Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006

Sponsored by Novartis Pharma AG 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

Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006 VARIABLE 3: Hypertension and Microalbuminuria

Sponsored by Novartis Pharma AG Pathophysiology of Microalbuminuria in Hypertension Michel Burnier CHUV, Lausanne, Switzerland

Definition of Microalbuminuria 24-hour urinesUrine spot Category mg/24 hoursµg/minmg/L mg/mmol creatinine Normal<30<20 <2 Microalbuminuria30–30020–200 2–20 Macroalbuminuria>300>200 >20

Functional changes* Proteinuria Clinical type 2 diabetes Structural changes † Rising blood pressure Rising serum creatinine levels Cardiovascular death Microalbuminuria Onset of diabetes Years *Renal haemodynamics altered, glomerular hyperfiltration † Glomerular basement membrane thickening , mesangial expansion , microvascular changes +/- Natural History of Diabetic Nephropathy End-stage renal disease

Ang II Increased glomerular pressure Ang II Urinary protein Glucose AGEs Glycoxidation (glycation) Efferent arteriolar constriction = angiotensin AT 1 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 cytokines Proliferation of fibroblasts and extracellular matrix Development of fibrosis and renal atrophy Remuzzi et al. Kidney Int 1997;51:2–15 Albuminuria and Progression of Nephropathies

Diercks et al. Can J Cardiol 2002;18:525–35 Bigazzi 1992 Calvino 1999 Grandi 2000 Pontremoli 1997 Palatini 1996 Jensen 1997 Mean Prevalence of Microalbuminuria in Patients with Hypertension* Prevalence (%) *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 indexIntima/media thickness Microalbuminuria is Associated with Left Ventricular Hypertrophy and Carotid Hypertrophy in Hypertensive Patients LVMI (g/m 2 ) CHt AI–Ht AI IMT (mm) CHt 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/m 2 ) 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

Relative risk MI/Stroke/CV deathAll-cause mortality CHF hospitalisation Gerstein et al. JAMA 2001;286:421–6 Adjusted for age, sex, SBP/DBP, waist-hip ratio, diabetes and HbA 1c 1.62 Microalbuminuria and Risk of CV Events, CHF and Death in the HOPE Trial Alb/Crea (mg/mmol)

S. creat >124 µmol/L MicroalbuminuriaBoth 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 HR for primary outcome (CV death, MI, stroke)

Wachtell et al. J Hypertens 2002;20:405–12 LIFE study, 8,029 subjects with hypertension and LV hypertrophy, mean age 66 years Albuminuria and CV Diseases Prevalence (%) DiabetesCerebrovascularPeripheralCoronary diseasevascularvasculardisease Normoalbuminuria Microalbuminuria (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 Endpoint rate (%) Month >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 Hazard ratio CV deathNon-CV death Urinary albumin concentration (mg/L) ,000 Urinary albumin concentration (mg/L) 1101, Hazard ratio

Microalbuminuria and CV Complications in Hypertension: Is the Threshold Correct? The Copenhagen City Heart Study Klausen et al. Hypertension 2005;46:33– Cumulative mortality (%) RR of death RR of CHD 10 UAE (µg/min) Years from entry UAE  4.8 µg/min UAE <4.8 µg/min Cox-estimated age-adjusted curves of cumulative incidence of coronary heart 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– Percentage Years < Median  Median Survival free of CVD According 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– Clock time Blood pressure (mmHg)

Endothelial dysfunction Impaired endothelium-dependent vasodilation Reduces vasodilation Increased endothelinFavours vasoconstriction Increased transcapillary escape rate of albuminIncreases permeability (microalbuminaria) Increased von Willebrand factorIncreases prothrombotic activity Increased tPA and PAI-1Reduces profibrinolytic activity Increased E-selectin and VCAM-1Leucocytes adhesion and permeability Increased ICAM-1Induces inflammation Increased fibronectin and type IV collagen fragmentsAlters matrix synthesis Expression of Endothelial Dysfunction in Humans

NormoalbuminuriaElevated UAE Flow-associated dilatation (%) 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 DiabetesSmoking Oxidative stress Endothelial dysfunction  NO,  local mediators,  RAAS (Ang II) VasoconstrictionThrombosisInflammationPlaque ruptureVascular lesion and remodelling Pathobiological Processes Potentially Involved in the Development and Progression of Vascular Diseases

