Transcript Telmisartan plus Amlodipine - Medical Education Slide Resource - (Final Version 1.1)

Telmisartan plus Amlodipine
- Medical Education Slide Resource (Final Version 1.1)
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Frequently Used Abbreviations and Trial
Acronyms
• AASK
African American Study of Kidney Disease
and Hypertension
• ABCD
Appropriate Blood Pressure Control in
Diabetes
• ABPM
ambulatory blood pressure monitoring
• ACE
angiotensin-converting enzyme
• ACE-I
angiotensin-converting enzyme inhibitor
• ACCOMPLISH Avoiding Cardiovascular events
through Combination Therapy in
Patients Living with Systolic Hypertension
• ACCORD
Action to Control Cardiovascular Risk in
Diabetes
• AE
adverse event
• AHA
American Hypertension Association
• ALLHAT
Antihypertensive and Lipid-Lowering
Treatment to prevent Heart Attack Trial
• ARB
angiotensin II receptor blocker
• ASCOT-BPLA Blood Pressure-Lowering Arm of the
Anglo-Scandinavian Cardiac Outcomes Trial
• ASCOT-CAFÉ Anglo-Scandinavian Cardiac Outcomes
Trial Conduit Artery Functional
Evaluation study
• AT1
angiotensin II receptor type 1
• AT2
angiotensin II receptor type 2
• AUC
area under curve
• βB
beta-blocker
• BMI
body mass index
• BP
blood pressure
• CAD
coronary artery disease
• CAMELOT
Comparison of Amlodipine vs Enalapril
to Limit Occurrences of Thrombosis
• CCB
calcium channel blocker
• CHARM
Candesartan in Heart failure
Assessment of Reduction in Mortality
and Morbidity
• CHEP
Canadian Hypertension Education Program
• CHF
chronic heart failure
• CI
confidence interval
• CKD
chronic kidney disease
• CV
cardiovascular
• DBP
diastolic blood pressure
• DHP
dihydropyridine
• ECG
• ELITE II
• ESH/ESC
•
•
•
•
•
•
•
•
•
•
•
•
•
•
ESRD
FDC
GFR
HCTZ
HIV
HOPE
HOT
HR
HTN
HYVET
IDNT
IHD
INVEST
IRMA 2
• JNC VII
•
•
•
•
I-Preserve
JSH
LDL
LIFE
•
•
•
•
LVH
MDRD
MI
MOSES
• MPR
• NA
• NAVIGATOR
• NHANES
• NICE
electrcardiogram
Evaluation of Losartan In The Elderly-II
European Society of Hypertension/
European Society of Cardiology
end-stage renal disease
fixed-dose combination
glomerular filtration rate
hydrochlorothiazide
human immunodeficiency virus
Heart Outcomes Prevention Evaluation
Hypertension Optimal Treatment
hazard ratio
hypertension
HYpertension in the Very Elderly Trial
Irbesartan Type II Diabetic Nephropathy Trial
ischaemic heart disease
International Verapamil SR-Trandalopril
IRbesartan in patients with type 2 diabetes
and MicroAlbuminuria
The Seventh Report of the Joint National
Committee on the Prevention, Detection,
Evaluation, and Treatment of High Blood
Pressure
Irbesartan in HF with preserved EF
Japanese Society of Hypertension
low-density lipoprotein
Losartan Intervention For Endpoint Reduction
in hypertension
left ventricular hypertrophy
Modification of Diet in Renal Disease
myocardial infarction
Morbidity and Mortality after Stroke
Eprosartan vs Nitrendipine for Secondary
Prevention
medication possession ratio
noradrenaline
Nateglinide And Valsartan in Impaired
Glucose Tolerance Outcomes Research
National Health and Nutrition Examination
Survey
National Institute for Clinical Excellence
• ONTARGET®
ONgoing Telmisartan Alone and in
combination with Ramipril Global Endpoint
Trial
• OPTIMAAL
OPtimal Therapy In Myocardial infarction
with the Angiotensin II Antagonist Losartan
• PAR
population attributable risk
• PPARy
peroxisome proliferator-activated receptor
gamma
• PREVENT
Prospective Randomized Evaluation of the
Vascular Effects of Norvasc Trial
• PRoFESS®
Prevention Regimen For Effectively
avoiding Second Strokes
• RAS
renin-angiotensin system
