Transcript Slide 1

eprosartan mesylate
eprosartan and hydrochlorothiazide
Eprosartan in the
treatment of essential
hypertension, with
special emphasis on
systolic blood pressure
and the secondary
prevention of stroke
© 2005 Solvay Pharmaceuticals GmbH
® registered trademark
Date of preparation: May 2005
Please see
Summary of Product Characteristics
before prescribing eprosartan
Other tradenames include Tevetens®, Tevetenz®,
Teveten® HCT, Teveten® Comp, and Tevetens® Plus
References cited in this slide set are numbered to correspond with
those in the companion eprosartan e-monograph
Hypertension - is it well controlled?
“a large body of evidence suggests that, in
overall terms, blood pressure is not well
controlled, and in particular, that elevated
systolic blood pressure is poorly controlled”13
“surveys continue to show substantial
underdiagnosis, undertreatment and poor
rates of blood pressure control”2
2. Williams B, et al. J Hum Hypertens 2004;18:139-185., 13. Swales JD. J Hypertens 1999;17(suppl2):S15-S19
Why should hypertension be treated?
• ischaemia
• myocardial infarction
• cardiac hypertrophy
• congestive heart failure
• stroke
• TIA (transient ischaemic attack)
• PRIND (prolonged, reversible,
ischaemic, neurological deficit)
HYPERTENSION
• nephrosclerosis
• atrophy of nephrons
• renal failure
• retinopathy
• lesions
• swelling of optic disc
• blindness
A major risk factor for CVD
“The relationship between BP and risk of
cardiovascular disease (CVD) events is
continuous, consistent, and independent of
other risk factors”14
“elevated systolic blood pressure is a
particularly strong predictor for risk of
stroke”13
14. Chobanian AV, et al. JAMA 2003;289:2560-2572., 13. Swales JD. J Hypertens 1999;17(suppl2):S15-S19
Mortality and morbidity
• 12-14% of deaths from coronary heart disease
are due to high blood pressure … 6% of these
deaths could be avoided if the incidence of
hypertension was reduced by 50%1
• Approximately 20% of people die within the first
few months after a stroke
• Up to 35% of stroke victims will be dependent
at 1 year2
1. Petersen S, Rayner M. Coronary heart disease statistics 2002 edition. British Heart Foundation Statistics
Database Annual Compendium., 2. Williams B, et al. J Hum Hypertens 2004;18:139-185
Classification of hypertension2,15
Grade 1 (mild)
140-159 mmHg systolic
90-99 mmHg diastolic
Grade 2 (moderate)
160-179 mmHg systolic
100-109 mmHg diastolic
Grade 3 (severe)
>180 mmHg systolic
>110 mmHg diastolic
The JNC-7 Report14 combines Grades 2 and 3
2. Williams B, et al. J Hum Hypertens 2004;18:139-185., 14. Chobanian AV, et al. JAMA 2003;289:2560-2572.,
15. ESH Guidelines Committee. J Hypertens 2003;21(6):1011-1053
Isolated systolic hypertension (ISH)2,15
• ISH means raised systolic BP with
normal or low diastolic BP
• Most older hypertensive patients
have isolated systolic (or systolic
predominant) hypertension
Grade 1 ISH = 140-159/<90 mmHg
Grade 2 ISH = >160/<90 mmHg
2. Williams B, et al. J Hum Hypertens 2004;18:139-185., 15. ESH. J Hypertens 2003;21(6):1011-1053
Importance of SYSTOLIC hypertension
• Systolic blood pressure (SBP) is a powerful
predictor of all-cause mortality, coronary
artery disease, stroke and renal disease16
• SBP is regarded as the major factor to
control in patients over 50 years of age2,14
• Optimal therapy for these patients should be
