Nhi teveten

1. Cardiovascular and
Cerebrovascular health
in the management of
hypertensive patients

2. Not all ARBs looks
after your patient
heart as well as
his mind

3. Cardiovascular Disease: A Worldwide Epidemic
World Health Organization Burden of Disease Estimates 2002.
0 5 10 15 20 25 30 35 40 45 50
CVDs
Infectious/parasitic diseases
Malignant neoplasms
Respiratory infections
Respiratory diseases
Unintentional injuries
Perinatal conditions
Digestive diseases
Intentional injuries
Neuropsychiatric conditions
Diabetes mellitus
Cause of death
Worldwide
Developed world
CVD is responsible for one third of all deaths worldwide and almost half of all
deaths in the developed world

4. Contribution of Risk Factors to Burden of
Disease Mortality*
*Based on The World Health Report 2003.*Based on The World Health Report 2003.
Yach et al.Yach et al. JAMAJAMA. 2004;291:2616-2622.. 2004;291:2616-2622.
0 5 10 15 20
Percentage of Mortality Attributable to Risk Factors
DevelopingDeveloping
countriescountries
DevelopedDeveloped
countriescountries
Blood pressureBlood pressure
TobaccoTobacco
UnderweightUnderweight
AlcoholAlcohol
CholesterolCholesterol
Unsafe sexUnsafe sex
OverweightOverweight
Unsafe water, sanitation,Unsafe water, sanitation,
hygienehygiene
Low fruit and vegetableLow fruit and vegetable
intakeintake
Indoor smoke from solid fuelsIndoor smoke from solid fuels
Physical inactivityPhysical inactivity

5. Hypertension: A Growing Problem
Prevalence (%)
United StatesUnited States77
EgyptEgypt99
JapanJapan88
ItalyItaly77
SwedenSweden77
EnglandEngland77
SpainSpain77
FinlandFinland77
GermanyGermany77
00 1010 2020 3030 4040 5050
TaiwanTaiwan99
CanadaCanada77
South KoreaSouth Korea99
*Defined as systolic/diastolic blood pressure*Defined as systolic/diastolic blood pressure ≥≥140/90, (140/90, (≥≥160/95 for Taiwan)160/95 for Taiwan) or receiving treatment.or receiving treatment.
††
South Korea is defined as men, aged 30 to 59.South Korea is defined as men, aged 30 to 59.
7. Wolf-Maier et al.7. Wolf-Maier et al. JAMAJAMA. 2003;289:2363-2369; 8. Data on file. Pfizer Inc, New York, NY;. 2003;289:2363-2369; 8. Data on file. Pfizer Inc, New York, NY;
9.9. WHO Collaborating Centre on Surveillance of Cardiovascular Disease Web site. Available at: www.cvdinfobase.ca. Accessed February 22, 2005.WHO Collaborating Centre on Surveillance of Cardiovascular Disease Web site. Available at: www.cvdinfobase.ca. Accessed February 22, 2005.

6. Lewington et al. Lancet 2002 ; 360 : 1903–13.
CARDIOVASCULAR MORTALITY DOUBLES FOR EVERY
INCREMENT IN SBP/DBP OF 20/10 mm Hg

7.  Meta-analysis of 61 prospective, observational studies
 1 million adults
 12.7 million person-years
BENEFITS OF BP DECREASE
Lewington S, et al. Lancet. 2002;360:1903-1913.

8. Effect of antihypertensive therapy on all
CV events: Comparison of more or less
intensive BP control
Relative risk (95% CIs)
1.0 1.25
More
intensive BP
control better
Less
intensive BP
control
better
0.5
Stroke
Coronary heart disease
Heart failure
Major CV events
CV death
Total mortality
BPLTTC Lancet 2003

9. Benefits of Lowering BP
Average Percent ReductionAverage Percent Reduction
Stroke incidenceStroke incidence 35–40%35–40%
Myocardial infarctionMyocardial infarction 20–25%20–25%
Heart failureHeart failure 50%50%

