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First clear evidence
for the treatment of hypertensive patients aged 80
or over with Natrilix SR
Agenda
Importance of hypertension in the very elderly
HYVET design
Baseline characteristics of HYVET population
HYVET results
Clinical implications
World Population Ageing 1950-2050, Population Div., DESA, United Nations
Global increase in population aged 80 and
over
World population aged 80 or over 1950-2050 (millions)
0
50
100
150
200
250
300
350
400
1950 1975 2000 2025 2050
13.8
69.2
153.4
379.0
31.4
Blood pressure change with age
60
70
80
90
100
110
120
130
140
150
160
16-24 25-34 35-44 45-54 55-64 65-74 75+
Age group (years)
BP
(m
m H
g)
WomenMen
Diastolic blood pressure (DBP)
Systolic blood pressure (SBP)
Framingham Heart StudyKannel WB. Am Heart J 1999;138:205-210.
BP specificity in the elderly•High SBP
•High pulse pressure
Lethal strokes in USA by age
0
200
400
600
800
1000
1200
1400
1600
1800
35-44 45-54 55-64 65-74 75-84 85+
Number of events x 100
Rate/100,000
Agegroups
Source: www.cdc.gov
Aging is a major risk factor for stroke
Stroke in USA•Leading cause of disability•Third leading cause of death•275 000 deaths in 2002•72% occurred at age 65 or over
The heart failure epidemic
Thom T et al. Circulation. 2006;113:e85–e151.
Hospital discharges for heart failure
Dis
ch
arg
es in
th
ou
san
ds 600
500
400
300
200
100
0
1979 1983 1987 1991 1995 1999 2003
Year
Males
Females
+ 174%
CV risk increaseswith SBP and age
• Age and SBP are two major components of CV risk
• SBP predicts CV risk
• Antihypertensive therapy reduces CV risk and mortality in patients under 80
• Very few studies have included patients over 80
Prospective studies collaboration. Lancet. 2002;360:1903-1913.
Evidence for BP-lowering treatment in the over-
80s
EWPHE STOP-H SHEP Syst-EurNo benefit No benefit
in nonfatal
stroke events
Fatal events no effect
in nonfatal stroke events
Fatal events no effect
• No clear evidence of treatment benefits
Syst-Eur results by age
Age (years
)
n Hazard ratioTotal
mortality
Hazard ratioStrokes
60-69 2501 0.59* 0.46*
70-79 1753 0.58 0.54*
≥ 80 441 1.11 0.67
All 4695 0.86 0.58*
Staessen et al. Arch Int Med 1998;158:1681-1691
• Benefits observed in the young elderly fade in the very elderly
* Statistically significant
0.2 0.4
0.6 0.8 1.0 1.2 1.4 1.6 1.8
2.0
Treatment better
Stroke events
(-36%, P=0.01)
Total mortality
(+14%, P=0.05)
Major cardiovascular
events (-23 %, P=0.01)
Heart failure
(-42 %, P=0.01)
Double-blind trials
Gueyffier F, et al. Lancet. 1999:353:793-796.
Control better
Treatment reduces CV events but not overall mortality
INDANA meta-analysis
0
Uncertainty regarding the benefits of blood pressure
lowering in the very elderly
• Predominance of isolated systolic hypertension (ISH)– High systolic BP– Low diastolic BP
• Diastolic BP is important for cardiac perfusion
• Would lowering BP further lower the diastolic BP and compromise cardiac perfusion, resulting in ischemia and risk of arrhythmias and sudden death?
What do guidelines say?
Guidelines
Statement
JNC7 2003 No mention of over-80s, treated as other patients
BHS 2004 “For those aged over 80 at the time of diagnosis of hypertension, no clear guidance can be given”
NICE 2007 “offer patients over 80 years of age the same treatment as other patients over 55, taking account of any comorbidity and their existing burden of drug use, but patients over 80 years of age are poorly represented in clinical trials and the effectiveness of treatment in this group is less certain”
ESH/ESC 2007
“In subjects aged 80 years or over, evidence for antihypertensive treatment is as yet inconclusive”
HYVET results eagerly awaited
The results of the HYVET trial “should eventually provide reliable evidence about the effect of BP–lowering therapy in this very high-risk population”
WHO/ISH guidelines 1999
This dilemma provided the rationale for the
HYpertension in the Very Elderly Trial
To treat or not to treat?
