Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February...

Sponsored by Novartis Pharma AG

7th Annual International Diovan Symposium

Lisbon, 3–5 February 2006

From the Expert’s Files: Case Presentation

Victor Dzau

Duke University, Durham, USA

Presentation

52-year-old African-American woman

Museum curator

History of– Type II diabetes (diet controlled)

– Retinopathy and nephropathy

Referred to specialist due to BP = 160/100 mmHg despite amlodipine 10 mg, bendrofluazide 2.5 mg and atenolol 50 mg

Examination

Not overweight

Questioning reveals– ex-smoker for 5 years having smoked 20 cigarettes a day

from age 16 years

– some breathlessness on exertion

Clinic BP = 164/103 mmHg

Pulse regular

Auscultation: – Abdominal bruit

– AF

Investigations

Creatinine = 250 μmol/L (2.82 mg/dL)

Mid-stream urine (MSU) = 2+ protein

Sugar = 9 mmol/L (162 mg/dL)

HbA1C = 7% (normal <5%)

Total cholesterol = 5 mmol/L (193 mg/dL)

Chest x-ray = normal

ECG = sinus rhythm, LVH on voltage criteria

Echo = EF 55%, LVH

VARIABLE 3: Hypertension andMicroalbuminuria

Pathophysiology of Microalbuminuria in Hypertension

Michel Burnier

CHUV, Lausanne, Switzerland

Definition of Microalbuminuria

24-hour urines Urine spot

Categorymg/24 hours µg/min mg/L

mg/mmol

creatinine

Normal <30 <20 <20 <2

Microalbuminuria 30–300 20–200 20–200 2–20

Macroalbuminuria >300 >200 >200 >20

Functional changes*

Proteinuria

Clinical type 2 diabetes

Structural changes†

Rising blood pressure

Rising serum creatinine levels

Cardiovascular death

Microalbuminuria

Onset of diabetes 2 5 10 20 30

*Renal haemodynamics altered, glomerular hyperfiltration†Glomerular basement membrane thickening , mesangial expansion ,microvascular changes +/-

Natural History of Diabetic Nephropathy

End-stagerenal disease

Ang II

Increasedglomerularpressure

Ang II

Urinary proteinGlucose

Glycoxidation (glycation)

Efferent arteriolar

constriction

= angiotensin AT1 receptor

Pathophysiological Processes Leading to Albuminuria and Glomerular Lesions

Glomerular permeability for macromolecules

Excessive reabsorption of proteins in the proximal tubule

Intracellular accumulation of protein degradation products

Gene activations chemokines and cytokinesGene activations chemokines and cytokines

Proliferation of fibroblasts and extracellular matrix

Development of fibrosis and renal atrophyRemuzzi et al. Kidney Int 1997;51:2–15

Albuminuria and Progression of Nephropathies

Diercks et al. Can J Cardiol 2002;18:525–35

Bigazzi1992

Calvino1999

Grandi2000

Pontremoli1997

Palatini1996

Jensen 1997

Prevalence of Microalbuminuria in Patients with Hypertension*

6.7 6.14.1

38.040

*Defined as > 140/90 mmHg except Calvino, Palatini (135/85 mmHg)Jensen (> 140/90 mmHg or on AHY)

Pontremoli et al. Am J Hypertens 1998;11:430–8

Left ventricular mass index Intima/media thickness

Microalbuminuria is Associated with Left Ventricular Hypertrophy and Carotid Hypertrophy in Hypertensive Patients

C Ht AI– Ht AI+

******

C = control; Ht = hypertensive; Al– = no albuminuria; Al+ = with albuminuria

*p<0.001 intergroup comparison; **p<0.001 compared to C;***p<0.05 compared to Ht Al–; ****p<0.01 compared to Ht Al–

Odds ratio

Odds ratio for coronary heart disease

Microalbuminuria

Diabetes or insulin resistance

Treatment of hypertension

Current or ex-smoker

Body mass index (10 kg/m2)

Systolic BP

Male sex

Age (10 years)

Diastolic BP

Yudkin et al. Lancet 1988;2:530–3

Microalbuminuria as a Predictor of Vascular Disease in Non-diabetic Subjects

1 5 10 15 20

tive r

MI/Stroke/CV death All-cause mortality CHF hospitalisation

Gerstein et al. JAMA 2001;286:421–6

Adjusted for age, sex, SBP/DBP, waist-hip ratio, diabetes and HbA1c

<0.22 0.22–0.57 0.58–1.62 >1.62

Microalbuminuria and Risk of CV Events, CHF and Death in the HOPE Trial

Alb/Crea (mg/mmol)

S. creat >124 µmol/L

Microalbuminuria Both

Systolic and diastolic BP NOT significant risk factors

Mann et al. Ann Intern Med 2001;134:629–36

Renal Insufficiency, Albuminuria and CV Survival in the HOPE Trial

Wachtell et al. J Hypertens 2002;20:405–12

LIFE study, 8,029 subjects with hypertensionand LV hypertrophy, mean age 66 years

Albuminuria and CV Diseases

0 Diabetes Cerebrovascular Peripheral Coronarydisease vascular vascular

disease disease

NormoalbuminuriaMicroalbuminuria (Alb/Crea >3.5 mg/mmol)Macroalbuminuria (Alb/Crea >35 mg/mmol)

Composite Endpoints (CV Death, Non-fatal Stroke and MI) Stratified by Time-varying Albuminuria in the LIFE Trial

Ibsen et al. Hypertension 2005;45:198–202

2422201816141210

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

>3 mg/mmoL (n=2,435, 1,708, 1,760)

1–3 mg/mmoL (n=2,219, 1,827, 1,946)

0.5–1 mg/mmoL (n=1,591, 1,587, 1,814)

0.5 mg/mmoL (n=1,961, 3,385, 2,458)

n=85,421 subjects, age: 28–75 years from the Groningen area

Hillege et al. Circulation 2002;106:1777–82

Microalbuminuria and Mortality in the General Population: the PREVEND Study

CV death Non-CV death

6.05.55.04.54.03.53.02.52.01.51.00.5

Urinary albumin concentration (mg/L)

1 10 100 1,000

Urinary albumin concentration (mg/L)