to reduce SBP while minimising the
reduction of DBP18
2. Williams B, et al. J Hum Hypertens 2004;18:139-185., 14. Chobanian AV, et al. JAMA 2003;289:2560-2572.,
16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32., 18. Kannel W. Drugs Aging 2003;20:277-286
MRFIT study – importance of SBP4
MRFIT showed a strong correlation between risk of stroke and
increased blood pressure, especially SBP
4. Stamler J, et al. Arch Intern Med 1993;153:598-615 (This diagram shows SBP and DBP at baseline and adjusted
stroke mortality for men. Relative Risk was adjusted to take into account several factors including age, race,
serum cholesterol, smoking and diabetic medication)
Benefits of reducing raised SBP
Syst-Eur20
• 4,695 elderly patients with ISH
• treatment with the Ca-blocker nitrendipine
gave a 42% risk reduction for total stroke
SHEP19
• 4,736 elderly patients with ISH
• antihypertensive treatment reduced stroke
by 36%, CAD by 27%, and CHF by 49%
19. SHEP Cooperative Research Group. JAMA 1991;264:3255-3264., 20. Staessen JA, et al. Lancet 1997;350:757-764
Syst-Eur (elderly patients with ISH)20
Fatal or
non-fatal
stroke
(events
per 100
patients)
6
placebo
* p=0.003
5
4
3
*
active
treatment
2
1
0
0
1
2
3
Time since randomisation (years)
20. Staessen JA, et al. Lancet 1997;350:757-764
4
Arterial compliance and raised SBP
• A major factor contributing to raised SBP is
decreased arterial compliance, associated with
altered aortic wave travel and reflection16,21
• Reduced arterial compliance is generally caused
by arterial stiffening
• This is usually a consequence of aging or
atherosclerosis, which may be why hypertension
in older people is predominantly systolic
16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32., 21. London GM, Guerin A. J Hypertens
1999;17(Suppl 2):S3-S6
RAS and SNS both control of SBP16
RAS = renin-angiotensin system; SNS = sympathetic nervous system;
HTN = hypertension; CHF = congestive heart failure; ESRD = end-stage renal
disease; CAD = coronary artery disease; LVH = left ventricular hypertrophy
16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32
The neuro-effector junction16
Angiotensin II … postsynaptic and presynaptic effects
sympathetic
neurone
presynaptic
AT1 receptor
(+)
angiotensin II
postsynaptic
AT1 receptor
norepinephrine
postsynaptic
alpha-1 receptor
16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32
blood vessel
Renin-angiotensin system (RAS)
Primary intervention studies
• Early trials found that treatment with diuretics
or Ca-blockers reduced blood pressure and
decreased morbidity and mortality19,20
• It became a common conclusion that any drug
which reduced blood pressure would reduce
the risk of cardiovascular disease25
• However, it has since been found that this is
not the case for beta-blockers26-29 or the ACE
inhibitor perindopril30
19. SHEP Cooperative Research Group. JAMA 1991;264:3255-3264., 20. Staessen JA, et al. Lancet 1997;360:757764., 25. Messerli F. XXVI ESC, Munich, 2004., 26. MRC Working Party. BMJ 1985;291:97-104., 27. MRC Working
Party. BMJ 1992;304:405-413., 28. The Dutch TIA trial study group. Stroke 1993;24:543-548., 29. Eriksson S, et al.
Cerebrovasc Dis 1995;5:21-25., 30. PROGRESS Collaborative Group. Lancet 2001;358:1033-1041
AIIA intervention studies -1
LIFE31
Stroke rate was 5% with losartan and 7% with
atenolol (RRR=25%)