• RAS-I
renin-angiotensin system inhibitor
• RENAAL
Reduction of Endpoints in NIDDM with the
Angiotensin II Antagonist Losartan
• ROADMAP
Randomized Olmesartan And Diabetes
MicroAlbuminuria Protection
• RR
relative risk
• SBP
systolic blood pressure
• SCOPE
Study on Cognition and Prognosis in the
Elderly
• SHEP
Systolic Hypertension in the Elderly Program
• SIGN
Scottish Intercollegiate Guidelines Network
• SNS
sympathetic nervous system
• Syst-Eur
Systolic Hypertension in Europe
• STITCH
Simplified Treatment Intervention To Control
Hypertension
• TEAMSTA
Telmisartan plus Amlodipine Study in
Amlodipine
• TOD
target organ damage
• tPA
tissue plasminogen activator
• TRANSCEND® Telmisartan Randomized AssessmeNt
Study in ACE-I iNtolerant subjects with
cardiovascular Disease
• UAER
urinary albumin excretion rate
• UKPDS
United Kingdom Prospective Diabetes
Study
• Val-HeFT
Valsartan in Heart Failure Trial
• VALIANT
VALsartan in Acute myocardial iNfarcTion
• VALUE
Valsartan Antihypertensive Long-term Use
Evaluation
2
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Table of Contents
• Unmet needs in the treatment of hypertension
• Hypertension – a major CV risk factor
• Why is combination therapy needed?
• Why combine a RAS-I and a CCB?
• Why telmisartan plus amlodipine?
• For which patients?
• What about other single-pill combinations?
• Conclusions
3
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Prevalence of hypertension (%)
High Prevalence of Hypertension Worldwide
60
55
47
38
40
38
49
49
42
28
20
0
USA
Italy
Sweden England Spain Finland Japan* Germany
Adults aged 35–64 y (data are age- and sex-adjusted), except* (adults aged ≥ 30 y)
Hypertension defined as BP  140/90 mmHg or on treatment
4
Wolf-Maier et al. JAMA. 2003;289:23632369;
Sekikawa, Hayakawa. J Hum Hypertens. 2004; 2004;18:911–912.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Prevalence of hypertension (%)
Prevalence of Hypertension Increases With
Age and is > 60% in Patients 60 y or Older
100
80.3
Men
Women
80
71.2
60.3 61.3
60
44.8 42.0
40
32.6
23.3
21.2
20
14.4
9.9
6.2
0
2029
3039
4049
5059
Age (y)
6069
Data for established market economies:
Australia, Canada, England, Germany, Greece, Italy, Japan, Spain, Sweden, USA
5
Kearney et al. Lancet. 2005;365:217223.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
 70
Prevalence of hypertension (%)
Prevalence of Hypertension Differs With Ethnicity
60
40.5
40
25.1
27.4
20
0
Mexican–American
White non-Hispanic
Ethnic group
Black non-Hispanic
Estimated non-institutionalized US adults, 19992002.
Adapted from Centers for Disease Control and Prevention
6
Brown. BMJ. 2006;332:833836.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
JNC VII Guidelines: BP Categories (USA)
BP category
SBP
(mmHg)
Normal
7
DBP
(mmHg)
< 120
and
< 80
Pre-hypertension
120–139
and/or
80–89
Stage 1
140–159
and/or
90–99
Stage 2
 160
and/or
 100
Chobanian et al. JAMA. 2003;289:25602572.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
ESH/ESC Guidelines: BP Categories (EU)
BP category
SBP
(mmHg)
DBP
(mmHg)
Optimal
< 120
and
< 80
Normal
120–129
and/or
80–84
High normal
130–139
and/or
85–89
Grade 1 (mild)
140–159
and/or
90–99
Grade 2 (moderate)
160–179
and/or
100–109
 180
and/or
 110
Hypertension
Grade 3 (severe)
8
Mancia et al. Eur Heart J. 2007;28:1462–1536.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Recommended Target BP is the Same Worldwide
Type of hypertension
BP goal
(mmHg)
Uncomplicated
< 140/90
Complicated
Type 2 diabetes
Very high CV risk*
* Patients with established CV disease (e.g., stroke, MI) and/or CKD.