1 10 1,00 1000

6.05.55.04.54.03.53.02.52.01.51.00.5

Microalbuminuria and CV Complications in Hypertension: Is the Threshold Correct?The Copenhagen City Heart Study

Klausen et al. Hypertension 2005;46:33–7

<2.5 2.5–5 5–10 >10UAE (µg/min)

<2.5 2.5–5 5–10 >10

0 2 4 6 8 10 12Years from entry

UAE 4.8 µg/minUAE 4.8 µg/minUAE <4.8 µg/min

Cox-estimated age-adjusted curves of cumulative incidence of coronaryheart disease for a 60-year-old person based on 1,734 hypertensive

subjects with microalbuminuria and normoalbuminuria

Microalbuminuria and Incidence of CV Events: The Framingham Study

Arnlov et al. Circulation 2005;112:969–75

0 1 2 3 4 5 6 7 8Years

< Median

Median

Survival free of CVDAccording to sex-specific median UACR

Microalbuminuria

What Links Microalbuminuria to CV Risk ?

Microalbuminuria (n=26)

Normoalbuminuria (n=45)

24-hour Blood Pressure Profile in Clinically Healthy Subjects With or Without Microalbuminuria

Clausen et al. Hypertension 1998;32:71–7

0 4 8 12 16 20 24Clock time

Endothelial dysfunction

Impaired endothelium-dependent vasodilation Reduces vasodilation

Increased endothelin Favours vasoconstriction

Increased transcapillary escape rate of albumin Increases permeability (microalbuminaria)

Increased von Willebrand factor Increases prothrombotic activity

Increased tPA and PAI-1 Reduces profibrinolytic activity

Increased E-selectin and VCAM-1 Leucocytes adhesion and permeability

Increased ICAM-1 Induces inflammation

Increased fibronectin and type IV collagen fragments Alters matrix synthesis

Expression of Endothelial Dysfunction in Humans

Normoalbuminuria Elevated UAE

p<0.05

Flow-associated Vasodilation of Brachial Artery in Clinically Healthy Subjects According to Microalbuminuria

Clausen et al. Circulation 2001;103:1869–74

Adapted from Dzau. Hypertension 2001;37:1047–52

Dyslipidaemia Hypertension Diabetes Smoking

Oxidative stress

Endothelial dysfunction

NO, local mediators, RAAS (Ang II)

Vasoconstriction Thrombosis Inflammation Plaque rupture Vascular lesionand remodelling

Pathobiological Processes Potentially Involved in the Development and Progression of Vascular Diseases

Chronic Kidney Disease and CV Risk

Traditional risk factors Non-traditional risk factors

Hypertension

HDL and LDL cholesterol

Diabetes

Smoking

Physical activity

Family history of CVD

Albuminuria

Homocysteine

LP(a) and apolipoproteins

Anaemia

Ca/phosphate metabolism

Salt and water overload

Oxidative stress

Inflammation

Malnutrition

Thrombogenic factors

Sleep disturbance

NO/endothelin balance…

Vasoconstriction Stimulation of Ang II type 1 receptors

Release of endothelin and norepinephrine

Reduction of NO bioactivity and production of peroxynitrite

Inflammation Activation NADH/NADPH oxidase and production of superoxide anion

Induction of MCP-1, VCAM, TNF-, IL-6 expression

Activation of monocytes and macrophages

Remodelling Stimulation of SMC migration, hypertrophy and replication

Induction of PDGF, FGF, IGF-1, TGF- expression

Stimulation of matrix glycoproteins and metalloproteinase expression

Thrombosis Stimulation of PAI-1 synthesis and change in tPA/PAI-1 ratio

Activation of platelet with increased aggregation and adhesion

Vascular Effects of Angiotensin II

Early stage Late stage Terminal stage

Severity of renal disease

IRMA 2

MARVAL

RENAAL

Microalbuminuria Macroalbuminuria ESRD

CV morbidity and mortality

Prevention ProtectionBenedict

Normoalbuminuria

Angiotensin II Inhibition Retards the Progression of Renal Diseases

Reduction in Albuminuria Translates Into a Decrease in CV Events in Hypertensive Patients: LIFE Study

High baseline/high year 1High baseline/low year 1Low baseline/high year 1Low baseline/low year 1

Follow-up (months)0 10 20 30 40 50 60 70

Asselbergs et al. Circulation 2004;110:2809–16

Effect of Fosinopril on CV Event Rates in Patients with Microalbuminuria

0 10 20 30 40

Follow-up (months)

Placebo

Fosinopril

HR 0.60 [0.33–1.10], p=0.098 (Log-rank)

Event-free Survival According to the Level of Microalbuminuria

Follow-up (months)

UAE <50 mg/24 hours, placeboUAE >50 mg/24 hours, placeboUAE <50 mg/24 hours, fosinoprilUAE >50 mg/24 hours, fosinopril

0 10 20 30 40

p=0.008

Asselbergs et al. Circulation 2004;110:2809–16

Conclusions

Microalbuminuria is frequent in hypertension and is associated with target organ damage and the incidence of CV complications

The pathophysiological link between microalbuminuria and CV risk is not completely understood but it may be due to endothelial dysfunction with an impaired NO balance, activation of local mediators and increased activity of the RAAS system

Blockade of the RAAS with ACE inhibitors or AT1 receptor blockers is an important therapeutic approach to reduce microalbuminuria and to prevent the development of CV and renal complications in hypertension

Point-CounterpointAre Benefits Beyond Blood Pressure Lowering Clinically Relevant?

Albuminuria-associated Disease:Are Benefits Beyond BP Lowering

Clinically Relevant?

