angiotensin receptor blockers in different clinical settings

MEDICAL CME

10 Nov 2011

Dr Mohd Rafizi Bin Mohamed Rus

Angiotensin Receptor Blockers in Cardiovascular Continuum

Cardiovascular Continuum

Cardiovascular disease: Role of angiotensin II in the CV continuum

Adapted from Dzau V. and Braunwald E., Am Heart J 1991;121:1244–1263

Cardio/ cerebrovascular death

End-stage renal disease

Nephrotic proteinuria

Macro- proteinuria

Micro- albuminuria

Endothelial dysfunction

Hypertension risk factors diabetes, obesity, elderly

Atherosclerosis and LVH

Myocardial infarction & stroke

Remodelling Ventricular dilation/ cognitive dysfunction

Cognitive heart failure/ secondary stroke

End-stage heart disease, brain damage and dementia

Blood pressure

Renin

Angiotensinogen

Angiotensin I

Angiotensin II

Vasoconstriction

Peripheral vascular resistance

ACE

Na + and H 2 O retention

Blood volume

Aldosterone secretion

Blood Pressure

Afterload Preload

ACE

Bradykinin (vasodilator)

Inactive kinins

Lungs

Juxtaglomerular cells in kidney

Liver cells

Renin-angiotensin-aldosterone system

ACE inhibition

Hanon S., et al. J Renin Angiotensin Aldosterone Syst 2000;1:147–150; Chen R., et al. Hypertension 2003;42:542–547; Hurairah H., et al. Int J Clin Pract 2004;58:173–183; Steckelings U.M., et al. Peptides 2005;26:1401–1409

Bradykinin/NO

Inactive fragments Vasodilation Tissue protection

ACE Inhibitor

Angiotensin I

Angiotensin II

Chymase tPA Cathepsin

AT1 RECEPTOR Vasoconstriction Sodium retention SNS activation Inflammation Growth-promoting effects Aldosterone Apoptosis

AT2 RECEPTOR Vasodilation Natriuresis Tissue regeneration Inhibition of inappropriate cell growth Differentiation Anti-inflammation Apoptosis

‘Angiotensin II escape’

Selective AT-1 receptor blockade (ARB)


Bradykinin/NO

Inactive fragments

Angiotensin I

Angiotensin II




ARB Bradykinin?

NO?

ACE

GFR Proteinuria Aldosterone release Glomerular sclerosis

Angiotensin II Plays a Central Role in Organ Damage

Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): 9971008; Dahlöf B J Hum Hypertens 1995; 9(suppl 5): S37S44; Daugherty A et al J Clin Invest 2000; 105(11): 16051612; Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5): S19S24; Booz GW, Baker KM Heart Fail Rev 1998; 3: 125130; Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories 1999: 16821704; Anderson S Exp Nephrol 1996; 4(suppl 1): 3440; Fogo AB Am J Kidney Dis 2000; 35(2): 179188.

A II AT1 receptor

Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction

LV hypertrophy Fibrosis Remodeling Apoptosis

Stroke

DEATH

*preclinical data LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate

Hypertension

Heart failure MI

Renal failure

BENEFITS OF RAS INHIBITION

Heart Failure with/without LV systolic dysfunction

Post MI LV dysfunction

Secondary Prevention Post CVD event

Primary prevention in high risk patients

Hypertension with multiple CVD risk factors

Stroke risk reduction

Major trials with ARB in specific cardiovascular conditions

ARB in HYPERTENSION

Average no. of antihypertensive medications

1 2 3 4

Multiple Antihypertensive Agents are Needed to Reach BP Goal

Trial (SBP achieved)

Bakris et al. Am J Med 2004;116(5A):30S–8 Dahlöf et al. Lancet 2005;366:895–906

ASCOT-BPLA (136.9 mmHg)

ALLHAT (138 mmHg)

IDNT (138 mmHg)

RENAAL (141 mmHg)

UKPDS (144 mmHg)

ABCD (132 mmHg)

MDRD (132 mmHg)

HOT (138 mmHg)

AASK (128 mmHg)

ARB in Hypertension Trial Drug Population Outcome

LIFE Losartan 100 mg od versus atenolol 100 mg od

Hypertension (55 – 80 yrs) ≥ 160/95 with LVH, including those with prior MI/CVA, CHF (EF < 40%); 4.8 years

1. Effective in reducing composite end point (CV death, stroke, MI) Main contributory factor is reduction in stroke.* 2. Systolic BP reduction significantly better in Losartan. 3. LVH reduction significant in Losartan. 4. New onset Diabetes less often in Losartan group.

