1. Hypertension in the Elderly - Its Different From in the Young From in the Young Physiology Physiology HYVET Trial Results HYVET Trial Results Managing the Elderly Hypertensive Managing the Elderly Hypertensive

3. Mrs M M- 84 yo F with BPs from 184/85 – 107/58 Hx of Sjogrens syncope and CVA

4. Prevalence of High BP in Americans Aged 20 Years and Older by Age and Gender (NHANES IV: 1999-2000)

5. Benefits of Lowering BP in all patients Average Percent Reduction Stroke incidence 35–40% Myocardial infarction 20–25% Heart failure50%

6. SHEP Study; JAMA 265:3255; 1991 35% reduction in stroke rate Ave Age 73

7. 18-2930-3940-4950-5960-6970-7980+ 0 70 80 110 130 150 18-2930-3940-4950-5960-6970-7980+ 0 70 80 110 130 150 0 70 80 110 130 150 0 70 80 110 130 150 DBP (mm Hg) SBP (mm Hg) DBP (mm Hg) SBP (mm Hg) DBP (mm Hg) SBP (mm Hg) DBP (mm Hg) SBP (mm Hg) Men, Age (y)Women, Age (y) Non-Hispanic Black Non-Hispanic White Mexican American Pulse pressure Mean Systolic and Diastolic BP by Age and Race/Ethnicity for Men and Women (US Population ³Age 18 Years, NHANES III) Burt VI, et al. Hypertension. 1995;25:305-313.

8. Aging: Vascular Changes Increased thickness of intima and media. Matrix –collagen deposition –increased fibronectin –crosslinking (Advanced Glycosylation Endproducts) Net result is increased vascular stiffness.

9. Bentley Dw, Izzo JL. J Am Geriatr Soc. 1982; 30:352-359. Stroke Volume Aorta Resistance Arterioles Pressure (Flow) Young Artery SystoleDiastole Elastic Vessel Arteriosclerotic Artery Stiff Vessel SystoleDiastole Arterial Wall Compliance and Pulse Pressure Wave

10. Consequences of decreased vascular compliance Relative increase in systolic pressure. Increase in pulse pressure (SBP – DBP) Decreased baroreceptor sensitivity? Increased impedance of flow Increased afterload for the LV to overcome

11. Consequences of Decreased Baroreceptor Sensitivity Increased BP variability Impaired BP homeostasis –Hypertension –Postural (orthostatic) hypotension –Post-prandial hypotension Increase in sympathetic nervous system activity

12. Dengel et al., Am J Physiol 274:E403, 1998 Salt Sensitivity of Blood Pressure Definition: Mean arterial blood pressure on high vs. low Na+ diet –> 5 mm Hg increase => Sodium Sensitive – Sodium Resistant Two thirds of older hypertensives are sodium sensitive.

13. Increased Systolic blood pressure and pulse pressure Left ventricular mass and wall thickness Arterial stiffness Calculated total peripheral resistance Decreased Cardiac output and heart rate Renal blood flow, plasma renin activity, and angiotensin II levels Arterial compliance and blood volume Diastolic blood pressure Black H. JCH 2003; 5:12 Characteristics of Hypertension in the Elderly

14. Cerebral Blood flow Percent of Control Strandgaard et al. Lancet 1987; 2:658-661

15. Blood Pressure & The Very Elderly (aged 80 or more) Epidemiologic population studies suggest better survival with higher levels of blood pressure Worse survival reported in hypertensives with SBP levels below 140 mmHg (Oates et al. 2007) Clinical trials recruited too few. Meta-analysis (n=1670) (Gueyffier et al. 1997) –36% reduction in the risk of stroke (BENEFIT) –14% (p=0.05) increase in total mortality (RISK) Hypertension in the Very Elderly Trial (HYVET) pilot results (n=1273) similar to meta-analysis (Bulpitt et al. 2003)

16. The Trial: International, multi-centre, randomised double-blind placebo controlled Inclusion Criteria: Exclusion Criteria: Aged 80 or more,Standing SBP < 140mmHg Systolic BP; 160 -199mmHg Stroke in last 6 months + diastolic BP; <110 mmHg, Dementia Informed consentNeed daily nursing care CHF or Cr more than 1.7 Primary Endpoint: All strokes (fatal and non-fatal ) Target blood pressure 150/80 mmHg

17. 4761 Entered into Placebo Run-in Placebo 1912 Active 1933 916 not randomised 3845 randomised; Western Europe (86) Eastern Europe (2144), China (1526), Australasia (19), Tunisia (70) At end of trial; 1882 still in double blind, 17 vital status not known, 220 in open follow-up

