Angiotensin Receptor Blockers in Cardiovascular Continuum

MEDICAL CME 10 Nov 2011 Dr Mohd Rafizi Bin Mohamed Rus

Cardiovascular Continuum

Cardiovascular disease: Role of angiotensin II in the CV continuum

Remodelling Myocardial infarction & stroke Microalbuminuria Endothelial dysfunction Macroproteinuria

Ventricular dilation/ cognitive dysfunction

Cognitive heart failure/ secondary stroke End-stage heart disease, brain damage and dementia Cardio/ cerebrovascular death

Atherosclerosis and LVH

Nephrotic proteinuria

Hypertension risk factors diabetes, obesity, elderly

End-stage renal disease

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

Renin-angiotensin-aldosterone system
Blood pressure

Liver cells
Angiotensinogen Renin Angiotensin I ACE

Juxtaglomerular cells in kidney Lungs Bradykinin (vasodilator) ACE

Angiotensin II
Vasoconstriction Peripheral vascular resistance Blood Pressure Aldosterone secretion Na + and H 2 O retention Blood volume Afterload Preload Inactive kinins

ACE inhibition
Bradykinin/NO ACE Inhibitor Inactive fragments Vasodilation Tissue protection 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 Angiotensin I Chymase tPA Cathepsin Angiotensin II escape

Hanon S., et al. J Renin Angiotensin Aldosterone Syst 2000;1:147150; Chen R., et al. Hypertension 2003;42:542547; Hurairah H., et al. Int J Clin Pract 2004;58:173183; Steckelings U.M., et al. Peptides 2005;26:14011409

Selective AT-1 receptor blockade (ARB)

Bradykinin/NO ACE Inactive fragments Angiotensin II ARB AT1 RECEPTOR Vasoconstriction Sodium retention SNS activation Inflammation Growth-promoting effects Aldosterone Apoptosis Bradykinin? NO? AT2 RECEPTOR Vasodilation Natriuresis Tissue regeneration Inhibition of inappropriate cell growth Differentiation Anti-inflammation Apoptosis Angiotensin I Chymase tPA Cathepsin

Hanon S., et al. J Renin Angiotensin Aldosterone Syst 2000;1:147150; Chen R., et al. Hypertension 2003;42:542547; Hurairah H., et al. Int J Clin Pract 2004;58:173183; Steckelings U.M., et al. Peptides 2005;26:14011409

Angiotensin II Plays a Central Role in Organ Damage

Stroke Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction Hypertension

A II

AT1 receptor

LV hypertrophy Fibrosis Remodeling Apoptosis GFR Proteinuria Aldosterone release Glomerular sclerosis

Heart failure MI

DEATH

Renal failure

*preclinical data LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate
Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): 9971008; Dahlf 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.

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

Multiple Antihypertensive Agents are Needed to Reach BP Goal

Trial (SBP achieved)
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)
1 2 3 4

Average no. of antihypertensive medications

Bakris et al. Am J Med 2004;116(5A):30S8 Dahlf et al. Lancet 2005;366:895906

ARB in Hypertension
Trial LIFE Drug Losartan 100 mg od versus atenolol 100 mg od Population Hypertension (55 80 yrs) 160/95 with LVH, including those with prior MI/CVA, CHF (EF < 40%); 4.8 years Outcome 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.

