Hypertension and its management

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Hypertension and its management
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Contents

• Hypertension a major CV risk factor
• Treatment goals algorithm
• The challenge of BP control
• The importance of treatment adherence
• The RAS a cornerstone in modern
  antihypertensive therapy
• Telmisartan a unique ARB
• Combination therapy
• Conclusions

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• Hypertension a major CV risk factor

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Hypertension the worlds number 1 CV risk factor

• 7.6 million premature deaths worldwide
• 13.5 of global total deaths
• Causes more deaths than any other risk factor,
  including smoking or high cholesterol

Lawes et al. Lancet 200837115138 Lopez et al.
Lancet 2006 367 174757
5
Hypertension is the most powerful risk factor for
cardiovascular morbidity and mortality
Global mortality
Global burden of disease
16 million
128 million
78 million
59 million
39 million
43 million
All cardiovascular
High BP
23 million
30 million
High cholesterol
Overweight and obesity
Ezzati et al. PloS Med 20052e133
6
Hypertension is a leading cause of death and
disability in all regions
Region Death Disability
East Asia Pacific 13.6 6.5
Europe Central Asia 35.0 19.6
Latin America The Caribbean 13.0 5.1
Middle East North Africa 16.5 6.1
South Asia 9.6 4.3
Sub-Saharan Africa 4.0 1.7
Low-/ middle-income economies 12.9 5.6
High-income economies 17.6 9.3
World 13.5 6.0
Disability-adjusted life years
Lawes et al. Lancet 200837115138
7
Each 20/10 mmHg BP increase doubles the risk of
CV mortality
Fold Increase in Relative CV Risk
135/85
155/95
175/105
115/75
SBP/DBP, mmHG
Individuals aged 4069 years (N 1
million). Lewington S, et al. Lancet.
200236019031913.
8
Hypertension adds to other CV risk factors
Other risk factors SBP 120129DBP 8084 SBP 130139DBP 8589 SBP 140159DBP 9099 SBP 160179DBP 100109 SBP 180DBP 110
None Average risk Average risk Low added risk Moderate added risk High added risk
1-2 Low added risk Low added risk Moderate added risk Moderate added risk Very high added risk
3, OD, MS or diabetes Moderate added risk High added risk High added risk High added risk Very high added risk
CV or renal disease Very high added risk Very high added risk Very high added risk Very high added risk Very high added risk
MS, metabolic syndrome OD, subclinical organ
damage
ESHESC Guidelines. J Hypertens 20072511051187
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Lowering BP reduces cardiovascular risk

Meta-analysis of 61 prospective, observational
studies One million adults, 12.7 million
person-years
7 reduction in risk of ischaemic heart disease
and other vascular disease mortality
2 mmHg decrease in mean SBP
10 reduction in risk of stroke mortality
Small SBP reductions yield significant benefit
Lewington et al. Lancet. 200236019031913
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24h ABPM is the gold-standard and best predictor
of CV risk
Increased risk of CV death ()
Risk associated with a 10 mmHg increase
Total n2,051
CV, cardiovascular
Sega et al. Circulation 200511117771783
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24-h ABPM is the gold-standard and better
predictor of CV risk than office BP
Relative risk of event with a 1 SD increase in
24-h BP
Risk due to increased 24-h BP after adjustment
for office BP
Increased risk
Total n1,963
SBP
DBP
CV, cardiovascular
Clement et al. N Engl J Med 200334824072415
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• Treatment goals and algorithms

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Blood pressure goals
Target BP for all (lower if tolerated)
lt140/90 mmHg
Diabetes and renal impairment
lt130/80 mmHg
CV Disease e.g. stroke, myocardial infarction
ESHESC Guidelines. J Hypertens
20072511051187 JNC VII Guidelines. JAMA 2003
2560-2572 WHO-ISH Guideline s. J Hypertens 2003
1983-1992 BHS IV Guidelines. 2006
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Current BP targets according to guidelines
JNC VII 2003 ESH-ESC 2007 WHO-ISH BHS IV 2006
lt140/90 lt140/90 SBP lt140 lt140/90
lt130/80 lt130/80 lt130/80 According to national guidelines
DM renal DM renal post stroke post MI DM renal CVD DM renal CVD
Lower if tolerated
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Hypertension treatment algorithm (JNC 7)
Hypertension withoutcompelling indications
Hypertension withcompelling indications
Stage 1 hypertension Thiazide-type diuretic for
most May consider ACE-I, ARB, ß-blocker, CCB or
combination
Stage 2 hypertension Two-drug combination for
most Usually thiazide-type diuretic and ACE-I,
ARB, ß-blocker or CCB
Drug(s) for the compelling indications Other
antihypertensive drugs (diuretic and ACE-I, ARB,
ß-blocker, CCB) as needed
JNC VII Guidelines. JAMA 20032892560?2572
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Hypertension treatment algorithm (ESH 2007)
Choose between
Marked BP elevation High/very high CV risk Lower
BP target
Mild BP elevation Low/moderate CV
risk Conventional BP target
Low-dose 2-drug combination
Low-dose single agent
Not at BP goal
Full dose ofsingle agent
Switch todifferent agentat low dose
Full dose of2-drugcombination
Add athird drugat low dose
Not at BP goal
23 drugcombination at full dose
Full doses of 23-drug combination
Full-dosesingle agent
ESHESC Guidelines. J Hypertens 20072511051187
17