SCOPE32
Candesartan significantly reduced the risk of
non-fatal stroke in elderly patients by 27.8%
31. Dahlöf B, et al. Lancet 2002;359:995-1003., 32. Lithell H, et al. J Hypertens 2003;21:875-886
AIIA intervention studies -2
VALUE33
No significant differences between valsartan
and amlodipine in CVD; valsartan significantly
reduced the number of new cases of diabetes
CHARM34
Candesartan significantly reduced all-causes
mortality and the number of patients
developing new diabetes
33. Julius S, et al. Lancet 2004;363:2022-2031., 34. Kulbertus H. Rev Med Liege 2003;58(10):646-652
AIIA intervention studies -3
PRIME35
Irbesartan reduced the risk of progressing to
more advanced stages of kidney disease in
hypertensive patients with type-2 diabetes and
kidney disease
It also significantly reduced the number of
hospitalisations due to congestive heart failure
35. Program for irbesartan mortality and morbidity evaluations (PRIME). Data on file.
eprosartan mesylate
eprosartan and hydrochlorothiazide
Eprosartan - unique dual action10,11,16
blockade of
postsynaptic AT1
receptor inhibits action
of angiotensin II
blockade of presynaptic
AT1 receptor inhibits
norepinephrine release
into the synapse
10. Ohlstein EH, et al. Pharmacology 1997;55(5):244-251., 11. Balt JC, et al. J Hypertens 2001;19(3):465-473.,
16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32
Affinity for AT1 receptors
• Inhibition of AT1 receptors by eprosartan is
dose-dependent and ‘surmountable’ 37
• Eprosartan can be displaced if angiotensin II
output increases, eg. in response to a fall in
blood volume
• Most other AIIAs bind non-competitively to AT1
receptors and are not readily displaced by
increased angiotensin II output38
37. Edwards RM, et al. J Pharmacol Exp Ther 1992;260:175-181., 38. Hollenberg NK. Pharmacotherapy
1999;19(4 Pt 2):71S-72S
Dose-related inhibition of AT1 in man39
Percentage inhibition of the effects of angiotensin II by
various doses of eprosartan in healthy volunteers
Inhibition of
angiotensin II
(%)
100 86%
80 60 -
71%
56%
40 20 070mg
100mg
eprosartan dosage
39. Ilson B. Am J Hypertens 1998;11(4 Pt 2):108A (Abstract E051)
200mg
Sympatho-inhibitory effects10
Acute effects on the pressor response to spinal cord
stimulation in pithed rats of eprosartan, losartan, valsartan
irbesartan (0.3mg/kg iv; n=4 for each AIIA)
Change in
DBP vs
controls
(%)
40 20 eprosartan
losartan
valsartan
irbesartan
0-
- 20 - 40 -
p<0.05
10. Ohlstein EH, et al. Pharmacology 1997;55(5):244-251
Sympathetic stimulation at 1Hz.
Drugs were given intravenously 10
min before stimulation (acute effect)
Sympathetic inhibition in man40
• Randomised, double-blind, crossover study
• 16 healthy male volunteers received a single
dose of eprosartan 600mg or placebo, followed
by insulin-induced hypoglycaemia
• The pulse pressure response to sympathoadrenal activation was significantly reduced by
eprosartan compared with placebo (p=0.02)
40. Christensen M, et al. Clin Sci 2005;108:113-119
Overview of efficacy
•
•
•
•
•
•
•
•
•
•
Effect on SBP and pulse pressure
Studies versus active comparators
Studies versus placebo
Efficacy in older patients
Efficacy in black patients
Long-term efficacy
Efficacy in combination with other drugs
Secondary prevention of stroke (MOSES)
Effect on blood platelets / fibrinolytic function
Renoprotective effects
Sega – more effective than enalapril5
• 118 patients with severe hypertension
• Randomised, parallel group study
• 8-week double-blind titration phase was
followed by a 2-week maintenance phase
- eprosartan 400mg/day (up to 600 or 800mg)
- enalapril 10mg/day (up to 20 or 40mg)
- HCTZ 25mg/day added at week 6
in patients not achieving target BP
5. Sega R, et al. Blood Pressure 1999;8:114-121
Sega – more effective than enalapril5
Mean reduction from baseline of sitSBP and sitDBP, following
treatment with eprosartan or enalapril in severe hypertension
sitting systolic BP
sitting diastolic BP
Reduction - 0 in blood
pressure
from - 10 baseline
(mmHg)
- 20 -
-16.2
-21.2
-20.1
N.S.