Giancarlo Viberti, MDProfessor of Diabetes and Metabolic Medicine

Cardiovascular DivisionKCL School of Medicine

Guy’s HospitalKing’s College London

London, UK

Prospective Studies Collaboration. Lancet 2002;360:1903–13

Age-specific Relation of Usual BP to Vascular Mortality In Individuals With No Previous Vascular Disease

Adler et al. Kidney Int 2003;63:225–32

Annual Transition Rates Through Stages of Diabetic Nephropathy

No nephropathy

Microalbuminuria

Macroalbuminuria

Elevated plasma creatinine or renal replacement therapy

2.0%(1.9% to 2.2%)

2.8%(2.5% to 3.2%)

2.3%(1.5% to 3.0%)

1.4%(1.3% to 1.5%)

3.0%(2.6% to 3.4%)

4.6%(3.6% to 5.7%)

19.2%(14.0% to 24.4%)

SBP mmHg

24022020018016014012010080

Relationship Between SBP and ACR in T2DM Patients with Different Degrees of AER

Smith et al. JASN 2005;16:1069–75

Risk factors for microalbuminuria in type 1

diabetic patients with baseline normoalbuminuria

(7 yr follow-up)

Excess Mortality With Hypertensionand Proteinuria In Type 2 Diabetes

Standardisedmortality ratio

Status of hypertension (H) and proteinuria (P) in type 2 diabetes

Wang et al. Diabetes Care 1996;19:305–12

P-H- P-H+ P+H- P+H+ P-H- P-H+ P+H- P+H+Men Women

Epidemiology

Relative Risk of Cardiovascular Disease and Mortality in Diabetes Mellitus By Quartile of Albuminuria (ACR)

1st 2nd 3rd 4th

Variable <0.22 0.22–0.57 0.58–1.62 >1.62 p for trend

MI, strokeand CV death

1 0.85

(0.63–1.14)

(0.86–1.43)

(1.52–2.63)

<0.001

All-cause mortality

1 0.86

(0.58–1.28)

(1.01–1.95)

(1.80–3.20)

<0.001

CHF 1 0.72

(0.32–1.63)

(0.98–3.43)

(2.06–6.46)

<0.001

ACR (mg/mmol) quartiles RR (95% CI)

n=3,498

Rachmani et al. Diabetes Res Clin Pract 2000;49:187–94

Rate of eGFR Decline in Type 2 DM With Normoalbuminuria

AER categories:I = ≤10 mg/24hII = 10.1 to 20 mg/24hIII = 20.1 to 30 mg/24h

Survival Curves in Type 2 DM According To Baseline AER Category

AER categories:I = ≤10 mg/24hII = 10.1 to 20 mg/24hIII = 20.1 to 30 mg/24h

Rachmani et al. Diabetes Res Clin Pract 2000;49:187–94

ACR (mg/mmol)

Composite endpoint

<0.25≥0.25 to

<0.82≥0.82

to<1.62≥1.67

to<4.32≥4.32 to

<9.45P value

for trend

HR 1 1.3 1.8 2.3 2.7 <0.001

Adjusted HR

1 1.3 1.5 1.9 2 <0.001

Composite endpoint = CVD death, fatal or non-fatal stroke, fatal or non-fatal MI

Albuminuria and CVD risk in hypertensive patients with LVHThe LIFE Study

Relative Risk of CVD and Mortality in5,545 High-risk Patients Without Diabetes by

Quartile of Albuminuria (ACR)

1st 2nd 3rd 4th

Variable <0.22 0.22–0.57 0.58–1.62 >1.62 p for trend

MI, stroke and CV death

1 1.24

(1.03–1.49)

(1.29–1.85)

(1.52–2.20)

<0.001

All-cause mortality

1 1.17

(0.93–1.47)

(1.19–1.87)

(1.82–2.82)

<0.001

CHF 1 1.45

(0.87–2.44)

(1.12–3.10)

(1.79–4.81)

<0.001

ACR (mg/mmol) quartiles RR (95% CI)

Arnlov et al. Circulation 2005;112:969–75

Albuminuria and Incidence of CVD Events in Non-hypertensive and Non-diabetic Subjects

The Framingham Heart Study

Median UAER:M: 3.9 μg/mg F: 7.5 μg/mg

Survival free of CVDAccording to sex-specific median UACR

Klausen et al. Circulation 2004;110:32–35

Albuminuria and Risk of CHD and Death In The General Population

Third Copenhagen City Heart Study

25%-ile: 2.1 μg/min50%-ile: 3.0 μg/min75%-ile: 4.8 μg/min

Hillege et al. Circulation 2002;106:1777–82

Albuminuria and CVD/Non-CVD Mortality in The General Population

PREVEND Study

The Clinical Trial Evidence

Change in AER Predicts Loss of GFR

Rossing et al. Diabetologia 1994;37:511–16

*Proteinuria measured as the urine albumin:creatinine ratio from a first morning void

0 12 24 36 48Months

Medianpercent change

751 661 558 438 167L (+CT)P (+CT) 762 632 529 390 130

p=0.0001 35% overall reduction

RENAAL: Change From Baselinein Proteinuria*

Placebo

Losartan

Brenner et al. N Engl J Med 2001;345:861–9

RENAAL: Baseline Proteinuria As A Determinant of Renal Events In T2DM

De Zeeuw et al. Kidney Int 2004;65:2309–20

Composite Endpoint ESRD

0 12 24 36 48

3.0 g/24h

<1.5 g/24h

0 12 24 36 48

3.0 g/24h

<1.5 g/24h

RENAAL: Baseline Proteinuria As A Determinant For Cardiac Events In T2DM

De Zeeuw et al. Circulation 2004;110:921–7

CV Endpoint Heart Failure

0 12 24 36 48

≥3.0g/24h

<1.5 g/24h

0 12 24 36 48

3.0 g/24h

<1.5 g/24h

RENAAL: Initial Antiproteinuric Response vs Renal Risk

Albuminuria reduction (%)

-90 -25 0 25 50 72

Albuminuria reduction (%)

-90 -25 0 25 50 72

Renal Endpoint ESRD

De Zeeuw et al. Kidney Int 2004;65:2309–20

RENAAL: Proteinuria Reduction (<0% versus >30%) Determines the Cardiovascular Outcome

CV Endpoint Heart Failure

0 12 24 36 48

int >30%

0 12 24 36 48

De Zeeuw et al. Circulation 2004;110:921–7

Viberti et al. Circulation 2002;106:672–8

Mean BP change (mmHg)

-11.2 -11.6

-6.6 -6.5

SBP DBP

UAER (µg/min)