• The challenge of BP control

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BP is often not controlled, even when treated
Individuals ()

Threshold of SBP/DBP 140/90 mm Hg
Wolf-Maier et al. Hypertension 2004431017
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BP control is particularly poor in hypertensive
patients at high risk
Hypertension controlled ()
Total n4,646
CAD, coronary artery disease CHF, congestive
heart failure CKD, chronic kidney disease DM,
diabetes mellitus HTN, hypertension PAD,
peripheral arterial disease. Based on BP
target lt130/80 mmHg
Wong et al. Arch Intern Med 20071672431-2436
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Uncontrolled hypertension carries the same CV
risk as untreated hypertension
Third National Health and Nutrition Examination
Survey (NHANES III)
48(n 2,458)
Not treated
Both are at equally increased risk compared with
controlled BP (pgt0.05)
35(n 1,756)
BP uncontrolled
17 (n 872)
BP controlled
Gu Q, et al. Am J Hypertens 2009
doi10.1038/ajh.2009.191
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• The importance of treatment adherence

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Patients who are adherent are more likely to
attain BP control
Controlled BP ()
45 greater probability of control
Adherence
(n 165)
(n 46)
(n 629)
lt140/90 mmHg or lt130/85 mmHg for patients with
diabetes
Bramley et al. J Manag Care Pharm 20061223945
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Patients who are adherent are at lower CV risk
Relative risk of a CV event
50 lower risk of a CV event
Adherence
(n 7,624)
(n 9,666)
(n 1,516)
Mazzaglia et al. Circulation 20091201598-1605
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Treatment adherence is highest with ARBs
Diuretics ß-blockers a-blockers Calcium
channel blockers ACE inhibitors ARBs
1.83 1.64 1.23 1.08 1.00 0.92
Total n 445,356
-

1.0
0.5
2.0
Cause-specific hazard ratio (95 CI) for
discontinuation
Relative to ACE inhibitors after 1 year of
treatment
ARB, angiotensin II receptor blocker CI,
confidence interval
Corrrao et al. J Hypertens 200826819-24.
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• The RAS - the cornerstone in modern
  antihypertensive therapy

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Each of the main classes of anti-hypertensive
drugs affects the renin-angiotensin system
Angiotensinogen
Beta-blockers
Renin

Volume
Na
Renin
Kidney


Angiotensin I
Diuretic Calciumchannel blocker


ACE inhibitor
ACE
Angiotensin II
Angiotensin receptorblocker

AT1 receptor

Arteries vascular tone
Brown. Heart 200793102633
27
ACEI and ARBs block the renin-angiotensin system
(RAS) in different ways
Bradykinin/NO
Angiotensin I
Inactive fragments
Angiotensin II
AT2 RECEPTOR
AT1 RECEPTOR
Vasoconstriction Sodium retention SNS
activation Inflammation Growth-promoting
effects Aldosterone Apoptosis
Vasodilation Natriuresis Tissue
regeneration Inhibition of inappropriate cell
growth Differentiation Anti-inflammation Apoptosis
SNS sympathetic nervous system Hanon S, et al.
J Renin Angiotensin Aldosterone Syst
20001147150 Chen R, et al. Hypertension
200342542547 Hurairah H, et al. Int J Clin
Pract 200458173183Steckelings UM, et al.
Peptides 20052614011409
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Properties of the ideal antihypertensive

• The ideal antihypertensive should
• be CV protective - reduce cardiovascular
  morbidity and mortality
• Provide powerful and long lasting 24h BP
  reductions
• be safe and well tolerated

Mustone-Alexander. Drugs 20066612391252
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• Telmisartan a unique ARB

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Telmisartan has a different structure which
explains its unique pharmacology
Ries et al. J Med Chem 19933640404051
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Telmisartans unique pharmacology among ARBs
Longest half life, Highest receptor affinity,
Highest tissue penetration and selective PPARg
activation
Longest plasma half life within ARB class
Highest receptor affinitywithin ARB class
Plasma half life (h)
range
Epro-sartan
Lo-sartan
Val-sartan
Cande-sartan
Olme-sartan
Irbe-sartan
Telmi-sartan
Most lipophilic within ARB class (high tissue
penetration)
Highest selective PPARg activation within ARB
class
500
PPARg fold activation
Volume of distribution (L)
range
Cande-sartan
Olme-sartan
Val-sartan
Lo-sartan
Irbe-sartan
Epro-sartan
Telmi-sartan
EXP 3174(Losartan)
Val-sartan
Cande-sartan
Olme-sartan
Telmi-sartan
Epro-sartan
Irbe-sartan
Burnier M. Brunner H.R., Lancet
2000355637645 Brunner H.R., J Hum Hypertens
200216(Suppl 2)S13S16 Kakuta H., et al. Int J
Clin Pharmacol Res 2005254146 Wienen W., et
al. Br J Pharmacol 1993110245-252 Song J.C.
White C.M., Formulary 200136487499 Asmar,R.,
Int J Clin Pract. 200660315-320 Israili,Z.H.,
J Hum.Hypertens. 200014 Suppl 1 S73-S86 Benson
S.C. et al. Hypertension 2004439931002
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Telmisartan is superior to ramiprilin 24 hour
ABPM reduction
DBP change from baseline (mmHg)
Time after dosing (h)
PRISMA II
(n 405)
(n 407)

