1. Managing ISOLATED SYSTOLIC HYPERTENION in the Elderly Ass. Prof. Roland KASSAB Head of Division of Cardiology Hotel-Dieu de France, Beirut 12 April 2003

2. ISH DefinitionPrevalencePathophysiology Risk Statification Outcomes Studies Therapy

3. DEFINITION According to JNC-VI and WHO/ISH: According to JNC-VI and WHO/ISH: SBP ≥ 140 mmHg, DBP < 90 mmHg SBP ≥ 140 mmHg, DBP < 90 mmHg Grade 1: SBP < 160 mmHg Grade 1: SBP < 160 mmHg Subgr. borderline SBP < 150 mmHg Subgr. borderline SBP < 150 mmHg Grade 2: SBP < 180 mmHg Grade 2: SBP < 180 mmHg Grade 3: SBP ≥ 180 mmHg Grade 3: SBP ≥ 180 mmHg

4. JNC VI Guidelines for Definition and Dg of HTA Defined as SBP ≥ 140, DBP ≥ 90mmHg, or taking any antihypertensive medication. or taking any antihypertensive medication. ■ When SBP and DBP fall into different categories, the Higher one is used to classify the BP. ■ Measurements are based on the average of 2 or more BP readings at each of 2 or more visits after the initial screening. ■ Measurements must be taken with equipment that meets certification criteria, and in a standardized fashion.

5. Definition of HTA (JNC VI) Hypertension is defined as consistent readings  140/90 mm Hg in young and older adults Classification of BP for adults age 18 and older CategorySystolic(mmHgDiastolic(mmHg) Optimal<120and<80 Normal<130and<85 High-normal130-139or85-89 Hypertension Stage 1 Stage 1140-159or90-99 Stage 2 Stage 2160-179or100-109 Stage 3 Stage 3  180 or  110 The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. November 1997. NIH publication 98-4080

6. PREVALENCE Latest Definition: ≥140/<90 : little data Prevalence of ISH  with age Most common type of HTA in the elderly Most preval. type of untreated HTA ≥ 60 y. Age Age ( % ) ( % ) 50 50 60 60 70 70 80+ 80+ 0,8 0,8 5,0 5,0 8-12,6 8-12,6 23 - 25 23 - 25 Old Definition: ≥ 160 / < 90

7. Hypertension in the Elderly (>60 Years) in Spain Prevalence of arterial hypertension: 68.3% Prevalence of ISH in untreated hypertensives: 71.6% Banegas J et al. J Hypertens (submitted)

8. <40 40-49 50-59 60-69 70-79 80+ Age (y) 100 % 80%60%40%20%0% Franklin et al, Hypertension 2001 4% 10% 18% 28% 27% 13% 4% 10% 18% 28% 27% 13% NHANES III Frequency of treatment Failures by HTN subtype (%) ISHS/DH IDH

9. Framingham: Prevalence of Isolated Systolic Hypertension in the Elderly* Wilking SV et al. JAMA.1988;260:3451-3455. Isolated Diastolic Hypertension Isolated Systolic Hypertension Combined Hypertension *Age range: 65-89 years Men Women

10. PATHOPHYSIOLOGY B.P. = Cardiac Output X Periph. Resistance B.P. = Cardiac Output X Periph. Resistance ( Qc ) ( R ) ( Qc ) ( R ) ↑ B.P. ↔ ↑ Qc ↑ B.P. ↔ ↑ Qc or or ↑ R ↑ R

11. Characteristics of Hypertension in the Elderly Increased arterial stiffness Altered renal function Frequent diabetes and hyperlipidemia Frequent association with CV disease and heart failure Frequent occurrence with other complications and disease states (polypharmacy, noncompliance are common issues)

12. The Effects of Age on Blood Pressure Systolic BP rises continuously with age Diastolic BP rises continuously until age 60-70 years –It falls thereafter as a consequence of increased arterial stiffness Pulse pressure increases continuously with age

13. PATHOPHYSIOLOGY Stiffened aorta  Increased pulse-wave velocity  More stroke volume returned to aorta in systole rather than diastole  SBP augmented further, DBP reduced Potential harm of reducing DBP (J curve) Smulyan H, Safar ME. Ann Intern Med. 2000;132:233-237.

