Avoiding End Organ Damage DR SHAHBAZ AHMED KURESHI

Avoiding End Organ Damage DR. SHAHBAZ AHMED KURESHI MBBS, MCPS, D. CARD, D. Med. Sc, FACC, FAHA, FACP, FPAMS Consultant Cardiologist, Head Department of Cardiology and Nuclear Cardiology, Federal Government Services Hospital, Islamabad

Destination <120/80 Lower is Better !

Hypertension Represents a Significant Burden on Healthcare • Worldwide, hypertension is responsible for – 62% of strokes 1 – 49% of heart attacks 1 • Hypertension is the third leading risk factor for disease – Causes 7. 1 million premature deaths each year 1 – 4. 5% of global burden of disease 1 • Hypertension represents a high burden on healthcare expenditure – In 2004, the direct and indirect cost of high blood pressure in the US was $55. 5 billion; drug costs accounted for $21 billion 2 Thus, hypertension management is a public health priority 1. WHO, 2002; 2. AHA, 2004

National Health Survey • Circulatory diseases account for over 100, 000 deaths a year or 12% of all cause mortality. • Overall 18% of adults in Pakistan suffer from HBP, 21. 5% in urban areas and 16. 2% in rural areas. • One in every 3 adults over age 45 suffer from hypertension. • Very few Pakistanis with hypertension (<3%) have their B. P controlled. PROCOR: 7/25/99 The National Health Survey in Pakistan published in 1998 by (PMRC) 1

Potentially Preventable Causes of Death

BP and increasing age Kearney et al, Lancet 2005

Prevalence of hypertension is high Prevalence of hypertension in people aged 20 years and older Prevalence of hypertension (%) 2000 2025 Kearney PM et al. , Lancet. 2005; 365: 217 -223.

Factors Necessary to Assess the Risk or Target Organ Damage Risk stratification Target organ damage Systolic / diastolic BP Left ventricular hypertrophy Men > 55; Women > 65 years Ultrasound: Evidence of thickening Tobacco smoking or plaques Dyslipidemia Increased creatininemia Family history + Microalbuminuria (malb/creat ratio) Protein C-reactive > 6 mg/dl men: >2. 5 mg/mmol women: >3. 5 mg/mmol ESH-ESC guidelines, 2003, J Hypertens

Hypertension is a leading cause for cardiovascular morbidity 36 -Year Follow-up in Patients Aged 35 -64 Years 1, 2 Biennial Age-Adjusted Rate per 1, 000 50 Coronary Disease 45. 4 Peripheral Arterial Disease Stroke Heart Failure 40 Normotensive Hypertensive 30 22. 7 21. 3 20 9. 5 10 3. 3 0 Men Women 13. 9 12. 4 Men 9. 9 6. 2 2. 4 Women 5. 0 Men 7. 3 2. 0 Women 3. 5 Men 6. 3 2. 1 Women 1. Kannel W. B. et al. , JAMA 1996; 275: 1571 -1576 2. Kannel W. B. et al. , J Hum Hypertens 2000; 14: 83 -90

High-Normal BP and CVD Risk High normal 130 -139/85 -89 mm Hg Normal 120 -129/80 -84 mm Hg Optimal <120/80 mm Hg Men Cumulative Incidence (%) 14 Prehypertension Women 12 P<. 001 10 10 8 8 6 6 4 4 2 2 0 0 0 2 4 6 8 10 12 14 P<. 001 0 2 Time (years) 4 6 8 10 12 Time (years) Vasan et al. N Engl J Med. 2001 14

256 Age at risk: 80– 89 years 128 70– 79 years 64 60– 69 years 32 50– 59 years 16 40– 49 years 8 4 2 1 b Ischaemic heart disease mortality (floating absolute risk and 95% CI) a Blood pressure, heart disease and age correlate closely Age at risk: 256 80– 89 years 128 70– 79 years 64 60– 69 years 32 50– 59 years 16 40– 49 years 8 4 2 1 120 140 160 180 Usual SBP (mm. Hg) 70 80 90 100 110 Usual DBP (mm. Hg) Relationship between (a) systolic blood pressure (SBP) and (b) diastolic blood pressure (DBP) and ischaemic heart disease mortality in one million individuals in the general population. CI, confidence interval. Lewington S et al. Lancet. 2002; 360: 1903 -1913.