- 30 -
-29.1
p=0.025
eprosartan 400-800mg/day (n=43)
5. Sega R, et al. Blood Pressure 1999;8:114-121
enalapril 10-40mg/day (n=46)
Ruilope – effective control of SBP41
• 12-week, double-blind, randomised trial in 334
patients aged >65 years with predominantly
systolic hypertension
• Eprosartan (600-800mg/day) and enalapril
(5-20mg/day) reduced sitSBP to a similar extent
• At week 3 there were significantly more
responders with eprosartan than with enalapril
for SBP (30% versus 20%, p=0.033)
41. Ruilope L, et al. Blood Pressure 2001;10:223-229
Punzi – effective control of SBP42
Mean change from baseline in sitSBP in ISH patients >60yrs
of age: 9 weeks of monotherapy followed by 4 weeks in
combination with HCTZ
week 3
-0Mean
change in
-5sitSBP
from - 10 baseline - 15 (mmHg)
- 20 - 25 * p<0.0001 between treatments
42. Punzi HA, et al. J Human Hypertens 2004:1-7
week 6
week 9
week 13
placebo
*
**
eprosartan
** p<0.002 between treatments
Teitelbaum – effective control of SBP43
• Evaluated eprosartan (600mg/day alone or with
HCTZ) in 195 patients aged 60-84yrs with ISH or
combined systolic-diastolic hypertension
• SBP was significantly reduced at study
endpoint from baseline (p<0.0001)
• Reduction in DBP was significantly greater in
patients with combined systolic-diastolic
hypertension than in those with ISH (12.2
versus 5.0 mmHg, respectively, p<0.0001)
43. Teitelbaum I, et al. Can J Cardiol 2004;20(Suppl C):11C-16C
Teitelbaum – pulse pressure reduction43
Mean pulse pressure during eprosartan treatment in patients
with ISH or combined systolic-diastolic hypertension
Mean
pulse
pressure
(mmHg)
90 -
* p<0.0001 ISH versus non-ISH
ISH
non-ISH
** p<0.05 ISH versus non-ISH
p<0.0001 versus baseline
80 70 60 - *
50 -
**
40 baseline
week 2
week 4
follow-up (weeks)
43. Teitelbaum I, et al. Can J Cardiol 2004;20(Suppl C):11C-16C
week 6
week 10
de la Sierra – pulse pressure reduction46,47
• 3,133 hypertensive patients in primary care
• Eprosartan significantly reduced pulse pressure
at 12 weeks (mean -13.5 mmHg from baseline,
p<0.001)
• In 895 patients with ISH, mean SBP and pulse
pressure were reduced by 25.6 mmHg and
22.5 mmHg (both p<0.05 versus baseline)
• DBP decreased by 3.1 mmHg in ISH patients
(versus 16.7 mmHg for non-ISH patients)
46. de la Sierra A, et al. Can J Cardiol 2004;20(Suppl C):17C-22C., 47. de la Sierra A, et al. Blood Pressure
2004;13(Suppl 2):5-10
Robles – pulse pressure reduction48
Reduction in mean pulse pressure, arterial pressure, SBP
and DBP in a 16-week open-label study (n=566)
pulse
pressure
Reduction - 0 in blood
pressure
from - 10 baseline
(mmHg)
- 20 -
arterial
pressure
systolic
pressure
-13
- 30 -
diastolic
pressure
-13
-17.4
-26
all changes p<0.0001 versus pretreatment baseline
48. Robles NR, et al. Int J Clin Pract 2005;59(4):478-484
Elliott – study versus enalapril8
Responders to eprosartan (400-600mg/day) and enalapril
(5-20mg/day) at the end of 26 weeks of treatment in 528
patients with mild-to-moderate hypertension
% responders
p=0.018
100 80 -
81.7%
70.3%
73.4%
62.6%
60 40 20 0-
eprosartan
eprosartan
monotherapy
+ HCTZ
8. Elliott WJ, et al. J Hum Hypertens 1999;13:413-417
enalapril
monotherapy
enalapril
+ HCTZ
Oparil – study versus enalapril9
Reduction in sitDBP from baseline to endpoint after 6 weeks
of eprosartan (600mg/day), enalapril (20mg/day) or placebo
in 136 patients with mild-to-moderate essential hypertension
eprosartan
600mg/day
Reduction
in sitDBP
from
baseline
(mmHg)
placebo
enalapril
20mg/day
-0-2-4-
- 4.4
-6-8- 10 -
- 7.9
- 8.7
p<0.002
9. Oparil S. Curr Ther Res 1999;60(1):1-14
p<0.035
Puig – study versus losartan49
• Compared 4 weeks of treatment with eprosartan
(600mg/day) or losartan (50mg/day) in a
randomised, double-blind study in 60 outpatients
with mild-to-moderate hypertension
• Mean sitting BP was reduced by 12.4/12.7 mmHg
with eprosartan and by 9.6/10.9 mmHg with
losartan (N.S.)