9
Chobanian et al. JAMA. 2003;289:25602572; Mancia et al. Eur Heart J. 2007;28:1462–1536;
Ogihara et al. Hypertens Res. 2009;32:3–107.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
< 130/80
However, There is Conflicting Evidence, if
Diabetes Patients Benefit From Lower Targets (1)
CV outcomes from the HOT trial (n = 18,790)
Major CV events per
1,000 patient-years
30
20
10
24.4
DBP ≤ 80 mmHg
DBP ≤ 85 mmHg
DBP ≤ 90 mmHg
9.3
10
18.6
9.9
11.9
0
Patients with
essential hypertension
Patients with
hypertension and diabetes
Chobanian et al. Hypertension. 2003;42:1206–1252;
10 Hansson et al. Lancet. 1998;351:1755–1762.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
However, There is Conflicting Evidence, if
Diabetes Patients Benefit From Lower Targets (2)
CV outcomes from the
ACCORD trial
CV outcomes from the
INVEST trial
Standard (SBP < 140 mmHg) vs
intensive (SBP < 120 mmHg)
Not controlled (SBP > 140 mmHg) vs
usual control (SBP 130–140 mmHg) vs
tight control (SBP < 130 mmHg)
Outcome (%)
20
19.8
Not controlled (n = 2,175)
Usual control (n = 1,970)
Tight control (n = 2,255)
15.4
12.612.7
10.2
11
10
3.1
1.7 1.3
2.4
1.3 1
0
Death/
MI/
stroke
Allcause
mortality
The ACCORD Study Group. N Engl J Med. 2010 (10.1056/NEJM0a1001286);
11 INVEST retrospective analysis. ACC 2010.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Non-fatal
MI
Non-fatal
stroke
Awareness, Treatment and Control of
Hypertension is Rather Low Worldwide
Proportion of patients in the population (%)
Country
Aware
Treated
Controlled*
Japan
16.0
–
4.1
England
35.8
24.8
10.0
Germany
36.5
26.1
7.8
Spain
38.9
26.8
5.0
Sweden
48.0
26.2
5.5
Italy
51.8
32.0
9.0
USA
69.3
52.5
28.6
* BP < 140/90 mmHg
Wolf-Maier et al. Hypertension. 2004;43:10–17;
12 Sekikawa, Hayakawa. J Hum Hypertens. 2004;18:911–912.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Table of Contents
• Unmet needs in the treatment of hypertension
• Hypertension – a major CV risk factor
• Why is combination therapy needed?
• Why combine a RAS-I and a CCB?
• Why telmisartan plus amlodipine?
• For which patients?
• What about other single-pill combinations?
• Conclusions
13
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Risk of CV Mortality Doubles With Each
20/10 mmHg BP Increase
• Meta-analysis of 61 prospective, observational studies
• 1 million adults aged 40–69 y with BP > 115/75 mmHg
• 12.7 million person-years
Fold increase in
relative CV risk
10
8-fold
8
6
4-fold
4
2
2-fold
1-fold
0
115/75
135/85
155/95
SBP/DBP (mmHg)
14 Lewington et al. Lancet. 2002;360:1903–1913.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
175/105
Each 2 mmHg Decrease in SBP
Reduces CV Risk by 7–10%
• Meta-analysis of 61 prospective, observational studies
• 1 million adults aged 40–69 y with BP > 115/75 mmHg
• 12.7 million person-years
2 mmHg
decrease in
mean SBP
7% reduction in
risk of IHD and
other vascular
disease mortality
10% reduction in
risk of stroke
mortality
15 Lewington et al. Lancet. 2002;360:1903–1913.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Strong Evidence From Clinical Trials That
BP Lowering Reduces CV Risk
Odds ratio for CV mortality
(experimental/reference)
Actively controlled trials
1.50
MIDAS/NICS/VHAS
UKPDS C vs A
1.25
1.00
NORDIL
p = 0.002
INSIGHT
HOT L vs H
STOP2/ACE-Is
HOT M vs H
MRC2
SHEP
CAPPP
Negative values indicate
tighter BP control on
reference treatment
MRC1
STOP2/CCBs
0.75
Placebo-controlled studies
or trials with an untreated
control group
HEP
STONE
Syst-Eur
HOPE
UKPDS L vs H
Syst-China
EWPHE
RCT70-80
0.50
PART2/SCAT
ATMH
STOP1
0.25
–5
0
5
10
15
20
25
Difference (reference treatment minus
experimental treatment) in SBP (mmHg)
16 Staessen et al. Hypertens. Res 2005;28:385–407.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Table of Contents
• Unmet needs in the treatment of hypertension
• Hypertension – a major CV risk factor
• Why is combination therapy needed?
