1. Adel E. Berbari, MD, FAHA, FACP Professor of Medicine and Physiology Head, Division of Hypertension and Vascular Medicine American University of Beirut- Medical Center Venue: Crown Plaza Hotel Hamra-Beirut-lebanon Hamra-Beirut-lebanon Date: Saturday, Nov 11, 2006 Date: Saturday, Nov 11, 2006 Lebanese Society of Family Medicine 5 th Annual Conference Chronic Disease: An Update Hypertension Guidelines and Practice

2. Introduction

3. Hypertension guidelines published in 2003 (JNC VII and ESH/ESC/generally still valid In light of recent findings initiation of process of changing guidelines.

4. Hypertension major risk for –Cardiovascular events Myocardial infarction Heart failure Stroke Renal failure –Impaired quality of life Impaired cognitive function Memory loss Dementia Sexual dysfunction Decreased general well being. BP reduction associated with –Reduction in cardiovascular events –Improvement in quality of life

5. Reduction of cardiovascular events by active antihypertensive treatment.

6. Benefits of Lowering BP by Average Percent Reduction Stroke incidence 35 – 40% Myocardial infarction 20 – 25% Heart failure50% -12 -4-5 AboutmmHg

7. Despite evidence that BP control associated with reduction in risk of cardiovascular events, hypertension control remains poor.

9. Determinants of Poor Hypertension Control

10. Prognostic Importance of Different BP Components

12. Systolic hypertension recently recognized as more important than diastolic hypertension: - Cardiovascular risk factor - Therapeutic decision making in older subjects

13. SBP, rather than DBP, of greater importance in long-term risk of CVD in middle aged patients. CVD risk associated with DBP dependent on SBP level – Low CVD risk/similar to Normotension in SBP 90 mm Hg – Increased CVD risk with SBP>140/DBP<90 mm Hg

14. Alli C et al. Arch Intern Med. 1999;159:1205-1212. Predictive Power of Systolic Blood Pressure on Overall Cardiovascular Outcomes Total Mortality 0.5 1 1 1.5 2 2 2.5 Prognosis better Prognosis worse Prognosis better Prognosis worse Systolic Blood Pressure <90 90-99 ≥100 DBP DBP (mm Hg) <90 90-99 ≥100 1 1 1.5 2 2 2.5 0.5 <140 140-159 160-179 ≥180 SBP SBP (mm Hg) 1 1 1.5 2 2 2.5 1 1 1.5 2 2 2.5 Cardio- vascular Mortality <140 140-159 160-179 ≥180 0.5 Relative Risk Diastolic Blood Pressure

15. SBP, rather than DBP, of greater importance in long-term risk of CVD in middle aged patients. CVD risk associated with DBP dependent on SBP level – Low CVD risk/similar to Normotension in SBP 90 mm Hg – Increased CVD risk with SBP>140/DBP<90 mm Hg

16. Relation between SBP and DBP and risk of cardiovascular disease

17. Compelling evidence that benefits of hypertension reduction related primarily to extent of SBP reduction not to DBP reduction

18. Goal SBP Levels

19. SBP < 140 mmHg In Uncomplicated Essential Hypertension

20. SBP < 130 mmHg In High Risk Hypertensive Patients (Diabetes or Chronic Kidney Disease)

21. Difficulty in Achieving Goal SBP In Contrast to DBP

22. mmHg Rates of Achieved Goal SBP and DBP with Antihypertensive Treatment. LlOYD JONES (FRAMINGHAM HEART STUDY) Hypertension 2000; 36: 594-599

25. Blood Pressure Patterns

26. Classification

27. 1. Normotension (True / Persistent) 2. Prehypertension 3. White coat hypertension 4. Masked hypertension. 5. Hypertension (True / Sustained)

28. Prehypertension

29. Definition –SBP / DBP = 120-139 / 80-89 mmHg Prognostic significance –Progression to hypertension –Cardiovascular events

30. Increasing increments of blood pressure are associated with increasing risk of cardiovascular mortality. mm Hg

31. Progression Rates to Hypertension in Non-Hypertensive Participants in Framingham Study BP Category Age 35-64 Age 65-94 Optimal Optimal5.316.0 Normal Normal17.625.5 High normal High normal37.349.5

32. Definition –SBP/DBP = 120-139/80-89 mmHg Prognostic Significance –Progression to hypertension –Cardiovascular events Therapy –Lifestyle modification –Antihypertensive medications in patients with Diabetes Mellitus Chronic Kidney Disease

33. Masked Hypertension (Reverse White Coat Hypertension)

34. Definition Normal office/clinic BP levels and elevated home / ambulatory BP levels. Prevalence 10-15% of population (children, adolescent, adults) Tendency to decrease with age. Prognostic Significance Increased risk for: –Progression to sustained hypertension –Target organ involvement –Cardiovascular morbidity/mortality.

