Get to Goal, Achieve Control

Get to Goal, Achieve Control
PROFESSOR Dr.ALAA ETMAN MD NATIONAL HEART INSTITUTE

Cardiovascular diseases leading causes of global mortality
Maternal and perinatal conditions Nutritional deficiencies Other non-infectious diseases Infectious and parasitic diseases Injuries Cancer Respiratory diseases CV disease leading cause of global mortality Cardiovascular disease is the leading cause of death across the world. According to the World Health Report 2004, cardiovascular disease accounted for nearly one third of all disease-related mortality1. Cancer, by comparison, accounted for less than half the number of deaths (12.5%) compared to death due to cardiovascular disease. References: 1. The World Health Report 2004, statistical annex. Respiratory infections CV diseases WHO World Health Report 2004

Prevalence of Hypertension
References

Proportion of Patients Treated/Not Treated for Hypertension in Europe*
England Sweden Germany Spain Italy In this study, data from national surveys on hypertension treatment and control in Europe and North America (data for US and Canada not shown on slide) were analyzed. Based on a definition of hypertension as ≥140/90 mmHg, England had the lowest level of treatment, followed very closely by Sweden, Germany, Spain and Italy. Treatment of hypertension was highest in the US and Canada (53% and 36%, respectively). The proportion of patients achieving BP goal was low. Reference Wolf-Maier K, et al. Hypertension treatment and control in five European countries, Canada, and the United States. Hypertension 2004;43:1017. *Age adjusted; patients aged 35–64 years Hypertension = 140/90mmHg threshold Wolf-Maier et al. Hypertension 2004;43:10–17 4

Prevalence of Hypertension Increases with Age
2039 4059 60 Estimated non-institutionalized US adults, 19992002 Adapted from Centers for Disease Control and Prevention The prevalence of hypertension (defined as BP ≥140/90 mmHg or use of antihypertensive medication) increases with advancing age, with a sharp rise at age 60 or above.1 Much of the increasing prevalence of hypertension with age can be explained by the age-related increase in systolic BP, whereas diastolic BP tends to rise until approximately 50 years of age and then tends to level-off or decline for the remainder of the individual’s life.2 References 1. Brown MJ. Hypertension and ethnic group. BMJ 2006;332:833–6. 2. Franklin SS, et al. Hemodynamic patterns of age-related changes in blood pressure: the Framingham Heart Study. Circulation 1997;96:308–15. Age (years) Brown. BMJ 2006;332:8336

Stroke & IHD* Mortality Rate in Each Decade of Age, vs Usual Systolic BP at the Start of that Decade
These data are taken from a meta-analysis of 61 prospective observational studies on deaths from vascular disease among subjects without vascular disease at baseline. The results demonstrated that the relationship of stroke mortality (left panel) and ischemic heart disease (IHD) mortality (right panel) to usual BP is strong and direct at all ages. As highlighted on the following slide, each difference of 20 mmHg in usual systolic BP is associated with a two-fold difference in the risk of stroke mortality and IHD mortality (between ages 40–69 years). The annual absolute difference in risk is greater in old age. Reference Lewington S, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13. *IHD= Ischaemic Heart Disease

Cardiovascular Mortality Risk Systolic BP/Diastolic BP (mmHg)
Cardiovascular Mortality Risk Doubles with Each 20/10 mmHg Increment in Systolic/Diastolic BP* Cardiovascular Mortality Risk 115/75 135/85 155/95 175/105 2 4 8 6 8X risk 4X risk For individuals aged 4069 years, each increment in systolic BP of 20 mmHg or diastolic BP of 10 mmHg doubles the risk of cardiovascular disease (stroke, ischemic heart disease, other vascular diseases) across the entire BP range. Benefits are therefore to be gained from lowering BP in terms of reduced risk of cardiovascular mortality. Reference Lewington S, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13. 2X risk 1X risk Systolic BP/Diastolic BP (mmHg) *Individuals aged 40–69 years Lewington et al. Lancet 2002;360:1903–13

BP Reduction of 2 mmHg Decreases the Risk of CV Events by 7–10%
Meta-analysis of 61 prospective, observational studies 1 million adults 12.7 million person-years 7% reduction in risk of ischaemic heart disease mortality 2 mmHg decrease in mean SBP Trials have shown that BP lowering can produce rapid reductions in cardiovascular disease risk. In fact, even a 2 mmHg decrease in systolic BP would result in approximately 7% lower mortality risk from ischemic heart disease and a 10% lower mortality risk from stroke. Reference Lewington S, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13. 10% reduction in risk of stroke mortality Lewington et al. Lancet 2002;360:1903–13

Hypertension in Egypt Hypertension is a major health problem in Egypt with a prevalence rate of 26.3% among the adult population (> 25 years)1. Only 8% of hypertensive Egyptians have their blood pressure controlled1. 1- Ibrahim MM, Rizk H, Apple LJ, et al. For the NHP investigation team. Hypertension, prevalence, awareness, treatment and control in Egypt. Results from the Egyptian National hypertension Project (NHP). Hypertension 1995; 26:880.

More Than 80% Of hypertensive Patients have additional Co-morbidities

Controlling SBP Is the Main Problem
Ref 1, p 595, C1, ¶2, L1-4; p 596, Fig 1 220 54% 13% 200 Not at SBP or DBP goal 67% did not reach SBP goal 180 Historically, efforts to control BP and limit associated morbidity and mortality have focused on DBP.1 A community-based sample from the Framingham Heart Study showed that control of SBP is more difficult among patients with hypertension1: As this slide shows, 67% of hypertensive patients had SBP above the goal of 140 mmHg1 In contrast, elevated DBP (>90 mmHg) was observed in only 17% of patients1 These findings suggest that greater emphasis should be placed on helping hypertensive patients—especially those who are older, obese, or have target-organ damage—achieve goal SBP.1 Context: This analysis included data for 1959 hypertensive patients in the Framingham Heart Study, an ongoing, prospective epidemiologic cohort study designed to evaluate the impact of risk factors on coronary heart disease. These patients were examined between 1990 and 1995 for hypertension defined on the basis of SBP of 140 mmHg or greater, DBP of 90 mmHg or greater, or the use of antihypertensive medication. The mean patient age was 66 years; 54% were women and 60.7% were receiving antihypertensive medication.1 Ref 1, p 594, C2, ¶1, L3-5 Ref 1, p 595, C1, ¶1, L1-3, C2, ¶2, L4-8; p 598, C1, ¶1, L3,4 Ref 1, p 596, Fig 1 Ref 1, p 596, Fig 1 + calc Calc: =17.1 Ref 1, p 598, C1, ¶1, L5-8 Ref 1, p 595, C1, ¶1, L1-3, ¶2, L1-4, C2, ¶1, L1,2, ¶2, L1,2 SBP, mmHg 160 140 140 120 At SBP and DBP goal 100 90 29% 4% 80 20 40 60 80 100 120 140 DBP, mmHg Adapted from Lloyd-Jones DM, et al. Hypertension. 2000;36:594–599. Reference Lloyd-Jones DM, Evans JC, Larson MG, et al. Differential control of systolic and diastolic blood pressure: factors associated with lack of blood pressure control in the community. Hypertension. 2000;36:594–599.

Predictive Power of Systolic BP on Cardiovascular Mortality
Systolic BP (mmHg) Diastolic BP (mmHg) <140 <90 140–159 90–99 160–179 100 ≥180 0.5 1 1.5 2 2.5 0.5 1 1.5 2 2.5 Relative risk Relative risk The results of this observational prospective cohort study, which followed patients (65 years or older) for 10 years, demonstrated a strong and independent association between systolic BP and with cardiovascular mortality (p<0.001). Reference Alli C, et al. The long-term prognostic significance of repeated blood pressure measurements in the elderly: SPAA (Studio sulla Pressione Arteriosa nell'Anziano) 10-year follow-up. Arch Intern Med 1999;159:1205–12. Prognosis better Prognosis worse Prognosis better Prognosis worse Alli et al. Arch Intern Med 1999;159:1205–12

11-Year Increase in Risk of CV Death for 10 mmHg Increase
in SBP at Different Baseline SBP Values 4.5 Increase in risk of CV death (%) 2.4 2.0 1.8 1.3 0.9 1.1 0.8 0.6 Baseline SBP (mmHg) Sega et al., Circulation 2005 14

Evolution of Cardiovascular Risk in Hypertension
Low Risk Higher Risk Highest Risk Clinical Trial Treatment Guidelines Disease Evolution; 20 – 50 years Hypertension: No TOD No CVD Younger Target Organ Damage: LVH Vascular Structure Albuminuria Cardiovascular Disease: CHD / CHF Stroke / TIA Renal Disease Blood pressure reduction should clearly be the focus of risk management of patients with hypertension. An emerging dilemma in the development of treatment guidelines is how much weight should be given to individual trials and the benefits of different drug classes on surrogate markers of cardiovascular risk and longer-term outcomes, such as LVH and albuminuria. Moreover, the emergence of drug effects on the risk of developing diabetes is also beginning to influence drug selection for the treatment of hypertension. The challenge is to identify the ideal combination of drugs to achieve modern blood pressure goals, prevent and/or regress the development of target organ damage and restrain the development of diabetes. Ultimately, the goal is to reduce the risk of cardiovascular morbidity and mortality – this will involve the selection of effective and proven blood pressure lowering regimens, alongside lifestyle measures and statins, to optimally reduce cardiovascular disease risk. Williams B. Drug specific benefits and cardiovascular and stroke outcomes. J Hypertens 2004;21: Williams B, Poulter NR, Brown MJ et al. British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): Summary. BMJ 2004; 328: Williams B. State of the Art Review: Recent Hypertension Trials; Implications and controversies. J Am Coll Cardiol 2005; 45: Surrogate Endpoints Hard Endpoints Atrial Fibrillation Systolic Dysfunction Diastolic Dysfunction Drug Treatment Metabolic Syndrome to Diabetes