10. SBP-Associated Risks: MRFIT
Adapted from Neaton JD et al. Arch Intern Med. 1992;152:56-64.
SBP versus DBP in Risk of CHD Mortality
Diastolic BP
(mm Hg)
Systolic BP
(mm Hg)
CHD Death Rate
100+
90–99
80–89
75–79
70–74
<70 <120
120–139
140–159
160+
48.3
20.6
10.3
11.8
8.8
8.5
9.2
23.8
16.9
13.9
12.8
12.6
11.8
31.0
25.5
24.6 25.3
25.2
24.9
37.4
34.7
43.8
38.1
80.6

11. Pulse Pressure
• Increase in pulse pressure (PP) indicates
greater stiffness in large conduit arteries,
primarily the thoracic aorta.
• PP may be a better marker of increased
CV risk than either systolic BP or diastolic
BP alone in older persons.
PP = SBP – DBPPP = SBP – DBP

12. 2007 ESH/ESC Hypertension Guidelines2007 ESH/ESC Hypertension Guidelines
First Choice Drug TreatmentFirst Choice Drug Treatment
 DiureticsDiuretics
 ACE-inhibitorsACE-inhibitors
 Calcium antagonistsCalcium antagonists
 Angiotensin receptor antagonistsAngiotensin receptor antagonists
 Beta-blockersBeta-blockers

13. Rationale for Use of ARB’s in
Hypertension

14. Rationale for Use of ARB’s in Hypertension
• Specific blockade of the renin-angiotensin-
aldosterone system provides:
– More complete blockade of BP response to angiotensin
II (specific for ATII receptor blockade)
– Reduced potential for target organ damage
– Reduced potential for bradykinin “cough”
– Best tolerability (specific for ATII receptor blockade)
– Some studies suggest a reduced risk of vascular events
compared with other BP lowering regimens
Guidelines recognize the additive positive effect of ARBs in hypertensives with:
• Type 2 diabetes
• End-organ disease, particularly that affecting the kidney

15. RR (95% CI)
Favors
ARB
Favors
Other
0.5 1.0 2.0
Relative risk
0.79 (0.69,0.90)Stroke
0.96 (0.85,1.09)CHD
Heart failure 0.84 (0.72,0.97)
Major CV events 0.90 (0.83,0.96)
CV death 0.96 (0.85,1.08)
Total mortality 0.94 (0.86,1.02)
Outcome
BP
difference
(mmHg)
-2/-1
-2/-1
-2/-1
-2/-1
-2/-1
-2/-1
Angiotensin Receptor Antagonists Reduce RiskAngiotensin Receptor Antagonists Reduce Risk
of Vascular Events And Total Mortalityof Vascular Events And Total Mortality
BPLTTC Lancet 2003; 362: 1527-35
Based on analysis of data from the SCOPE, IDNT, RENAAL and LIFE trials

16. Diuretics
β-blockers
Ca-antagonists
ACE-Inhibitors
LVMassreduction,%
-16
-14
-12
-10
-8
-6
-4
-2
0
- 8%
- 6%
- 11%
- 10% ARBs
- 13%
80 randomized controlled trials;
4113 patients
Meta-analysis of Randomized, Controlled Trials
of LV Hypertrophy Regression in Essential Hypertension
Klingbeil AU et al. Am J Med 2003; 115:41-46

17. ARBs significantly increased probability
of maintaining sinus rhythm
0
20
40
60
80
100
Probability
of maintaining
sinus rhythm (%)
ARB
+ amiodarone
Madrid A et al. Circulation
p = 0.008 vs. amiodarone
Amiodarone
85%
63%
159 patients with persistent atrial fibrillation were randomized159 patients with persistent atrial fibrillation were randomized
to either amiodarone or amiodarone + ARBto either amiodarone or amiodarone + ARB
Results are taken at 2-month follow-up visitResults are taken at 2-month follow-up visit

18. Mancia G et al. J Hypertens 2007; 25:1105-1187.
Antihypertensive treatment: Preferred drugs as
per new European guidelines
Clinical eventClinical event TreatmentTreatment
Atrial fibrillationAtrial fibrillation
•RecurrentRecurrent Angiotensin receptor blockers, ACEAngiotensin receptor blockers, ACE
inhibitorsinhibitors
•PermanentPermanent Beta blockers, nonhydropyridineBeta blockers, nonhydropyridine
calcium antagonistscalcium antagonists
ESRD/proteinuriaESRD/proteinuria ACE inhibitors, angiotensin receptorACE inhibitors, angiotensin receptor
blockers, loop diureticsblockers, loop diuretics
PADPAD Calcium antagonistsCalcium antagonists
LVH=left ventricular hypertrophy
ESRD=end-stage renal disease
PAD=peripheral arterial disease
ISH=isolated systolic hypertension