0

2

4

6

8

10

12

14

16

Pro

po

rtio

n o

f p

atie

nts

wit

h f

irst

eve

nt

(%)

Composite of CV death, stroke and MI

Losartan

Atenolol

LIFE: Primary Composite Endpoint

Study Month 0 6 12 18 24 30 36 42 48 54 60 66

Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876

Adjusted Risk Reduction 13.0%, p=0.021 Unadjusted Risk Reduction 14.6%, p=0.009

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

Number at risk

13% Reduction over and

above the benefits of atenolol

Number at risk Atenolol 666 662 648 637 631 619 608 597 593 566 256 103 Losartan 660 657 651 642 636 624 614 602 597 575 283 112

Adjusted risk reduction 46%,

p=0.010

Unadjusted risk reduction 49%,

p=0.004

Adapted from Kjeldsen SE et al JAMA 2002;288(12):1491-1498.

ISH Patients — Cardiovascular Mortality1

Pat

ien

ts, %

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

0

2

4

6

8

10

Study month

ISH 17

Losartan Atenolol

Conclusion LIFE demonstrated that ARB has direct cardiac effect

despite comparable reduction in blood pressure.

ARB in Hypertension Trial Drug Population Outcome

SCOPE Candesartan (8/16 mg od) versus placebo

Elderly 70 – 89 yrs old, BP ≥ 160-179/90-99 mmHg

1. Only slightly greater BP reduction compared to placebo leading to modest non-significant reduction in CV event. 2. Significantly marked reduction in non-fatal stroke (? BP-related) – 42% esp. in >160/90mmHg gp 3. No significant reduction in non-fatal MI or cognitive deficit.

VALUE Valsartan (80/160 mg) versus Amlodipine

≥ 50 yrs, Hypertensive

1. No difference in CV mortality and morbidity.

2. Effect of amlodipine on BP reduction more pronounced in first 6 months.

3. Valsartan reduced new onset diabetes (23% RR)

SCOPE

1. assess cognitive / prognosis in elderly

2. 2004 trial

3. 42% reduction in stroke esp. >160/90mmHg

VALUE

1. compared with Norvasc

2. Valsartan antiHT LT use evaluation in 2004 trial

3. 23% RR in new onset DM

4. high risk for CV events

5. Selected HT but <210/115

40%

Stroke/TIA

JIKEI HEART 3 year Study: Valsartan-based Therapy Improved Outcomes in Patients with HPT, CAD and/or HF

Ris

k re

du

ctio

n (

%)

65%

Hospitalization for angina

47%

Hospitalization for heart failure

39%

CV mortality and morbidity (primary endpoint)

0

20

40

60

80

Mochizuki et al. Lancet 2007;369:1431–9

Primary endpoint occurred in 6% in valsartan versus 9.75% non-ARB group (p = 0.0002)

Driven by stroke reduction

Japanese population

>3000 patients

3 years period

2007 trial

40-160mg daily Valsartan based VERSUS non-based regime

20-79 years old

Also RR 33% of onset DM (p=0.02)

ONTARGET Study population: high risk hypertensive patients or DM with EOD

Selective AT-1 receptor blockade (ARB)


Bradykinin/NO

Inactive fragments

Angiotensin I

Angiotensin II




ARB Bradykinin?

NO?

ACE

ON TARGET trial

High risk HPT patients with CAD, CVA, PVD or DM with end organ damage

No HF patients

similar concept to HOPE trial using Ramipril)

Combination of both had more SEs (syncope / hypotension / renal impairment) compared to alone therapy with no extra benefits!

Trial shows no differences in outcomes in BP reduction effects on CAD CVA and HF

HOPE

1. 5 years; Ramipril vs placebo

2. >9000 patients; >55 years old;

3. vascular disease OR DM

4. +/- 1 CV risk factors

5. +/- low EF/HF

6. reduced death / MI and stroke even normal EF

ARB & Left Ventricular Hypertrophy

LVH has significant impact on clinical outcomes

ECG changes for LVH has LOW sensitivity but HIGH specificity if criteria used

Cornel criteria

- R wave V3 and S wave lead aVL

- >24mm in male / >20mm in female

Normal LVH via ECHO is <115g/m2

Valsartan from 127 reduced to 106g/m2 at 8 months (regression regardless age and sex)

Losartan has LVH regression ~15.3% from baseline!