• At study endpoint there were 73% eprosartan
responders and 53% losartan responders (N.S.)
49. Puig JC, et al. J Hypertens 1999;17:1033-1039
Hedner – study versus placebo50
Reduction in sitDBP from baseline to endpoint after 13 weeks
treatment with eprosartan 400-800mg bd or od compared with
placebo in 243 patients with mild-to-moderate hypertension
Reduction
in sitDBP
from
baseline
(mmHg)
0-
eprosartan
400-800mg
twice-daily
placebo
eprosartan
400-800mg
once-daily
-2-4-
-4
-6-8–
- 10 -
-9
-9
p<0.0001
50. Hedner T, et al. J Hypertens 1999;17(1):129-136
p<0.001
Hedner – study versus placebo50
Overall response rate after 13 weeks treatment with
eprosartan 400-800mg bd or od compared with placebo in
243 patients with mild-to-moderate hypertension
* p=0.05
Response
rate (%)
50 -
46.8%*
40 -
35.1%
30 20 10 0-
eprosartan
once-daily
50. Hedner T, et al. J Hypertens 1999;17(1):129-136
placebo
Gradman – study versus placebo51
Change in mean sitSBP and sitDBP from baseline after
8 weeks of treatment with eprosartan (600mg/day) or placebo
in 243 patients with mild-to-moderate hypertension
Change in
sitBP from
baseline
(mmHg)
2-
SYSTOLIC BP
DIASTOLIC BP
eprosartan placebo
0.8
eprosartan placebo
0-2-
- 1.9
-4-6-
- 6.0
-8- 10 -
- 7.5
p<0.0001
51. Gradman AH, et al. Clin Ther 1999;21:442-453
p<0.0001
Argenziano – study in older patients52
Percentage of elderly and younger responders after 26 weeks
of treatment with eprosartan (400-600mg/day) and enalapril
(5-20mg/day) in patients with mild-to-moderate hypertension
% responders
100 80.0%
87.3%
80 -
72.1%
77.4%
enalapril
< 65 yrs
enalapril
> 65 yrs
60 40 20 0eprosartan
< 65 yrs
eprosartan
> 65 yrs
52. Argenziano L, Trimarco B. Curr Med Res Opin 1999;15(1):9-14
Levine – study in black patients53
Response in black patients after 26 weeks of treatment with
eprosartan (400-600mg/day) or enalapril (5-20mg/day) with or
without HCTZ in patients with mild-to-moderate hypertension
% responders
p<0.018
p<0.05
100 80 60 -
66.7%
52%
40 -
42.1%
26%
20 0-
eprosartan eprosartan
monotherapy + HCTZ
53. Levine B. Curr Med Res Opin 1999;15:25-32
enalapril
enalapril
monotherapy + HCTZ
Levine – long-term study54
Mean sitSBP and sitDBP in a 24-month study in patients
with mild-to-moderate hypertension who received eprosartan
(400-800mg/day) with or without HCTZ (12.5-25mg/day)
mean sitDBP
mean sitSBP
Mean
BP
(mmHg)
160 -
145.9
139.5
136
136.7
120 94.9
80 -
86.9
88.7
86.4
40 0baseline
(n=591)
54. Levine B. Curr Med Res Opin 2001;17(1):8-17
titration
endpoint
(n=577)
12 months
(n=571)
24 months
(n=300)
Sachse – combination with HCTZ55
Mean change in sitDBP from baseline after 8 weeks treatment
with eprosartan 600mg/day with or without HCTZ 12.5mg/day
eprosartan
(n=156)
Mean
change in
sitDBP from
baseline
(mmHg)
eprosartan + HCTZ
(n=149)
0-2-4-6-8- 10 -
- 7.9
- 10.7
- 12 p=0.001
55. Sachse A, et al. J Hum Hypertens 2002;16: 169-176
Sachse – combination with HCTZ55
Percent responders after 8 weeks treatment with eprosartan
600mg/day with or without HCTZ 12.5mg/day
p=0.004
%
responders
100 80 -
73.2%
57.1%
60 40 20 0-
eprosartan
55. Sachse A, et al. J Hum Hypertens 2002;16: 169-176
eprosartan + HCTZ
Secondary stroke prevention (MOSES)6
• Eprosartan (n=710) versus nitrendipine (n=695)