19. ESH/ESC Guidelines
“A blocker of the renin-
angiotensin system should be
a regular component of
combination treatment and
the one preferred when
monotherapy is sufficient”

20. Others
2.2%
(-13.9%)
ACEi
26.9%
(-4.0%)
CCB
13.9%
(+4.8%)
DIU
15.7%
(+3.0%)
ARB
17.7%
(+17.9%)
BB
23.5%
(+9.1%)
Overall Hypertension Market in Egypt
ARBs are most rapidly growing group
Source: IMS Rx Audit MAT QIII’2007
HT Market Definition: C2, C3, C7, C8, C9

21. Teveten among other ARBs

22. Change in mean SBP and DBP from baseline after 8 weeks
of treatment with eprosartan (600mg/day) or placebo in
patients with mild-to-moderate hypertension
Eprosartan vs Placebo in Mild-to-Moderate HTN
-26
-17.1
-12.6 -13.5
-50
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
mmHg
SBP
MBP
DBP
PP

23. Sega. Blood Press 1999;8:114
ReductioninsitSBP(mmHg)
p=0.025
–29.1
–21.2
–15
–25
–20
–30
0
–5
–10
ReductioninstaSBP(mmHg)
p=0.032
–27.8
–20.0
–15
–25
–20
–30
0
–5
–10
Eprosartan
Enalapril
Eprosartan reduces sitSBP and staSBP in
patients with severe hypertension

24. Argenziano & Trimarco. Curr Med Res Opin 1999;15:9
<65 years
(n=201)
≥65 years
(n=63)
0
–2
–4
–6
–8
–10
–12
–14
–16
–18
–20
MeanchangefrombaselineinsitSBP(mmHg)
Eprosartan has similar efficacy in young
and elderly patients
0
–2
–4
–6
–8
–10
–12
–14
–16
–18
–20
<65 years
(n=201)
≥65 years
(n=63)
MeanchangefrombaselineinsitDBP(mmHg)

25. Puig et al. J Hypertens 1999;17:1033
ReductioninsitBP(mmHg)
–18
–15
–12
–9
–6
–3
0
Diastolic Systolic
–12.4
–9.6
–12.7
–10.9
0
20
40
60
80
Responserate(%)
73
53
100
Eprosartan
Losartan
Eprosartan is more effective than losartan
in mild hypertension

26. PULSE PRESSURE REDUCTION
Robles NR, et al. Int J Clin Pract 2005;59(4):478-484
Reduction in mean pulse pressure, arterial pressure, SBP and DBP in
a 16-week open-label study (n=566)

27. Teveten effect on fibrinolytic/hemostatic
variables: Comparative study to losartan
In conclusion, the results indicate
that 6-month monotherapy with an
angiotensin II type 1 receptor blocker,
eprosartan, is associated with a more
favorable modification of hemostatic
& fibrinolytic status than with
losartan
Drugs Exp Clin Res. 2004;30(3):125-32

28. Effect of Teveten on cytoplasmic free calcium
mobilization, platelet activation, and
microparticle formation in hypertension
CONCLUSIONS: Teveten
significantly reduces blood
pressure and normalizes
undesirable changes in platelet
function
Am J Hypertens. 2004 Sep;17(9):757-63.