Natural History of Cardiovascular Disease
Treatment of Clinical Events Treatment of Silent Lesions To Interrupt Vascular Disease Progression MI, Angina Stroke Congestive Cardiac Failure Renal Failure Periferal Artery Disease LVH > IM thickness Lacunar infarcts Microalbuminuria Non-fatal recurrent events Arteriosclerosis Vascular remodeling CRF Dialysis Dementia - Monitoring blood pressure alone represents only a partial understanding of hypertension - Need to identify patients at risk for CVD, even if their blood pressure is in normal range - Must expand definition of hypertension beyond numbers to focus more on overall CVD risk - Hypertension is a progressive CV syndrome adversely affecting heart and vascular system Early markers of CV syndrome may be present before blood pressure elevation is sustained Coronary heart disease is a major cause of morbidity and mortality in the industrialized world.1 The disease develops through a chain of events The presence of certain risk factors elicits changes in the heart and vasculature, some of which may initially be beneficial but may be maladaptive or become pathologic when they progress. An example is left ventricular hypertrophy which develops in response to an increased workload in the chamber. Eventually ventricular wall remodeling occurs with increased muscle mass and cardiac dilation, ultimately resulting in heart failure. Similarly coronary vascular obstruction and myocardial ischemia are the ultimate consequences of the proliferate response of the coronary vasculature. The ischemic state elicits further changes in the ventricle, which culminate in congestive heart failure and end-stage heart disease.1 The ultimate goal of therapies is to prevent the development of conditions and disorders that lead to cardiovascular (CV) morbidity and death. Therapies which prevent or reverse the presence of LVH can break a major link in the development of CV morbidity and death.2 1 Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: A workshop consensus statement. Am Heart J. 1991;121: 2 Kahan T. The importance of left ventricular hypertrophy in human hypertension. J Hypertens.1998;16(suppl 7):23-29. Treatment of Cardiovascular Risk Factors Hypertension Diabetes Dislipidemia Central Obesity Life Style Changes Genes Life style Death 16

Angiotensin II Plays a Central Role in Organ Damage
Stroke Atherosclerosis* Vasoconstriction Vascular hypertrophy Hypertension A II LV hypertrophy Fibrosis Remodeling Apoptosis DEATH Heart failure MI Angiotensin II Plays a Central Role in Organ Damage In adult tissues, virtually all known deleterious effects of angiotensin II (A II)  the end product of the renin-angiotensin system  are attributable to the AT1 receptor.21 The adverse cerebral and cardiovascular effects of A II, which have potentially lethal sequelae, are pervasive. Preclinical data implicate A II in cerebro-vascular ischaemia through the development of atherosclerosis.22 By potentiating the activity of other neurohormonal systems, A II exerts harmful cardiovascular effects by means of the AT1 receptor 23  including vasoconstriction,23 vascular hypertrophy,24 left ventricular hypertrophy,24 myocardial and vascular wall fibrosis,23 myocardial remodeling24 and cardiac myocyte apoptosis under some conditions25 and thereby contributes to the development of hypertension, heart failure, and myocardial infarction.21,25 A II also plays a central role in the development of renal insufficiency in response to heart failure. As cardiac function deteriorates, decreased renal blood flow leads to a reduced glomerular filtration rate.26 Intense sympathetic activation in heart failure stimulates production of A II in the kidney 26 that initiates a cascade of potentially deleterious renal effects including proteinuria,27 increased aldosterone release,21,26 and cell growth and matrix accumulation leading to glomerular sclerosis.28 AT1 Receptor GFR Proteinuria Aldosterone release Glomerular sclerosis 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): ; Dahlöf B J Hum Hypertens 1995;9(suppl 5):S37-S44; Daugherty A et al J Clin Invest 2000;105(11): ; Fyhrquist F et al J Hum Hypertens 1995;9(suppl 5):S19-S24; Booz GW, Baker KM Heart Fail Rev 1998;3: ; Beers MH, Berkow R, eds. The Merck Manual. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories, 1999: ; Anderson S Exp Nephrol 1996;4(suppl 1):34-40; Fogo AB Am J Kidney Dis 2000;35(2): 17

“Controlling blood pressure with medication is unquestionably one of the most cost-effective methods of reducing premature CV morbidity and mortality” Elliott. J Clin Hypertens 2003;5(Suppl. 2):313

Associated risk factors

Blood Pressure and Cardiovascular Risk: ESHESC Guidelines
Other RF, OD or disease BP (mmHg) Normal SBP 120–129 or DBP 80–84 High normal SBP 130–139 or DBP 85–89 Grade 1 SBP 140–159 or DBP 90–99 Grade 2 SBP 160–179 or DBP 100–109 Grade 3 SBP 180 or DBP 110 No other RF Average risk Low added risk Moderate added risk High added risk 1–2 RF Very high added risk 3 RF, MS, OD or diabetes High added risk Established CV or renal disease The risk of cardiovascular (CV) disease is influenced by the severity of hypertension and the co-existence of complications (other risk factors, organ damage and disease). A stratification for total CV risk, as shown on this slide, has been defined by the ESHESC guidelines. Treatment decisions such as initiation of therapy, BP targets, use of combination therapy, etc. are dependent on the level of CV risk. Notes to table Low, moderate, high and very high refer to the 10-year risk of a CV fatal or non-fatal event. The dashed curve indicates how the definition of hypertension may be variable, depending on the level of total CV risk. Reference The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) guidelines for the management of arterial hypertension. J Hypertens 2007;25:110587. MS = metabolic syndrome OD = subclinical organ damage RF = risk factors Reproduced from the Task Force of ESH–ESC. J Hypertens 2007;25:1105–87; Copyright © 2007, with permission from Lippincott Williams and Wilkins

Factors influencing prognosis in hypertension. Subclinical organ damage
2007 Guidelines for the management of arterial hypertension Electrocardiographic LVH Sokolow-Lyon >38 mm Cornell >2440 mm x ms Echocardiographic LVH (Left ventricular mass index): ≥125 g/m2 (males) ≥110 g/m2 (females) Carotid wall thickening (IMT >0.9 mm) or plaque Carotid-femoral pulse wave velocity >12 m/s Ankle / brachial blood pressure index >0.9 LVH: Left ventricular hypertrophy IMT: Intima media thickness Mancia G, et al. J Hypertens. 2007;25:

ESH/ESC & JNC 7 Summary: Target BP Goals
Types of Hypertension BP Goal (mmHg) Uncomplicated <140/90 Complicated Diabetes mellitus <130/80 Kidney disease <130/80* Other high risk (stroke, myocardial infarction) Based on published evidence, such as that from the Framingham Heart Study, the ESHESC guidelines1 and the JNC 7 guidelines2 have made recommendations for target BP goals that should be achieved in order to maximize the reduction in the long-term risk of cardiovascular (CV) disease and death. Target BP goals are particularly aggressive (at least <130/80 mmHg) for patients with hypertension complicated by diabetes or renal disease. The same is true for those patients considered high risk (e.g. history of stroke or previous myocardial infarction). Aggressive goals are necessary for such patients because the presence/history of these diseases compounds their total CV risk. References The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) guidelines for the management of arterial hypertension. J Hypertens 2007;25:110587. Chobanian AV, et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA 2003;289:256072. *Lower if proteinuria is >1 g/day Task Force of ESH–ESC. J Hypertens 2007;25:110587 Chobanian et al. JAMA 2003;289:256072

Blood Pressure Thresholds (mmHg) for Definition of Hypertension with Different Types of Measurement
SBP DBP Office or Clinic 140 90 24-hour 80 Day 85 Night 120 70 Home

Cont…

Causes of Inadequate Responsiveness to Therapy….cont.

