Diapositiva 1

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Workshop Drug innovation
Erice, May 24th - 27th, 2007
THERAPEUTIC INNOVATION The Clinical
View Giulio Masotti Department of Gerontology
and Geriatrics Università degli Studi di Firenze
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Workshop Drug innovation
Erice, May 24th - 27th, 2007

• Topics of the presentation
• Hypertension
• Congestive heart failure
• in older patients

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Population over 65 in Italy, 2006
Italy
North
South
Center
From Gesano, Golini, 2006, ISTAT
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Italian population increase between 1950-2030
700
Age (years)
600
gt
80
60-79
500
20-59
0-19
400
Population
300
200
100
Data from ISTAT for the years 1951-1988, and CNR
projection for 1998-2028.
0
1950
1970
2010
1990
2030
Year
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Workshop Drug innovation
Erice, May 24th - 27th, 2007

• Topics of the presentation
• Hypertension
• Congestive heart failure
• in older patients

6
Blood pressure and age in Europe and North
America Population based study conducted in the
'90thies
Systolic Blood Pressure
Diastolic Blood Pressure
160
110
150
100
140
90
mmHg
mmHg
130
80
120
70
110
60
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
Years
Years
Wolf-Mayer K et al., JAMA 2003 2892363-2369
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Prevalence of hypertension in the
elderlyItalian Epidemiological Study

• UD U D
• ILSA (n5632) 59 67
• CASTEL (n3282) 86 83 88
• ICARe (n692) 72 67 76
• InCHIANTI (n1033) 83 83 84

Int J Epidemiol 1997 26995 Casiglia E et al., J
Hum Hypertens 2002 1621 Di Bari M et al., J
Hypert 1999 171633
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Relative risk of stroke adjusted by age, sex and
risk factors in 6545 subjects
5
He J et al., Am Heart J, 1999
4
Women
Men
3
RR
2
1
0
NT
IDH
SDH
ISH
NT
IDH
SDH
ISH
9
E. Mannucci, L. Lambertucci, M. Monami, A.
Fedeli, V. Chiasserini, N. Marchionni, G.
Masotti, A. Ungar
OFFICE PULSE PRESSURE
AMBULATORY 24-H PULSE PRESSURE
Cumulative survival
Cumulative survival
Follow-up (days)
Follow-up (days)
I to IV represent blood pressure quartiles
DIABETES/METABOLISM RESEARCH AND REVIEWS, 2005
21 467
10
Mortality and Diastolic Blood Pressure in
Isolated Systolic Hypertension
Baseline Diastolic Blood Pressure (mmHg)
36
68
79
83
88
32
92
Trials considerati
28
SHEP
2 year-Mortality/100 patients
Syst-Eur
24
Syst-China
EWPHE
HEP
20
STOP
MRC1
16
MRC2
160
170
180
190
200
210
220
Baseline Systolic Blood Pressure (mmHg)
Staessen JA et al., The Lancet, 2000
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Syst-Eur Trial, Lancet 1997
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Mechanism(s) of Selective Systolic Blood Pressure
(SBP) Reduction After Low-Dose Combination of
Perindopril/Indapamide in Hypertensive Subjects
Comparison With Atenolol
SBP
DBP
p0.01
London GM, Hypertension 2004
13
Hypertension in the elderly objective of future
research To develop new drugs and/or
strategies, or to re-evaluate existing ones, for
selectively decreasing SBP
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Workshop Drug innovation
Erice, May 24th - 27th, 2007

• Topics of the presentation
• Hypertension
• Congestive heart failure
• in older patients