Valsartan Amlodipine

p <0.001

Baseline

Valsartan 24 Wks

Amlodipine 24 Wks

The MARVAL Study

Changes In BP and AER By Valsartan and Amlodipine in T2DM Patients With Microalbuminuria

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Systolic

Diastolic

Follow-up (months)

VerapamilTrandolapril

Trandolapril plus VerapamilPlacebo

Ruggenenti et al. N Engl J Med 2004

Blood Pressure According To Treatment Group

0 6 12 18 24 30 36 42 48

Follow-up (months)

No. at risk

ACE inhibitor

No ACE inhibitor

No ACE inhibitor(66 events)

ACE inhibitor (35 events)

A.F. (95 % C.I.) = 0.44 (0.27 – 0.70) p=0.001

Ruggenenti et al. N Engl J Med 2004

Rate of CVD Events By Time-varying Albuminuria In Subjects With Essential Hypertension and LVH

The LIFE Study

Composite endpointCV death, fatal or non-fatal stroke,fatal or non-fatal MI

Lea et al. Arch Intern Med 2005;165:947–953

Risk of ESRD vs Initial Change( 6–0 months) in Proteinuria in African Americans with Hypertension

and Non-diabetic Kidney DiseaseAASK

How do we obtain better evidence?

Antihypertensive and Antiproteinuric Responses To Increasing ACE-I Dose

% reduction vs control

05 mg 10 mg 15 mg 20 mg

Lisinopril dose (mg)

BP Urinary protein

Adapted from Palla et al. Int J Clin Pharmacol Res 1994;14:35–43

ConclusionsAlbuminuria is a powerful and independent risk factor for renal and cardiovascular disease. The relationship is linear across a range which includes normalcy

Correction of albuminuria per se appears to be related to reduction of risk of renal and cardiovascular events

To acquire direct clinical evidence a trial is required that compares different doses of the same compound with similar BP-lowering effects but different albuminuria reduction potency

Are Benefits Beyond BP Lowering Clinically Relevant? No

Giuseppe Mancia

University of Milan-Bicocca, Italy

The Question

Does BP reduction per se substantially contribute to CV protection (i.e. reduction in CV morbidity and mortality) in hypertension?

* BP –2/–1 mmHg

Effects of Antihypertensive Drugs on CVD in Controlled Trials

CVD (%) Comparator

Diuretics –16 Placebo

Beta-blockers –21 Placebo

Calcium antagonists –28 Placebo

ACE inhibitors –24 Placebo

Ang II antagonists –10 Active therapy*

SBP difference between randomised groups (mmHg)Turnbull et al. Lancet 2003;362:1527–35

Metanalysis of Trials Comparing Different Treatments or Treatment Versus Placebo in Hypertension

0.25–10 –8 –6 –4 –2 0 2 4

Stroke1.50

0.25–10 –8 –6 –4 –2 0 2 4

Major CVD1.50

0.25–10 –8 –6 –4 –2 0 2 4

CVD death1.50

0.25–10 –8 –6 –4 –2 0 2 4

Total mortality

VALUE: Analysis of Results Based on BP Control at 6 Months

Fatal/non-fatal cardiac events

Fatal/non-fatal stroke

All-cause death

Myocardial infarction

Heart failure hospitalisations

*p<0.01; †SBP <140 mmHg at 6 months

Patients treated with valsartan Patients treated with amlodipine

Hazard ratio 95% CI

0.4 0.6 0.8 1.0 1.2

Controlled patients†

(n=5,253)

Non-controlled patients(n=2,396)

0.4 0.6 0.8 1.0 1.2

Controlled patients†

(n=5,502)

Non-controlled patients(n=2,094)

Hazard ratio 95% CI

0.76 (0.66–0.88)

0.60 (0.48–0.74)

0.79 (0.69–0.91)

0.83 (0.66–1.03)

0.62 (0.50–0.77)

Odds ratio

0.73 (0.63–0.85)

0.50 (0.39–0.64)

0.79 (0.69–0.92)

0.91 (0.71–1.17)

0.64 (0.52–0.79)

Odds ratio

Weber et al. Lancet 2004;363:2047–49

StrokeFatalNon-fatal

All CV eventsAll cardiac eventsAll-cause deathCV deathCoronary eventsHeart failureNew-onset diabetesCancer

Felodipine(138.1/82.3 mmHg)

11.2 2.1 9.115.2 4.6 7.1 4.6 4.5 1.1 3.1 2.6

Placebo(141.6/83.9 mmHg)

15.9 3.112.721.2 6.6 9.6 6.4 6.2 1.7 2.7 3.9

Hazard ratio (95% CI)

Per 1,000 patient-years

0.4 0.6 0.81.0 1.5 2.0

Felodipine better Placebo better

0.72 0.70 0.72 0.72 0.66 0.70 0.68 0.68 0.76 1.03 0.60

FEVER: Endpoint Analysis (First Time Occurrence in Each Category)

Liu Lisheng et al. J Hypertens 2005

Turnbull et al. Arch Intern Med 2005;165:1410–19

*Statistically significant

More Versus Less Intensive Treatmentin DM +

DM + (n=3,599) BP –6.0/–4.6 mmHg

TotalStroke CHD CHF CVD CV death mortality

–40–36*

–25*

–27*

MI (fatal + non-fatal)<25% 1.0025%–<50% 0.70 (0.57–0.86)50%–<75% 0.63 (0.53–0.76)75% 0.55 (0.46–0.65)

Clinical Outcomes – Unadjusted

0.40 0.60 0.80 1.00 1.20HR (95% CI)

Reduced riskPercent of visits with BPcontrol (<140/90 mmHg) HR (95% CI)Primary outcome<25% 1.0025%–<50% 0.67 (0.59–0.76)50%–<75% 0.60 (0.53–0.67)75% 0.54 (0.48–0.61)

Increased risk

Group with <25% of visits with BP control used as referencePrimary Outcome = first occurrence of death (all cause), non-fatal MI, or non-fatal stroke

BP control by visit

Stroke (fatal + non-fatal)<25% 1.0025%–<50% 0.88 (0.66–1.18)50%–<75% 0.62 (0.47–0.82)75% 0.43 (0.32–0.58)

Does CV protection (reduction in CV morbidity and mortality) exclusively depend on BP reduction per se?