(the calcium channel blocker shown to reduce
strokes in Syst-Eur)
• The study included hypertensive patients with
proven ischaemia, TIA/PRIND or intracerebral
haemorrhage during the previous 24 months
MOrbidy and mortality after Stroke - Eprosartan
compared with nitrendipine for Secondary
prevention
6. Schrader J, et al. Stroke 2005;36: (In Press). Additional information: ESC, Munich, 2004/data on file
Secondary stroke prevention (MOSES)
• Combined primary endpoint: total mortality plus
the total cardiovascular and cerebrovascular
events, including all recurrent events
• Secondary endpoints: The single components
of the combined primary endpoint, and an
assessment of functional status and cognitive
function
• Mean follow-up: 2.5 years
• Mean dosages: 623mg eprosartan
16mg nitrendipine
MOSES - blood pressure changes
Effect of eprosartan and nitrendipine on blood pressure in
hypertensive patients with previous stroke/TIA/PRIND
eprosartan
nitrendipine
Blood 160 pressure
(mmHg) 140 120 -
SBP
100 DBP
80 60 0
3
weeks
6
3
6
12
18
24
36
48
months
76% of patients on eprosartan had their BP normalised.
This was higher than in LIFE (46%) or VALUE (64%)
MOSES - primary endpoint
Reduction in total mortality, cardiovascular and cerebrovascular
events during treatment with eprosartan or nitrendipine in
hypertensive patients with previous stroke/TIA/PRIND
Number
of
events
300 -
21% risk reduction
with eprosartan
(p=0.014)
nitrendipine
250 200 eprosartan
150 100 50 00
250
500
750
1000
days
1250
1500
1750
MOSES - stroke recurrence
Reduction in stroke recurrence during treatment with
eprosartan or nitrendipine in hypertensive patients with
previous stroke/TIA/PRIND
Number
of
events
150 -
25% risk reduction
with eprosartan
(p=0.02)
nitrendipine
100 eprosartan
50 00
250
500
750
1000
days
1250
1500
1750
MOSES - other efficacy data
• Eprosartan showed a trend towards a reduced
risk of fatal/non-fatal cardiac events (p=0.06)
• There was a statistically significant difference
in favour of eprosartan for first occurrence of
cardiovascular events (p=0.03)
• No difference between groups in overall mortality
• No difference between groups in functional status
and cognitive function
MOSES - conclusion
• Both agents produced similar reductions in
blood pressure
• Therefore the reduced incidence of
cerebrovascular and cardiovascular events in
patients receiving eprosartan indicates that it
offers additional protection above that offered
by blood pressure reductions
Effect on platelets/fibrinolysis
• Hypertension is often associated with
undesirable changes in platelet function59
• Abnormalities of the coagulation/fibrinolytic
system may predispose to a procoagulant state,
which increases the risk of cardiovascular
disease60
• The renin-angiotensin system appears to play an
important role in regulating fibrinolytic balance
and haemostatic function60
59. Labios M, et al. Am J Hypertens 2004;17(9):757-763., 60. Makris TK, et al. Drugs Exptl Clin Res
2004;30(3):125-132
Makris - effect on platelets/fibrinolysis60
Percentage change in haemodynamic and haemostatic factors
after six months of eprosartan 600mg/day or losartan 100mg/day
compared with baseline in 86 hypertensive patients. Differences
between the drugs were statistically significant.