LIFE: Primary Composite Endpoint

16

Composite of CV death, stroke and MI

Proportion of patients with first event (%)

14

12

13%
Reduction over and above the benefits of atenolol

Atenolol

10

Losartan

Adjusted Risk Reduction 13.0%, p=0.021 Unadjusted Risk Reduction 14.6%, p=0.009
6 4524 4494 12 4460 4414 18 4392 4349 24 4312 4289 30 4247 4205 36 4189 4135 42 4112 4066 48 4047 3992 54 3897 3821 60 1889 1854 66 901 876

0 Study Month 0 Number at risk Losartan (n) 4605 Atenolol (n) 4588

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

ISH Patients Cardiovascular Mortality1

10 8 6 Losartan Atenolol

Patients, %

4
2 Adjusted risk reduction p=0.010 Unadjusted risk reduction p=0.004 46%, 49%,

0 0
Number at risk Atenolol Losartan

12

18

24

30

36

42

48

54

60

66

Study month
666 660 662 657 648 651 637 642 631 636 619 624 608 614 597 602 593 597 566 575 256 283 103 112

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

ISH 17

Conclusion
LIFE demonstrated that ARB has direct cardiac effect

despite comparable reduction in blood pressure.

ARB in Hypertension
Trial SCOPE Drug Candesartan (8/16 mg od) versus placebo Population Elderly 70 89 yrs old, BP 160179/90-99 mmHg Outcome 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 nonfatal MI or cognitive deficit. 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)

VALUE

Valsartan (80/160 mg) versus Amlodipine

50 yrs, Hypertensive

 SCOPE

assess cognitive / prognosis in elderly 2. 2004 trial 3. 42% reduction in stroke esp. >160/90mmHg
1.
VALUE 1.

2.
3. 4. 5.

compared with Norvasc Valsartan antiHT LT use evaluation in 2004 trial 23% RR in new onset DM high risk for CV events Selected HT but <210/115

JIKEI HEART 3 year Study: Valsartan-based Therapy Improved Outcomes in Patients with HPT, CAD and/or HF
CV mortality and morbidity (primary endpoint) Stroke/TIA Hospitalization for heart failure Hospitalization for angina

39% 20

40%

47%

65%

Risk reduction (%)

40 Driven by stroke reduction Primary endpoint occurred in 6% in valsartan versus 9.75% non-ARB group (p = 0.0002)
Mochizuki et al. Lancet 2007;369:14319

60

80

 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 ACE Inactive fragments Angiotensin II ARB AT1 RECEPTOR Vasoconstriction Sodium retention SNS activation Inflammation Growth-promoting effects Aldosterone Apoptosis Bradykinin? NO? AT2 RECEPTOR Vasodilation Natriuresis Tissue regeneration Inhibition of inappropriate cell growth Differentiation Anti-inflammation Apoptosis Angiotensin I Chymase tPA Cathepsin

Hanon S., et al. J Renin Angiotensin Aldosterone Syst 2000;1:147150; Chen R., et al. Hypertension 2003;42:542547; Hurairah H., et al. Int J Clin Pract 2004;58:173183; Steckelings U.M., et al. Peptides 2005;26:14011409

Selective AT-1 receptor blockade (ARB)

Bradykinin/NO ACE Inactive fragments Angiotensin II ARB AT1 RECEPTOR Vasoconstriction Sodium retention SNS activation Inflammation Growth-promoting effects Aldosterone Apoptosis Bradykinin? NO? AT2 RECEPTOR Vasodilation Natriuresis Tissue regeneration Inhibition of inappropriate cell growth Differentiation Anti-inflammation Apoptosis Angiotensin I Chymase tPA Cathepsin

Hanon S., et al. J Renin Angiotensin Aldosterone Syst 2000;1:147150; Chen R., et al. Hypertension 2003;42:542547; Hurairah H., et al. Int J Clin Pract 2004;58:173183; Steckelings U.M., et al. Peptides 2005;26:14011409

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.
2. 3.

4.
5. 6.

