Transcript Document 7435930

Hypertension and its management
Hypertension: a major
CV risk factor
Hypertension:
the world’s 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 2008;371:1513–8; Lopez et al. Lancet 2006; 367: 1747–57
Each 20/10 mmHg BP increase doubles the risk
of CV mortality
Fold Increase in Relative CV Risk*
10
8-fold
8
6
4-fold
4
2-fold
2
1-fold
0
115/75
135/85
155/95
SBP/DBP, mmHG
* Individuals aged 40–69 years (N = 1 million).
Lewington S, et al. Lancet. 2002;360:1903–1913.
175/105
Hypertension adds to other CV risk factors
Other risk SBP 120–129 SBP 130–139 SBP 140–159 SBP 160–179
factors
DBP 80–84
DBP 85–89
DBP 90–99 DBP 100–109
None
1−2
≥3, OD,
MS or
diabetes
CV or
renal
disease
SBP ≥180
DBP ≥110
Average
risk
Average
risk
Low
added risk
Moderate
added risk
High
added risk
Low
added risk
Low added
risk
Moderate
added risk
Moderate
added risk
Very high
added risk
Moderate
added risk
High
added risk
High
added risk
High
added risk
Very high
added risk
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
ESH–ESC Guidelines. J Hypertens 2007;25:1105–1187
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. 2002;360:1903–1913
24h ABPM is the gold-standard and best
predictor of CV risk
Increased risk of CV death (%)
8
Office
Risk associated with
a 10 mmHg increase
Home
7.1
24 hour ABPM
6
4.5
Total n=2,051
4
3.1
2.4
2
0.8
1.3
2
1.1
1.5
0
130 mmHg
140 mmHg
Baseline SBP
CV, cardiovascular
Sega et al. Circulation 2005;111:1777–1783
150 mmHg
Treatment goals and
algorithms
Blood pressure goals
Target BP for all
(lower if tolerated)
<140/90 mmHg
Diabetes and renal
impairment*
<130/80 mmHg
* CV Disease e.g. stroke, myocardial infarction
ESH–ESC Guidelines. J Hypertens 2007;25:1105–1187
JNC VII Guidelines. JAMA 2003; 2560-2572
WHO-ISH Guideline s. J Hypertens 2003; 1983-1992
BHS IV Guidelines. 2006
Hypertension treatment algorithm
(ESH 2007)
Choose between
Mild BP elevation
Low/moderate CV risk
Conventional BP target
Marked BP elevation
High/very high CV risk
Lower BP target
Low-dose single agent
Low-dose 2-drug combination
Not at BP goal
Full dose of
single agent
Switch to
different agent
at low dose
2–3 drug
combination
at full dose
Full-dose
single agent
ESH–ESC Guidelines. J Hypertens 2007;25:1105–1187
Full dose of
2-drug
combination
Not at BP goal
Add a
third drug
at low dose
Full doses of 2–3-drug
combination
The challenge of BP
control
BP is often not controlled, even when treated
Individuals (%)
USA
Canada
Italy
Sweden
Spain
England
Germany
80
70
60
50
40
30
20
10
0
Aware
* Threshold of SBP/DBP 140/90 mm Hg
Wolf-Maier et al. Hypertension 2004;43:10–17
Treated
Controlled *
BP control is particularly poor in hypertensive
patients at high risk
Hypertension controlled (%)
70
65
Total n=4,646
60
50
50
49
47
40
35
35
30
23
20
10
0
HTN only
CAD
CHF
PAD
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 <130/80 mmHg
Wong et al. Arch Intern Med 2007;167:2431-2436
DM*
Stroke
CKD*
Uncontrolled hypertension carries the same CV
risk as untreated hypertension