Chronic Kidney Disease and CV Risk Traditional risk factorsNon-traditional risk factors Age Sex Hypertension HDL and LDL cholesterol Diabetes Smoking Physical activity Family history of CVD LVH 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 IDNT RENAAL Microalbuminuria Macroalbuminuria ESRD CV morbidity and mortality PreventionProtection Benedict Study 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 Ibsen et al. Hypertension 2005;45:198–202 High baseline/high year 1 High baseline/low year 1 Low baseline/high year 1 Low baseline/low year 1 Follow-up (months) Fraction suffering composite endpoint

Asselbergs et al. Circulation 2004;110:2809–16 Effect of Fosinopril on CV Event Rates in Patients with Microalbuminuria Event-free survival 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 Event-free survival Follow-up (months) UAE <50 mg/24 hours, placebo UAE >50 mg/24 hours, placebo UAE <50 mg/24 hours, fosinopril UAE >50 mg/24 hours, fosinopril 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 AT 1 receptor blockers is an important therapeutic approach to reduce microalbuminuria and to prevent the development of CV and renal complications in hypertension

Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006

Sponsored by Novartis Pharma AG Point-Counterpoint Are Benefits Beyond Blood Pressure Lowering Clinically Relevant?

Albuminuria-associated Disease: Are Benefits Beyond BP Lowering Clinically Relevant? Giancarlo Viberti, MD Professor of Diabetes and Metabolic Medicine Cardiovascular Division KCL School of Medicine Guy’s Hospital King’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 ACR mg/mmol 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 Hypertension and Proteinuria In Type 2 Diabetes Standardised mortality ratio Status of hypertension (H) and proteinuria (P) in type 2 diabetes Wang et al. Diabetes Care 1996;19:305– 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) Gerstein et al. JAMA 2001;286:421–6 1 st 2 nd 3 rd 4 th Variable< – –1.62>1.62p for trend MI, stroke and CV death (0.63–1.14) 1.11 (0.86–1.43) 1.89 (1.52–2.63) <0.001 All-cause mortality (0.58–1.28) 1.41 (1.01–1.95) 2.38 (1.80–3.20) <0.001 CHF10.72 (0.32–1.63) 1.83 (0.98–3.43) 3.65 (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/24h II = 10.1 to 20 mg/24h III = 20.1 to 30 mg/24h

Survival Curves in Type 2 DM According To Baseline AER Category AER categories: I = ≤10 mg/24h II = 10.1 to 20 mg/24h III = 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 <9.45 P value for trend HR <0.001 Adjusted HR <0.001 Composite endpoint = CVD death, fatal or non-fatal stroke, fatal or non-fatal MI Albuminuria and CVD risk in hypertensive patients with LVH The LIFE Study

Relative Risk of CVD and Mortality in 5,545 High-risk Patients Without Diabetes by Quartile of Albuminuria (ACR) Gerstein et al. JAMA 2001;286:421–26 1 st 2 nd 3 rd 4 th Variable< – –1.62>1.62p for trend MI, stroke and CV death (1.03–1.49) 1.54 (1.29–1.85) 1.83 (1.52–2.20) <0.001 All-cause mortality (0.93–1.47) 1.49 (1.19–1.87) 2.27 (1.82–2.82) <0.001 CHF11.45 (0.87–2.44) 1.86 (1.12–3.10) 2.93 (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 CVD According 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/min 50%-ile: 3.0 μg/min 75%-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 Months Median percent change L (+CT) P (+CT) p= % overall reduction RENAAL: Change From Baseline in 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 Month % with renal endpoint  3.0 g/24h <1.5 g/24h Month % with ESRD endpoint  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 EndpointHeart Failure Month % with CV endpoint ≥3.0g/24h <1.5 g/24h Month % with heart failure endpoint  3.0 g/24h <1.5 g/24h

RENAAL: Initial Antiproteinuric Response vs Renal Risk Albuminuria reduction (%) Albuminuria reduction (%) Hazard ratio Renal Endpoint ESRD De Zeeuw et al. Kidney Int 2004;65:2309–20