Are there specific protective effects of different drugs or drug classes?

CV Events in Patient Subgroups

DiabetesNo diabetesCurrent smokerNon-current smokerObeseNon-obeseLVHNo LVHOlder (>60 years)Younger (≤60 years)FemaleMalePrevious vascular diseaseNo previous vascular diseaseRenal dysfunctionNo renal dysfunctionWith metabolic syndromeWithout metabolic syndrome

1.000.80 1.50

Amlodipine/perindopril(BP 164.1/94.8 135.5/79.1 mmHg)

Atenolol/thiazide(BP 163.9/94.5 136.3/78.4 mmHg)

0.70 0.90

2.9/1.7 mmHg

ACE-I versus D/BBDiabetesNo diabetesOverall

CA versus D/BBDiabetesNo diabetesOverall

ACE-I versus CADiabetesNo diabetesOverall

BP (mmHg)

–0.5/0.1 0.6/0.1

0.7/–0.6 1.4/–0.2

0.4/1.2 0.4/0.8

RR (95% CI)

0.90 (0.74–1.11)1.04 (0.98–1.10)p homog = 0.19

0.95 (0.82–1.10)1.04 (0.98–1.10)p homog = 0.82

0.92 (0.79–1.07)0.99 (0.92–1.07)p homog = 0.37

I2 (%)

Turnbull et al. Arch Intern Med 2005;165:1410–19

Favoursfirst

Favourssecond

0.25 0.5 1 2Risk ratio

Major CVD with ACE-I Versus D/BB Versus CA

Blood Pressure Lowering Treatment Trialists’ Collaboration

Outcome

Stroke

Major CHD

Heart failure

ELITE IIOPTIMAALVALIANTOverall

Relative risk (95% CI)

1.63 (0.77–3.44)1.06 (0.84–1.33)0.95 (0.76–1.17)1.02 (0.87–1.19)

1.24 (1.00–1.55)1.01 (0.88–1.15)0.97 (0.89–1.05)1.03 (0.92–1.16)

0.87 (0.59–1.28)1.14 (0.99–1.31)1.01 (0.93–1.11)1.05 (0.95–1.15)

Favours ARB Favours ACE-I

0.5 1.0 1.5Relative risk

Meta-analysis of Trials Comparing ACE-I-based with ARB-based Regimens for the Outcomes of Stroke, CHD and Heart Failure

Volpe et al. J Hypertens 2005;23:2113–18

ARBs versus ACE-I

ARBs versus placebo and active drug

ARBs versus active drug

ARBs versus placebo

0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4

Favours other drugFavours ARB

Relative Risk of MI for ARBs and ACE-Is Versus Active Drugs and Placebo

Should Guidelines Convey the Message that What Matters for CV Protection is Only BP Control?

CVD by many drugs (and drug combinations), provided BP

For a given BP little/no CVD between treatments

Benefit proportional to degree of BP

BP control versus lack of control associated with large CVD

Tighter BP control (well below 140/90 mmHg) associated with greater CV protection (high-risk patients)

BPreduction

Mancia, 2004

Short-term Protection

May Event-based Trials Underestimate Potential Differences Between Drugs?

Trial limitations

– High-risk patients

– Patients’ drop-out/cross-over (dilution factor)

– Short-term duration

Prevention of events not superimposable to prevention of disease

Pseudoequivalence?

Probably not

Yes, minor

Differences Between Drugs on Factors Responsible for Progression of Disease

BP lowering

Lipid profile

Insulin resistance

New-onset diabetes

Metabolic syndrome

LVH progression/regression

Small vessel remodelling

Large artery structure/function/atherosclerosis

Renal protection

Short-termprotection

Long-termprotection

BPreduction

Role of Drug-specific Properties Versus BP Reduction per se in CV Protection of Hypertensive Patients

Mancia, 2004

Parving et al. Lancet 1983;2:1175–9

Start of treatment

Effect of Antihypertensive Treatment (n=10)

–30 –24 –18 –12 –6 0 6 12 18 24 30 36

Months

From the Expert’s Files: Case Presentation

Marc Pfeffer

Harvard Medical School, USA

Presentation

60-year-old Turkish male lawyer presents for routine check-up

History of ischaemic heart disease and hypertension

Myocardial infarction 3 years previously, uncomplicated recovery

Progressive shortness of breath on exertion for past 3 weeks

Current meds– ASA

– statin

– beta-blocker

– ACE-I

Examination

BP = 110/70 mmHg

Height = 1.85

Weight = 93 kg– BMI = 27

Heart rate = 76

No peripheral oedema

JVP elevated at 30°

Carotid upstrokes normal, no bruit

Lungs: basal crepitations

Systolic murmur, no S3

Investigations Dipstick protein –ve Creatinine = 141 mmol/L (1.5 mg/dL) eGFR = 52 ECG = Evidence of old anterior MI

aVR V1 V4

Echo = Ejection fraction 35%; dilated left ventricle

The Multiplicative Effect of Global Risk Factors in Post-MI HF Patients: The Root Cause

Peter Liu

University of Toronto, Canada

Incidence of Post-MI HF

The incidence of HF approaches 10 per 1,000 population after age 65

Approximately 22% of male and 46% of female MI patients will experience HF within 6 years

NHLBI = National Heart, Lung, and Blood Institute

Hurst. The Heart, Arteries and Veins. 10th ed. New York,NY: McGraw-Hill, 2001; American Heart Association. Heart Disease and Stroke Statistics – 2005 Update. Dallas, Texas: American Heart Association, 2004

Based on the 44-year follow-up of the NHLBI’s Framingham Heart Study…

0.91.42.3

Death Reinfarction AF Stroke LOS (days)

HF/LVSD (n=2,347) No HF/LVSD (n=3,219)

VALIANT Registry: In-hospital Clinical Events Among Post-MI Patients With and Without HF/LVSD

LVSD = left ventricular systolic dysfunction; AF = atrial fibrillationLOS = length of stay

Velazquez et al. Eur Heart J 2004;25:1911–9

Beta-blocker: Carvedilol Post-MI Reduces Cardiovascular Mortality

Adapted from The CAPRICORN Investigators. Lancet 2001;357:1385–90

0 0.5 1.0 1.5 2.0

Time (years)