CV Mortality Risk Doubles with Each 20/10 mm Hg BP Increment* 8 7 6 CV mortality risk 5 4 3 2 1 0 115/75 135/85 155/95 175/105 SBP/DBP (mm Hg) *Individuals aged 40 -70 years, starting at BP 115/75 mm Hg. CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressure Lewington S, et al. Lancet. 2002; 60: 1903 -1913. JNC 7. JAMA. 2003; 289: 2560 -2572.

Absolute Risk Of Coronary Artery Disease And Stroke Mortality

Curvilinear Relation Of Blood Pressure And Cardiovascular Risk

Geographical Variation In Hypertension Prevalence In Population Of African And European Ancestry

Age- Dependent Changes In Systolic and Diastolic Blood Pressure In USA

Vascular Remodeling Of Small And Large Arteries

The Renin- Angiotensin- Aldosterone System

Schematic Representation Of The Central Role Played By Angiotensin 1 Receptor (AT 1 R)

Superiority Of Ambulatory Over Office Blood Pressure Measurements

24 -Hour Ambulatory Blood Pressure Recording

Relation Between Systolic Blood Pressure And The Rate Of Progression Of Coronary Atheroma

Blood Pressure Risk Stratification (ESH/ESC 2007) Mancia G et al. , J Hypertens 2007; 25: 1105– 87

Blood pressure reductions of as little as 2 mm. Hg reduce the risk of cardiovascular events by up to 10%1 • Meta-analysis of 61 prospective, observational studies • One million adults • 12. 7 million person-years 7% reduction in risk of ischemic heart disease 2 mm. Hg decrease in mortality mean systolic blood pressure 10% reduction in risk of stroke mortality 1. Lewington S et al. Lancet. 2002; 360: 1903– 1913.

Effective blood pressure control reduces cardiovascular morbidity and mortality Systolic–diastolic hypertension Relative Risk Reduction (%) 10 0 Fatal and nonfatal events Stroke CHD Fatal and nonfatal events Mortality All Causes CV Isolated systolic hypertension Non CV Stroke CHD Mortality All Causes CV NS Non CV NS -10 <0. 01 -20 0. 02 <0. 01 <0. 001 0. 01 -30 <0. 001 -40 -50 <0. 001 ESH/ESC guidelines consider systolic values of <139 mm. Hg and diastolic values of <89 mm. Hg to be normal Event reduction in patients on active antihypertensive treatment vs placebo or no treatment CHD: coronary heart disease; CV: cardiovascular Cifkova R, et al. J Hypertens. 2003; 21: 1011– 1053.

Relations Between Achieved Blood Pressure Control And Declines In Glomerular Filtration Rate

Absolute Benefits For The Prevention Of Fatal Nonfatal Cardiovascular Events

Odds Ratio For Cardiovascular Events And Systolic Blood Pressure

Trials Comparing The Effect On Primary End Point Of Treatment Based On Different Antihypertensive Drugs

Antihypertensive Therapy: Number of Agents Required to Achieve BP Goal UKPDS (<85 mm Hg, diastolic) MDRD (<92 mm Hg, MAP) HOT (<80 mm Hg, diastolic) AASK (<92 mm Hg, MAP) RENAAL (<140/90 mm Hg) IDNT ( 135/85 mm Hg) 1 2 3 4 Number of BP Medications Bakris et al. Am J Kidney Dis. 2000; 36: 646 -661; Bakris et al. Arch Intern Med. 2003; 163: 15551565; Lewis et al. N Engl J Med. 2001; 345: 851 -860.