That is the question
Increase inmortality
Reduction in strokes
HYVET, an international trial
The trial:International, multicenter, randomized, double-blind, placebo-controlled
Inclusion criteria: Exclusion criteria:Aged 80 or more, Standing SBP <140 mm HgSystolic BP 160-199 mm Hg Stroke in last 6 months+ diastolic BP <110 mm Hg, DementiaInformed consent Need for daily nursing care
Primary end point: All strokes (fatal and nonfatal)
Ancillary projects
Cognitive function and assessment for incident dementia:MMSE completed at baseline and annually thereafter
Quality of life: Self-assessment questionnaire: SF36, Geriatric Depression Scale, 25 symptoms, Clock Drawing Test
ABPM and arterial complianceArterial compliance is measuredusing the Q wave (ECG) toKorotkoff diastole sound interval
FracturesIndapamide reduces urinary calcium and may increase bone mineral density
HYVET timelines
1999 Main protocol finalized
2001 First patient randomized
2005 First interim analysis
2007 (July) Second interim analysisRecommended early termination due to reduction
in all strokes and total mortality2007 (Oct) Final visits completed
2008 (31 Mar) Results announced
Patients have been offered one-year, open, follow-up with Natrilix SR +/- Coversyl
Design
Reasons for the choice of Natrilix SR
Natrilix SR, a simple, effective, and well tolerated treatment strategy that:
• Provides superior reduction in SBP• Protects target organs from hypertension
– Heart: reversal of LVH, protection against heart failure– Kidney: reduction in microalbuminuria– Brain: protection against stroke
• Preserves metabolic profiles
Bulpitt C, et al. Drugs Aging. 2001;18:151-64.Gosse P, et al. J Hypertens. 2000;18:1465-475.Garcia Puig J, Marre M, Kokot F. Am J Hypertens. 2007;20:90-97. Marre M, et al. J Hypertens. 2004.22:1613-1622.
4761 enteredplacebo run-in
Placebo1912
Natrilix SR1933
916 not randomized
• 3845 randomized; Western Europe (86) Eastern Europe (2144), China (1526), Australasia (19), Tunisia (70)
• Mean follow-up : 1.8 years• At end of trial: 1882 still in double-blind, 17 vital status not
known, 220 in open follow-up
Recruitment and follow-up
Beckett N, et al. NEJM 2008;358:1887-1898.
Placebo
(n= 1912)
Natrilix SR+/- Coversyl(n= 1933)
Age (years) 83.5 83.6
Female 60.3% 60.7%
Blood pressure:
Sitting SBP (mm Hg) 173.0 173.0
Sitting DBP (mm Hg) 90.8 90.8
Orthostatic hypotension‡ 8.8% 7.9%
Isolated systolic hypertension
32.6% 32.3%
Patient characteristics
‡ Fall in SBP ≥ 20 mm Hg and/or fall in DBP ≥ 10 mm Hg Beckett N, et al. NEJM 2008;358:1887-1898.
Patient characteristics(cardiovascular history)
Placebo
(%)
Natrilix SR+/- Coversyl
(%)
Known hypertension 89.9 89.9
Antihypertensive treatment
65.1 64.2
Cardiovascular disease 12.0 11.5
Stroke 6.9 6.7
Myocardial infarction 3.2 3.1
Heart failure 2.9 2.9
Beckett N, et al. NEJM 2008;358:1887-1898.
Placebo Natrilix SR+/- Coversyl
Current smoker 6.6% 6.4%
Diabetes
(known DM/DM treatment/glucose>11.1 mmo/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
Patient characteristics(cardiovascular risk factors)
Beckett N, et al. NEJM 2008;358:1887-1898.
Results: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
Natrilix SR +/- Coversyl
SBP
DBP
-14.5 mm Hg-29.5 mm Hg
BP reduction at 2 years
average follow-up
-6.8 mm Hg-12.9 mm Hg
Patients at BP target after 2 years •48.0% with Natrilix SR +/- Coversyl•19.9% with placebo (P<0.001)
Natrilix SR/placebo
15/6 mm Hg
SBP reduction over 25 mm Hg is easily achieved with Natrilix SR
Beckett N, et al. NEJM 2008;358:1887-1898.
