Active treatment of isolated systolic hypertension in elderly patients using indapamide with or without perindopril resulted in significant reductions in mortality, stroke, and heart failure compared to placebo. Systolic blood pressure was reduced by 15 mmHg in the active treatment group. The benefits of treatment were seen early with number needed to treat of 94 for stroke and 40 for mortality reduction over 2 years. Treatment was also found to be safe with no significant differences in adverse lab values between groups.

1. Ahad Lodhi, M.D.
PGY-2 Internal Medicine
Dept of Geriatrics
Crozer-Chester Medical Center

5. BP Classification SBP mmHg DBP mmHg
Normal <120 and <80
Prehypertension 120–139 or 80–89
Stage 1 Hypertension 140–159 or 90–99
Stage 2 Hypertension >160 or >100

6. The HYpertension
in the
Very Elderly Trial
N. Beckett, R. Peters, A. Fletcher, C. Bulpitt
on behalf of the HYVET committees and
investigators
N Engl J Med
Volume 358(18):1887-1898
May 1, 2008

7. • In this study, patients 80 years of age or older with sustained
systolic hypertension were randomly assigned to receive either
the diuretic indapamide, with or without the angiotensin-
converting-enzyme inhibitor perindopril, or matching placebos,
for a target blood pressure of 150/80 mm Hg
• Active treatment resulted in a nearly significant reduction of the
risks of fatal or nonfatal stroke and death from cardiovascular
causes and a significant reduction in the rates of death from
stroke and death from any cause, suggesting that
antihypertensive treatment in these persons may be beneficial

8. 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 consent Need daily nursing care
Primary Endpoint:
All strokes (fatal and non-fatal)

10. Entry,
Randomiza
tion, and
Follow-up
of Patients
in the
Hypertensi
on in the
Very
Elderly
Trial

11. 4761 Entered into
Placebo Run-in
916 not randomised
Placebo Active
1912 1933

13. Baseline data
Placebo Active
(n= 1912) (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%
‡ Fall in SBP ≥ 20mmHg and/or fall in DBP ≥ 10mmHg

14. 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

15. Baseline data
(Cardiovascular Risk factors)
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

16. Mean Blood Pressure, Measured while Patients Were Seated, in the Intention-to-Treat
Population, According to Study Group
Beckett NS et al. N Engl J Med 2008;358:1887-1898

17. 180
170 15 mmHg
160
150
Blood Pressure (mmHg)
140
Placebo
130
120 Indapamide SR +/-
Median follow-up 1.8 years
I perindopril
110
100
6 mmHg
90
80
70
0 1 2 3 4 5
Follow-up (years)

18. Main Fatal and Nonfatal End Points in the Intention-to-Treat Population
Beckett NS et al. N Engl J Med 2008;358:1887-1898

19. All stroke
Kaplan-Meier Estimates of
the Rate of End Points,
According to Study Group
(30% reduction)
P=0.055

20. Kaplan-Meier Estimates of
the Rate of End Points,
According to Study Group
Total Mortality
(21% reduction)
P=0.019

21. Kaplan-Meier Estimates of
the Rate of End Points,
According to Study Group
Fatal Stroke
(39% reduction)
P=0.046

22. Kaplan-Meier Estimates of
the Rate of End Points, Heart Failure
(64% reduction)
According to Study Group
P<0.0001

23. ITT – Summary
HR 95% CI
All Stroke 0.70 (0.49, 1.01)
Stroke Death 0.61 (0.38, 0.99)
All cause
0.79 (0.65, 0.95)
mortality
NCV/Unknown 0.81 (0.62, 1.06)
death
CV Death 0.77 (0.60, 1.01)
Cardiac Death 0.71 (0.42, 1.19)
Heart Failure 0.36 (0.22, 0.58)
CV events 0.66 (0.53, 0.82)
0.1 0.2 0.5 0 2

24. HR 95% CI P
All stroke - 34% 0.46 - 0.95 0.025
Total mortality - 28% 0.59 - 0.88 0.001
Fatal stroke - 45% 0.33 - 0.93 0.021
Cardiovascular mortality -27% 0.55-0.97 0.029
Heart failure -72% 0.17-0.48 <0.001
Cardiovascular events - 37% 0.51-0.71 <0.001

25. •In 2 year cohort there were no significant
differences between the groups with regard to
change in serum….
•Potassium
•Uric acid
•Glucose
•Creatinine