5 years; Ramipril vs placebo >9000 patients; >55 years old; vascular disease OR DM +/- 1 CV risk factors +/- low EF/HF 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

1.7 - 2.2 mm reduction in LVH

Change from Baseline in LVH Regression

Cornell Product Sokolow-Lyon

0
-2 Mean change from baseline (%) -4 -6 -8 -10 -12 -14

4.4 % 9.0 %

10.2 %
p<0.0001

-16 -18
Losartan

15.3 %
p<0.0001 Atenolol

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

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

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

Copyright American Heart Association

ARB in HEART FAILURE

The Evaluation of Losartan in the Elderly ELITE

Study Design
>60 yrs; NYHA IIIV; EF <40% Nave to ACE inhibitors/A II antagonists* Captopril
50 mg 3 times daily

Losartan
50 mg once daily

n = 722 Study duration = 48 weeks Clinical outcomes Primary endpoint: Secondary endpoint:

Persisting rise in serum creatinine Composite of death and hospital admission for heart failure

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 StudyELITE II

Study Design
>60 yrs; NYHA IIIV; EF <40% Nave to ACE inhibitors/A II antagonists* Captopril
50 mg 3 times daily** (n=1574)

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

Clinical outcomes Primary endpoint: Secondary endpoint: Other endpoints:

(event driven, target 510 deaths over ~2 years) All-cause mortality Sudden cardiac death and/or resuscitated cardiac arrest All-cause mortality/hospitalizations Safety and tolerability

*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.

 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

The Losartan Heart Failure Survival StudyELITE II Primary Endpoint: All-Cause Mortality
Kaplan-Meier Estimates for Survival 1.0 0.8

No significant

Probability of survival

0.6 0.4 0.2 0 0 100 200 300 400 500 Hazard ratio (95.7% CI): 1.13 (0.95, 1.35); p=0.16)

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

difference between losartan and captopril in reducing all-cause mortality in heart failure

600

700

Days of follow-up

CI = confidence interval Adapted from Pitt B et al Lancet 2000;355:1582-1587.

The Losartan Heart Failure Survival StudyELITE II

Secondary Endpoint: Sudden Death or Resuscitated Cardiac Arrest

1.0

Event-free probability

0.8 0.6 0.4 0.2 Hazard ratio (95% CI): 1.25 (0.98, 1.60); p=NS) Losartan (n=1578) Captopril (n=1574)

0
0 100 200 300 400 500 600 700

Days of follow-up

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

The Losartan Heart Failure Survival StudyELITE II

Tertiary Endpoint: Combined All-Cause Mortality and AllCause Hospitalization

1.0 0.8 Losartan (n=1578) Captopril (n=1574)

Event-free probability

0.6
0.4 0.2 0 Hazard ratio (95% CI): 1.25 (0.97, 1.19); p=NS)

100

200

300

400

500

600

700

Days of follow-up
Adapted from Pitt B et al Lancet 2000;355:1582-1587.

 ELITE II

Rate of decline is similar 2. No beneficial effects on death or hospitalization

1.

ARB studies in heart failure

Trial ELITE Drug Losartan versus Captopril Valsartan + ACEi versus placebo + ACEi Study population Elderly LVEF < 40% Conclusion No significant differences in allcause mortality / hospitalization BUT Better tolerability Lower incidence of primary endpoint (resuscitated cardiac arrest and heart failure re-hospitalization) All-cause mortality not reduced.

ValHeFT

IHD with stable HF 3 months; Standard therapy of HF Intolerant to ACEi

< 40%

CHARMAlternative

Candesartan versus placebo

< 40%

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

ARB studies in heart failure

Trial CHARM-Added Drug Candesartan + ACEi versus ACEi +Placebo Population IHD with NYHA class II IV, on standard therapy for HF LVEF < 40% Conclusion Significant reduction in CV event (CV death, MI, CVA, coronary revascularization, HF rehospitalization)

CHARMPreserve

Candesartan versus placebo Irbesartan versus placebo

IHD with NYHA class II - IV

> 40%* Modest reduction of heart failure rehospitalization. > 40%* No significant primary composite endpoints, all cause mortality or rate of hospitalization

I-PRESERVE

Age > 60

 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

SAVE* Radionuclide EF 40% 0.40 AIRE Clinical and/or radiographic signs of HF Placebo ACE inhibitor TRACE Echocardiographic EF 35%