30. CEREBROVASCULAR RISK EPIDEMIOLOGY
Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and
stroke statistics—2009 update: a report from the American Heart Association Statistics
Committee and Stroke Statistics Subcommittee.Circulation 2009;119:e21–181.
 CVD is the 3rd
leading cause of death in the U.S. and the first
cause of long-term major disability
 There are 795,000 incident strokes in the U.S. each year
 8–12% of individuals die within the first 30 days of their initial
stroke
 Patients who survive the initial attack face an increased risk of
subsequent vascular events and stroke (21.5%)
 The consequences of stroke are socioeconomic
 Therefore, in light of this disease burden, prevention of initial
and recurrent stroke is a major priority for healthcare providers

31. STROKE IS MORE FREQUENT THAN AMI
Gentil, A et al. J Neurol Neurosurg Psychiatry 2009;80:1006-1011C

32. STROKE AND AMI MORTALITY
ARE SIMILAR
Copyright ©2009 BMJ Publishing Group Ltd.
Gentil, A et al. J Neurol Neurosurg Psychiatry 2009;80:1006-1011C

33. RISK FACTORS FOR STROKE

34. SYSTOLIC BLOOD PRESSURE
AND RISK OF STROKE
Lewis et al. Lancet 2002;360:1903–13

35. CAN WE EXTRAPOLATE DATA
FROM PRIMARY PREVENTION
TRIALS TO SECONDARY
PREVENTION IN STROKE ?

36. DECREASING BP DECREASE
THE RISK OF STROKE
Law, M R et al. BMJ 2009;338:b1665

37. ANTIHYPERTENSIVES DO NOT HAVE THE SAME
BENEFICIAL EFFECT ON PREVENTING STROKE
Law, M R et al. BMJ 2009;338:b1665

38. PROGRESS
Lancet 2001; 358:1033

39. ANTIHYPERTENSIVE THERAPY AFTER STROKE
PROFESS TRIAL
N Engl J Med 2008; 359 (12) : 1225-37

40. POST STROKE TRIAL
 ACCESS: candesartan, post acute STROKE, positive
but pilot study
 SCAST: candesartan, negative.
 PROFESS: telmisartan, post stroke negative
 MOSES: eprosartan, post stroke only positive trial with
an active comparator, benefits beyond simple BP
reduction.

41.  Primary endpoint:
 Total mortality plus total number of
cardiovascular and cerebrovascular events
 Secondary endpoints:
 Change in mental capacity and functional status
(Barthel Index and Rankin Scale)
 Individual elements of the combined primary
endpoint
 Mean follow-up:
 2.5 years

42. 29 in total:
14 withdrew consent prior
to first intake of study drug
1 without known vital status
14 lost for follow-up monitoring
24 in total:
10 withdrew consent prior to
first intake of study drug
2 without known vital status
12 lost for follow-up monitoring
1,405 patients eligible for randomization
710 assigned to
eprosartan-based
regimen
695 assigned to
nitrendipine-based
regimen
681 available for intention-
to-treat analyses
671 available for intention-
to-treat analyses

43. Schrader J. et al. Stroke 2005;36:1218-1226

44. Schrader J. et al. Stroke 2005;36:1218-1226
25%
Primary end points

45. First cardiovascular events
0
0.05
0.1
0.15
0.2
0.25
0 400 800 1200 1600
Eprosartan
Nitrendipine
Risk
reduction
30%
P=0.03
Schrader J, et al. Stroke 2005; 36: 1218
CHF: 34%
MI: 10%

46. Is it BP reduction effect ?

47. Blood pressure Blood pressure
Riskofcoronaryheartdisease
Nitrendipine
Nitrendipine
Teveten
Teveten
-25%vs
CCB
-31%vs CCB
)1st time occurrence(
Risk of Stroke and CHD – MOSES StudyRisk of Stroke and CHD – MOSES Study
Benefits beyond BP LoweringBenefits beyond BP Lowering
Riskofcerebrovascularevents

48. Adverse Remodeling of the VasculatureAdverse Remodeling of the Vasculature
Alpha-1
vasoconstriction
Ang II
Doxazosin
Prazosin
Eprosartan
NE
Eprosartan
(ARBs)
Vasoconstriction
Vasoconstriction
Media hypertrophy
Collagen deposition
Dual mechanism of
action

49. CONCLUSIONS
 Cerebrovascular health protection is cardiovascular
prevention
 Prevention is primary, secondary prevention of stroke but
also dementia and global cardiovascular protection
 Evidence based approach:
 Eprosartan
 Efficient in BP reduction
 Specific and dual mode of action
 Prevention of cardiovascular and cerebrovascular
Health