Cardiovascular and Cerebrovascular health in the management of hypertensive patients

Not all ARBs looks after your patient heart as well as

his mind

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

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

Developing Developing

countries countries Developed Developed countriescountries

Blood pressureBlood pressure

TobaccoTobacco

UnderweightUnderweight

AlcoholAlcohol

CholesterolCholesterol

Unsafe sexUnsafe sex

OverweightOverweightUnsafe water, sanitation, Unsafe water, sanitation,

hygienehygieneLow fruit and vegetable Low fruit and vegetable intakeintake

Indoor smoke from solid fuelsIndoor smoke from solid fuels

Physical inactivityPhysical inactivity

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.

Lewington et al. Lancet 2002 ; 360 : 1903–13.

CARDIOVASCULAR MORTALITY DOUBLES FOR EVERY INCREMENT IN SBP/DBP OF 20/10 mm Hg

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.

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

Benefits of Lowering BP

Average Percent ReductionAverage Percent Reduction

Stroke incidence Stroke incidence 35–40% 35–40%

Myocardial infarction Myocardial infarction 20–25% 20–25%

Heart failureHeart failure 50% 50%

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

80–8975–79

70–74<70 <120

120–139

140–159

160+

48.3

20.6

10.311.8

8.88.5

9.2

23.8

16.9

13.912.8

12.611.8

31.0

25.524.6 25.3

25.224.9

37.434.7

43.8

38.1

80.6

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

2007 ESH/ESC Hypertension Guidelines2007 ESH/ESC Hypertension GuidelinesFirst Choice Drug TreatmentFirst Choice Drug Treatment

DiureticsDiuretics

ACE-inhibitorsACE-inhibitors

Calcium antagonistsCalcium antagonists

Angiotensin receptor antagonistsAngiotensin receptor antagonists

Beta-blockersBeta-blockers

Rationale for Use of ARB’s in Hypertension

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

RR (95% CI)Favors ARB

Favors Other

0.5 1.0 2.0Relative 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 Risk Angiotensin Receptor Antagonists Reduce Risk of Vascular Events And Total Mortalityof Vascular Events And Total Mortality

BPLTTC Lancet 2003; 362: 1527-35Based on analysis of data from the SCOPE, IDNT, RENAAL and LIFE trials

Diuretics

β-blockers

Ca-antagonists

ACE-Inhibitors

LV

Mas

s r

edu

cti

on

, %

-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 Trialsof LV Hypertrophy Regression in Essential Hypertension

Klingbeil AU et al. Am J Med 2003; 115:41-46

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 2002;106:331–6.

p = 0.008 vs. amiodarone

Amiodarone

85%

63%

159 patients with persistent atrial fibrillation were randomized 159 patients with persistent atrial fibrillation were randomized to either amiodarone or amiodarone + ARB to either amiodarone or amiodarone + ARB Results are taken at 2-month follow-up visitResults are taken at 2-month follow-up visit

Mancia G et al. J Hypertens 2007; 25:1105-1187.

Antihypertensive treatment: Preferred drugs as

per new European guidelines Clinical event Clinical event TreatmentTreatmentAtrial f ibri l lationAtrial f ibri l lation   •RecurrentRecurrent Angiotensin receptor blockers, ACE Angiotensin receptor blockers, ACE

inhibitorsinhibitors•PermanentPermanent Beta blockers, nonhydropyridine Beta blockers, nonhydropyridine

calcium antagonistscalcium antagonistsESRD/proteinuriaESRD/proteinuria ACE inhibitors, angiotensin receptor ACE inhibitors, angiotensin receptor

blockers, loop diureticsblockers, loop diureticsPADPAD Calcium antagonistsCalcium antagonistsLVH=left ventricular hypertrophyESRD=end-stage renal diseasePAD=peripheral arterial diseaseISH=isolated systolic hypertension

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”

Others 2.2%

(-13.9%) ACEi26.9%(-4.0%)

CCB13.9%

(+4.8%)