%
difference
from
baseline
20 10.3
0-
6.3
PAI-1
TM
tPA
- 20 -
-17.6
-5.5
-2.3
-9.5
-16.9
-31.0
- 40 PAI-: plasminogen activator inhibitor-1 TM: thrombomodulin
tPA: tissue plasminogen activator inhibitor antigen
60. Makris TK, et al. Drugs Exptl Clin Res 2004;30(3):125-132
fibrinogen
eprosartan (n=45)
losartan (n=41)
Labios - effect on platelet function59
• Assessed platelet function in 30 patients with
mild-to-moderate hypertension before and after
8 weeks of treatment with eprosartan 600mg/day
• There was a significant reduction in platelet
microparticles after blood shear exposure
(p<0.01) and after exposure to calcium-ion
ionophore activation (p<0.05)
• Eprosartan reduced the trend for platelets to be
more readily activated in hypertensive patients
59. Labios M, et al. Am J Hypertens 2004;17(9):757-763
Neumann – renoprotective effects61
Mean muscle sympathetic nerve activity (MSNA) in nine
hypertensive patients with chronic renal failure given 6 weeks
of treatment with eprosartan alone or in combination with the
centrally-acting sympatholytic agent moxonidine
p<0.05
Mean
MSNA
(burst
per
min)
p<0.05
40 20 0baseline
eprosartan
61. Neumann J, et al. J Am Soc Nephrol 2004;15:2902-2907
eprosartan
+
moxonidine
healthy
controls
Frank – renoprotective effects63
• Double-blind, placebo-controlled study of
eprosartan (600mg/day for 7 days) in 10
normotensive and 14 borderline hypertensive
patients
• In patients receiving eprosartan, disturbing
cardiopulmonary baroreceptors by lower body
negative pressure did not alter GFR
• GFR was significantly decreased in patients
receiving placebo (p<0.05)
63. Frank H, et al. Kidney Int 2003;63:617-623
Treatment-emergent adverse events
• Cumulative exposure to eprosartan worldwide is
currently over 300 million patient days
• Well tolerated in controlled studies - most
adverse events were mild or transient,
irrespective of dose7
• Frequency of adverse events is not affected by
age, gender or race
• Incidence of impotence, oedema, flushing,
fatigue and dizziness is similar to placebo7
7. Gavras I, Gavras H. Pharmacotherapy 1999;19(4 Pt 2):102S-107S
Adverse events from SmPC
Nervous system
disorders
Rare:
headache, dizziness
Vascular disorders
Very
rare:
hypotension,
including postural
hypotension
Skin and subcutaneous
tissue disorders
Rare:
skin reactions (rash,
pruritis, urticaria)
Very
rare:
facial swelling,
angio-oedema
Rare:
asthenia
General disorders and
administration site
reactions
Adverse events in older patients66
Most common therapy-related adverse events (>5%) by age in
patients receiving eprosartan; data from 15 studies (n=2,334)
% patients with
adverse event
<65yrs (n=1653)
>65yrs (n=681)
20 -
15 10 50headache
URTI
myalgia pharyngitis
66. Harland D, et al. Am J Hypertens 1998; 11:78A (Abstract D039)
cough
rhinitis dizziness
Low incidence of “ACEi” cough8
Incidence of dry persistent cough (not due to URTI) during
12 weeks of treatment with eprosartan or enalapril. The low
incidence of cough has been confirmed in other studies,9
including in the elderly41,52 and in black patients53
% patients
10 -
p=0.018
85.4%
64-
2-
1.5%
0eprosartan
(n=259)
enalapril
(n=261)
8. Elliott WJ, et al. J Hum Hypertens 1999;13:413-417., 9. Oparil S. Curr Ther Res 1999;60(1):1-14., 41. Ruilope L,
et al. Blood Pressure 2001;10:223-229., 52. Argenziano L, Trimarco B. Curr Med Res Opin 1999;15(1):9-14.,
53. Levine B. Curr Med Res Opin 1999;15:25-32
No effect on uric acid excretion49
Change from baseline in the ratio of uric acid to creatinine
in the urine after 4 weeks of treatment with eprosartan
(600mg/day) or losartan (50mg/day) in 60 outpatients with
mild-to-moderate hypertension in a double-blind study
Change in
ratio from
baseline
0.2 0.11
0.1 - 0.04
0-
losartan
- 0.1 -
eprosartan
- 0.2 p<0.01
49. Puig JC, et al. J Hypertens 1999;17:1033-1039