Third National Health and Nutrition Examination Survey (NHANES III)
Not treated
48%
(n = 2,458)
BP uncontrolled
35%
(n = 1,756)
BP controlled
17%
(n = 872)
Gu Q, et al. Am J Hypertens 2009; doi:10.1038/ajh.2009.191
Both are at equally
increased risk compared
with controlled BP
(p>0.05)
The importance of
treatment adherence
Patients who are adherent are more likely to
attain BP control
Controlled BP (%)
50
45
40
35
30
25
20
15
10
5
0
45% greater probability of control
Low (<50%)
Medium (50-79%)
High (>=80%)
(n = 46)
(n = 165)
(n = 629)
* <140/90 mmHg or <130/85 mmHg for patients with diabetes
Bramley et al. J Manag Care Pharm 2006;12:239–45
Adherence
Patients who are adherent are at lower CV risk
Relative risk of a CV event
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
50% lower risk of a CV event
Low (<40%)
Medium (40-79%)
(n = 9,666)
Mazzaglia et al. Circulation 2009;120:1598-1605
(n = 7,624)
High (>=80%)
(n = 1,516)
Adherence
Treatment adherence is highest with ARBs
Diuretics
1.83
Total n = 445,356
β-blockers
1.64
α-blockers
1.23
Calcium channel blockers
1.08
ACE inhibitors
1.00
ARBs
0.92
0.5
-
1.0
+
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 2008;26:819-24.
The RAS - the cornerstone
in modern
antihypertensive therapy
Each of the main classes of anti-hypertensive
drugs affects the renin-angiotensin system
Angiotensinogen
Volume
Beta-blockers
–
Renin
Na+
+
Renin
+
Kidney
Angiotensin I
–
Diuretic
Calcium
channel
blocker
ACE
ACE inhibitor
Angiotensin II
–
AT1 receptor
Angiotensin receptor
blocker
–
Arteries – vascular tone
Brown. Heart 2007;93:1026–33
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 2006;66:1239–1252
Telmisartan –
a unique ARB
Telmisartan has a different structure which explains its
unique pharmacology
Ries et al. J Med Chem 1993;36:4040–4051
Telmisartan’s unique pharmacology among
ARBs
Longest plasma half life
within ARB class
Plasma half life (h)
24
18
12
range
6
Receptor dissociation
half life (min)
Longest half life, Highest receptor affinity, Highest tissue penetration and selective PPARg activation
0
LoValCande- Olmesartan sartan sartan sartan
† Active metabolite EXP 3174
150
†
100
50
IrbeTelmisartan sartan
Most lipophilic within ARB class
(high tissue penetration)
100
80
60
range
40
20
Valsartan
PPARg fold activation
Volume of distribution (L)
200
0
Eprosartan
500
250
Highest receptor affinity
within ARB class
30
Losartan
Candesartan
Olmesartan
Telmisartan
Highest selective PPARg
activation within ARB class
25
20
15
10
5
0
0
Cande- Olmesartan sartan
ValLosartan sartan
Irbesartan
Epro- Telmisartan sartan
Telmi- Irbe- Cande- ValOlme- Epro- EXP 3174
sartan sartan sartan sartan sartan sartan (Losartan)
Burnier M. & Brunner H.R., Lancet 2000;355:637–645; Brunner H.R., J Hum Hypertens 2002;16(Suppl 2):S13–
S16; Kakuta H., et al. Int J Clin Pharmacol Res 2005;25:41–46; Wienen W., et al. Br J Pharmacol 1993;110:245252; Song J.C. & White C.M., Formulary 2001;36:487–499; Asmar,R., Int J Clin Pract. 2006;60:315-320;