14. RISK STRATIFICATION Components of Risk Stratification: JNC VI: Components of Risk Stratification: JNC VI: MAJOR RISK FACTORS MAJOR RISK FACTORS ♥ Smoking ♥ Dyslipidemia ♥ Diabetes Mellitus ♥ Age ≥ 60 y. ♥ Sex ( ♂, post-menopausal ♀ ) ♥ Family history or Co-vx disease:♀< 65y, ♂< 55y

15. RISK STRATIFICATION TARGET ORGAN DAMAGE ( TOD ) TARGET ORGAN DAMAGE ( TOD ) ♥ Heart Disease: LVH, Angina or previous MI, prior CABG, HF MI, prior CABG, HF ♥ Stroke or TIA ♥ Nephropathy ♥ PAD ♥ Retinopathy.

16. Risk Stratification and Treatment Stage Group A Group B Group C No risk factors; no TOD/CCD At least 1ris f, no DM or TOD, CCD TOD/CCD and/or DM, ±other risk f High-Norm.LMLMDrug Stage 1 LM (up to 1 year) LM ( up to 6 m.) Drug Stage 2 DrugDrugDrug

17. Systolic vs Diastolic Blood Pressure as Predictors of Cardiovascular Outcomes Systolic blood pressure (SBP) is a stronger predictor of future cardiovascular events than diastolic blood pressure (DBP) 1 Patients with a combination of hypertension and diabetes and/or older patients benefit most from well- controlled systolic blood pressure 2 In addition, pulse pressure (PP = SBP minus DBP) is increasingly seen as an independent predictor of risk for coronary artery disease 3 1. Neaton JD, Wentworth D. Arch Intern Med. 1992;152:56-64. 2. Lee ML et al. Ann Epidemiol. 1999;9:101-107. 3. Franklin SS et al. Circulation.1999;100:354-360.

18. Adapted from Neaton JD, Wentworth D. Arch Intern Med. 1992;152:56-64. Adapted from Neaton JD, Wentworth D. Arch Intern Med. 1992;152:56-64. Effect of Systolic Blood Pressure and Diastolic Blood Pressure on Coronary Heart Disease Mortality: MRFIT <120 120-139 140-159 160+ Systolic BP (mm Hg) Diastolic BP (mm Hg) CAD Death Rate per 10,000 Person-Years 100+ 80-89 70-74 <70 75-79 90-99 48.3 37.4 34.7 43.8 38.1 80.6 31.0 25.5 24.6 25.3 25.2 24.9 23.8 16.9 13.9 12.8 12.6 11.8 20.6 10.3 11.8 8.8 8.5 9.2

19. 3.0 2.5 2.0 1.5 1.0 0.5 30405060708090100110 SBP 170 mm Hg (P = 0.0487) SBP 150 mm Hg (P = 0.0194) SBP 130 mm Hg (P = 0.0086) SBP 110 mm Hg (P = 0.2076) CoronaryArteryDisease Hazard Hazard Ratio Ratio Pulse Pressure (mm Hg) Franklin SS et al. Circulation. 1999;100:354-360. *Pulse pressure = systolic blood pressure (SBP) minus diastolic blood pressure (DBP). N = 1,924 Framingham Study: At Any Level of Systolic BP, Pulse Pressure* is a Strong Predictor of Cardiovascular Events

21. OUTCOMES STUDIES Major Studies of Pharmacologic Tt in Major Studies of Pharmacologic Tt in ISH ISH ►► SHEP ►► SHEP ►► Syst-EUR ►► Syst-EUR ►► Syst-China ►► Syst-China ►► ARBs studies: LIFE sub-study ►► ARBs studies: LIFE sub-study