RENAAL: Proteinuria Reduction ( 30%) Determines the Cardiovascular Outcome CV EndpointHeart Failure Month % with CV endpoint >30% <0% Month % with heart failure <0% >30% De Zeeuw et al. Circulation 2004;110:921–7

Viberti et al. Circulation 2002;106:672–8 Mean BP change (mmHg) SBP DBP UAER (µg/min) ValsartanAmlodipine 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

Systolic Diastolic Arterial blood pressure (mmHg) Follow-up (months) Verapamil Trandolapril Trandolapril plus Verapamil Placebo Ruggenenti et al. N Engl J Med 2004 Blood Pressure According To Treatment Group

Cumulative incidence of microalbuminuria (%) Follow-up (months) No. at risk ACE inhibitor No ACE inhibitor (66 events) ACE inhibitor (35 events) 20 A.F. (95 % C.I.) = 0.44 (0.27 – 0.70) p=0.001 Ruggenenti et al. N Engl J Med 2004

Ibsen et al. Hypertension 2005;45:198–202 Rate of CVD Events By Time-varying Albuminuria In Subjects With Essential Hypertension and LVH The LIFE Study Composite endpoint CV 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 Disease AASK

How do we obtain better evidence?

Antihypertensive and Antiproteinuric Responses To Increasing ACE-I Dose % reduction vs control mg10 mg15 mg20 mg Lisinopril dose (mg) BPUrinary protein Adapted from Palla et al. Int J Clin Pharmacol Res 1994;14:35–43

Conclusions Albuminuria 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

Sponsored by Novartis Pharma AG 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–16Placebo Beta-blockers–21Placebo Calcium antagonists–28Placebo ACE inhibitors–24Placebo Ang II antagonists–10Active therapy*

SBP difference between randomised groups (mmHg) Turnbull et al. Lancet 2003;362:1527–35 Relative risk of outcome event Metanalysis of Trials Comparing Different Treatments or Treatment Versus Placebo in Hypertension –10–8–6–4–2024 Stroke –10–8–6–4–2024 Major CVD –10–8–6–4–2024 CHD –10–8–6–4–2024 CVD death –10–8–6–4–2024 Total mortality Relative risk of outcome event

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 valsartanPatients treated with amlodipine Hazard ratio 95% CI Controlled patients † (n=5,253) Non-controlled patients (n=2,396) * * * * 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

Stroke Fatal Non-fatal All CV events All cardiac events All-cause death CV death Coronary events Heart failure New-onset diabetes Cancer Felodipine (138.1/82.3 mmHg) Placebo (141.6/83.9 mmHg) Hazard ratio (95% CI) Per 1,000 patient-years Felodipine betterPlacebo better 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 Treatment in DM + DM + (n=3,599)  BP –6.0/–4.6 mmHg Total StrokeCHDCHFCVDCV deathmortality 0 –10 –20 –30 –40 –36* –16 –31 –25* –33 –27* Risk ratio

MI (fatal + non-fatal) <25% 1.00  25%–<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 HR (95% CI) Reduced risk Percent of visits with BP control (<140/90 mmHg)HR(95% CI) Primary outcome <25% 1.00  25%–<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 reference Primary Outcome = first occurrence of death (all cause), non-fatal MI, or non-fatal stroke BP control by visit Stroke (fatal + non-fatal) <25% 1.00  25%–<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 Diabetes No diabetes Current smoker Non-current smoker Obese Non-obese LVH No LVH Older (>60 years) Younger (≤60 years) Female Male Previous vascular disease No previous vascular disease Renal dysfunction No renal dysfunction With metabolic syndrome Without metabolic syndrome Amlodipine/perindopril (BP 164.1/94.8  135.5/79.1 mmHg) Atenolol/thiazide (BP 163.9/94.5  136.3/78.4 mmHg)  2.9/1.7 mmHg

ACE-I versus D/BB Diabetes No diabetes Overall CA versus D/BB Diabetes No diabetes Overall ACE-I versus CA Diabetes No diabetes Overall  BP (mmHg) –0.5/ / /– /– / /0.8 RR (95% CI) 0.90 (0.74–1.11) 1.04 (0.98–1.10) p homog = (0.82–1.10) 1.04 (0.98–1.10) p homog = (0.79–1.07) 0.99 (0.92–1.07) p homog = 0.37 I 2 (%) 55 0 Turnbull et al. Arch Intern Med 2005;165:1410–19 Favours first Favours second Risk ratio Major CVD with ACE-I Versus D/BB Versus CA