35. VariableNormotension White Coat Hypertension Masked Hypertension Sustained Hypertension Office BP SBP SBP DBP DBP 117.9 ± 10.3 76.8 ± 6.9 144.2 ± 14.2 89.9 ± 6.8 126.6 ± 3.7 82.1 ± 5.2 156.8 ± 18.3 94.2 ± 9.3 Home BP SBP SBP DBP DBP 113.1 ± 13 71 ± 8.8 128.3 ± 15 79.1 ± 8.9 127.8 ± 12.2 79.6 ± 7 144.5 ± 17.2 85.1 ± 9.3 ABPM SBP 24hrs SBP 24hrs DBP 24hrs DBP 24hrs 112.7 ± 6.6 70.2 ± 4.9 117.3 ± 5.4 72.4 ± 4.6 127.2 ± 5.7 80 ± 4.8 135.2 ± 10.1 82.5 ± 6.9 CV Deaths (%) 1.13.74.17.3 All Cause Deaths (%) 5.715.512.819.2 Relation between office, home, ambulatory blood pressures and cardiovascular / all cause mortality in various BP patients.

36. Predisposing Factors Obesity, especially android obesity Strong family history of hypertension at an early age. Characteristic Clinical Features Rapid pulse rate Elevated nocturnal BP levels. Diagnostic Procedure Ambulatory BP monitoring Home BP measurement Treatment Lifestyle modification Pharmacologic treatment in high CV risk individuals

37. ClinicABPMHome NormotensionNormalNormalNormal Hypertension (Sustained) ElevatedElevatedElevated White Coat Hypertension ElevatedNormalNormal Masked Hypertension NormalElevatedElevated Blood Pressure Levels Blood Pressure Patterns Diagnostic Procedures Groups

38. BP Pattern Office BP Home BP Risk of CV Events Requirement for therapy Prehypertension 120-139/ 80-89 YesYes White coat hypertension >140/90<140/90YesYes Masked hypertension <140/90>140/90YesYes Sustained hypertension >140/90>140/90YesYes Blood Pressure Patterns Definition, Risk of CV Events, Therapy

39. Novel Cardiovascular Risk Factors

41. Protein excretion in the urine is a strong predictor of cardiovascular disease in middle- aged men and women. Independent from effects of various well recognized CV risk factors

42. Relative prognostic value of microalbuminuria in type 2 Diabetes Eastman RC, Keen H. Lancet 1997;350(Suppl 1):29–32. Microalbuminuria Smoking Diastolic BP Mortality from CHD (odds ratio) Mortality from CHD (odds ratio) Cholesterol 10.02 6.52 2.32 3.20 10 8 8 6 6 4 4 2 2 0 0

43. Multivariate Hazard Ratios for Primary Outcome in HOPE HOPE Study Investigators. N Engl J Med 2000;342:145-53. 01 2 Microalbuminuria CAD Diabetes Creatinine  1.4 mg/dL Male WHR (0.1) Age (1y) Ramipril 1.59 1.51 1.42 1.4 1.20 1.13 1.03 0.79 Hazard Ratio

44. (Conventional)

45. Normoalbuminuria Microalbuminuria Macroalbuminuria (Proteinuria)

47. Increased urinary albumin excretion (UAE) not detected by routine urinalysis (urinary strips detect UAE levels greater than 300mg/D) Special strips available Quantitative assessment: –24 hours urine collection –Timed overnight urinary collection –SPOT urine albumin/creatinine in first morning urine sample (best accurate/practical method). Special techniques required

48. Macroalbuminuria (Proteinuria)

49. Detected by routine urinalysis strips. Regular 24hr urine collection for Proteinuria.

51. Threshold levels for urinary Albumin excretion Timed Collections Spot Collections Timed Collections Spot Collections 24 h Overnight mg/l Alb/Cr Alb/Cr 24 h Overnight mg/l Alb/Cr Alb/Cr mg/D µg/min mg/mmol mg/g mg/D µg/min mg/mmol mg/g Normal <30 <20 <20 <3 <27 Microalbuminuria 30-300 20-200 20-2002.5-20M 22-177M 3.5-30F 31-265F Macroalbuminuria >300 >200 >200 >20M >177M (Proteinuria)>30F >265F Alb: albuminCr: creatinine M: male F: female

54. Prevalence of microalbuminuria in nondiabetic non hypertensive, hypertensive and diabetic subjects in general population. PREVEND STUDY J INTERN MED 2001;249:519-526.