Patient-Related Barriers to Effective Antihypertensive Treatment
Increased susceptibility Advanced age Obesity Secondary causes (less common) Sleep apnea Drug side effects Chronic kidney disease Primary aldosteronism Renovascular disease Cushing syndrome Pheochromocytoma Coarctation of the aorta Thyroid/parathyroid disease Limited access to health care Lack of health insurance Lack of a regular provider Nonadherence to therapy Knowledge deficits Medication cost Complicated regimens Side effects Medication not taken by patient Poor physician-patient communication Lack of social support Patient-Related Barriers to Effective Antihypertensive Treatment There are many patient factors that interfere with effective antihypertensive treatment. Some of these factors are listed on this slide. References: Wang TJ, Vasan RS. Epidemiology of uncontrolled hypertension in the United States. Circulation. 2005;112: Chobanian AV, Bakris GL, Black HR, et al, for the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289: Wang TJ, Vasan RS. Circulation. 2005;112: ; Chobanian AV, et al. JAMA. 2003;289: 26

Physician-Related Barriers to Effective Antihypertensive Treatment
Unfamiliarity with current treatment guidelines Blood pressure thresholds Isolated systolic hypertension Threshold for diabetic patients Use of monotherapy to treat patients with difficult-to-control blood pressure Belief that in-office blood pressure tends to be higher than at-home blood pressure Lack of time at office visits Therapeutic inertia Overestimation of adherence to guidelines Disagreement with guidelines Isolated systolic hypertension Concern about the relationship between diastolic blood pressure and myocardial infarction (i.e., the J curve) Reluctance to treat a seemingly “asymptomatic condition” Physician-Related Barriers to Effective Antihypertensive Treatment There also are many physician factors that interfere with effective antihypertensive treatment. Some of these factors are listed on this slide. References: Wang TJ, Vasan RS. Epidemiology of uncontrolled hypertension in the United States. Circulation. 2005;112: Chobanian AV, Bakris GL, Black HR, et al, for the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289: Okonofua EC, Simpson KN, Jesri A, Rehman SU, Durkalski VL, Egan BM. Therapeutic inertia is an impediment to achieving the Healthy People 2010 blood pressure control goals. Hypertension. 2006;47: Wang TJ, Vasan RS. Circulation. 2005;112: ; Chobanian AV, et al. JAMA. 2003;289: ; Okonofua EC, et al. Hypertension. 2006;47: 27

Recommended Lifestyle Modifications and Their Individual Effects on Blood Pressure
Recommendation Approximate SBP Reduction Reduce weight Maintain normal body weight (BMI of 18.524.9 kg/m2) 320 mm Hg Adopt DASH diet Rich in fruit, vegetables, and low-fat dairy; reduced saturated and total fat content 814 mm Hg Reduce dietary sodium <100 mmol (2-4 g)/day 28 mm Hg Increase physical activity Aerobic activity >30 min/day most days of the week 49 mm Hg Moderate alcohol consumption Men: ≤ 2 drinks/day Women: ≤ 1 drink/day 24 mm Hg Recommended Lifestyle Modifications and Their Individual Effects on Blood Pressure The adoption of a healthy lifestyle is critical to preventing high blood pressure and to the management of persons who already have hypertension. This slide depicts the lifestyle modifications that are recommended by the JNC-7 Committee to prevent or to manage hypertension and their effects on systolic blood pressure. Whether there is an additive effect on blood pressure reduction when 2 or more lifestyle modifications are combined has not been extensively investigated. References: Chobanian AV, Bakris GL, Black HR, et al, for the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289: Blumenthal JA, Sherwood A, Gullette ECD, et al. Exercise and weight loss reduce blood pressure in men and women with mild hypertension: effects on cardiovascular, metabolic, and hemodynamic functioning. Arch Intern Med. 2000;160: *Combining 2 or more of these modifications may or may not have an additive effect on blood pressure reduction. SBP = systolic blood pressure; BMI = body mass index; DASH = Dietary Approaches to Stop Hypertension Chobanian AV, et al. JAMA. 2003;289: ; Blumenthal JA, et al. Arch Intern Med. 2000;160:

Causes of Essential Hypertension
Age Excess Sodium Consumption Overweight Elevated Systolic and/or Diastolic Blood Pressure Excess Alcohol Consumption Physical Inactivity Family History Stress

Pathophysiology of Hypertension
… The lack of efficacy observed resulting at least partly of the complex pathophysiology of hypertension As observations in man strongly indicate that high BP arises as the result of a complex interplay between various environmental factors and an underlying genetic predisposition. There is thus a wide heterogeneity underlying hypertension. The number of hypertensive phenotypes resulting from different environmental-genetic interactions may explain, therefore, why there is marked heterogeneity in response to treatment, and why any single antihypertensive agent would be unlikely to control BP in more than 30% of patients. Sever P. J Cardiovasc Pharmacol ;31(suppl 2):S1-S4. Sever P. J Cardiovasc Pharmacol ;31(suppl 2):S1-S4. 30

Hypertension Syndrome!! It’s More Than Just Blood Pressure
Decreased Arterial Compliance Obesity Endothelial Dysfunction Abnormal Lipid Metabolism Abnormal Glucose Metabolism Accelerated Atherogenesis Neurohormonal Dysfunction Hypertension LV Hypertrophy and Dysfunction Renal-Function Changes Abnormal Insulin Metabolism Blood-Clotting Mechanism Changes Kannel WB. JAMA. 1996;275: Weber MA et al. J Hum Hypertens. 1991;5: Dzau VJ et al. J Cardiovasc Pharmacol. 1993;21(suppl 1):S1-S5.

Blood Pressure Regulation

Short Term Regulation of Blood Pressure: Pressure Natriuresis
Arterial pressure is a signal for regulation of NaCl excretion.  Arterial pressure   NaCl reabsorbed in the proximal tubule  more NaCl to Macula Densa  Tuboglomerular Feedback (TGF)  autoregulation RBF, GFR In addition, there is an accompanying increase in urine Na+, volume output: pressure natriuresis/diuresis. Pressure natriuresis can normalize BP by decreasing the effective circulating volume – this response connects BP and ECFV. ECFV: Extracellular fluid volume, a function of Na+ reabsorption ; RBF: Renal blood flow; PT: Proximal tubule; GFR: Glomerular filtration rate; TGF: tubuloglomerular feedback

Predicted Long-Term Effects of a Hypertensive Stimulus
Renal function curve Predicted long-term effects of a hypertensive stimulus, caused by increased total peripheral resistance (normal renal-pressure natriuresis mechanism). Blood pressure is initially elevated (from point A to point B), but hypertension cannot be sustained because sodium excretion exceeds intake, thereby reducing extracellular fluid volume until blood pressure returns to normal and intake and output of sodium are balanced. Hall et al. Kidney Int Suppl, Volume 49 Supplement 55.June 1996.S-35-S-41

The Renin Angiotensin Aldosterone System (RAAS)
The renin–angiotensin system The renin–angiotensin (RAS) system is one of the longest recognised hormonal systems: it was first described 100 years ago in remarkable detail. It helps to regulate long-term blood pressure and blood volume in the body by the production of aldosterone, a corticosteroid that regulates electrolyte balance. Renin, an aspartyl protease, is produced in the kidneys and released into the plasma in response to a drop in blood pressure or volume. It catalyses the conversion of an inactive peptide angiotensinogen to angiotensin I. Angiotensin I is also fairly inactive until converted to its active form, angiotensin II, by the angiotensin-converting enzyme, or ACE as we know it. ACE is expressed on endothelial surfaces, particularly in the lung and by non-endothelial parenchymal cells in the heart and kidney. Angiotensin II is a vasopressor interacting with cellular receptors. Two subtypes of angiotensin II receptors have been well characterised: angiotensin II type 1 (AT1) and type 2 (AT2). The AT1 mediates all the known actions of angiotensin II on blood pressure control.4 The AT1 receptor modulates cardiac contractility and glomerular filtration, increases renal tubular sodium reabsorption, and cardiac and vascular hypertrophy. It also causes oxidative stress and endothelial dysfunction.5 Less is known about the functions of the AT2 receptor. It is known to inhibit cell proliferation and reverse AT1 receptor-induced hypertrophy and thought to modulate neuroplasticity, vascular regeneration and apoptosis.4,6 Interestingly, the effects of the two receptors seem to be opposing, an important feature that we will explore in detail later. It is also important to note that angiotensin can be converted to angiotensin II by other pathways, with enzymes such as chymase that do not involve ACE. ACE also has an important role in the breakdown of bradykinin. Bradykinin, a physiologically and pharmacologically active peptide, is a potent vasodilator that acts through the release of prostacyclin, nitric oxide and endothelial-derived hyperpolarising factor.7 References 1. Hanon S., et al. Persistent formation of angiotensin II despite treatment with maximally recommended doses of angiotensin converting enzyme inhibitors in patients with chronic heart failure. J Renin Angiotensin Aldosterone Syst 2000;1:147–150. 2. Chen R., et al. Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. Hypertension 2003;42:542–547. 3. Hurairah H. & Ferro A., The role of the endothelium in the control of vascular function. Int J Clin Pract 2004;58:173–183. 4. Crowley S.D., et al. AT(1) Receptors and Control of Blood Pressure: The Kidney and More. Trends Cardiovasc. Med 2007;17:30–34. 5. Annuk M., et al. Endothelial function, CRP and oxidative stress in chronic kidney disease. J Nephrol 2005;18:721–726. 6. Gendron L., et al. The angiotensin type 2 receptor of angiotensin II and neuronal differentiation: from observations to mechanisms. J Mol Endocrinol 2003;31:359–372. 7. Gainer J.V., et al. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998;339:1285–292. Hanon S., et al. J Renin Angiotensin Aldosterone Syst 2000;1:147–150; Chen R., et al. Hypertension 2003;42:542–547; Hurairah H., et al. Int J Clin Pract 2004;58:173–183; Steckelings U.M., et al. Peptides 2005;26:1401–1409 35

