Hypertension in the Hypertension in the Elderly -Elderly -Its DifferentIts Different

From in the YoungFrom in the Young

PhysiologyPhysiology HYVET Trial ResultsHYVET Trial Results Managing the Elderly HypertensiveManaging the Elderly Hypertensive

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

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

Benefits of Lowering BP in all patients

Average Percent Reduction

Stroke incidence 35–40%

Myocardial infarction 20–25%

Heart failure 50%

SHEP Study; JAMA 265:3255; 1991

35% reduction in stroke rate

Ave Age 73

18-29 30-39 40-49 50-59 60-69 70-79 80+0

70

80

110

130

150

18-29 30-39 40-49 50-59 60-69 70-79 80+0

70

80

110

130

150

0

70

80

110

130

150

0

70

80

110

130

150D

BP

(mm

Hg

)S

BP

(mm

Hg

)D

BP

(mm

Hg

)S

BP

(mm

Hg

)

DB

P(m

m H

g)

SB

P(m

m H

g)

DB

P(m

m H

g)

SB

P(m

m H

g)

Men, Age (y) Women, Age (y)

Non-Hispanic BlackNon-Hispanic WhiteMexican American

Pulse pressure 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.

Aging: Vascular Changes

• Increased thickness of intima and media.

• Matrix– collagen deposition– increased fibronectin– crosslinking (Advanced

Glycosylation Endproducts)

Net result is increased vascular stiffness.

Bentley Dw, Izzo JL. J Am Geriatr Soc. 1982; 30:352-359.

Stroke Volume

Aorta

Resistance Arterioles

Pressure (Flow)

Young Artery

Systole Diastole

Elastic Vessel

Arteriosclerotic Artery

Stiff Vessel

Systole Diastole

Arterial Wall Compliance and Pulse Pressure Wave

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

Consequences of Decreased Baroreceptor Sensitivity

• Increased BP variability

• Impaired BP homeostasis– Hypertension– Postural (orthostatic) hypotension– Post-prandial hypotension

• Increase in sympathetic nervous system activity

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– < 5 mm Hg increase => Sodium

Resistant

• Two thirds of older hypertensives are sodium sensitive.

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

Cer

ebra

l Blo

od f

low

P

erce

nt

of C

ontr

ol

Autoregulation of cerebral blood flood

mmHg

Mean Arterial Blood Pressure

Cerebral Blood flowPercent of Control

Normotensive Patients

Treated Hypertensive Paitents

Hypertensive Patients

100

50

050 100 150 200

Strandgaard et al. Lancet 1987; 2:658-661

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)

The Trial:International, multi-centre, randomised double-blind placebo controlled

Inclusion Criteria: Exclusion Criteria:Aged 80 or more, Standing SBP < 140mmHgSystolic BP; 160 -199mmHg Stroke in last 6 months+ diastolic BP; <110 mmHg, DementiaInformed consent Need daily nursing care

CHF or Cr more than 1.7Primary Endpoint: All strokes (fatal and non-fatal)

Target blood pressure

150/80 mmHg

4761 Entered intoPlacebo Run-in

Placebo1912

Active1933

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

Placebo(n= 1912)

Active(n= 1933)

Age (years) 83.5 83.6

Female 60.3% 60.7%

Blood Pressure:

Sitting SBP (mmHg) 173.0 173.0

Sitting DBP (mmHg) 90.8 90.8

Orthostatic Hypotension‡ 8.8% 7.9%

Isolated Systolic Hypertension 32.6% 32.3%

Baseline data

‡ Fall in SBP ≥ 20mmHg and/or fall in DBP ≥ 10mmHg

Baseline Data (Previous Cardiovascular

History)Placebo

(%)Active

(%)

Cardiovascular disease 12.0 11.5

Known Hypertension 89.9 89.9

Anti-hypertensive treatment 65.1 64.2

Stroke 6.9 6.7

Myocardial Infarction 3.2 3.1

Heart Failure 2.9 2.9

Placebo Active

Current smoker 6.6% 6.4%

Diabetes

(Known DM/ DM treatment/glucose>11.1mmo/l) 6.9% 6.8%

Total cholesterol (mmol/l) 5.3 5.3

HDL Cholesterol (mmol/l) 1.35 1.35

Serum Creatinine (μmol/l) 89.2 88.6

Uric acid (µmol/l) 279 280

Body Mass Index (kg/m2) 24.7 24.7

Baseline data (Cardiovascular Risk factors)

Blood pressure separation

70

80

90

100

110

120

130

140

150

160

170

180

0 1 2 3 4 5

Follow-up (years)

Blo

od

Pre

ssu

re (

mm

Hg

)

Placebo

Indapamide SR +/-perindoprilIMedian follow-up 1.8 years

15 mmHg

6 mmHg

All stroke(30% reduction)

PlaceboIndapamideSR ±perindopril

Indapamide

SR

±perindopril

Placebo

P=0.055

Fatal Stroke(39% reduction)

Indapamide

SR

±perindopril

Placebo

P=0.046

PlaceboIndapamideSR ±perindopril

Heart Failure(64% reduction)

P<0.0001

Placebo

IndapamideSR

±perindopril

PlaceboIndapamideSR ±perindopril

Total Mortality(21% reduction)

Placebo

Indapamide

SR

±perindopril

P=0.019

PlaceboIndapamideSR ±perindopril

0 20.50.20.1

HR 95% CI NNT

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

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

5 Year NNTs for younger and older

• Age <60 Age ≥60• 12 trials, n = 33,000 13 trials, n = 16,564• Stroke NNT = 168 Stroke NNT = 43• CHD event NNT = 184 CHD event NNT = 61• Stroke & CHD NNT = NA Stroke & CHD NNT = 18• CV mortality NNT = 205 CV mortality NNT = 52

• Mulrow et al. JAMA 1994; 272:1932-1938

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)

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

“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.

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