Carvedilol n=975

Placebo n=984

Risk reduction: 25% (4%, 42%)

p=0.024

Cardiovascular mortality rates:placebo 14%; carvedilol 11%

Day 28 Day 29 to 1 year Composite

Antiplatelet Therapy: Clopidogrel and AspirinReduce Risk of Death, MI or Stroke at One Year

Adapted from Steinhubl et al. for the CREDO Investigators. JAMA 2002;288:2411–20

RRR = Relative risk reduction; NS = non significant

RRR19.7%p=NS RRR

37.4%p=0.04

RRR 26.9%p=0.02

Aspirin/clopidogrel

Placebo

Statin: Fluvastatin Significantly Reduces the Risk of Cardiac Events After A First Successful PCI

In patients with average cholesterol levels, fluvastatin significantly reduced the risk of MACE by 22% (p=0.0127)

Serruys et al. JAMA 2002;287:3215–19

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0Time post-randomisation (years)

Placebo(n=833)

Fluvastatin (80 mg/d, n=844)

Risk reduction

PCI = percutaneous coronary intervention; MACE = Major Adverse Cardiac Events

Modified from Jessup and Brozena. New Engl J Med 2003;348:2007–18

Remodelling Post MI: Renin–Angiotensin Activation

Initial infarct Infarct expansion(hours to days)

Global remodelling(days to months)

Acute Ischemia

IschemicMyocytes

ECMOsteopontinTIMPs, MMPs

Chronic Repair

ApoptoticMyocytes

HypertrophiedMyocytes

CytokineAII, OFR

AngiogenesisVEGF, AngiopoietinsIntergin 3

= Neutrophils = Macrophages

Mechanical stressOxydative stressHypoxia

Initial cytokine release

= Monocyte

NecroticMyocytes

Cytokine Angiotensin

= Mast Cells = Collagen = Angiogenesis

Nian et al. Circ Res 2004;94:1543–53

Myocyte Stretch and AII Production

Angiotensin II Myocyte Transillum’n

Leri. J Clin Invest 1998;101:1326–42

Inflammatory Cytokine Levels in Post-MI Patients With and Without HF/Death

Valgimigli et al. Circulation 2005;111:863–70

Group 1: made up of patients free from death and HF; Group 2: patients with HF and/or death

p<0.0001

p<0.01TNF- IL- 6

Group 1 Group 2 Group 1 Group 2(n=140) (n=44) (n=141) (n=30)

Intrahospital Follow-up

p<0.0001

p<0.01

202,000

Control

Deoxyuridine triphosphate labelling

CM = cardiomyopathy; DCM = dilated cardiomyopathy

Olivetti et al. N Engl J Med 1997;336:1131–41

Propidium Iodide

Deoxyuridine Triphosphate

IschaemicCM

IdiopathicDCM

Apoptosis in the Failing Human Heart

Matrix Metalloproteinase (MMP) post MI

uPA/PlasminuPA/PlasminMTMMP/ADAMsMTMMP/ADAMsIL-1, CD40IL-1, CD40

TNF, EMPRINNTNF, EMPRINN

OFR, ChymaseOFR, ChymaseACE / AIIACE / AII

Sun et al. Circulation 2004;110:3221–8;Kassiri et al. Circulation Research 2005;97:380–90

MMP InhibitorsACEi/ARBs

Pathophysiology of Ventricular Remodelling in Post-MI HF

Increased levels of inflammatory cytokines

Changes in the extracellular matrix: increased fibroblast and myocardial matrix metalloproteinase (collagenase) activity

Myocyte apoptosis or necrosis

Hypertrophy of remaining myocytes

Localised ACE/Chymase Presence Post MI

Control 3 days

7 days 28 days

Renin–Angiotensin Aldosterone System (RAAS)

Angiotensinogen

Non-ACE pathways(e.g. chymase)

Vasoconstriction Cell growth Na/H2O retention Sympathetic activation

ReninAngiotensin I

Angiotensin II

Cough,angio-oedema

benefits? Bradykinin

Inactivefragments

Vasodilation Antiproliferation

(kinins)

Aldosterone

AT1 receptor

AT2 receptor

ACE = angiotensin-converting enzyme;AT1 = angiotensin II type 1; AT2 = angiotensin II type 2

Post-MI Remodelling: Ang II Modulationby RAAS Blockade

Control Ang II modulation

Effects of ACE Inhibitor Treatment onAll-Cause Mortality Post-MI

EF = ejection fraction; OR = odds ratioFlather et al. Lancet 2000;355:1575–81

ACE inhibitor

Placebo

OR: 0.74 (0.66–0.83)OR: 0.74 (0.66–0.83)

ACE inhibitor: 702/2995 (23.4%)ACE inhibitor: 702/2995 (23.4%)

Placebo: 866/2971 (29.1%)Placebo: 866/2971 (29.1%)

TRACEEchocardiographicEF ≤ 35%

AIREClinical and/or radiographic signs of HF

SAVERadionuclideEF ≤ 40%

0.0Years 0 1 2 3 4

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

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

VALIANT: Valsartan Shows Non-inferiority to ACE Inhibitors

Hazard ratio for death from any cause

Favoursactive drug

Favoursplacebo

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

0.5 1 2

SAVE, TRACE andAIRE combined

VALIANT

(Imputed placebo)

Valsartan

preserves

99.6% of the

mortality

benefit of

captopril

Summary

Patient post-MI with LV dysfunction is at very high risk for deaths, arrhythmias and recurrent events

Pathophysiology of ventricular remodelling in post-MI HF

– Inflammatory cytokines

– Myocyte apoptosis

– Hypertrophy of remaining myocytes and hyperplasia of fibroblasts

RAAS activation post-MI contributes to adverse ventricular remodelling and mortality

Deleterious effects of angiotensin II mediated via AT1 receptor

Standard post-MI therapy should include a platelet inhibitor,beta-blocker, statin, and an ACE-I/ARB

RAAS Blockade in Post-MI HF and Chronic HF: What’s the Evidence for This Treatment Strategy?