ACE Inhibition Bradykinin/NO Angiotensin I ACE Inhibitor
Chymase tPA Cathepsin ACE Inhibitor Inactive fragments Vasodilation Tissue protection Angiotensin II ‘Angiotensin II escape’ 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 ACE inhibiton Angiotensin-converting enzyme (ACE) inhibitors inhibit the action of the ACE and hence there is no production of angiotensin II from angiotensin I. Angiotensin II is a potent vasoconstrictor and growth promoter, and ACE inhibition leads to decreased systemic arteriolar resistance and mean diastolic and systolic blood pressure. Increased concentrations of the vasodilator bradykinin occur because its degradation is also inhibited. Bradykinin has been shown to have beneficial effects associated with the release of nitric oxide (NO) and prostacyclin, which may contribute to the positive haemodynamic effects seen with ACE inhibitors. Bradykinin may also be responsible, however, for some of the adverse effects, such as dry cough, hypotension and angio-oedema.1 However, ACE inhibition only stops one mechanism for the production of angiotensin II. Other pathways – e.g. chymase – continue to produce angiotensin II and these can lead to a gradual return of angiotensin levels to baseline, a phenomenon termed ‘angiotensin II escape’.2 Their efficacy, despite angiotensin escape, has led to the hypothesis that much of the beneficial response is indeed at the tissue level from the actions of kinins, NO and prostaglandins. References 1. Chen R., et al. Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. Hypertension 2003;42:542–547. 2. Hanon S., et al. Persistent formation of angiotensin II despite treatment with maximally recommended doses of angiotensin converting enzyme inhibitors in patients with chronic heart failure. J Renin Angiotensin Aldosterone Syst 2000;1:147–150. S., et al. J Renin Angiotensin Aldosterone Syst–150; Chen R., et al. Hypertension 2003;42:542–547; Hurairah H., et al. Int J Clin Pract 200H2000;1:147anon 4;58:173–183; Steckelings U.M., et al. Peptides 2005;26:1401–1409

Selective AT1 Receptor Blockade (ARB)
Bradykinin/NO Angiotensin I Chymase tPA Cathepsin ACE Inactive fragments Angiotensin II Bradykinin? NO? ARB AT2 RECEPTOR Vasodilation Natriuresis Tissue regeneration Inhibition of inappropriate cell growth Differentiation Anti-inflammation Apoptosis ACE inhibiton Angiotensin-converting enzyme (ACE) inhibitors inhibit the action of the ACE and hence there is no production of angiotensin II from angiotensin I. Angiotensin II is a potent vasoconstrictor and growth promoter, and ACE inhibition leads to decreased systemic arteriolar resistance and mean diastolic and systolic blood pressure. Increased concentrations of the vasodilator bradykinin occur because its degradation is also inhibited. Bradykinin has been shown to have beneficial effects associated with the release of nitric oxide (NO) and prostacyclin, which may contribute to the positive haemodynamic effects seen with ACE inhibitors. Bradykinin may also be responsible, however, for some of the adverse effects, such as dry cough, hypotension and angio-oedema.1 However, ACE inhibition only stops one mechanism for the production of angiotensin II. Other pathways – e.g. chymase – continue to produce angiotensin II and these can lead to a gradual return of angiotensin levels to baseline, a phenomenon termed ‘angiotensin II escape’.2 Their efficacy, despite angiotensin escape, has led to the hypothesis that much of the beneficial response is indeed at the tissue level from the actions of kinins, NO and prostaglandins. References 1. Chen R., et al. Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. Hypertension 2003;42:542–547. 2. Hanon S., et al. Persistent formation of angiotensin II despite treatment with maximally recommended doses of angiotensin converting enzyme inhibitors in patients with chronic heart failure. J Renin Angiotensin Aldosterone Syst 2000;1:147–150. AT1 RECEPTOR Vasoconstriction Sodium retention SNS activation Inflammation Growth-promoting effects Aldosterone Apoptosis Hanon S., et al. J Renin Angiotensin Aldosterone Syst 2000;1:147–150; Chen R., et al. Hypertension 2003;42:542–547; Hurairah H., et al. Int J Clin Pract 2004;58:173–183; Steckelings U.M., et al. Peptides 2005;26:1401–1409 37

Rationale for Dual RAAS Blockade with ACEI & ARB
Bradykinin/NO Angiotensin I Chymase tPA Cathepsin ACE Inhibitor Inactive fragments Vasodilation Tissue protection Angiotensin II ‘Angiotensin II escape’ Bradykinin? NO? ARB 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 ACE inhibiton Angiotensin-converting enzyme (ACE) inhibitors inhibit the action of the ACE and hence there is no production of angiotensin II from angiotensin I. Angiotensin II is a potent vasoconstrictor and growth promoter, and ACE inhibition leads to decreased systemic arteriolar resistance and mean diastolic and systolic blood pressure. Increased concentrations of the vasodilator bradykinin occur because its degradation is also inhibited. Bradykinin has been shown to have beneficial effects associated with the release of nitric oxide (NO) and prostacyclin, which may contribute to the positive haemodynamic effects seen with ACE inhibitors. Bradykinin may also be responsible, however, for some of the adverse effects, such as dry cough, hypotension and angio-oedema.1 However, ACE inhibition only stops one mechanism for the production of angiotensin II. Other pathways – e.g. chymase – continue to produce angiotensin II and these can lead to a gradual return of angiotensin levels to baseline, a phenomenon termed ‘angiotensin II escape’.2 Their efficacy, despite angiotensin escape, has led to the hypothesis that much of the beneficial response is indeed at the tissue level from the actions of kinins, NO and prostaglandins. References 1. Chen R., et al. Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. Hypertension 2003;42:542–547. 2. Hanon S., et al. Persistent formation of angiotensin II despite treatment with maximally recommended doses of angiotensin converting enzyme inhibitors in patients with chronic heart failure. J Renin Angiotensin Aldosterone Syst 2000;1:147–150. Hanon S., et al. J Renin Angiotensin Aldosterone Syst 2000;1:147–150; Chen R., et al. Hypertension 2003;42:542–547; Hurairah H., et al. Int J Clin Pract 2004;58:173–183; Steckelings U.M., et al. Peptides 2005;26:1401–1409 38

ESH/ESC Algorithm for the Treatment of Hypertension
Consider: BP level before treatment Absence or presence of TOD and risk factors Mild BP elevation Low/moderate CV risk Conventional BP target Marked BP elevation High/very high CV risk Lower BP target Choose between Single agent at low dose 2-drug combination at low dose If goal BP not achieved Previous agent at full dose Switch to different agent at low dose Previous combination at full dose Add a third drug at low dose ESHESC has developed a treatment algorithm for the treatment of hypertension, but instead of specifying antihypertensive drug class, these guidelines recommend that the physician should tailor the choice of drugs to the individual patient. As seen on this slide, drug therapy can be initiated with a low-dose of a single agent or with a low-dose combination of two agents. Reference The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) guidelines for the management of arterial hypertension. J Hypertens 2007;25:110587. If goal BP not achieved 2–3-drug combination at full doses 2-3 drug combination at full dose Full-dose monotherapy TOD = target organ damage Task Force of ESH/ESC. J Hypertens 2007;25:1105–87

Advantages of Multiple-mechanism Therapy: Efficacy
Multiple-mechanism therapy results in a greater BP reduction than seen with its single-mechanism components1,2 Components with a different mechanism of action interact on complementary pathways of BP control1 Each component can potentially neutralize counter- regulatory mechanisms, e.g. Diuretics reduce plasma volume, which in turn stimulates the renin angiotensin system (RAS) and thus increases BP; addition of a RAS blocker attenuates this effect1,2 Multiple-mechanism therapy may result in BP reductions that are additive2 The most important reason for using multiple-mechanism antihypertensive therapy in clinical practice is to improve efficacy. Amalgamating two (or more) agents with complementary mechanisms produces significantly greater BP-lowering efficacy than either of its single-mechanism counterparts. In many patients, reducing BP via one mechanism will activate counter-regulatory mechanisms that can result in a return to elevated BP. By targeting two complementary physiologic systems, however, these counter-regulatory mechanisms are frequently neutralized, enabling greater reductions in BP. As such, BP can be controlled by carefully selecting the antihypertensive amalgamation based on mode of action. For example, long-term diuretic use has a tendency to activate the renin angiotensin system (RAS) and/or the sympathetic nervous system, which brings about an increase in BP. Control of BP can be re-established by addition of an agent with a complementary mode of action, such as a RAS blocker. Reference Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension. The cycle repeats. Drugs 2002;62:44362. 1Sica. Drugs 2002;62:44362 2Quan et al. Am J Cardiovasc Drugs 2006;6:10313

Advantages of Multiple-mechanism Therapy: Safety/Tolerability
Multiple-mechanism therapy may have an improved tolerability profile compared with its single-mechanism components1,2 Components of multiple-mechanism therapy can be given at lower dosages to achieve BP goal than those required as monotherapy therefore better tolerated1,2 Compound-specific adverse events can be attenuated, e.g.,1,2 RAS blockers may attenuate the edema that is caused by CCBs In addition to improved efficacy with multiple-mechanism therapy, another advantage concerns that of an equivalent or perhaps improved safety/tolerability profile. Optimizing efficacy with a single mode of action agent may come at the expense of more adverse events as a result of increasing the dose; this may have a knock-on effect because the patient may become non-compliant to treatment as a result. Multiple-mechanism therapy can overcome this barrier to effective BP control because: Smaller doses of each component are needed, thereby reducing dose-dependent adverse events Compound-specific adverse events can be minimized by the supporting physiologic mechanisms of the additional compound. Reference Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension. The cycle repeats. Drugs 2002;62:44362. 1Sica. Drugs 2002;62:44362 2Quan et al. Am J Cardiovasc Drugs 2006;6:10313