18. Placebo (n= 1912) Active (n= 1933) Age (years)83.583.6 Female60.3%60.7% Blood Pressure: Sitting SBP (mmHg)173.0 Sitting DBP (mmHg)90.8 Orthostatic Hypotension ‡ 8.8%7.9% Isolated Systolic Hypertension32.6%32.3% Baseline data ‡ Fall in SBP ≥ 20mmHg and/or fall in DBP ≥ 10mmHg

19. Baseline Data ( Previous Cardiovascular History ) Placebo (%) Active (%) Cardiovascular disease12.011.5 Known Hypertension89.9 Anti-hypertensive treatment65.164.2 Stroke6.96.7 Myocardial Infarction3.23.1 Heart Failure2.9

20. PlaceboActive Current smoker6.6%6.4% Diabetes (Known DM/ DM treatment/glucose>11.1mmo/l) 6.9%6.8% Total cholesterol (mmol/l)5.3 HDL Cholesterol (mmol/l)1.35 Serum Creatinine (μmol/l)89.288.6 Uric acid (µmol/l)279280 Body Mass Index (kg/m 2 )24.7 Baseline data ( Cardiovascular Risk factors )

21. Blood pressure separation Median follow-up 1.8 years 15 mmHg 6 mmHg

22. All stroke (30% reduction) Placebo IndapamideSR ±perindopril Indapamide SR ±perindopril Placebo P=0.055

23. Fatal Stroke (39% reduction) Indapamide SR ±perindopril Placebo P=0.046 Placebo IndapamideSR ±perindopril

24. Heart Failure (64% reduction) P<0.0001 Placebo IndapamideSR ±perindopril Placebo IndapamideSR ±perindopril

25. Total Mortality (21% reduction) Placebo Indapamide SR ±perindopril P=0.019 Placebo IndapamideSR ±perindopril

26. 020.50.20.1 HR95% CINNT 0.70(0.49, 1.01)NS 0.61(0.38, 0.99)241 0.79(0.65, 0.95)82 0.81(0.62, 1.06)NS 0.77(0.60, 1.01)NS 0.71(0.42, 1.19)NS 0.36(0.22, 0.58)106 0.66(0.53, 0.82)60 All Stroke Stroke Death All cause mortality NCV/Unknown death CV Death Cardiac Death Heart Failure CV events Summary at median 1.8 Yrs

27. Conclusions Antihypertensive treatment based on indapamide (SR) 1.5mg (± perindopril) reduced stroke mortality and total mortality in a very elderly cohort. NNT (2 years) = 94 for stroke and 40 for mortality Large and significant benefit in reduction of heart failure events and for combined endpoint of cardiovascular events Benefits seen early Treatment regime employed was safe

28. 5 Year NNTs for younger and older Age <60Age ≥60 12 trials, n = 33,00013 trials, n = 16,564 Stroke NNT = 168Stroke NNT = 43 CHD event NNT = 184CHD event NNT = 61 Stroke & CHD NNT = NAStroke & CHD NNT = 18 CV mortality NNT = 205 CV mortality NNT = 52 Mulrow et al. JAMA 1994; 272:1932-1938

29. J curve of all cause Mortality found in several studies The risk for the primary outcome, all-cause death, and MI, but not stroke, progressively increased with low diastolic blood pressure. Excessive reduction in diastolic pressure should be avoided in patients with CAD who are being treated for hypertension. INVEST Trial Secondary analysis AIM 144:884 (2006)

30. Treatment Recs for the Elderly with HTN Don’t have to have goal lower than 150/80 –DBP lower than 65 are possibly undesirable Diuretics are generally preferred –Effective, have best data in reducing complications Don’t overuse diuretics –Keep the dose low –Combo Rx is usually necessary and desirable Keep an eye for orthostatic symptoms and if present back off on Rx – Check standing BPs Lifestyle changes can be effective –Low Salt diet, aerobic exercise and weight loss

31. “If the standing blood pressure is consistently much lower than the sitting blood pressure, the standing blood pressure should be used to titrate drug dosages during treatment.” National High Blood Pressure Education Program Working Group Report on Hypertension in the Elderly.

33. References Beckett NS et al, “Treatment of HTN in Patients 80 Yrs of age or Older”(HYVET) NEJM 358:1887-98 2008 Psaty, Bruce, et al Health Outcomes Associated With Various Antihypertensive Therapies Used as First-Line Agents: A Network Meta-analysis. JAMA 289:2534-44 Oates DJ et al “Blood Pressure and Survival in the Oldest Old” J Am Geriatr Soc 55:383-388, 2007 SHEP Coop Research Group, SHEP Trial JAMA 265:3255; 1991 Messerli, Franz H. MD; Mancia, et al; “ Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous? AIM: 144:884 (2006) Chobanian, A “Isolated Systolic HTN in the Elderly” Clinical Practice NEJM: 357:789-96 2007