An Algorithm For The decision To Manage Patients With Different Average Blood Pressure Levels

Algorithm For Therapy Of Hypertension

What qualities do you want to see in an effective Anti Hypertensive agent? Get patients to BP goal l Provides 24 hour BP control l Has good tolerability l Has ‘added’ protection l

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Conclusion In patients with MI complicated by heart failure, left ventricular dysfunction or both: • Valsartan is as effective as a proven dose of captopril in reducing the risk of: – Death – CV death or nonfatal MI or heart failure admission • Combining valsartan with a proven dose of captopril produced no further reduction in mortality—and more adverse drug events. Implications: In these patients, valsartan is a clinically effective alternative to an ACE inhibitor.

Treatment Enables Retardation of the Progression of Renal Disease Benedict study Prevention Protection IRMA 2 IDNT MARVAL RENAAL Microalbuminuria Macroalbuminuria ESRD Cardiovascular morbidity and mortality Early stage Late stage Severity of renal disease Terminal stage

Conclusions • In type 2 diabetic pts with microalbuminuria arterial BP was reduced to the same extent in the valsartan and amlodipine groups • AER was significantly reduced in the valsartan group compared with the amlodipine group. • Significantly more pts regressed to normoalbuminuria in the valsartan group • The effect of valsartan on AER was similar in both the normotensive and hypertensive subgroups

“First do no harm”

The Mechanisms By Which Chronic Diuretic Therapy May Lead TO Various Complications

Theoretical Therapeutic And Toxic Logarithmic And Linear Dose Response Curve

Classification Of Beta- Adrenoreceptor Blockers On The Basic Of Cardioselectivity And Intrinsic Sympathomimetic Activity

Worldwide blood pressure control rates in treated hypertensive patients are low Germany 33. 6 Canada 41. 0 Japan* 55. 7 England 29. 2 USA 53. 1 Greece 49. 5 China 28. 8 Turkey 19. 8 Mexico 21. 8 Taiwan 18. 0 Egypt 33. 5 South Africa* 47. 6 Kearney P. M. et al. , J Hypertens 2004; 22: 11– 19; * Data for men on

Simplified Schematic View Of The Adrenergic Nerve

RAA system targets multiple receptor sites Na+ Angiotensinogen K+ Aldosterone Renin Other ACTH Chymase Angiotensin I CE Bradykinin Angiotensin II Inactive Adapted from Unger T. Am J Cardiol 2002; 89 (suppl): 3 A-10 A.

• Hypertension has a multifactorial origin Major mechanisms – (1) increased adrenergic drive, as often found in young people (aged 30– 49 years); – (2) high-renin hypertension, as seen in individuals with renal dysfunction; – (3) low-renin hypertension, as recorded in individuals with inherently raised aldosterone concentrations; – (4) increased peripheral vascular resistance (PVR), as seen in elderly patients. CO=cardiac output. β=β-adrenergic stimulation α=αadrenergic stimulation. AII=angiotensin II. Kaplan NM & Opie LH. Lancet 2006; 367: 168 -176.

Angiotensin (AT 1) receptor blockade provides vascular protection Angiotensinogen Renin Angiotensin I ACE Non-ACE Pathways* Angiotensin II *not affected by ACE inhibitors ARB Blockade AT 1 receptor • Vasoconstriction • Hypertrophy and Proliferation • Oxidation and Inflammation • PAI-1 expression and release Blockade of AT 1 receptor Activation of AT 2 receptor Vascular Protection AT 2 receptor • Vasodilation • Nitric Oxide release • Antiproliferation Adapted from: Kaschina E and Unger T. Blood Press 2003; 12: 7088. Unger T. J Hypertens 1999; 17: 1775 -1786.

Renin profile correlates with CV risk Events per 1000 person-years High Yes Smok ing No Low Normal e rofil P enin R 34. 5 Events per 1000 person-years 8. 4 6. 3 Chole s (mmo terol l/L) Events per 1000 person-years 10. 2 0. 9 6. 3 8. 4 3. 2 Low High Normal Ren ro in P file 7. 8 Fastin g Blood Gluco (mmo se l/L) High 7. 8 Low Normal e fil Pro n i en R Alderman MH et al. N Engl J Med. 1991; 324: 1098 -1104.