14 different ECHO findings META-ANALYSIS – proves TARGET and ORGAN protection

Change from Baseline in LVH Regression

-18

-16

-14

-12

-10

-8

-6

-4

-2

0 Cornell Product Sokolow-Lyon

Me

an c

han

ge f

rom

bas

elin

e (

%)

Losartan Atenolol

p<0.0001

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

10.2 % 9.0 %

15.3 %

4.4 %

p<0.0001

1.7 - 2.2 mm reduction in LVH

.

Thürmann P A et al. Circulation 1998;98:2037-2042

Copyright © American Heart Association

Influence of the Angiotensin II Antagonist Valsartan on Left Ventricular Hypertrophy in Patients With Essential Hypertension

ARB in HEART FAILURE

The Evaluation of Losartan in the Elderly – ELITE

Study Design

>60 yrs; NYHA II–IV; EF <40% Naïve to ACE inhibitors/A II antagonists*

n = 722

Study duration = 48 weeks

Clinical outcomes

Primary endpoint: Persisting rise in serum creatinine

Secondary endpoint: Composite of death and hospital admission for heart failure

Captopril 50 mg 3 times daily

Losartan 50 mg once daily

RESULTS: 1. No difference in primary end point 2. Total mortality significantly lower in Losartan group (4.8% versus 8.7%, p = 0.03)

The Losartan Heart Failure Survival Study–ELITE II

Study Design

*Or exposure <7 days within three months prior to entry **Concomitant treatments (diuretics, cardiac glycosides, aspirin or salicylates, calcium-channel blockers) were allowed; beta blockers were limited to 25% of patients in the protocol. Randomization was stratified based on concurrent use of beta blockers.

Adapted from Pitt B et al Lancet 2000;355:1582-1587.

>60 yrs; NYHA II–IV; EF <40% Naïve to ACE inhibitors/A II antagonists*

Clinical outcomes (event driven, target 510 deaths over ~2 years)

Primary endpoint: All-cause mortality

Secondary endpoint: Sudden cardiac death and/or resuscitated cardiac arrest

Other endpoints: All-cause mortality/hospitalizations

Safety and tolerability

Captopril 50 mg 3 times daily** (n=1574)

Losartan 50 mg once daily** (n=1578)

B-blocker is proven for survival in poor EF

ACEI did improve survival not consistently improved ET and LVEF in systolic HF

Evaluation of Losartan in the Elderly (ELITE) trial

Captopril as it is standard for HF at that time (SOLVD trial – in poor EF subjects)

year 2000

Proceeded with ELITE II for SUPERIORITY trial - due to reduced secondary endpoint (total mortality) in ELITE I

But no reduction in primary & secondary endpoints

Comparable to Captopril (not superior to )

?Reason – LOW DOSE 50mg only used! (compared to maximum Captopril 50mg TDS


Primary Endpoint: All-Cause Mortality

No significant difference between losartan and captopril in reducing all-cause mortality in heart failure

CI = confidence interval


Pro

bab

ility

of

surv

ival

Days of follow-up

Hazard ratio (95.7% CI): 1.13 (0.95, 1.35); p=0.16)

Losartan (n=1578) Captopril (n=1574)

0 100 200 300 400 500 600 700

1.0

0.8

0.6

0.4

0.2

0

Kaplan-Meier Estimates for Survival


Even

t-fr

ee

pro

bab

ilit

y

Days of follow-up

Hazard ratio (95% CI):

1.25 (0.98, 1.60); p=NS)

Losartan (n=1578)

Captopril (n=1574)

0 100 200 300 400 500 600 700

1.0

0.8

0.6

0.4

0.2

0


Secondary Endpoint: Sudden Death or Resuscitated Cardiac Arrest



Days of follow-up

Hazard ratio (95% CI):

1.25 (0.97, 1.19); p=NS)

0 100 200 300 400 500 600 700

1.0

0.8

0.6

0.4

0.2

0

Losartan (n=1578)

Captopril (n=1574)

Even

t-fr

ee p

rob

ab

ilit

y

Tertiary Endpoint: Combined All-Cause Mortality and All-Cause Hospitalization

ELITE II

1. Rate of decline is similar

2. No beneficial effects on death or hospitalization

ARB studies in heart failure Trial Drug Study

population LVEF Conclusion

ELITE Losartan versus Captopril

Elderly < 40% No significant differences in all-cause mortality / hospitalization BUT Better tolerability

ValHeFT Valsartan + ACEi versus placebo + ACEi

IHD with stable HF 3 months; Standard therapy of HF

< 40% Lower incidence of primary end-point (resuscitated cardiac arrest and heart failure re-hospitalization) All-cause mortality not reduced.