Advantages of Fixed Versus Free Combinations of Two Antihypertensive Drugs
Simplicity of treatment + – Compliance Efficacy Tolerability +* Price Flexibility One of the key advantages of fixed versus free combinations is that of simplicity of treatment: a single pill provides a more convenient means of managing hypertension, especially considering that these patients may also be taking other medications for concomitant cardiovascular risk factors. Convenience and simplicity of treatment through a reduced pill burden supports improved compliance to medication. This is a particularly important point because non-compliance is a major problem among patients with hypertension and is one of the main causes of failure to adequately control BP.1 Improved compliance is likely to translate into health-economic benefits:2 Fixed combinations are likely to cost less than the individual components prescribed separately and costs associated with managing high BP and its associated complications are likely to be reduced owing to improvements in medication-taking behavior. Another advantage concerns that of an improved tolerability profile owing to the generally lower doses used in fixed combinations. References 1. Burnier M. Medication adherence and persistence as the cornerstone of effective antihypertensive therapy. Am J Hypertens 2006;19:1190–6. 2. Neutel JM. Fixed combination antihypertensive therapy. In: Oparil S, Weber MA, editors. Hypertension. Companion to Brenner & Rector’s The Kidney. 2nd ed. Philadelphia: Elsevier Saunders, p. 5229. *Lower doses generally used in fixed-dose combinations + = potential advantage

Better Compliance with Antihypertensive Drugs Leads to a Lower Risk of Hospitalization
* Level of compliance (%) n=562 * n=344 * This retrospective cohort observation of 137,277 patients receiving medical and prescription benefit plans between June 1997 and May 1999 evaluated the effects of medication compliance on all-cause medical costs. Individuals were identified for analysis (disease-specific) based on claims for emergency room, inpatient or outpatient services during the first 12 months of the study. Medical and drug utilization during the 12 months following patient identification were measured by integrated analysis of administrative claims data. Disease-related and all-cause medical costs, drug costs and hospitalization costs were measured and modelled at varying levels of compliance by regression analysis. As shown on this slide, hospitalization rates were significantly lower for patients with high medication compliance. Reference Sokol MC, et al. Impact of medication adherence on hospitalization risk and healthcare cost. Med Care 2005;43:521–30. n=350 * All-cause hospitalization risk (%) *p<0.05 vs 80–100% compliant group Sokol et al. Med Care 2005;43:521–30

Multiple Antihypertensive Agents are Needed to Reach BP Goal
Trial (SBP achieved) MDRD (132 mmHg) HOT (138 mmHg) RENAAL (141 mmHg) AASK (128 mmHg) ABCD (132 mmHg) IDNT (138 mmHg) UKPDS (144 mmHg) Major clinical trials have demonstrated that patients typically needed treatment with multiple antihypertensive agents to get to, and stay at, BP goal. The number of antihypertensive agents required for BP control in many patients typically averages 24, with co-morbid conditions (such as kidney disease or diabetes mellitus) imposing greater drug requirement.1,2 For example, in the Hypertension Optimal Treatment (HOT) study, an average of 3.3 drugs were required to attain a diastolic BP goal of <80 mmHg, and in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), most patients were taking at least two antihypertensive agents by the end of the trial.2,3 In the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, patients were receiving initial treatment with fixed-dose combinations, i.e. 2-drug combination. The interim 6-month results have shown that BP control rates achieved in this study are higher than any other multinational trial to date.4 References 1. Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension. The cycle repeats. Drugs 2002;62:44362. 2. Bakris GL, et al. The importance of blood pressure control in the patient with diabetes. Am J Med 2004;116(5A):30S–8S. 3. Dahlöf B, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895906. 4. Jamerson K, et al. Exceptional early blood pressure control rates: The ACCOMPLISH trial. Blood Press 2007;16:80–6. ASCOT-BPLA (136.9 mmHg) ALLHAT (138 mmHg) ACCOMPLISH* (132 mmHg) Initial 2-drug combination therapy 1 2 3 4 Average no. of antihypertensive medications *Interim 6-month data Bakris et al. Am J Med 2004;116(5A):30S–8 Dahlöf et al. Lancet 2005;366:895–906; Jamerson et al. Blood Press 2007;16:80–6

Recommendations for Multiple-mechanism Therapy: What the Treatment Guidelines Say: ESH–ESC
More than one agent is necessary to achieve target BP in the majority of patients Treatment can be initiated with monotherapy or a combination of two drugs at low doses Drug dose or number of drugs may be increased if necessary A combination of two drugs at low doses preferred 1st step when Initial BP in grade 2–3 range Total CV risk high/very high Fixed combinations of two drugs simplify treatment/favor compliance The ESH–ESC guidelines recognize that few patients are able to achieve BP goal with antihypertensive monotherapy. These guidelines, now updated, recommend initiating therapy with monotherapy or a combination of two drugs at low doses. A combination of drugs is advised as the first step treatment approach in patients with grade 2 or 3 hypertension or when total cardiovascular risk is high/very high. Reference The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) guidelines for the management of arterial hypertension. J Hypertens 2007;25:110587. Task Force of ESH/ESC. J Hypertens 2007;25:1105–87

Interaction of CCBs and ARBs on Vascular and Renal Function, SNS and RAS Activity
Natriuresis Vasodilation Arterial Arterial + Venous CCB ARB The calcium channel blocker (CCB)/angiotensin receptor blocker (ARB) targets two key effector pathways and as such provides two different and complementary ways to reduce BP: Calcium channel blockade results in compensatory activation of the sympathetic nervous system (SNS), and the SNS, in turn, activates the renin angiotensin system (RAS). These effects tend to attenuate the BP-lowering efficacy of CCBs. Administering an ARB counteracts these effects by blocking the RAS, which in turn decreases SNS activity. Because CCBs have diuretic and natriuretic properties, they induce a state of negative sodium balance. This reinforces the antihypertensive effects of ARBs. Both CCBs and ARBs induce vasodilation, but while CCBs cause arterial vasodilation, ARBs bring about both arterial and venous dilation. ↑ RAS ↑ SNS RAS ↓ SNS ↓

CCB/ARB: Synergy of Counter-regulation
Arteriodilation Peripheral edema Effective in low-renin patients Reduces cardiac ischemia ARB RAS blockade Congestive heart failure and renal benefits ARB Venodilation Attenuates peripheral edema Effective in high-renin patients No effect on cardiac ischemia CCB RAS activation No renal or congestive heart failure benefits

Tolerability and Risk Factor Modification: CCB-induced Peripheral Edema Minimized by the ARB
ARB dilates arteries and veins CCB dilates arteries Veins remain constricted Capillary overload forces fluid into surrounding tissue Reduces CCB-induced peripheral edema Peripheral edema is a problem associated with all calcium channel blockers (CCBs), brought about by its potent vasodilatory effects. Since the CCB does not promote venodilation comparable to the arterial effect, an imbalance of hydrostatic forces in peripheral capillaries is created which facilitates fluid extravasation into the interstitial space. This results in lower extremity edema due to the force of gravity. However, the presence of an angiotensin receptor blocker promotes both arterial and venous dilation, so balancing the hydrostatic pressure in peripheral capillaries and thus reducing fluid extravasation into the interstitium. The end result is a difference in lower extremity edema. Notes: Peripheral edema is not related to volume overload. Adding a diuretic does not help solve CCB-induced peripheral edema. Reference Messerli FH. Vasodilatory edema: a common side effect of antihypertensive therapy. Am J Hypertens 2001;14:978–9. Single mode of action of the CCB Dual mode of action of the CCB/ARB Illustration modified from Messerli et al. Am J Hypertens 2001;14:978–9

The importance of BP control for CV protection
calls for use of effective antihypertensive drugs in the context of effective antihypertensive treatment strategies 12418 M

Choose the treatment…!!!

Maximum home blood pressure: a novel indicator of target-organ damage in hypertension
Blood pressure variability has recently been shown to be a strong predictor of stroke and cardiovascular events, independently of the mean systolic blood pressure level.1 The clinical implication of variability in blood pressure, as measured by home blood pressure monitoring, has never been reported. A new study has investigated the association between maximum home blood pressure and target-organ damage in 356 never-treated hypertensive subjects. Recently, Prof. Rothwell has demonstrated that blood pressure variability is the strongest predictor of stroke and cardiovascular events in hypertensive patients. In the ASCOT study, a greater decrease in cardiovascular events and mortality with amlodipine/perindopril was explained by better reduction in blood pressure variability. Blood pressure variability is a fluctuation in blood pressure values with time and could be measured within minutes (in the doctor’s office) over 24 hours (ABMP), for days and months. Home blood pressure measurement is a method in which blood pressure is tested by patients at home. In comparison with previous investigation of blood pressure variability, this study used home blood pressure monitoring and assessed the relationship between maximal home systolic blood pressure and target-organ damage (left ventricular mass index (LVMI), and carotid intima-media thickness (IMT). 1. Rothwell PM et al. Lancet. 2010;375: Matsui Y et al. Hypertens, 2011;57: in press 52

Number of episodes per/day
Maximum home systolic blood pressure measurements were observed up to 50 times per day Number of episodes per/day 356 never-treated hypertensive patients were included into this study. The mean age of the total population was 66.6 years, and 44.7% (n=159) was aged 70 years or older. The average number of home blood pressure measurements per subject during the 14-day study period was 79.8±7.9 (mean ± SD). The fluctuation in blood pressure values and the maximum systolic blood pressure was observed on every one of the 14 days of this study. Between 10 and 50 incidences of maximal systolic blood pressure were registered per day, suggesting a high level of blood pressure variability among the study population. Matsui Y et al. Hypertens. 2011;57: in press 53