15
Incidence of HF, by gender and age.The Rotterdam
Study
Men
n7983 age 55 years
Mean 17.6 / 1000 p-y
(per 1,000 p-y)
Women
Mean 12.5 / 1000 p-y
(per 1,000 p-y)
Bleumink GS et al., Eur Heart J 2004 25 1614
16
Heart failure, an emerging problem for most
healthcare systems
NHLBI. Morbidity and Mortality 2000 Chartbook on
Cardiovascular, Lung, and Blood Diseases. Geneva
World Health Organization 1996.
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Workshop Drug innovation
Erice, May 24th - 27th, 2007
Beta-blockers and older patients.
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Deedwania PC et al, Eur Heart J 2004 25
13001309
In patients 65 years old total mortality was
reduced by 37, sudden death by 43 and death
from worsening heart failure by 61.
Hospitalizations for worsening heart failure was
reduced by 36. Elderly patients with severe
heart failure (NYHA class III/IV with ejection
fraction lt0.25) and patients above 75 years
showed similar risk reductions.
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Death for worsening heart failure
Deedwania PC et al, Eur Heart J 2004 25
13001309
20
Prescriptions of beta-blockers from 1995 to 1998
in 3327 outpatients in the Italian Network on
Congestive Heart Failure Registry, by age
Pulignano G, Am Heart J 200214345-55
21
Sympathetic nerve terminal
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a2ARs in the cardiovascular system
The a2 pre-synaptic adrenergic receptors are
responsible for a negative feed back regulation
of catecholamine release in SNC, sympathetic
nerve terminals, and adrenal medulla which
provides the most of circulating catecholamines
(Hein et al., 1999 Nature 402181-184 Brede et
al., Mol. Endocrinol. 2003171640-1646).
In heart failure, lack of functional a2C
receptors due to genetic polymorphisms (deletions
or mutations), is associated with poor prognosis
(Small et al., 2002 N. Engl. J. Med.
3471135-1142).
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Circulating plasma catecholamine levels and
adrenal GRK2 over-expression in rats 10 weeks
after myocardial infarction (HF) and in
age-matched sham-operated controls (sham)
Lymperopoulos A. et al Nat. Med. 2007
25
Normalization of circulating plasma catecholamine
levels in HF rats 7 days post-in vivo adrenal
bARKct (GRK2 inhibitor) delivery
Lymperopoulos A. et al Nat.Med. 2007
26
Echocardiography in HF rats pre- and 7 days
post-in vivo adrenal gene delivery

40
35
30
25
Total cardiac bAR density (fmol/mg of membrane
protein)
20
15
10
5
0
AdGFP
AdbARKct
Lymperopoulos A. et al Nat.Med. 2007
27
Lymphocyte GRK2 Negatively Associated with
Cardiac Function
Iaccarino G et al. Eur Heart J. 2006
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Exercise and metoprolol down-regulate GRK2 in
aged hearts
6000

5000

4000
LV dP/dt Delta mmHg/s
3000

2000


1000

0
Baseline
0.1
0.5
1.0
Isoproterenol (µg/Kg/min)
Leosco D et al. Am J Physiol. 2007
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Workshop Drug innovation
Erice, May 24th - 27th, 2007

• Heart failure
• A new action for beta-blockers
• A new therapeutic pathway

30
Workshop Drug innovation
Erice, May 24th - 27th, 2007
Thank you for your attention
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Survival Mortality
Survival
HR (95 CI)
ACEI-ARBbB
1.0
p0.006
ACEI-ARB
2.9 (1.3-6.1)
Diuretics
4.9 (2.3-10.5)
plt0.001
Other
4.7 (2.2-10.5)
p0.858
Adjusted for age, gendere, history of diabetes,
hypertension and hospitalization for
cardiovascular events and chronic renal failure
Follow-up (days)
Di Bari M et al., J Am Coll Cardiol 2004 5 180
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Survival by use of b-blockers (adjusted for age,
sex, Charlson comorbidity score, HTA, CHD, other
CHF drugs, b-blockers propensity score, follow-up
time)
HR 0.72 (0.65-0.80)
Sin McAlister Am. J. Med. 2002
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Age and Use of Beta Blockers and ACE-inhibitors
a European Society of Cardiology
population-based study
0
-10
-20
Differences 75 vs. lt74 years ()
OR 0.77 (0.64-0.87)
-30
- 40
- 50
- 60
OR 0.40 (0.33-0.47)
- 70
b-blockers
ACE- inhibitors
Cleland JGF et al., Lancet 2002 360 1631