CHARM-Alternative

Candesartan versus placebo

Intolerant to ACEi

< 40% Significantly reduced primary composite end point (CV death and hospitalization) All cause mortality did not differ.

ARB studies in heart failure Trial Drug Population LVEF Conclusion

CHARM-Added Candesartan + ACEi versus ACEi +Placebo

IHD with NYHA class II – IV, on standard therapy for HF

< 40% Significant reduction in CV event (CV death, MI, CVA, coronary revascularization, HF re-hospitalization)

CHARM-Preserve

Candesartan versus placebo

IHD with NYHA class II - IV

> 40%* Modest reduction of heart failure re-hospitalization.

I-PRESERVE Irbesartan versus placebo

Age > 60 > 40%* No significant primary composite endpoints, all cause mortality or rate of hospitalization

All 3 trials NOT REDUCED all cause mortality but each has its own benefits!

Only 2 studies (valHEFT and CHARM added) showed +ve benefits with DUAL combination (ACEI and ARB) – improve CV outcomes in CHF

But ValHEFT use Valsartan 160mg BD! But it is the 1st trial showed TRIPLE combination have significant adverse outcomes

Only 2 studies (CHARM-preserve and I-preserve) used subjects with EF>40% but NOT show benefits if already chronic HF with preserved EF

Summary: Addition of ARB to Standard Therapy has Proven Efficacy in Heart Failure Patients

Significant effects on combined mortality and morbidity endpoint in overall population

Substantially decreased occurrence of heart failure hospitalizations

Demonstrated improvements in left ventricular function and reversed left ventricular remodelling

Improvements in HF signs/symptoms

Significantly reduced risk of atrial fibrillation occurrence

ARB in MYOCARDIAL INFARCTION

Mortality Post-MI Lower with ACE Inhibitors Than with Placebo

Flather et al. Lancet 2000;355:1575–81

TRACE Echocardiographic EF ≤35%

AIRE Clinical and/or radiographic signs of HF

SAVE* Radionuclide EF ≤40%

0.40

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0

2,995 2,250 1,617 892 223 ACE inhibitor

ACE inhibitor

Placebo

Odds ratio (OR): 0.74 (0.66–0.83), p<0.0001

ACE inhibitor: 702/2,995 (23.4%)

Placebo: 866/2,971 (29.1%)

Cu

mu

lati

ve m

ort

alit

y (%

)

Time (years) 0 1 2 3 4

2,971 2,184 1,521 853 138 Placebo

Systematic overview of data from SAVE, AIRE and TRACE,

SAVE (survival and ventricle enlargement) trial -used Captopril; reduced another CHF / recurrent MI and hospitalization; 4 years trial

OPTIMAAL (optimal trial in MI with ATII antagonist Losartan) - >50 years old; non-inferiority trial; >5000 patients; event drive study; 2.7 years; dose ONLY 50mg OD (NOT 100mg OD!)

VALIANT – BD dose; year 2000; post MI with HF/LV dysfunction; 14000 patients; 2 years trial; is effective as captopril

50 mg od*

50 mg tds

VALIANT: Study Design and Inclusion Criteria

Primary endpoint: All-cause mortality Secondary endpoints: CV morbidity and mortality Other endpoints: Safety and tolerability

Captopril 50 mg t.i.d (n=4,909)

DIOVAN 160 mg b.i.d (n=4,909)

Captopril 50 mg t.i.d + DIOVAN 80 mg b.i.d (n=4,885)

0.5–10 days after acute MI – SAVE, AIRE or TRACE eligible (either clinical/radiological signs of HF or LVSD)

Major exclusion criteria

–Serum creatinine >2.5 mg/dL

–DBP <100 mmHg

–Prior intolerance of an ARB or ACE-I

Double-blind active-controlled, stepwise titration

Median duration: 24.7 months Event-driven

Pfeffer et al. Am Heart J 2000;140:727–50; Pfeffer et al. N Engl J Med 2003;349:1893–906

VALIANT: Risk of Mortality is Similarly Reduced with DIOVAN and Captopril

Pfeffer et al. N Engl J Med 2003;349:1893–906

0.30

Pro

bab

ility

of

de

ath

0

0.05

0.10

0.15

0.20

0.25

0 6 12 18 24 30 36 Time (months)