Blood Pressure Lowering Treatment Trialists’ Collaboration Outcome Stroke Major CHD Heart failure Trial ELITE II OPTIMAAL VALIANT Overall ELITE II OPTIMAAL VALIANT Overall ELITE II OPTIMAAL VALIANT Overall 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 ARBFavours ACE-I Relative 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 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)

BP reduction Drug 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 Yes 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-term protection Long-term protection BP reduction Drug BP reduction Drug 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 MAP (mmHg) GFR (ml/min/1.73 m 2 ) Albuminuria (  g/min) Start of treatment Effect of Antihypertensive Treatment (n=10) –30–24–18–12– , Months

Sponsored by Novartis Pharma AG 7th Annual International Diovan Symposium Lisbon, 3–5 February 2006

Sponsored by Novartis Pharma AG 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 I II III IV II V5 aVR V1V4 aVL aVF V2 V3 V5 V6 Echo = Ejection fraction 35%; dilated left ventricle

Sponsored by Novartis Pharma AG 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…

VALIANT Registry: In-hospital Clinical Events Among Post-MI Patients With and Without HF/LVSD LVSD = left ventricular systolic dysfunction; AF = atrial fibrillation LOS = 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 Proportion Event-free Time (years) Carvedilol n=975 Placebo n=984 Risk reduction: 25% (4%, 42%) p=0.024 Cardiovascular mortality rates: placebo 14%; carvedilol 11%

Antiplatelet Therapy: Clopidogrel and Aspirin Reduce Risk of Death, MI or Stroke at One Year Adapted from Steinhubl et al. for the CREDO Investigators. JAMA 2002;288:2411–20 Death, MI, or stroke (%) RRR = Relative risk reduction; NS = non significant RRR 19.7% 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– Patients free from MACE (%) Time post-randomisation (years) Placebo (n=833) Fluvastatin (80 mg/d, n=844) Risk reduction = 22% 0 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 infarctInfarct expansion (hours to days) Global remodelling (days to months)

Acute Ischemia Ischemic Myocytes ECM Osteopontin TIMPs, MMPs Chronic Repair Apoptotic Myocytes Hypertrophied Myocytes Cytokine AII, OFR Angiogenesis VEGF, Angiopoietins Intergin  3 = Neutrophils = Macrophages Mechanical stress Oxydative stress Hypoxia Initial cytokine release = Monocyte Necrotic Myocytes Cytokine  Angiotensin = Mast Cells = Collagen = Angiogenesis Nian et al. Circ Res 2004;94:1543–53

Myocyte Stretch and AII Production Angiotensin IIMyocyte 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 Inflammatory cytokine levels p< p<0.01 TNF-  IL- 6 Group 1Group 2Group 1Group 2 (n=140)(n=44)(n=141)(n=30) IntrahospitalFollow-up p< p<0.01

0 10 3,000 4,000 5, ,000 Control Deoxyuridine triphosphate labelling Number of labelled myocyte Nuclei/10 6 Nuclei CM = cardiomyopathy; DCM = dilated cardiomyopathy Olivetti et al. N Engl J Med 1997;336:1131–41 Propidium Iodide Deoxyuridine Triphosphate Ischaemic CM Idiopathic DCM Apoptosis in the Failing Human Heart

Matrix Metalloproteinase (MMP) post MI uPA/PlasminMTMMP/ADAMs IL-1, CD40 TNF, EMPRINN OFR, Chymase ACE / AII Zn Sun et al. Circulation 2004;110:3221–8; Kassiri et al. Circulation Research 2005;97:380–90 TIMP3 MMP Inhibitors ACEi/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 Control3 days 7 days28 days

Renin–Angiotensin Aldosterone System (RAAS) Angiotensinogen Non-ACE pathways (e.g. chymase)  Vasoconstriction  Cell growth  Na/H 2 O retention  Sympathetic activation Renin Angiotensin I Angiotensin II ACE Cough, angio-oedema benefits?  Bradykinin Inactive fragments  Vasodilation  Antiproliferation (kinins) Aldosterone AT 1 receptor AT 2 receptor ACE = angiotensin-converting enzyme; AT 1 = angiotensin II type 1; AT 2 = angiotensin II type 2