22. Chlorthalidone 12.5 mg (C 1 ) Chlorthalidone 25 mg (C 2 ) Atenolol 25 mg C 25 mg Atenolol 50 mg C 25 mg The Systolic Hypertension in the Elderly Program (SHEP) Trial Design SHEP Cooperative Research Group. J Clin Epidemiol. 1988;41:1197-1208. SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264. IC Randomization - 4 08 16 Week - 2 24 Placebo Placebo C 2 Placebo C 1 +_ C 25 mg +_ +_ +_ +_ +_ Indicates those with BP not reduced to or below goal +_ Indicates those with BP reduced to or below goal Placebo A 1 Placebo C 2 Placebo A 2 Placebo C 2 Placebo A 1 Placebo C 2 Atenolol 25 mg C 25 mg BV 1 IC = initial contact; BV 1 = baseline visit 1. Placebo C 2

23. The Systolic Hypertension in Europe (Syst-Eur) Trial Design Amery A et al. Aging. 1991;3:287-302. Staessen JA et al. Lancet. 1997;350:757-764. Entry criteria Age: >60 years Sitting SBP  160 mm Hg Sitting DBP <95 mm Hg Standing SBP:  140 mm Hg Informed consent Outcome Events Death Stroke Retinal changes Myocardial infarction Heart failure Dissecting aneurysm Serum creatinine  4mg % Placebo Active Treatment Nitrendipine 10-40 mg  Enalapril 5-20 mg  Hydrochlorothiazide 12.5-25 mg Single blind Visit monthly Duration: 3-4 months Double Blind Visit every 3 months Duration: 5 years N = 4,695

24. Landmark Trials in Isolated Systolic Hypertension CAD = coronary artery disease; CHF = congestive heart failure; CVD = cardiovascular disease. SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264. Staessen JA et al. Lancet. 1997;350:757-764. Relative Risk Reduction (%) Diuretic ± beta-blocker Long-acting DHP CCB (nitrendipine) Syst-Eur Syst-Eur SHEP 4,736  60 171/77-36-27-55-32 -31-29-26-42174/86 4,695 AgentNAge Entry BP StrokeCADCHF All CVD

25. SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264. Staessen JA et al. Lancet. 1997;350:757-764. Isolated Systolic Hypertension and Stroke Risk Reduction Cumulative Stroke Rate per 100 Participants Placebo 36% Reduction at 5 Years (P <0.0003 ) Follow-up (months) 012243648 6 0 4 2 8 10 60 Diuretic  beta-blocker 42% Reduction in Events (P = 0.003) Follow-up (months) 012243648 60 1 3 5 4 2 Nitrendipine Placebo Cumulative Rate of Fatal and Nonfatal Stroke SHEP Syst-Eur

29. *Other antihypertensives excluding ACE-Is, ARBs, beta-blockers; T = titration; R = randomization. LIFE: ISH Study Design and Dosing Day  14 Day 1Month 2Month 4 Month 6 Titration to target blood pressure: <140/<90 mm Hg Losartan 50 mg or Atenolol 50 mg Placebo Losartan 100 mg or Atenolol 100 mg Hydrochlorothiazide 12.5 mg Other Antihyper- tensive Medications* HCTZ 12.5 to 25 mg TTT Kjeldsen SE et al. JAMA. 2002;288:1491-1498.R N = 1326

30. LIFE Isolated Systolic Hypertension Substudy: Combination or Monotherapy at End of Titration HCTZ = hydrochlorothiazide; D/C = discontinued. Adapted from Kjeldsen SE et al. JAMA. 2002;288:1491-1498. 12.1% 3.6% 58.8% 25.5% 10.1% 2.6% 55.1% 32.3% 0 15 30 45 60 50 or 100 mg monotherapy 50 or 100 mg + HCTZ  add-on 100 mg + add-on Losartan (n = 660) Atenolol (n = 666) D/C therapy Percent