Plt0.0001 24-h mean Telmisartan vs Ramipril
Lacourcière et al. Am J Hypertens 2006 19104112
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Telmisartan is superior to Valsartan in 24 hour
ABPM reduction
SBP change from baseline (mmHg)
Time after dosing (h)
(n 430)
(n 447)
Plt0.001
Plt0.05
Plt0.0001
Plt0.005
P values are for Telmisartan vs Valsartan
comparison Pooled analysis of two independent
studies (MICADO I II) Lacourcière et al. Blood
Press Monit 20049203210
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Telmisartan has an excellent safety and
tolerability profile
Incidence of AEs per patient-year
lt 65 year(n 921)
lt 65 year(n 3817)
65 year(n 246)
65 year(n 1196)
lt 65 year(n 1444)
65 year(n 399)
Placebo
Telmisartan
Telmisartan/HCTZ
Schumacher H and Mancia G. Blood Press
200817(Suppl 1)32-40
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• Combination therapy

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The majority of hypertensive patients need
com-bination therapy to achieve their BP target
(SBP)
Trial (SBP achieved)
ASCOT-BPLA (136.9 mmHg)
ALLHAT (138 mmHg)
IDNT (138 mmHg)
RENAAL (141 mmHg)
UKPDS (144 mmHg)
ABCD (132 mmHg)
MDRD (132 mmHg)
HOT (138 mmHg)
AASK (128 mmHg)
1
2
3
4
Average no. of antihypertensive medications
Bakris et al. Am J Med 2004116(5A)30S8 Dahlöf
et al. Lancet 2005366895906
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ESH-ESC treatment recommendations
2009
2007
Diuretics
Diuretics
ß-blockers
ARB
ARB
ONTARGET ACCOMPLISHHYVET
CCB
CCB
a-blockers
ACEi
ACEi
Adapted from Mancia et al. J Hypertens
200725110587 Manchia et al J Hypertens 2009
27 2121-58
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Telmisartan plus HCTZ12.5 is superior to
Valsartan plus HCTZ12.5 in 24 hour ABPM reduction
SBP change from baseline (mmHg)





12.5 mg (n412)
12.5 mg (n428)
p lt 0.001 vs Valsartan HCTZ
Sharma AM, et al. Cardiovasc Diabetol 20076(1)28
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Telmisartan plus HCTZ25 is superior to valsartan
plus HCTZ25 in reducing blood pressure
SBP change from baseline (mmHg)
(n 942)
(n 952)
(n 227)
p0.0019
p0.0004
White WB et al. J Hum Hypertens 200923817-2
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Telmisartan plus amlodipine provides dose
dependent powerful 24h ABPM reduction
24-h mean SBP reduction (mmHg)
24-h mean DBP reduction (mmHg)
Amlodipine (mg)
Amlodipine (mg)
Telmisartan (mg)
Telmisartan (mg)
n1461
p lt 0.001 p lt 0.0001 vs telmisartan alone
p lt 0.0001 vs amlodipine alone SBP, systolic
blood pressure DBP, diastolic blood pressure
Littlejohn TW et al. J Clin Hypertension.
200911(4)207-213
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Telmisartan significantly reduces peripheral
oedema associated with Amlodipine
Incidence of peripheral oedema ()



p lt0.05 p lt0.0001
Littlejohn TW et al. J Clin Hypertension.
200911(4)207-213
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• Conclusions

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Conclusions

• Hypertension is a major CV risk factor and cause
  of CV disease worldwide
• Powerful, well-tolerated antihypertensives are
  essential to achieve antihypertensive treatment
  goals
• Poor tolerance leads to reduced adherence,
  reduced BP goal achievement, and greater
  cardiovascular risk
• ARBs are the best-tolerated antihypertensive
  class, and patients persist with ARB treatment
  longer than with other antihypertensives
• There are significant differences among the ARBs
  in terms of duration of effect, receptor binding
  and tissue penetration
• Telmisartan provides more powerful blood pressure
  lowering than valsartan
• Combination telmisartan/HCTZ and
  telmisartan/amlodipine therapy provides
  additional BP reductions and reduced side effects
  compared with amlodipine monotherapy