 (0.83-1.67)

0.76 (0.40-1.30)

0.90 (0.77-1.05)

0.99 (0.94-1.04)

Random effects model HR (95% CI) P

N=82 383

0.683


Among RAAS inhibitors, only ACE inhibitors have demonstrateda significant 10% mortality reduction in hypertensive patients (P=0.004).

No significant reduction in all-cause mortality could be demonstrated with ARBs (HR, 0.99 (0.95-1.04); P=0.683).

The difference in treatment effect between ACE inhibitors and ARBs was statistically significant (P-value for interaction 0.036).

The largest mortality reductions were observed in ASCOT-BPLA, ADVANCE, and HYVET, which studied the ACE inhibitor perindopril (pooled HR, 0.87 [0.81-0.93]; P<0.001).

Because of the high prevalence of hypertension, the widespread use of ACE inhibitors may result in an important gain in lives saved.


Savarese G,et al.J Am Coll Cardiol.In press.doi:10.1016/i.iacc.2012.10.011



Conclusion From Saverese G,et al Conclusion From Saverese G,et al Meta-analysisMeta-analysis

End Points ACEI ARB

Composite outcome

-14.9%p=0.001

-7%p=0.005

CV death -10%p=0.112

No benefit

MI -17.7%p<0.001

-9.5%NS

Stroke -19.6%p=0.004

-9.1%p=0.011

All cause death -8.3%p=0.008

No benefit

New-onset HF -20.5%p=0.001

No benefit

New-onset DM -13.7%p=0.012

-10.6%P<0.001

RAAS modulation in high-risk patients: Summary

• Opportunity for greater use of RAAS modulation in patients at high risk for CV events

• ACEIs reduce CV death, MI, HF, and stroke across a broad range of patients with vascular disease– With/without LVSD or HF– With/without other proven CV therapies– Annual event rates of 1.4%–22.6% in untreated

groups• ARBs reduce HF and stroke• ACEIs may be considered in all patients with

vascular disease• ARBs are an alternative in ACEI-intolerant patients• Dual RAAS inhibition is not better than single

therapy and causes more side effects

AHA/ACC secondary-prevention guidelines: ACEIs and ARBs

ACEIs• All patients with LVEF ≤40%, hypertension, diabetes,

or chronic kidney disease (IA)• Consider for all other patients (IB)• Optional: Lower-risk, post-revascularization patients

with normal LVEF and well-controlled risk factors (IIaB)

ARBs• ACEI-intolerant patients with HF or post-MI LVEF

≤40% (IA)• Consider in DM and other ACEI-intolerant patients

(IB)• Consider use in combination with ACEIs in systolic

dysfunction HF (IIbB)

Thank You

Healthcare

Role of raas inhibition in management of hypertension