31. LIFE: Primary Composite End Point in Patients With Isolated Systolic Hypertension Kjeldsen SE et al. JAMA. 2002;288:1491-1498. Blood pressure reduction was virtually identical in losartan (28/9 mm Hg) and atenolol (28/9 mm Hg) arms. Patients With First Event (%) 0 2 4 6 8 10 12 14 16 Study Month 0612182430364248546066 18 Losartan Atenolol Primary Composite End Point 0 2 4 6 8 10 12 14 16 Study Month 0612182430364248546066 18 Total Mortality Relative Risk = 0.75 (95% Cl, 0.56-1.01 P = 0.06 Relative Risk = 0.72 (95% Cl, 0.53-1.00) P = 0.046

32. LIFE: Components of the Composite Primary End Point in Patients With Isolated Systolic Hypertension Atenolol Losartan Kjeldsen SE et al. JAMA. 2002;288:1491-1498. 01224483660 Myocardial Infarction Relative Risk = 0.89 (95% Cl, 0.55-1.44) P = 0.64 Study Month 0 4 2 8 6 10 01224483660 Stroke Relative Risk = 0.60 (95% Cl, 0.38-0.92) P = 0.02 Study Month 0 4 2 8 6 10 Patients(%)Patients (%) (%) Study Month 01224483660 0 4 2 8 6 10 Cardiovascular Mortality Relative Risk = 0.54 (95% Cl, 0.34-0.87) P = 0.01 Study Month Patients(%)

33. LIFE Isolated Systolic Hypertension Substudy: Conclusions Most patients with ISH received combination treatment with hydrochlorothiazide (58.8% in the losartan group and 55.1% in the atenolol group) >70% of patients that finished the trial received combination therapy Reductions of 28 mm Hg in systolic blood pressure and 9 mm Hg in diastolic blood pressure were achieved in the losartan and the atenolol groups At the same levels of blood pressure control, losartan significantly reduced stroke risk and overall cardiovascular mortality but not the risk of suffering a myocardial infarction The impact of ARB + HCTZ treatment on cardiac morbidity and mortality alone needs to be further evaluated in future trials Kjeldsen SE et al. JAMA. 2002;288:1491-1498.

34. Reduction of BP in Patients  65 Years With Valsartan *P <0.001, valsartan vs placebo. Neutel JM et al. Clin Ther. 2000;22:961-969. Change from Baseline (mm Hg)

35. THERAPY As with any therapy, the pragmatic 4 W questions must be answered: As with any therapy, the pragmatic 4 W questions must be answered: W HY ? W HY ? W HEN ? W HEN ? W HO ? W HO ? W HAT ? W HAT ?

36. WHY ? According to the previous trials, in ISH: ► Treatment >> Placebo ► Treatment >> Placebo ► Significant ↓ Cardio-vx Morbidity ► Significant ↓ Cardio-vx Morbidity and Mortality and Mortality ■ Benefits of ↓ Systolic B.P. and Pulse Pressure

37. Tx = treatment; C = control (untreated); CAD = coronary artery disease; CV = cardiovascular. Staessen JA et al. Lancet. 2000;355:865-872. Meta-Analysis: Reduction of CV Events in Treated vs Untreated Patients With Isolated Systolic Hypertension Individuals Affected Individuals Affected(N) 279 100 387 136 293 193 373 244 647 329 835 392 656 734 327 342 Tx C C C C C Nonfatal Events Deaths StrokeCAD All CV Events Total Mortality Non-CV Mortality N = 15,693 30% P <0.0001 26% P <0.0001 Reduction in Odds (%) 23% P <0.001 13% P <0.02

38. WHEN ? Appropriate Diagnosis of ISH Institute Lifestyle Modifications: ♥ Weight loss ♥ Weight loss ♥ Salt restriction ♥ Salt restriction ♥ Exercise program ♥ Exercise program ♥ Reduction of alcohol intake ♥ Reduction of alcohol intake ■ If HT persists, institute Drug Treatment.