Total mortality(21% reduction)
Placebo
P=0.02Natrilix SR
+/- Coversyl
Nu
mb
er
of
even
ts p
er
10
0 p
ati
en
t s
Follow-up (years)
Beckett N, et al. NEJM 2008;358:1887-1898.
This result is at odds with findings from previous trials
All stroke(30% reduction)
Placebo
P=0.06Natrilix SR
+/- Coversyl
Nu
mb
er
of
even
ts p
er
10
0 p
ati
en
t s
Follow-up (years)
Beckett N, et al. NEJM 2008;358:1887-1898.
Fatal stroke(39% reduction)
P=0.046
Placebo
Natrilix SR
+/- Coversyl
Nu
mb
er
of
even
ts p
er
10
0 p
ati
en
t s
Follow-up (years)
Beckett N, et al. NEJM 2008;358:1887-1898.
Heart failure(64% reduction)
Placebo
P<0.001
Natrilix SR
+/- Coversyl
Nu
mb
er
of
even
ts p
er
10
0 p
ati
en
t s
Follow-up (years)
Beckett N, et al. NEJM 2008;358:1887-1898.
1 20.50.20.1
RRR 95% CI
-30% (0.49, 1.01)
-39% (0.38, 0.99)
-21% (0.65, 0.95)
-19% (0.62, 1.06)
-23% (0.60, 1.01)
-29% (0.42, 1.19)
-64% (0.22, 0.58)
-34% (0.53, 0.82)
All strokes
Stroke death
All-cause mortality
NonCV/Unknown
death
CV death
Cardiac death
Heart failure
CV events
ITT – Summary
Beckett N, et al. NEJM 2008;358:1887-1898.
Per protocol
RRR 95% CI P
All strokes -34% 0.46 - 0.95 0.03
Total mortality -28% 0.59 - 0.88 0.001
Fatal strokes -45% 0.33 - 0.93 0.02
Cardiovascular mortality
-27% 0.55 - 0.97 0.03
Heart failure -72% 0.17 - 0.48 <0.001
Results are linked to Natrilix SR’s protection of the heart and brain
Beckett N, et al. NEJM 2008;358:1887-1898.
Acceptability
Reported serious adverse events (after randomization)
• 448 in the placebo group versus 358 in the active group (P=0.001)
• Only 5 categorized as possible severe adverse drug reactions (3 in placebo group, 2 in Natrilix SR +/- Coversyl group)
Natrilix SR +/- Coversyl has a good acceptability profile, even in a very elderly population
Beckett N, et al. NEJM 2008;358:1887-1898.
Biochemical changes (2-year cohort)
No significant differences between the groups with regard to changes in serum…
• Potassium• Uric acid• Glucose• Creatinine
At 2 years, 73.4% of patients were receiving the combination treatment in the active group (85.2% placebo)
Natrilix SR stands out in the diuretic class in terms of metabolic neutrality
Beckett N, et al. NEJM 2008;358:1887-1898.
Why is HYVET so important?
No matter how old you are – who wants to suffer a stroke?
HYVET results are unequivocal.
Natrilix SR +/- Coversyl cuts:
•The risk of stroke by 30%
•The risk of heart failure by 64%
Clinical implications
In HYVET, a Natrilix SR +/- Coversyl strategy reduced mortality, stroke, and heart failure in patients over 80– Benefits apparent within the first year– 2-year treatment in 40 patients prevents 1 death– 2-year treatment in 94 patients prevents 1 stroke
A simple, effective, and well-tolerated treatment strategy that:– Adds extra years of life to millions of individuals
– Reduces stroke and cardiovascular disease
– Can be easily reproduced in practice
HYVET will clarify and change hypertension guidelines
Beckett N, et al. NEJM 2008;358:1887-1898.
Conclusion
We can now further improve the clinical outcomes of the very elderly – with a simple intervention: Natrilix SR, one tablet daily
“HYVET is a landmark clinical trial and
today’s results will change the practice
of medicine across the world”
Prof B. Williams, UK
www.hyvet.com
Presentation of results
Presentations in major US, European, and international conferences in 2008– ACC, Chicago– Europrevent, Paris– ESH/ISH, Berlin– ESC, Vienna
Publications– main trial results: New England Journal of
Medicine– cognitive function results– ancillary studies results