DIU15.7%

(+3.0%)

ARB 17.7%

(+17.9%)

BB 23.5%

(+9.1%)

Overall Hypertension Market in EgyptARBs are most rapidly growing group

Source: IMS Rx Audit MAT QIII’2007

HT Market Definition: C2, C3, C7, C8, C9

Teveten among other ARBs

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

MBPDBPPP

Sega. Blood Press 1999;8:114

Red

uct

ion

in

sit

SB

P (

mm

Hg

)

p=0.025

–29.1

–21.2

–15

–25

–20

–30

0

–5

–10

Red

uct

ion

in

sta

SB

P (

mm

Hg

)

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

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

Mea

n c

han

ge

fro

m b

asel

ine

in s

itS

BP

(m

mH

g)

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)

Mea

n c

han

ge

fro

m b

asel

ine

in s

itD

BP

(m

mH

g)

Puig et al. J Hypertens 1999;17:1033

Red

uct

ion

in s

itB

P (

mm

Hg

)

–18

–15

–12

–9

–6

–3

0Diastolic Systolic

–12.4

–9.6

–12.7

–10.9

0

20

40

60

80

Res

po

nse

rat

e (%

)

73

53

100

Eprosartan

Losartan

Eprosartan is more effective than losartan in mild hypertension

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)

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

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.

CEREBROVASCULAR RISK EPIDEMIOLOGY

Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease andstroke 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

STROKE IS MORE FREQUENT THAN AMI

Gentil, A et al. J Neurol Neurosurg Psychiatry 2009;80:1006-1011C

STROKE AND AMI MORTALITY ARE SIMILAR

Copyright ©2009 BMJ Publishing Group Ltd.

Gentil, A et al. J Neurol Neurosurg Psychiatry 2009;80:1006-1011C

RISK FACTORS FOR STROKE

SYSTOLIC BLOOD PRESSURE AND RISK OF STROKE

Lewis et al. Lancet 2002;360:1903–13

CAN WE EXTRAPOLATE DATA FROM PRIMARY PREVENTION

TRIALS TO SECONDARY PREVENTION IN STROKE ?

DECREASING BP DECREASE THE RISK OF STROKE

Law, M R et al. BMJ 2009;338:b1665

ANTIHYPERTENSIVES DO NOT HAVE THE SAME BENEFICIAL EFFECT ON PREVENTING STROKE

Law, M R et al. BMJ 2009;338:b1665

PROGRESS

Lancet 2001; 358:1033

ANTIHYPERTENSIVE THERAPY AFTER STROKEPROFESS TRIAL

N Engl J Med 2008; 359 (12) : 1225-37

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.

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

29 in total:14 withdrew consent priorto first intake of study drug

1 without known vital status14 lost for follow-up monitoring

24 in total:10 withdrew consent prior to first intake of study drug2 without known vital status12 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

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

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

25%

Primary end points

First cardiovascular events

0

0.05

0.1

0.15

0.2

0.25

0 400 800 1200 1600

EprosartanNitrendipine

Risk reduction

30%

P=0.03

Schrader J, et al. Stroke 2005; 36: 1218

CHF: 34%MI: 10%

Is it BP reduction effect ?

Blood pressure Blood pressure

Ris

k of

cor

onar

y he

art d

isea

se

NitrendipineNitrendipine

TevetenTeveten

-25% vs CCB

-31% vs CCB)1st time occurrence(

Risk of Stroke and CHD – MOSES StudyRisk of Stroke and CHD – MOSES StudyBenefits beyond BP LoweringBenefits beyond BP Lowering

Ris

k of

cer

ebro

vasc

ular

eve

nts

Adverse Remodeling of the VasculatureAdverse Remodeling of the Vasculature

Alpha-1vasoconstriction

Ang II

DoxazosinPrazosin

Eprosartan

NE

Eprosartan(ARBs)

Vasoconstriction

VasoconstrictionMedia hypertrophyCollagen deposition

Dual mechanism of action

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

Prevention of dementia