Post-MI Remodelling: Ang II Modulation by RAAS Blockade ControlAng II modulation

Effects of ACE Inhibitor Treatment on All-Cause Mortality Post-MI EF = ejection fraction; OR = odds ratio Flather et al. Lancet 2000;355:1575–81 ACE inhibitor Placebo OR: 0.74 (0.66–0.83) ACE inhibitor: 702/2995 (23.4%) Placebo: 866/2971 (29.1%) TRACE Echocardiographic EF ≤ 35% AIRE Clinical and/or radiographic signs of HF SAVE Radionuclide EF ≤ 40% Probability of event Years ,9952,2501, ACE inhibitor 2,9712,1841, Placebo

VALIANT: Valsartan Shows Non-inferiority to ACE Inhibitors Hazard ratio for death from any cause Favours active drug Favours placebo Pfeffer et al. N Engl J Med 2003;349:1893– SAVE, TRACE and AIRE combined TRACE SAVE AIRE 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

Sponsored by Novartis Pharma AG 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 organ damage Risk factors: diabetes, hypertension Vascular dysfunction Atherosclerosis and LVH Tissue injury (MI, stroke) Pathologic remodelling Target organ dysfunction (HF, renal) Endstage organ failure Death Oxidative stress/ endothelial dysfunction LVH = left ventricular hypertrophy MI = myocardial infarction; HF = heart failure Adapted from Dzau and Braunwald. Am Heart J 1991;121:1244–63 The Cardiovascular Continuum AT 1 receptor

The Scope of CHD and MI Worldwide, 17 million people die of CVD every year 1 More than 60% of the global burden of CHD occurs in developing countries 1 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 MI 2 1 http// 2 American Heart Association Heart and Stroke Statistical Update *Coronary attack=definite or probable MI, or fatal CHD CHD=coronary heart disease

MI and CAD: Secondary Prevention Treatment objectives Improve survival Prevent reinfarction Prevent LV remodelling Prevent progression to HF Reduce risk of arrhythmias

How can we help these high-risk patients?

Severity of LV damage Antiplatelet Statin Treatment of Post-MI Patients 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) 0.73* Reinfarction n= 324 n= 391 (0.69 – 0.95) 0.80* Placebo (n=2,971)ACE-I (n=2,995) Death/MI or Readmission for HF Events (%) n = 1,049 n = 1244 (0.67–0.83) 0.75* TRACE Echocardiographic EF  35% AIRE Clinical and/or radiographic signs of HF SAVE Radionuclide EF  40% Death and Major CV Events

+ Proven ACE-I SAVE/AIRE/TRACE Early Treatment of Post-MI Patients with LVSD/Acute HF Severity of LV damage Antiplatelet Statin LVSD or Acute HF LVSD and Acute HF +

Potential Pharmacological Benefits of AT 1 -receptor Blockade Versus ACE Inhibition AT 1 -R antagonistsACE inhibitors Chymase Ang II AT 2 AT 1 AT 2 NO Prostagladins Cardioprotection Vasodilation Negative chronotropism Anti-fibrosis Anti-growth Cardioprotection Vasodilation Plasma Ang II Bradykinin Cardioprotective effects via angiotensin II binding to AT 2 receptor Angiotensin II generated by non-ACE dependent pathways 1,2 also blocked from binding to the AT 1 receptor Reduced side-effect profile (ACE inhibition: increased bradykinin = cough) Adapted from Matsubara. Circ Res 1998;83:1182–91 1 Unger. JRAAS 2001;2(suppl 2):S4–S7 2 Petrie 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%.” 80% 9% 5% 1% 3% 2% 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 Event rate (%) Captopril (n=447 events) Relative risk = 1.13 (0.99–1.28); p= Losartan (n=499 events) Losartan2,7442,5042,4322,3902,3442,3011,285 Captopril2,7332,5342,4632,4232,3742,3291,309 Dickstein et al. Lancet 2002

+ Antiplatelet Statin Proven ACE-I or Losartan 50 mg qd SAVE/AIRE/TRACE OPTIMAAL Early Treatment of Post-MI Patients with LVSD/Acute HF + Severity of LV damage LVSD or Acute HF LVSD and Acute HF