0.35 Cumulative mortality (%)

0.30 0.25 0.20

0.15
0.10 0.05 0 0 1 2 3

Placebo: 866/2,971 (29.1%)

ACE inhibitor: 702/2,995 (23.4%) Odds ratio (OR): 0.74 (0.660.83), p<0.0001

Time (years)

ACE inhibitor Placebo

2,995
2,971

2,250
2,184

1,617
1,521

892
853

223
138

Systematic overview of data from SAVE, AIRE and TRACE, Flather et al. Lancet 2000;355:157581

 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

0.510 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 Double-blind active-controlled, ACE-I stepwise titration
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)

Median duration: 24.7 months Event-driven

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

Pfeffer et al. Am Heart J 2000;140:72750; Pfeffer et al. N Engl J Med 2003;349:1893906

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

Patients with acute myocardial infarction complicated by either HF or LVSD

0.30
Probability of death 0.25 0.20 0.15 0.10 0.05 0 0

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 vs captopril: hazard ratio (HR)=1.00; p=0.982 DIOVAN + captopril vs captopril: HR=0.98; p=0.726 6
4,909 4,909 4,885

12

18 24 Time (months)
4,241 4,272 4,265 4,018 4,007 3,994 2,635 2,648 2,648

30
1,432 1,437 1,435

36
364 357 382

Captopril Diovan Diovan + captopril

4,428 4,464 4,414

Pfeffer et al. N Engl J Med 2003;349:1893906

ARB and DIABETIC NEPHROPATHY

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

1.0

Survival (all-cause mortality)

0.9 0.8 0.7

Normoalbuminuria (n=191) Microalbuminuria (n=86) Macroalbuminuria (n=51)

0.6 0.5
0 1 2 3 4 5 6

Years
P<0.01 normo vs. micro- and macroalbuminuria P<0.05 micro vs. macroalbuminuria

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

ARB and Diabetic Nephropathy

Trial RENAAL Drug Population Outcome 16% decrease in primary composite end point (doubling of serum creatinine, ESRF, or both) Losartan 100 Diabetic type 2 with nephropathy mg od or 92 95% patients on antiplacebo hypertensives

ESRD
% with event

RENAAL Primary Components

30

30

20

10

Doubling of sCr
0 0 12
610 714

RR: 28% p=0.002

24 36
42 375

% with event

48

20

Months
Placebo (+CTx) 762715 Losartan (+CTx) 751 347 625
69

10

RR: 25% p=0.006 0 12

689 692

50 40

ESRD or Death

24

36
295 329

48
36 52

% with event

Months
Placebo (+CTx) 762 Losartan (+CTx) 751 554 583

30 20 10 0

RR: 20% p=0.010

0 12
610 714

sCr=serum creatinine; RR=risk reduction Adapted from Brenner BM et al N Engl J Med 2001;345(12):861-869.

24

36
347 625 42 375

48

Months
Placebo (+CTx) 762715 Losartan (+CTx) 751 69 Slide 56

RENAAL
Time to ESRD from Doubling of Serum Creatinine
80

% with event

60 40 20 0 0 6 12 18 24

RR: 30% p=0.013

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

Adapted from Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 1619, 2001.

ARB and Diabetic Nephropathy

Trial IRMA II Drug Irbesartan 150/300 mg od versus placebo Population Hypertensive Type 2 Diabetes with microalbuminuria (20 200 ug/min) and creatinine > 132.6 umol/l (men) or 97.2 umol/l (women) Outcome 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 Hypertensive Type 2 amlodipine versus Diabetes with nephropathy placebo

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

20 10

0
Change in UAER (%)

-10
-20 -30 -40 -50 0 4 8 Time (weeks) 12 18 24

- 8% Amlodipine (n = 145)

Valsartan (n = 146)

- 44%*

*P <0.001 vs amlodipine

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