26. Reported serious adverse events
(after randomisation)
 448 in the placebo group vs 358 in active (p=0.001)

27. 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. Major Outcomes in High-Risk Hypertensive Patients
Randomized to Angiotensin-Converting Enzyme
Inhibitoror Calcium Channel Blocker vs Diuretic
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial (ALLHAT)

29. Objective: To determine whether treatment with a calcium channel blocker or an
angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease
(CHD) or other cardiovascular disease (CVD) events vs treatment with a diuretic.
Design: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT), a randomized, double-blind, active-controlled clinical trial con- ducted from
February 1994 through March 2002.
Setting and Participants: A total of 33 357 participants aged 55 years or older with
hypertension and at least 1 other CHD risk factor from 623 North American centers

30. Primary outcome:
Combined fatal CHD or non-
fatal myocardial infarction,
analyzed by intent-to-treat
Secondary outcomes:
ll- cause mortality,
troke,
ombined CHD (primary outcome, coronary revascularization, or angina with hospitalization)
ombined CVD (combined CHD, stroke, treated angina without hospitalization,
heart failure [HF],
peripheral arterial disease

31. Mean follow-up was 4.9 years
The primary outcome occurred in 2956 participants, with no difference between treatments
All-cause mortality did not differ between groups.
Five-year systolic blood pressures were significantly higher in the amlodipine (0.8 mm Hg,
P=.03) and lisinopril (2 mm Hg, P<.001) groups compared with chlorthalidone
5-year diastolic blood pressure was significantly lower with amlodipine (0.8 mm Hg, P<.001)
Amlodipine vs Chlorthalidone, secondary outcomes were similar except for a higher 6-year
rate of HF with amlodipine (10.2% vs 7.7%; RR, 1.38; 95% CI, 1.25-1.52)
Lisinopril vs Chlorthalidone, lisinopril had higher 6-year rates of combined CVD (33.3% vs
30.9%; RR, 1.10; 95% CI, 1.05-1.16); stroke (6.3% vs 5.6%; RR, 1.15; 95% CI, 1.02-1.30); and
HF (8.7% vs 7.7%; RR, 1.19; 95% CI, 1.07-1.31)

32. Thiazide-type diuretics are superior in preventing 1
or more major forms of CVD and are less expensive.
They should be preferred for first-step antihyperten-
sive therapy.

33. Objective. To assess the ability of antihypertensive drug treatment to reduce the risk of
nonfatal and fatal (total) stroke in isolated systolic hypertension.
Design. Multicenter, randomized, double-blind, placebo-controlled.
Setting. Community-based ambulatory population in tertiary care centers.
Participants. 4736 persons (1.06%) from 447 921 screenes aged 60 years and above were
randomized (2365 to active treatment, 2371 to placebo).
Systolic blood pressure ranged from 160 to 219 mm Hg and diastolic blood pressure was
less than 90 mm Hg.
3161 were not receiving antihypertensive medication at initial contact, and 1575 were.
The average systolic blood pressure was 170 mm Hg; average diastolic blood pressure, 77
mm Hg. The mean age was 72 years, 57% were women, and 14% were black

34. Participants were stratified by clinical center and by antihypertensive medication status at
initial contact.
step 1 of the trial:
dose 1 was chlorthalidone, 12.5 mg/d, or matching placebo; dose 2 was 25 mg/d.
step 2:
dose 1 was atenolol, 25 mg/d, or matching placebo; dose 2 was 50 mg/d.
Main Outcome Measures
Primary. Nonfatal and fatal (total) stroke
Secondary. Cardiovascular and coronary morbidity and mortality, all-cause mortality, and
quality of life measures.

35. Average follow-up was 4.5 years
The 5-year average systolic blood pressure was 155mm Hg for the placebo group and
143mm Hg for the active treatment group, and the 5-year average diastolic blood
pressure was 72 and 68mmHg, respectively.
The 5-year incidence of total stroke was 5.2 per 100 participants for active treatment
and 8.2 per 100 for placebo
The relative risk by proportional hazards regression analysis was 0.64 (P=.0003).
For the secondary end point of clinical nonfatal myocardial infarction plus coronary
death, the relative risk was 0.73. Major cardiovascular events were reduced (relative
risk, 0.68). For deaths from all causes, the relative risk was 0.87.

36. In persons aged 60 years and over with isolated systolic
hypertension, antihypertensive stepped-care drug treatment
with low-dose chlorthalidone as 1 medication reduced the
incidence of total stroke 36%, with 5-year absolute benefit of 30
events per 1000 participants
Major cardiovascular events were reduced, with 5-year absolute
benefit of 55 events per 1000