High incidence of maximum home systolic blood pressure is associated with a high degree of cardiac and vascular remodeling - A direct relationship has been shown between the maximum home systolic blood pressure and left ventricular mass index (figure A) as well as the degree of carotid intima-media thickness (figure B). Matsui Y et al. Hypertens. 2011;57: in press 54

Conclusion This study provides additional information on the importance of blood pressure stabilization to prevent cardiovascular complication in hypertensive patients: Transiently high blood pressure readings at home should be taken seriously as meaningful indicators for hypertensive damage in the heart and artery.1 The variability in systolic blood pressure can be simply assessed by home blood pressure measurements.1 This study confirms, that effective antihypertensive treatment should not only reduce, but also stabilize blood pressure.2 1. Matsui Y et al. Hypertens. 2011;57: in press; 2.Rothwell PM. et al. Lancet. 2010;375: 55

Conditions favoring use of some antihypertensive drugs versus others:

Effects of RAS blockade on stroke: meta-analysis of ARBs and ACE inhibitors
MI Cardiovascular mortality All-cause mortality Stroke Favours ACE inhibitor Favours ARB Studies (N=63,409 ): ELITE; ELITE-II; OPTIMAAL; DETAIL; VALIANT; ONTARGET Reboldi et al. J Hypertension 2008;26:1282–1289

Better stroke protection with ARBs than with ACEIs
Suggests AT2-receptor mediated cerebroprotection

The multiple regression analysis showed that and against poor outcome:
Spansk studie ARB less severe strokes The multiple regression analysis showed that Previous treatment with ARB was independently associated with reduced stroke severity: OR: 0.40; 95% CI 0.24—0.65, p<0.001 and against poor outcome: OR: 0.41; 95%CI , p=0.003

Every molecule is unique
There is no such thing as a simple Class Effect that explains ,all about a particular molecule Every molecule is unique

Mortality and Morbidity Endpoint Trials‡¶ with ARBs
57,781 1. VALUE 2. VALIANT 3. NAVIGATOR 4. Val-HeFT 5. JIKEI HEART 6. KYOTO HEART* 7. VART* 8. VALISH* 9. ONTARGET 10. PRoFESS 11. TRANSCEND 12. HALT-PKD* 13. LIFE 14. OPTIMAAL 15. ELITE II 16. RENAAL 17. NCT * 18. VA NEPHRON-D* 19. CHARM 20. SCOPE 21. SCAST* 22. CASE-J 23. ACCOST 24. HIJ-CREATE 25. E-COST 26. I-PRESERVE 27. IDNT 28. ACTIVE-I* 29. NID-2 30. SUPPORT* 31. COLM* 32. OSCAR* 33. ORIENT* 34. MOSES 52,896 35 8 7 12 6 11 5 4 35. NAGOYA Heart S 3 10 Number of patients 24,841 23,940 2 18 25 15,693 17 24 23 16 22 15 29 21 14 6,577 20 28 Valsartan has been extensively studied during the past few years in a mega-trials program involving over 50,000 patients, larger than any other angiotensin receptor blocker trial program. Completed trials have investigated the influence of valsartan on morbidity and mortality in patients with post-myocardial infarction, heart failure as well as in patients at high cardiovascular (CV) risk. In addition, trials have examined valsartan in patients with specific risk factors for CV disease such as microalbuminuria and type 2 diabetes mellitus. The ongoing program extends the clinical observations to potential prevention of type 2 diabetes mellitus and/or a reduction in CV events in high-risk patients with impaired glucose tolerance. 33 1 9 13 1,405 19 27 32 26 31 30 34 Valsartan Telmisartan Losartan Candesartan Irbesartan Olmesartan Eprosartan *Expected enrolment Julius et al. 2004; 2. Pfeffer et al. 2003; 3. Califf et al 2008; 4. Cohn et al. 2001; 5. Mochizuki et al. 2007; (NCT ); 7. Nakayama et al. 2008; 8. NCT ; 9. ONTARGET Investigators 2008; 10. Yusuf et al 2008; 11. TRANSCEND Investigators 2008; (NCT ); 13. Dahlöf et al. 2002; 14. Dickstein et al. 2002; 15. Pitt et al. 2000; 16. Brenner et al. 2001; (NCT ); (NCT ); 19. Pfeffer et al 2003; 20. Papademetriou et al. 2004; (NCT ); 22. Ogihara et al. 2008; (NCT ); 24. Laufs et al. 2008; 25. Suzuki et al. 2005; 26. Massie et al 2008; 27. Lewis et al. 2001; (NCT ); (NCT ); (NCT ); (NCT ); (NCT ); (NCT ); 34. Schrader et al Kunihiro Matsushita ,et al , J of Cardiology Volume 56, Issue 1, July 2010, Pages ‡Ongoing and completed randomized controlled trials with death or hard CV events as or part of the primary endpoint ¶Valid as of January 2009

VALUE: Incidence of New-onset Diabetes
23% risk reduction with valsartan 18 16 P < 14 12 New-onset diabetes (% of patients in treatment group) 10 8 6 16.4% 13.1% 4 VALUE was the first trial to demonstrate a significant decrease in new-onset diabetes with an angiotensin receptor blocker when compared with a calcium channel blocker. Therapy with the valsartan-based regimen reduced the incidence of new-onset diabetes by 23% compared to the amlodipine-based regimen (690 vs 845 patients, P<0.0001).1 As diabetes mellitus is a significant risk factor for cardiovascular outcomes, this significant result provides support for use of valsartan in patients who are at risk for developing diabetes. 1. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens: VALUE, a randomised trial. Lancet. 2004;363. 2 Amlodipine-based regimen (n = 7,596) Valsartan-based regimen (n = 7,649) Julius S et al. Lancet. June 2004;363.

Valsartan Improves Insulin Sensitivity in Hypertensive Patients*
Normotensive (n = 20) Hypertensive pretreatment (n = 20) Hypertensive posttreatment (n = 20) 5 10 15 20 25 9.8† 19.6 8.7 2.2† 1.9 4.4 5 10 15 20 25 Fasting Insulin (µlU/mL) HOMA-IR *All patients in study group received valsartan 80 mg once daily. †P <0.001 vs hypertensive pretreatment. HOMA-IR = homeostasis model assessment – estimated insulin resistance. Top C et al. J Int Med Res. 2002;30:15-20.

Valsartan® Improves Insulin Sensitivity & Decreases Leptin in Obese Patients with HTN
Results from a 16-week study in 91 obese† patients with mild-to-moderate essential HTN‡ BMI Plasma Leptin HOMA-IR Plasma norepinephrine 38.8*§ 40 30 DIOVAN mg od (n=46) Felodipine 5-10 mg od (n=45) 20 Change from baseline (%) 10 0.1 0.6 * -4.7* -3.8 -10 -10.1** -13.8*** -20 -20.0** † †BMI ≥30kg/m2; ‡DBP >90 and <110 mmHg; *p<0.01, **p<0.05, ***p=NS vs. placebo; §p<0.01 vs. DIOVAN; BMI=Body mass index; HOMA-IR=Homeostasis model assessment of insulin resistance index Fogari et al. Hypertens Res 2005;28:

Valsartan® Significantly Increases Adiponectin in Obese Patients with HTN
Results from a 12-week study in 72 obese§ patients with mild-to-moderate HTN# Adiponectin (ng/mL) Leptin (ng/mL) Resistin (ng/mL) HOMA-IR 2 1.1* 1 0.3 -0.3 -3.7* -0.2 -1.1* -0.2 -1.0* Change in plasma levels from baseline to 12 weeks -1 -2 DIOVAN 160 mg/day (n=36) -3 Amlodipine 10 mg/day (n=36) -4 §BMI ≥30kg/m2; #DBP >90 mmHg and <110 mmHg; *p<0.05 vs. baseline Fogari et al. Am J Hypertens 2005;18:196A (abstract P-521)

Valsartan: Wealth of CV Outcomes Data
VALUE1 15,245 high-risk HTN patients; Double-blind, randomized study vs. amlodipine No difference in composite of cardiac mortality and morbidity (primary) 23%  new-onset diabetes VALIANT2 14,703 post-myocardial infarction patients; Double- blind, randomized study vs. captopril and vs. captopril + valsartan No difference vs. captopril in all-cause mortality (primary) (valsartan is as effective as standard of care) Val-HeFT3–5 5,010 heart failure II–IV patients; Double-blind, randomized study vs. placebo 13%  morbidity and mortality (primary)  left ventricular remodeling 37%  atrial fibrillation occurrence  heart failure signs/symptoms 28%  heart failure hospitalization JIKEI HEART6 3,081 Japanese patients on conventional treatment for hypertension, coronary heart disease, heart failure or combination of these; Multicenter, randomized, controlled trial comparing addition of valsartan vs. non-ARB to conventional treatment 39%  composite CV mortality and morbidity 40%  Stroke/transient ischemic attack 47%  Hospitalization for heart failure 65%  Hospitalization for angina Valsartan has been widely studied in large morbidity and mortality outcomes trials, such as VALUE, VALIANT, Val-HeFT and more recently the Jikei Heart Study in a range of patients including high-risk hypertensives, post-myocardial infarction patients and heart failure patients. This slide shows the results for primary outcomes and selected secondary outcomes in these trials. Abbreviations VALUE = Valsartan Antihypertensive Long-term Use Evaluation VALIANT = Valsartan in Acute Myocardial Infarction Val-HeFT = Valsartan Heart Failure Trial 1Julius et al. Lancet 2004;363:2022–31; 2Pfeffer et al. N Engl J Med 2003;349:1893–906; 3Maggioni et al. Am Heart J 2005;149:548–57; 4Wong et al. J Am Coll Cardiol 2002;40:970–5; 5Cohn et al. N Engl J Med 2001;345:1667–7; 6Mochizuki et al. Lancet 2007;369:1431–9