Eric J Velazquez

Duke University, Durham, USA

Target organdamage

Risk factors:diabetes,

hypertension

Vascular dysfunction

Atherosclerosis and LVH

Tissue injury(MI, stroke)

Pathologicremodelling

Target organdysfunction (HF, renal)

Endstageorgan failure

Oxidative stress/endothelialdysfunction

LVH = left ventricular hypertrophyMI = myocardial infarction; HF = heart failure

Adapted from Dzau and Braunwald. Am Heart J 1991;121:1244–63

The Cardiovascular Continuum

AT1 receptor

The Scope of CHD and MI

Worldwide, 17 million people die of CVD every year1

More than 60% of the global burden of CHD occurs in developing countries1

It is estimated that in 2005, 1.2 million Americans will have a new or recurrent coronary attack*2

In 2002, nearly 180,000 people died of an MI2

1http//www.who.int/cardiovascular_diseases2American Heart Association. 2005 Heart and Stroke Statistical Update. 2004

*Coronary attack=definite or probable MI, or fatal CHDCHD=coronary heart disease

MI and CAD: Secondary Prevention

Treatment objectives

Improve survival

Prevent reinfarction

Prevent LV remodelling

Prevent progression to

Reduce risk of arrhythmias

How can we help thesehigh-risk patients?

Severity of LV damage

Antiplatelet

Statin

Treatment of Post-MIPatients with LVSD/Acute HF

LVSD or Acute HF

LVSD and Acute HF

Flather et al. Lancet 2000;355:1575–81*Odds ratio (95% CI)

Readmission for HF

n = 460

n =355

(0.63 – 0.85)

Reinfarction

(0.69 – 0.95)

Placebo (n=2,971)ACE-I (n=2,995)

Death/MI or Readmission for HF

n =1,049

n =1244

(0.67–0.83)

TRACEEchocardiographicEF 35%

AIREClinical and/or radiographic signs of HF

SAVERadionuclideEF 40%

Death and Major CV Events

Proven ACE-I

SAVE/AIRE/TRACE

Early Treatment of Post-MIPatients with LVSD/Acute HF

Antiplatelet

Statin

LVSD or Acute HF

LVSD and Acute HF

Potential Pharmacological Benefits of AT1-receptor Blockade Versus ACE Inhibition

AT1-R antagonists ACE inhibitorsChymase

Ang II

AT2 AT1 AT1 AT2 NO

Prostagladins

CardioprotectionVasodilationNegative chronotropismAnti-fibrosisAnti-growth

CardioprotectionVasodilation

Plasma Ang II Plasma Ang II Bradykinin

Cardioprotective effects via angiotensin II binding to AT2 receptor

Angiotensin II generated by non-ACE dependent pathways1,2 also blocked from binding to the AT1 receptor

Reduced side-effect profile (ACE inhibition: increased bradykinin = cough)

Adapted from Matsubara. Circ Res 1998;83:1182–911Unger. JRAAS 2001;2(suppl 2):S4–S7 2Petrie et al. J Am Coll Cardiol 2001;37:1056–61

(–) (–) (+) (–) (–)

Bart BA et al. Eur Heart J 1999

Data from the SPICE registry; N=9,580

“Despite the proven benefits of ACE inhibitors, the reported prevalence of ACE inhibitor use among heart failure patients varies from 17% to 86%.”

On ACE-I

Intolerant

High risk

New diagnosis

Unable to determine

Data missing

HF Patients Not Receiving an ACE-I

OPTIMAAL:All-cause Mortality

Month 6 12 18 24 30 36

Captopril (n=447 events)

Relative risk = 1.13 (0.99–1.28); p=0.069

Losartan (n=499 events)

Losartan 2,744 2,504 2,432 2,390 2,344 2,3011,285Captopril 2,733 2,534 2,463 2,423 2,374 2,3291,309 Dickstein et al. Lancet 2002

Antiplatelet

Statin

Proven ACE-I

Losartan

50 mg qd

SAVE/AIRE/TRACEOPTIMAAL

Early Treatment of Post-MIPatients with LVSD/Acute HF

LVSD or Acute HF

LVSD and Acute HF

VALIANT

Primary endpoint: All-cause mortalitySecondary endpoints: CV Death, MI, or HFOther endpoints: Safety and tolerability

Captopril 50 mg tid(n=4,909)

Valsartan 160 mg bid(n=4,909)

Captopril 50 mg tid + Valsartan 80 mg bid

(n=4,885)

Acute MI (0.5–10 days)—SAVE, AIRE, or TRACE eligible(either clinical/radiological signs of HF or LV systolic dysfunction)

Major exclusion criteria– Serum creatinine >2.5 mg/dL– BP <100 mmHg– Prior intolerance of an ARB or ACE-I– Non-consent

Double-blind, active-controlled

Median duration: 24.7 monthsEvent-driven

Pfeffer et al. Am Heart J 2000;140:727–50

VALIANT: All-cause Mortality

HR = hazard ratio Pfeffer et al. N Engl J Med 2003;349:1893–906

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

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

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

Captopril0.30

00 6 12 18 24 30 36

No. at risk

Valsartan vs captopril: HR=1.00; p=0.982Valsartan + captopril vs captopril: HR=0.98; p=0.726

Valsartan

Valsartan + captopril

Time (months)

VALIANT: Valsartan is Effective at Reducing Cardiovascular Morbidity and Mortality

Hazard ratio(97.5% CI) p value

0.8 1 1.2

CV death(1,657 events)

CV death or HF(2,661 events)

CV death or MI(2,234 events)

CV death, MI, or HF

(3,096 events)0.20

Favours valsartan Favours captopril

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

Captopril (n=4,909)

The Effect of Valsartan, Captopril or Both on Atherosclerotic Events After Acute MI: An Analysis of VALIANT

Valsartan (n=4,909)

Valsartan + captopril (n=4,885)

Myocardial Angina Revascularisation Stroke infraction

Adapted from McMurray et al. Presented at ESC 2005

0 6 12 18 24 30 36

Months

Study Drug Discontinuation

Due to Adverse Events

*p<0.05 vs captopril

Captopril

Valsartan + Captopril

Valsartan

+Antiplatelet

Statin

Proven ACE-I (Captopril)orValsartan 160 mg bidorCaptopril + Valsartan

SAVE/AIRE/TRACE

Early Treatment of AMIPatients with LVSD/Acute HF

VALIANT

LVSD or Acute HF

LVSD and Acute HF

0 0.5 1 1.5 2 2.5

p=0.031OR 0.77 (0.60–0.98)

