hyvet slide set

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)

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

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


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)


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


Total mortality(21% reduction)

Placebo

P=0.02Natrilix SR Based Regimen

Nu

mb

er

of

even

ts p

er

10

0 p

ati

en

t s

Follow-up (years)


This result is at odds with findings from previous trials

All stroke(30% reduction)

Placebo

P=0.06Natrilix SR

Based Regimen

Nu

mb

er

of

even

ts p

er

10

0 p

ati

en

t s

Follow-up (years)


Fatal stroke(39% reduction)

P=0.046

Placebo

Natrilix SR

Based Regimen

Nu

mb

er

of

even

ts p

er

10

0 p

ati

en

t s

Follow-up (years)


Heart failure(64% reduction)

Placebo

P<0.001

Natrilix SR

Based Regimen

Nu

mb

er

of

even

ts p

er

10

0 p

ati

en

t s

Follow-up (years)


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


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


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 group)

Natrilix SR has a good acceptability profile, even in a very elderly population


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


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.

Sustained antihypertensive efficacy

When compared with the major antihypertensives, Natrilix SR provides the tightest SBP control

Baguet JP, Robitail S, Boyer L et al. Am J Cardiovasc Drugs. 2005;5:131-140.

End-organ protection

• Cardiac protection

Natrilix SR is significantly more effective than enalapril in reducing left ventricular hypertrophy

Gosse P, Sheridan DJ, Zannad F, et al, J Hypertens. 2000;18:1465-1475

End organ protection

• Kidney protectionNatrilix SR reduces microalbuminuria in elderly type 2 diabetics

Garcia Puig J, Marre M, Kokot F Am J Hypertens. 2007;20:90-97

Why is HYVET so important?

No matter how old you are – who wants to suffer a stroke?

HYVET results are unequivocal.

Natrilix SR Based Regimen cuts:

•The risk of stroke by 30%

•The risk of heart failure by 64%

hyvet slide set

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