Amlodipine: Wealth of CV Outcomes Data
PREVENT1 825 CAD patients (≥30%): Multicenter, randomized, placebo controlled Primary outcome: No difference in mean 3 yr coronary angiographic changes vs. placebo 35%  hospitalization for heart failure + angina 33%  revascularization procedures CAMELOT2 1,991 CAD patients (>20%): Double-blind, randomized study vs. placebo and enalapril 20 mg Primary outcome: 31%  in CV events vs. placebo 41%  hospitalization for angina 27%  coronary revascularization ASCOT-BPLA/CAFE3,4 19,257 HTN patients: Multicenter, randomized, prospective study vs. atenolol Primary outcome: 10%  in non-fatal MI & fatal CHD 16%  total CV events and procedures 30%  new-onset diabetes 27%  stroke 11%  all-cause mortality  central aortic pressure by 4.3 mmHg ALLHAT5 18,102 HTN patients: Randomized, prospective study vs. lisinopril Primary outcome: No difference in composite of fatal CHD + non-fatal MI vs. lisinopril 6%  combined CVD 23%  stroke Amlodipine has been widely studied in large morbidity and mortality outcomes trials, such as PREVENT, CAMELOT, ASCOT-BPLA/CAFE and ALLHAT. This slide shows the results for the primary outcome and selected secondary outcomes in these trials. Abbreviations PREVENT = Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial CAMELOT = Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis ASCOT-BPLA = Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm CAFE = Conduit Artery Function Evaluation Study ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial 1Pitt et al. Circulation 2000;102:1503–10; 2Nissen et al. JAMA 2004;292:2217–26; 3Dahlof et al. Lancet 2005;366:895–906 4Williams et al. Circulation 2006;113:1213–25; 5Leenen et al. Hypertension 2006;48:374–84

Valsartan and Amlodipine in High-risk Hypertension Have Proven Endpoint Benefits
ASCOT BPLA1 VALUE trial2 Non-fatal MI (excluding silent) + fatal CHD Primary cardiac composite endpoint Total coronary endpoint Cardiac mortality Total CV events and procedures Cardiac morbidity All-cause mortality All MI CV mortality All congestive heart failure Fatal/non-fatal stroke Fatal/non-fatal HF All stroke Development of renal impairment There is a wealth of cardiovascular (CV) outcomes data for both valsartan and amlodipine, with trials such as VALUE and ASCOT-BPLA showing benefits of each agent for a range of CV endpoints such as congestive heart failure, stroke, new-onset diabetes and renal impairment.1,2 This, together with their complementary mechanisms of action, provide a strong rationale for combining these two effective and well-tolerated agents. References 1. Julius S, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363:202231. 2. Dahlöf B, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895–906. All-cause death Development of diabetes New-onset diabetes 0.5 1 2 0.5 1 2 Amlodipine-based better Atenolol-based better Favors valsartan Favors amlodipine 1Dahlöf et al. Lancet 2005;366:895–906; 2Julius et al. Lancet 2004;363:2022–31

Exforge Clinical data

Amlodipine/Valsartan: BP Reductions Across All Grades of Hypertension - (Exzellent Trial1)
-19 n = 890 -32 -49 DBP ↓ (mmHg) – – –29 1Schrader J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June 2008.

Amlodipine/Valsartan FDC: BP Reductions for Patients with Diabetes– (Exzellent Trial1)
-19 syst.BP reduction (mmHg) -32 -48 DBP ↓ (mmHg) – – –18 1Schrader J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June 2008.

Amlodipine/Valsartan: Powerful SBP Drops of Over 40 mmHg in Patients with Baseline MSSBP ≥180 mmHg
EX-EFFeCTS1 Patients with Stage 2 Hypertension EX-STAND2 Black Patients with Stage 2 Hypertension Amlodipine/Valsartan 10/160 mg Amlodipine 10 mg Amlodipine/Valsartan 10/160–320 mg Amlodipine 10 mg N=46 N=55 N=38 N=42 −10 −10 −20 −20 −30 −30 −31.7 Amlodipine/valsartan has shown BP reductions of over 40 mmHg in patients with mean sitting systolic BP (MSSBP) ≥180 mmHg.1,2 EX-EFFeCTS (EXforge EFFicacy and Control in Treatment of Stage Two HypertenSion) was a randomized, double-blind, 8-week study designed to compare the efficacy and safety of amlodipine/valsartan with amlodipine monotherapy in patients with stage 2 hypertension (MSSBP ≥160 mmHg and <200 mmHg). At Week 4, the change from baseline in MSSBP in the subset of patients with a baseline MSSBP ≥180 mmHg was significantly greater with amlodipine/valsartan compared with amlodipine monotherapy (change in MSSBP: –40.1 mmHg vs. –31.7 mmHg, respectively; p=0.0018).1 EX-STAND (EXforge evaluation in Stage Two hypertensives of AfricaN Descent) was a 12-week, double-blind, parallel-group, multicenter study designed to compare the efficacy and tolerability of amlodipine/valsartan with amlodipine in black patients with stage 2 hypertension (mean systolic BP ≥160 mmHg and <200 mmHg). At Week 8, in the subgroup of patients with a baseline MSSBP ≥180 mmHg, the combination of amlodipine/valsartan resulted in a 43.5 mmHg reduction from baseline in MSSBP.2 Reference 1. Destro M, et al. Efficacy and safety of amlodipine/valsartan compared with amlodipine monotherapy in patients with stage 2 hypertension: a randomized, double-blind, multicenter study: the EX-EFFeCTS study. J Am Soc Hypertens 2008;2:294–302. 2. Flack JM, et al. Efficacy and safety of initial combination therapy with amlodipine/valsartan compared with amlodipine monotherapy in black patients with stage 2 hypertension. J Hum Hypertens 2009 (E-pub ahead of print). −40 −40 −37.2 –40.1 –43.5 p=0.0018 −50 p=0.1 LSM Change in MSSBP from baseline (mmHg) LSM Change in MSSBP from baseline (mmHg) LSM=least square mean MSSBP=mean sitting systolic blood pressure 1.Destro et al. J Am Soc Hypertens 2008;2:294–302 2.Flack et al. J Hum Hypertens 2009 (E-pub ahead of print). Amlodipine/Valsartan Speaker Slide Resource Item code: EXF09.203; Release Date: March 2009

Amlodipine/Valsartan 5/160 mg Amlodipine/Valsartan 10/160 mg
Amlodipine/Valsartan: Up to 9 Out of 10 Patients Reach BP Goal <140/90 mmHg 80.0 Patients (%) n=440 n=369 n=71 n=449 n=375 n=74 EX-FAST (EXforge in Failure After Single Therapy), a randomized, double-blind, multinational, parallel-group, 16-week study, was designed to evaluate BP control in patients whose BP was uncontrolled on prior monotherapy and who were switched directly to Amlodipine/Valsartan at two different doses. The study included 894 patients; 443 were randomized without washout to treatment with Amlodipine/Valsartan 5/160 mg and 451 to Amlodipine/Valsartan 10/160 mg. Mean BP at baseline was 150/91 mmHg. The antihypertensive efficacy of Amlodipine/Valsartan was well maintained across patient subgroups including patients with diabetes. BP control to <140/90 mmHg in patients with diabetes was similar to BP control in non-diabetic patients. At Week 8 of the study, BP control was achieved in 69.7% of patients receiving Amlodipine/Valsartan 5/160 mg and by 80.0% of those patients treated with Amlodipine/Valsartan 10/160 mg. The respective values in patients who did not have diabetes were 78.4% and 85.2%. Reference Allemann Y, et al. Efficacy of the combination of amlodipine and valsartan in hypertensive patients uncontrolled on previous monotherapy: The EX-FAST Study. J Clin Hypertens 2008;10:185–94. Amlodipine/Valsartan 5/160 mg Amlodipine/Valsartan 10/160 mg Diabetic patients with BP <130/80 mmHg at Week 8 were 47.0% and 49.2% for 5/160 mg and 10/160 mg doses, respectively Data shown are at Week 8 No hydrochlorothiazide add-on was permitted until after Week 8 Randomized, double-blind, multinational, parallel-group, 16-week study Adapted from Allemann et al. J Clin Hypertens 2008;10:185–94 Amlodipine/Valsartan Speaker Slide Resource Item code: EXF09.203; Release Date: March 2009