DIOVAN vs captopril: hazard ratio (HR)=1.00; p=0.982

Captopril 50 mg tid* (n=4,909)

DIOVAN 160 mg bid* (n=4,909)

DIOVAN 160 mg bid + captopril 50 mg tid* (n=4,885) *titration to target dose

DIOVAN + captopril vs captopril: HR=0.98; p=0.726

Patients with acute myocardial infarction complicated by either HF or LVSD

Captopril 4,909 4,428 4,241 4,018 2,635 1,432 364

Diovan 4,909 4,464 4,272 4,007 2,648 1,437 357

Diovan + captopril

4,885 4,414 4,265 3,994 2,648 1,435 382

ARB and DIABETIC NEPHROPATHY

Proteinuria Is an Independent Risk Factor for Mortality in Type 2 Diabetes

1.0

0.9

0.8

0.7

0.6

0.5

0 1 2 3 4 5 6

Years

Su

rviv

al

(all

-ca

use

mo

rta

lity

)

Normoalbuminuria

(n=191)

Microalbuminuria

(n=86)

Macroalbuminuria

(n=51)

Gall, MA et al. Diabetes 1995;44:1303

P<0.01 normo vs. micro- and macroalbuminuria

P<0.05 micro vs. macroalbuminuria

ARB and Diabetic Nephropathy

Trial Drug Population Outcome

RENAAL Losartan 100 mg od or placebo

Diabetic type 2 with nephropathy 92 – 95% patients on anti-hypertensives

16% decrease in primary composite end point (doubling of serum creatinine, ESRF, or both)

ESRD

Months

% w

ith

eve

nt

0 12 24 36 48

0

10

20

30

RR: 28% p=0.002

ESRD or Death

Months

% w

ith

eve

nt

sCr=serum creatinine; RR=risk reduction

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

RENAAL Primary Components

Doubling of sCr

Months

% w

ith

eve

nt

RR: 25% p=0.006

Placebo (+CTx) 762 689 554 295 36 Losartan (+CTx) 751 692 583 329 52

RR: 20% p=0.010

Placebo (+CTx) 762715 610 347 42 Losartan (+CTx) 751 714 625 375 69

0 12 24 36 48

0

10

20

30

40

50

0 12 24 36 48

0

10

20

30

Placebo (+CTx) 762715 610 347 42 Losartan (+CTx) 751 714 625 375 69

Slide 56

RENAAL Time to ESRD from Doubling of Serum Creatinine

Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.

Months

% w

ith

eve

nt

0 6 12 18 24

0

20

40

60

80

RR: 30% p=0.013

Placebo (+CTx) 198 111 48 11 4 Losartan (+CTx) 162 104 43 19 3

ARB and Diabetic Nephropathy Trial Drug Population Outcome

IRMA II Irbesartan 150/300 mg od versus placebo

Hypertensive Type 2 Diabetes with microalbuminuria (20 – 200 ug/min) and creatinine > 132.6 umol/l (men) or 97.2 umol/l (women)

1. 24% reduction in urinary albumin excretioin in 150 mg group and 38% reduction in 300 mg group (despite similar BP reduction) 2. High dose irbesartan restored normoalbuminura

IDNT Irbesartan versus amlodipine versus placebo

Hypertensive Type 2 Diabetes with nephropathy

1. Primary end point (doubling of serum creatinine, onset of ESRF or death): •20% lower risk (compared to placebo) •23% lower risk(compared to amlodipine)

MARVAL: Valsartan Significantly Lowers Urinary Albumin Excretion Rate

Change in UAER

(%)

*P <0.001 vs amlodipine

-50

-40

-30

-20

-10

0

10

20

0 4 8 12 18 24

Time (weeks)

Valsartan (n = 146)

Amlodipine (n = 145)

- 8%

- 44%*

Viberti G et al. Circulation. 2002;106:672-678.

Conclusion Intervention with ARBs at different steps of CVD

continuum is effective to slow down or block disease progression

There are differences among available ARBs from clinical trials

Specific pharmacological properties likely to influence clinical efficacy

angiotensin receptor blockers in different clinical settings

Documents

role of angiotensin

eur heart j

j kidney

int j clin pract

at1 receptor atherosclerosis

dahlf b j hum hypertens

receptor blockade arb

heart fail rev