56. TransientPersistent Albuminuria

57. Transient Albuminuria

58. Decompensated heart failure. Strenous exercise. Fever. Urinary tract infection. Postural changes. Sleep apnea.

60. Methods for assessment of urinary albumin excretion 1. Timed urine collection (a) 24h urine volume collection (b) Overnight timed urine collection 2. Spot urine sampling (a) Random urine sampling (b) Spot morning (first void) urine collection

61. Precautions In Measurement Of Albuminuria

62. Avoid determination in presence of states of transient albuminuria. Repeat measurement within 3 months of detection of increased albuminuria due to wide intra-individual day-to-day variation. Most practical approach for detection of increased albuminuria in spot albumin/creatinine ratio on first voided urine sample.

63. Treatment

64. Antihypertensive Therapy

65. General Principles

66. BP reduction major determinant of primary prevention of cardiovascular events

67. Beta blockers less effective in prevention of cardiovascular events than Angiotensin receptor blockers, calcium channel blockers, and Thiazide diuretics. Calcium channel blocker-based therapy Less protective in heart failure prevention Slightly more beneficial in stroke prevention Thiazide diuretics – drug of first choice in uncomplicated essential hypertension regardless of age/race –As effective (even more effective) as other classes in BP reduction Cardiovascular protection No evidence that risk of development of new onset diabetes mellitus associated with increased risk of cardiovascular events

68. Beta Blockers

69. Not to be recommended as first line (initiation) therapy in uncomplicated essential hypertension because –Suboptimal cardiovascular protection, especially in the elderly, despite BP reduction similar to other antihypertensive agents –Greater diabetogenic potential, independent of age Indication in patients with: –Augina pectoris –Previous myocardial infarction –Heart failure –Arrhythmias –Migraine

70. Recommended First Line (Initiation) Therapy Age / Ethnic Background First Choice (Initiation) Drug ≥ 55 years ≥ 55 years Blacks of any age Blacks of any age Calcium channel blockers Calcium channel blockers or or Thiazide type diuretic < 55 years < 55 years Angiotensin converting enzyme inhibitors (ACEI) Angiotensin converting enzyme inhibitors (ACEI) or or Angiotensin receptor blockers (ARB) Angiotensin receptor blockers (ARB) From National Institute of Health and Clinical Excellence (NICE) and Britsh Hypertension Society (BSH) UPTADE June 2006

71. Novel Class of Antihypertensive Medications

72. Renin Inhibitors

73. Aliskiren

74. Pharmacological Characteristics –Orally effective, nonpeptide low molecular weight renin inhibitor –Very potent / highly specific inhibitor of human renin –Suitable for once daily administration because of long terminal half life (25-30 hours) –Route of excretion : liver –Dose dependent (maximal dose = 300 ml) very effective BP reduction over 24 hrs Low adverse effect profile Minimal drug interactions. Potential advantages over other RAAS blockers Effective reduction in all RAAS components.

75. Pathways Blockade of Renin-Angiotensin-Aldosterone System

76. Angiotensinogen Aliskiren Renin Angiotensine ACE inhibitors ACE Angiotensin II AT1 receptors AT2 receptors Angiotensin Receptor Blockers Pathways of Angiotensin II Formation and Sites of Blockade of Renin-Angiotensin System Inhibition Stimulation

77. MoleculePRA Plasma AI Plasma AII Angiotensin converting enzyme inhibitor (ACEI) Angiotensin converting enzyme inhibitor (ACEI) Angiotensin receptor blocker (ARB) Angiotensin receptor blocker (ARB) Renin inhibitor Renin inhibitor ARB + Renin inhibitor unchangedunchangedunchanged PRA = Plasma Renin Activity AI= Angiotensin I AII = Angiotensin II Effect of inhibitors of renin-angiotensin- aldosterone system on system components