Well tolerated when used with HCTZ70
• Meta-analysis of 17 studies (n=1,899 )
• Eprosartan/HCTZ combinations were well
tolerated in all grades of hypertension
• In the controlled studies, headache, dizziness,
myalgia and upper respiratory tract infections
were the most frequently reported adverse
events
• Dizziness may be attributable more to HCTZ
70. Böhm M, Sachse A. Drug Safety 2002;25(8):599-511
Chemically distinct from other AIIAs
Eprosartan is a non-biphenyl, non-tetrazole AIIA (all other
AIIAs are biphenyl tetrazoles)
eprosartan
losartan, candesartan,
irbesartan, valsartan,
telmisartan, olmesartan
Plasma profile72
Plasma concentration following administration of single
doses of eprosartan 100-800mg to healthy volunteers (n=23)
Plasma concentration
(ng/ml)
800mg
400mg
200mg
100mg
10,000 1,000 100 00
4
8
12
16
20
time after administration (hours)
72. Chapelsky MC, et al. J Clin Pharmacol 1998;38:34-39
24
Other pharmacokinetic data
• 98% protein bound, unaffected by age, gender,
hepatic dysfunction or mild-to-moderate renal
impairment
• Low volume of distribution (approximately 13L)
• Negligible metabolism - no active metabolites
• Does not affect hepatic P450 enzymes, thereby
avoiding many potential drug interactions
• Mostly (90%) excreted in the faeces
Low potential for drug interactions
• Does not inhibit cytochrome P450 enzymes
(CYP1A, CYP2A6, CYP2C9/8, CYP2C19,
CYP2D6, CYP2E and CYP3A) in vitro at
clinically relevant concentrations
• No effect on the pharmacokinetics of digoxin,
warfarin, glibenclamide, ranitidine, fluconazole
or ketoconazole
• Has been used concomitantly with thiazides,
calcium channel blockers and hypolipidaemic
agents (eg. statins) without evidence of
clinically significant adverse interactions
Special patient groups
• No differences in safety or efficacy have been
observed in the elderly - dose adjustment is not
usually required
• AUC and Cmax are 30-50% higher in moderatesevere renal impairment - the daily dose should
not exceed 600mg for these patients
• AUC (but not Cmax) is increased in hepatic
impairment, but no dose adjustment is required
In some countries, licensed dosage recommendations may
vary from the above – please consult national SmPC
Dosage and administration
• Recommended starting
and maintenance dose
is 600mg once-daily,
to be taken in the morning
• Maximum blood pressure
reduction normally takes 2-3 weeks
• Doses up to 1200mg/day for 8 weeks have been
shown in clinical trials to be effective with no
apparent dose relationship in the incidence of
adverse experiences reported
Eprosartan – benefits to patients (1)
• The systolic component of blood pressure
is a better predictor of cerebrovascular and
cardiovascular risk than the diastolic
component
• Most hypertensive people over 50 years of age
have predominantly systolic hypertension
• Eprosartan gives a statistically significantly
greater reduction of systolic blood pressure
than enalapril
Eprosartan – benefits to patients (2)
• Recurrent stroke is a major cause of death
and disability. MOSES showed that
eprosartan is significantly more effective than
a calcium channel blocker in reducing
secondary stroke in hypertensive patients
• Cough is a frequent problem with ACE
inhibitors. Eprosartan is associated with a
lower incidence of dry, persistent cough than
enalapril (comparable incidence to placebo)
Eprosartan – benefits to patients (3)
• Eprosartan is effective in Afro-Caribbeans, who
may be less responsive to some other treatments
such as ACE inhibitors
• Eprosartan gives effective 24-hour control of
hypertension from a single 600mg once-daily
starting and maintenance dose for most patients.
It can be combined with other antihypertensive
agents such as HCTZ if required
• For patients taking concomitant medications,
eprosartan will not interfere with their metabolism
by cytochrome P450 enzymes