CAPRICORNSurvival

Carvedilol

Placebo

The CAPRICORN Investigators. Lancet. 2001

EPHESUSAll-cause Mortality

Pitt et al. for EPHESUS Investigators. N Engl J Med 2003;348:1309–21

Months since randomisation0 3 6 9 12 15 18 21 24 27 30 33 36

RR = 0.79 (95% CI, 0.64–0.97)p=0.03

Placebo

Eplerenone

Eplerenone 3,319 3,044 2,463 1,260 336 0 0

Placebo 3,313 2,983 2,418 1,213 323 2 0

Antiplatelet

Statin

Proven ACE-I

orvalsartan 160 mg bid

Eplerenone

25–50 mg qd

SAVE/AIRE/TRACEVALIANT

CAPRICORN

EPHESUS

Early Treatment of AMIPatients with LVSD/Acute HF

LVSD or Acute HF

LVSD and Acute HF

Carvedilol

0.50Any CV event

YEAR 1 YEAR 2 YEAR 3 YEAR 4

Cardiac Events Following High-risk MI: The VALIANT Experience

Heart failure

Recurrent MISudden death or cardiac arrest

The Framingham Heart Study: 1987

Cupples et al. The Framingham Study, NIH Publication No. 87–2703. 1987

Years following MI

Risk of heart failure after MI(Age 35 to 94 at diagnosis)

0 2 4 6 8 10 12 14 16 18 20

MI maleMI femaleMatched maleMatched female

Time Since Randomization, months

2010 300 40

BNP(pg/mL)

41–97

98–238

% Mortality

Time Since Randomization,months

274–394

395–572

NE(pg/mL)

% Mortality

2010 300 40

Anand IS. Circulation 2003;107:1278−83

Baseline BNP and NE and All-cause Mortality

Kaplan-Meier Analysis of Cumulative Rates of Survival in Patients with Heart Failure Chronically Treated With ACE Inhibitor Stratified By Plasma Angiotensin II Levels

Roig et al. Eur Heart J 2000;21:53–7

p=0.0002

Ang II >16 pg.mL–1

Normal Ang II1.0

00 2 4 6 8 10 12

Months

LVIDd = left ventricular internal diastolic diameter; BSA = body surface areaCohn J et al. Eur J Heart Fail 2000;2:439–46

Val-HeFT: Study Design

Primary endpoint was all-cause mortality and the combined endpoint of all-cause mortality and heart failure morbidity

5,010 heart failure patients≥ 18 years old; NYHA II–IV; EF <40 %; LVIDd >2.9 cm/m2 of BSA

Randomized to

ACE inhibitors (93%), diuretics (86%),digoxin (67%), beta-blockers (35%)

Valsartan 40 mg bid titrated to 160 mg bid Placebo

Receiving standard therapy

906 deaths (events recorded)

Val-HeFT: Valsartan Significantly Reduces Combined Endpoint of Mortality and Morbidity in Overall Population

Cohn et al. N Engl J Med 2001;345:1667–75

Time (months)

Valsartan (n=2,511)

Placebo (n=2,499)

13.2%Risk

reduction**

Combined endpoint of mortality and morbidity: All-cause mortality, cardiac arrest with resuscitation, hospitalisation for worsening heart failure, or therapy with IV inotropes or vasodilators; **p=0.009

0 3 6 9 12 15 18 21 24 27

First hospitalisation**p<0.001

Cohn et al. N Engl J Med 2001;345:1667–75

Placebo (n=2,499)

Val-HeFT: Valsartan Significantly Reduces Heart Failure-related Hospitalisations

27.5%Risk

reduction**

Valsartan (n=2,511)

Time (months)

00 3 6 9 12 15 18 21 24 27

Val-HeFT: Reduction in Combined Morbidity/Mortality*and Mortality With Valsartan (No ACE-I Subgroup)

*First morbid event, including death or hospitalisation

Valsartan (n=185) Placebo (n=181)

Time since randomisation (month)

p=0.0002

44.0% risk reduction

p=0.0171

33.1% risk reduction

Combined morbidity/mortality Mortality

Adapted from Maggioni et al. J Am Coll Cardiol 2002;40:1414–21

400 3 6 9 12 15 18 21 24 27 30

Time since randomisation (month)

500 3 6 9 12 15 18 21 24 27 30

CHARM-Added: CV Death or CHF Hospitalization

McMurray et al. Lancet 2003;362:767–71

0 1 2 3 3.5

Placebo

Candesartan

HR 0.85 (95% CI 0.75–0.96), p=0.011Adjusted HR 0.85, p=0.010

Number at risk

Candesartan 1,276 1,176 1,063 948 457

Placebo 1,272 1,136 1,013 906 422

538 (42%)

483 (38%)

NNT = 14

Val-HeFT: Change in Plasma BNP and NE Over Time

*Mean ± SEMLatini et al. J Card Fail 2001;7(Suppl 2):Abstract 198l Anand et al. Circulation 2001;104(suppl II):Abstract 2813

–100 4 12 24

Time (months)0 4 12 24

Time (months)

n=1,890

n=1,710

n=1,850

n=1,633

p<0.001 p<0.001 p<0.001

n=1,886 n=1,696

n=1,835 n=1,605 n=800

p=0.005 p=0.001 p<0.001

Valsartan Placebo

Conclusions

RAAS activation contributes to the chain of events (atherosclerosis, LVH) leading to coronary artery disease

Elevated RAAS activity is observed in post-MI HF and chronic HF

Potential pharmacological benefits of AT1-receptor blockade versus ACE inhibition

In high-risk post-MI patients, valsartan is as effective as captopril in reducing the risk of all-cause mortality, CV death, non-fatal MI or hospitalisation for HF

Valsartan reduces combined morbidity and mortality in patients receiving prescribed therapy for chronic HF, predominantly because of a reduction in HF hospitalisations

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