Amlodipine/Valsartan: Additional BP Drops in Non-responders to Ramipril/Felodipine
–14.3 mmHg –30.7 mmHg –15.4 mmHg p<0.0001 –7.0 mmHg p<0.0001 Of the 133 patients allocated to treatment with ramipril 5 mg/felodipine 5 mg, only 13% had their systolic BP normalized to <140 mmHg. Therefore, 105 patients were allocated to be treated with Amlodipine/Valsartan 10/160 mg. Amlodipine/Valsartan led to a significant additional BP reduction from that seen with ramipril/felodipine (p<0.0001), with a better safety and tolerability profile. After 5 weeks of treatment, Amlodipine/Valsartan 10/160 mg was associated with a 31/15 mmHg reduction from baseline in mean systolic BP/diastolic BP. Reference Trenkwalder P, et al. Efficacy and safety of the combination of amlodipine 10/valsartan 160 in hypertensive patients not controlled by the combination of ramipril 5/felodipine 5 – the EXPRESS-C trial. J Hypertens 2007;25(Suppl. 2):S228 (abstract P24.261). Week Week After Ram 5 + Fel 5 After Amlo/Val 10/160 After Ram 5 + Fel 5 After Amlo/Val 10/160 Open, sequential, non-responder, 10-week study Trenkwalder et al. J Hypertens 2007;25(Suppl. 2):S228 (abstract P24.261)

Ankle-foot volume increase (%)
EXFORGE® Significantly Reduces Fluid Retention Vs Amlodipine Monotherapy 25 20 15 10 5 n=80 70% difference Ankle-foot volume increase (%) In a randomized, crossover study of 80 patients with grade 1–2 essential hypertension (diastolic BP >90 mmHg and <110 mmHg and systolic BP >140 mmHg), amlodipine 10 mg was found to significantly increase ankle-foot volume (+23%, p<0.01 vs. baseline). By comparison, Amlodipine/Valsartan was associated with a significantly less pronounced increase in ankle-foot volume (+6.8%, p<0.01 vs. amlodipine). These results provide supporting evidence that angiotensin receptor blockers, such as valsartan, partially counteract the microcirculatory changes induced by calcium channel blockers such as amlodipine. Reference Fogari R, et al. Effect of valsartan addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients. J Hum Hypertens 2007;21:220–4. Amlodipine 10 mg EXFORGE® 10/160 mg *p<0.01 vs. amlodipine Fogari et al. J Hum Hypertens 2007;21:220-4

Amlodipine/Valsartan: Powerful SBP Drops of 43 mmHg in Patients with a Baseline MSSBP 180 mmHg
Amlodipine (5–10 mg) + valsartan (160 mg) Lisinopril (10–20 mg) + HCTZ (12.5 mg) Endpoint BP (mean) 145.4 mmHg mmHg –10 –20 –30 –40 –50 n=15 n=11 Change from baseline in MSSBP at 6-week endpoint (mmHg) In this multicenter, randomized study of patients with severe hypertension, significant reductions from baseline in both mean sitting systolic BP (MSSBP) and mean sitting diastolic BP (MSDBP) were evident at endpoint in patients (n=26) with a baseline MSSBP ≥180 mmHg. In particular, Amlodipine/Valsartan treatment was associated with a 43.0/26.1 mmHg reduction in MSSBP/MSDBP (p<0.001 vs. baseline), which was numerically greater than for the lisinopril/hydrochlorothiazide treatment group (31.2/21.7 mmHg decrease; p<0.002 vs. baseline for MSSBP; p<0.001 vs. baseline for MSDBP). Reference Poldermans D, et al. Tolerability and blood pressure-lowering efficacy of the combination of amlodipine plus valsartan compared with lisinopril plus hydrochlorothiazide in adult patients with stage 2 hypertension. Clin Ther 2007;29:279–89. Change in MSDBP (mmHg) –26.1* –21.7* *p<0.001; †p<0.002 vs. baseline Baseline mean sitting systolic BP (MSSBP): 188 mmHg Baseline mean sitting diastolic BP (MSDBP): 113 mmHg Randomized, double-blind, multicenter, active-controlled study Poldermans et al. Clin Ther 2007;29:279–89

Blood Pressure and Cardiovascular Risk: ESHESC Guidelines
Other RF, OD or disease BP (mmHg) Normal SBP 120–129 or DBP 80–84 High normal SBP 130–139 or DBP 85–89 Grade 1 SBP 140–159 or DBP 90–99 Grade 2 SBP 160–179 or DBP 100–109 Grade 3 SBP 180 or DBP 110 No other RF Average risk Low added risk Moderate added risk High added risk 1–2 RF Very high added risk 3 RF, MS, OD or diabetes High added risk Established CV or renal disease The risk of cardiovascular (CV) disease is influenced by the severity of hypertension and the co-existence of complications (other risk factors, organ damage and disease). A stratification for total CV risk, as shown on this slide, has been defined by the ESHESC guidelines. Treatment decisions such as initiation of therapy, BP targets, use of combination therapy, etc. are dependent on the level of CV risk. Notes to table Low, moderate, high and very high refer to the 10-year risk of a CV fatal or non-fatal event. The dashed curve indicates how the definition of hypertension may be variable, depending on the level of total CV risk. Reference The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) guidelines for the management of arterial hypertension. J Hypertens 2007;25:110587. MS = metabolic syndrome OD = subclinical organ damage RF = risk factors Reproduced from the Task Force of ESH–ESC. J Hypertens 2007;25:1105–87 Copyright © 2007, with permission from Lippincott Williams and Wilkins Page 77 77

Summary of Amlodipine/Valsartan Clinical Data
Amlodipine/Valsartan – the first antihypertensive agent available to physicians that reduces BP via dual calcium channel and angiotensin receptor blockade Data on Amlodipine/Valsartan demonstrate Powerful BP reductions across all grades of hypertension1,2 Up to 43 mmHg drop in patients with a mean sitting systolic BP (SBP) 180 mmHg2 Incremental BP drops over reductions achieved with previous medications ~21 mmHg SBP drop in patients uncontrolled on monotherapy3 ~15 mmHg SBP drop in patients uncontrolled on combination therapy4 References Smith et al. Amlodipine and valsartan combined and as monotherapy in stage 2, elderly and black hypertensive patients: subgroup analyses of 2 randomized, placebo-controlled studies. J Clin Hypertens 2007;9:355–64 Poldermans D, et al. Tolerability and blood pressure-lowering efficacy of the combination of amlodipine plus valsartan compared with lisinopril plus hydrochlorothiazide in adult patients with stage 2 hypertension. Clin Ther 2007;29:279–89. Allemann Y, et al. Efficacy of the combination of amlodipine and valsartan in hypertensive patients uncontrolled on previous monotherapy: The EX-FAST Study. J Clin Hypertens 2007 (In press). Trenkwalder P, et al. Efficacy and safety of the combination of amlodipine 10/valsartan 160 in hypertensive patients not controlled by the combination of ramipril 5/felodipine 5 – the EXPRESS-C trial. J Hypertens 2007;25(Suppl. 2):S228 (abstract P24.261). Philipp T, et al. Two multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as monotherapy in adult patients with mild to moderate essential hypertension. Clin Ther 2007;29:563–80. 1 Smith et al. J Clin Hypertens 2007;9:355–64; 2 Poldermans et al. Clin Ther 2007;29:279–89 3Allemann et al. J Clin Hypertens 2007 (In press); 4Trenkwalder et al. J Hypertens 2007;25(Suppl. 2):S228 (abstract P24.261); 5Philipp et al. Clin Ther 2007;29:563–80

Summary of Amlodipine/Valsartan Clinical Data
Up to 9 out of 10 patients achieved BP <140/90 mmHg3 Well tolerated with a reduction in the incidence of peripheral edema compared with amlodipine monotherapy5 ARB at least the same efficacy as ACEI but better tolerability/safety and potentially a stroke benefit Valsartan can preferably be combined with Amlodipine, HCTZ and Aliskiren SPC to a majority References Smith et al. Amlodipine and valsartan combined and as monotherapy in stage 2, elderly and black hypertensive patients: subgroup analyses of 2 randomized, placebo-controlled studies. J Clin Hypertens 2007;9:355–64 Poldermans D, et al. Tolerability and blood pressure-lowering efficacy of the combination of amlodipine plus valsartan compared with lisinopril plus hydrochlorothiazide in adult patients with stage 2 hypertension. Clin Ther 2007;29:279–89. Allemann Y, et al. Efficacy of the combination of amlodipine and valsartan in hypertensive patients uncontrolled on previous monotherapy: The EX-FAST Study. J Clin Hypertens 2007 (In press). Trenkwalder P, et al. Efficacy and safety of the combination of amlodipine 10/valsartan 160 in hypertensive patients not controlled by the combination of ramipril 5/felodipine 5 – the EXPRESS-C trial. J Hypertens 2007;25(Suppl. 2):S228 (abstract P24.261). Philipp T, et al. Two multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as monotherapy in adult patients with mild to moderate essential hypertension. Clin Ther 2007;29:563–80. 1 Smith et al. J Clin Hypertens 2007;9:355–64; 2 Poldermans et al. Clin Ther 2007;29:279–89 3Allemann et al. J Clin Hypertens 2007 (In press); 4Trenkwalder et al. J Hypertens 2007;25(Suppl. 2):S228 (abstract P24.261); 5Philipp et al. Clin Ther 2007;29:563–80

The Best Marker to Monitor in Treating Blood Pressure …
The Best Marker to Monitor in Treating Blood Pressure …. Is Blood Pressure Itself

Every two seconds, one person dies from cardiovascular disease
References 1. World Health Organisation, Fact Sheet 317: Cardiovascular Diseases February

The Paradox of Diseases
The majority of people continuously complain of allergic problems… …are frightened to death of cancer and AIDS…or H1N1 …and ultimately die of cardiovascular diseases

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