39. WHO ? All patients with ISH Risks higher in smokers and diabetic pts Tight control of diabetes, cessation of smoking +++ In the previous trials, ↓ in absolute risk from all major Co-vx events almost twice in diabetic sub-group.

41. WHAT ? Start with a Single Agent: Start with a Single Agent: ► Dose should be ↓ in elderly: ≈ ½ dose ► Dose should be ↓ in elderly: ≈ ½ dose ► Long-acting formulations preferred for ► Long-acting formulations preferred for better compliance better compliance ► Low-dose combinations helpful: ↓ S.E. ► Low-dose combinations helpful: ↓ S.E. ► Titrate ↑ and/or add 2 nd agent if goal not ► Titrate ↑ and/or add 2 nd agent if goal not reached after 1 to 2 months. reached after 1 to 2 months.

42. PHARMACOTHERAPY Avoid agents ↔ profound ↓ in Diastolic BP ( Pulse Pressure ++) Avoid agents causing serious Side Effects Theoretic advantage of vaso-dilators improving arterial compliance Recommendations of JNC VI :

43. DIURETICS First-line Tt of ISH in elderly ( SHEP ) Good control often seen at low doses Thiazides: Diuretics of choice Thiazide diuretics seem to be > to Beta- blockers in pts with ISH. blockers in pts with ISH.

44. CA CHANNEL BLOCKERS Improve arterial compliance Well tolerated in comorbid conditions Low-dose, slow-release agents First-line Tt in Syst-EUR and Syst-China Significant ↓ in key end points Benefit over Diuretics: ↓ rate of dementia (by 50%) in treated pts. (by 50%) in treated pts.

45. BETA BLOCKERS First-line Tt in combination with Thiazides Starting agents alone in some conditions: ♥ Tachycardia ♥ Tachycardia ♥ CAD ♥ CAD ♥ Prior MI ♥ Prior MI N.B. BB with intrinsec Σ activity or combined α blocker activity may be more effective α blocker activity may be more effective

46. ACEI and ARBs ► Numerous advantages: ♥ ↓ Proteinuria ♥ ↓ Proteinuria ♥ Slow renal disease ♥ Slow renal disease ♥ Improve systolic dysfunction ♥ Improve systolic dysfunction ♥ ↓ SBP in pts with ISH ♥ ↓ SBP in pts with ISH ► Indicated in ISH + HF, Proteinuria, Diabetic Nephropathy.. Diabetic Nephropathy.. → Before the LIFE ISH sub-study → Before the LIFE ISH sub-study

47. ARBs After the LIFE: ISH sub-study: ♥ First trial demonstrating superiority of ♥ First trial demonstrating superiority of one anti-HT agent vs another one anti-HT agent vs another ♥ Losartan > Atenolol in ↓ Stroke and ♥ Losartan > Atenolol in ↓ Stroke and Cardio-vx Mortality Cardio-vx Mortality ■ New Recommendations of JNC including ARBs (Losartan) as First-line Tt?? ARBs (Losartan) as First-line Tt??

48. NITRATES Vaso-dilatory action on conduit vx May alter timing of reflected pr. waves P.O.: ↓ SBP without sign. changes in DBP Well tolerated in elderly Advantageous in pts with angina No large and randomised trials.

49. α ADRENERGIC BLOCKERS NOT recommended as first-line agents by NOT recommended as first-line agents by JNC VI: JNC VI: ↑ Co-vx events ↑ Co-vx events ↑ Congestive HF ↑ Congestive HF Compared with other agents. Compared with other agents.

50. RECOMMENDATION In all cases, decisions and regimens must In all cases, decisions and regimens must be institued and tailored in accord with a be institued and tailored in accord with a patient’s other comorbid conditions and patient’s other comorbid conditions and responses to medication. responses to medication. THANK YOU FOR YOUR ATTENTION THANK YOU FOR YOUR ATTENTION