VALIANT Primary endpoint:All-cause mortality Secondary endpoints:CV Death, MI, or HF Other 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 months Event-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 4,9094,4644,2724,0072,6481, Captopril4,9094,4284,2414,0182,6351, Valsartan+Captopril4,8854,4144,2653,9942,6481, Captopril Probability of event No. at risk Valsartan vs captopril: HR=1.00; p=0.982 Valsartan + 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 CV death (1,657 events) 0.62 CV death or HF (2,661 events) 0.51 CV death or MI (2,234 events) 0.25 CV death, MI, or HF (3,096 events) 0.20 Favours valsartanFavours 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) Patients with at least one event (%) MyocardialAnginaRevascularisationStroke infraction Adapted from McMurray et al. Presented at ESC 2005

Months Probability of event Study Drug Discontinuation All Due to Adverse Events *p<0.05 vs captopril * Captopril Valsartan + Captopril Valsartan *

+ Antiplatelet + Statin Proven ACE-I (Captopril) or Valsartan 160 mg bid or Captopril + Valsartan SAVE/AIRE/TRACE Early Treatment of AMI Patients with LVSD/Acute HF VALIANT Severity of LV damage LVSD or Acute HF LVSD and Acute HF

p=0.031 OR 0.77 (0.60–0.98) CAPRICORN Survival Carvedilol Placebo The CAPRICORN Investigators. Lancet. 2001

EPHESUS All-cause Mortality Pitt et al. for EPHESUS Investigators. N Engl J Med 2003;348:1309–21 Months since randomisation Cumulative incidence (%) RR = 0.79 (95% CI, 0.64–0.97) p=0.03 Placebo Eplerenone Eplerenone3,3193,0442,4631, Placebo3,3132,9832,4181,

Severity of LV damage + + Antiplatelet Statin Proven ACE-I or valsartan 160 mg bid Eplerenone 25–50 mg qd SAVE/AIRE/TRACE VALIANT CAPRICORN EPHESUS Early Treatment of AMI Patients with LVSD/Acute HF LVSD or Acute HF LVSD and Acute HF + Carvedilol

Death Any CV event YEAR 1 YEAR 2 YEAR 3 YEAR 4 Cardiac Events Following High-risk MI: The VALIANT Experience Cumulative incidence Heart failure Recurrent MI Sudden death or cardiac arrest

The Framingham Heart Study: 1987 Cupples et al. The Framingham Study, NIH Publication No. 87– Cumulative probability of event Years following MI Risk of heart failure after MI (Age 35 to 94 at diagnosis) MI male MI female Matched male Matched female

Time Since Randomization, months Survival probability BNP (pg/mL) <41 41–97 98–238 >238 BNP % Mortality NE Time Since Randomization, months >572 < – –572 NE (pg/mL) % Mortality 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= Ang II >16 pg.mL –1 Normal Ang II Months

LVIDd = left ventricular internal diastolic diameter; BSA = body surface area Cohn 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 2.9 cm/m 2 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) Probability of event-free survival 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=

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) Probability of event-free survival

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= % risk reduction Probability of event-free survival p= % risk reduction Combined morbidity/mortality Mortality Adapted from Maggioni et al. J Am Coll Cardiol 2002;40:1414– Time since randomisation (month) Proportion survived (%)

CHARM-Added: CV Death or CHF Hospitalization McMurray et al. Lancet 2003;362:767– Years Placebo Candesartan % HR 0.85 (95% CI 0.75–0.96), p=0.011 Adjusted HR 0.85, p=0.010 Number at risk Candesartan 1,2761,1761, Placebo 1,2721,1361, (42%) 483 (38%) NNT = 14

Val-HeFT: Change in Plasma BNP and NE Over Time *Mean ± SEM Latini et al. J Card Fail 2001;7(Suppl 2):Abstract 198l Anand et al. Circulation 2001;104(suppl II):Abstract –20 –40  Plasma BNP * (pg/mL)  NE* (pg/mL) – Time (months) Time (months) n=1,890 n=1,710 n=1,850 n=1,633 n=823 p<0.001 n=844 n=1,886 n=1,696 n=1,835n=1,605n=800 p=0.005p=0.001p<0.001 n=829 ValsartanPlacebo

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 AT 1 -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