Israili,Z.H., J Hum.Hypertens. 2000;14 Suppl 1: S73-S86; Benson S.C. et al. Hypertension 2004;43:993–1002
Telmisartan is superior to ramipril
in 24 hour ABPM reduction
DBP change from baseline (mmHg)
PRISMA II
2
4
6
8
Time after dosing (h)
10
12
14
16
18
20
22
24
0
-2
Telmisartan 80 mg (n = 405)
Ramipril 10 mg (n = 407)
-4
-6
-8
-10
-12
-14
*** P<0.0001 24-h mean Telmisartan vs Ramipril
Lacourcière et al. Am J Hypertens 2006; 19:104–112
***
Telmisartan is superior to Valsartan in 24 hour
ABPM reduction
SBP change from baseline (mmHg)
2
4
6
8
Time after dosing (h)
10
12
14
16
18
20
22
0
-2
Valsartan 160 mg (n = 430)
Telmisartan 80 mg (n = 447)
P<0.001
-4
P<0.05
-6
-8
-10
-12
P<0.0001
-14
P<0.005
P values are for Telmisartan vs Valsartan comparison
Pooled analysis of two independent studies (MICADO I & II)
Lacourcière et al. Blood Press Monit 2004:9;203–210
24
Telmisartan has an excellent safety and
tolerability profile
Incidence of AEs per patient-year
3.0
2.9
2.5
2.3
2.1
2.0
2.2
2.0
1.8
1.5
1.0
0.5
0.0
< 65 year
(n = 921)
≥ 65 year
(n = 246)
< 65 year
(n = 3817)
Placebo
Schumacher H and Mancia G. Blood Press 2008;17(Suppl 1):32-40
≥ 65 year
(n = 1196)
Telmisartan
< 65 year
(n = 1444)
≥ 65 year
(n = 399)
Telmisartan/HCTZ
Combination therapy
The majority of hypertensive patients need combination 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
Average no. of antihypertensive medications
Bakris et al. Am J Med 2004;116(5A):30S–8
Dahlöf et al. Lancet 2005;366:895–906
4
Telmisartan plus HCTZ12.5 is superior to Valsartan plus
HCTZ12.5 in 24 hour ABPM reduction
SBP change from baseline (mmHg)
Last 6 h
24 h
Morning
Daytime
***
***
Night-time
0
-5
-10
-15
-20
***
-25
***p < 0.001 vs Valsartan + HCTZ
Sharma AM, et al. Cardiovasc Diabetol 2007;6(1):28
***
***
Valsartan 160 mg + HCTZ 12.5 mg (n=412)
Telmisartan 80 mg + HCTZ 12.5 mg (n=428)
Telmisartan plus HCTZ25 is superior to valsartan
plus HCTZ25 in reducing blood pressure
SBP change from baseline (mmHg)
SBP
DBP
0
-5
-10
Telmisartan/HC
TZ 80/25 mg (n = 942)
-15
Valsartan/HCTZ
160/25 mg (n = 952)
-20
p=0.0019
-25
-30
p=0.0004
White WB et al. J Hum Hypertens 2009;23:817-2
Placebo (n = 227)
Telmisartan plus amlodipine provides dose
dependent powerful 24h ABPM reduction
24-h mean SBP reduction
(mmHg)
***†††
24-h mean DBP reduction
(mmHg)
***†††
***†††
**†††
***†††
***†††
25
20
15
10
10
5
5
0
2.5
80
40
***†††
20
0
0
16
14
12
10
8
6
4
2
0
Telmisartan (mg)
***†††
5
2.5
80
40
20
0
0
Telmisartan (mg)
n=1461
**p < 0.001; ***p < 0.0001 vs telmisartan alone; †††p < 0.0001 vs amlodipine alone
SBP, systolic blood pressure; DBP, diastolic blood pressure
Littlejohn TW et al. J Clin Hypertension. 2009;11(4):207-213
10
Telmisartan significantly reduces peripheral
oedema associated with Amlodipine
Incidence of peripheral oedema (%)
20
17.8
15
8.9 *
10
5.2 †
5
1.7 †
0
A10
T40/80+A5
* p <0.05; † p <0.0001
Littlejohn TW et al. J Clin Hypertension. 2009;11(4):207-213
T40/80+A10
T/A pooled
Conclusions
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