– Clinical evidence
– Guidelines
– Treatment adherence
• Why combine a RAS-I and a CCB?
• Why telmisartan plus amlodipine?
• For which patients?
• What about other single-pill combinations?
• Conclusions
17
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Many Hypertensive Patients Remain Untreated or
do not Achieve BP Control (NHANES)
Percentage of population
100
75
50
90
Untreated
73
71
69
45
Failed to achieve BP control*
46
71
68
63
50 **
42
40
35
32
36 **
25
0
1976–1980 1988–1991 1991–1994 1999–2000 2001–2002 2003–2004 2005–2006 2007–2008
Year
* BP control defined as BP < 140/90 mmHg; BP < 130/80 mmHg for patients with diabetes or CKD; includes
treated and untreated patients, except ** (only treated patients)
Chobanian et al. Hypertension. 2003;42:1206–1252; Ong et al. Hypertension. 2007;49:69–75;
18 Ostchega et al. NCHS Data Brief. 2008;3:1–38; Egan et al. JAMA. 2010;303:2043–2050.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Patients with BP control (%)
The Minority of Patients Achieve
BP Control on Monotherapy
40
39
30
20
20
10
0
BP < 140/90 mmHg
BP < 135/85 mmHg
19 Dickerson et al. Lancet. 1999:353:2008–2013.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
The Majority of Hypertensive Patients Need
Combination Therapy to Achieve BP Goals
Trial (SBP achieved)
ASCOT-BPLA (137 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 number of antihypertensive medications
Bakris et al. Am J Med. 2004;116(5A):30S–38S;
20 Dahlöf et al. Lancet. 2005;366:895–906.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
JNC VII
ESH/ESC
• Combination treatment should be considered as first choice when
there is high CV risk
– i.e., in individuals in whom BP is markedly above the hypertension
threshold (> 20/10 mmHg), or associated with multiple risk factors
sub-clinical organ damage, diabetes, renal or CV disease
• Many patients will require more than one drug to achieve
adequate BP control
– Pathophysiological reasoning suggests that adding an ACE-I/ARB
to a CCB or a diuretic (or vice versa in the younger group) are
logical combinations
JSH
• Most patients with hypertension will require two or more
antihypertensive medications to achieve their BP goals
– When BP is > 20/10 mmHg above goal, consideration should be
given to initiating therapy with two drugs
NICE
Also Guidelines Acknowledge That Most Patients
Need Combination Therapy to Achieve BP Goals
The Japanese Society of
Hypertension Committee for
Guidelines for the
Management of Hypertension
2009
• The use of two or three drugs in combination is often necessary
to achieve the target BP control
– A low dose of a diuretic should be included in this combination
Chobanian et al. JAMA. 2003;289:2560–2572; Mancia et al. Eur Heart J. 2007;28:1462–1536; http://www.nice.org.uk/
21 download.aspx?o=CG034fullguideline (accessed January 2010); Ogihara et al. Hypertens Res. 2009;32:3–107.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
JNC VII: Treatment Algorithm of Hypertension
†
Heart failure, post-MI,
coronary disease risk, diabetes,
CKD and recurrent stroke
prevention
Lifestyle modifications
Not at goal BP*
Hypertension without
compelling indications†
Stage 1
Stage 2
Thiazide-type diuretics
for most. May consider
ACE-I, ARB, βB, CCB or
combination
Two-drug combination
for most
(usually including
thiazide-type diuretic)
*< 140/90 mmHg or
< 130/80 mmHg for those
with diabetes or CKD
Hypertension with
compelling indications†
Drug(s) for the
compelling indications
Other antihypertensive
drugs (diuretics, ACE-I,
ARB, βB, CCB) as
needed
If not at goal, optimize dosages or add additional drugs until goal BP is achieved.
Consider consultation with hypertension specialist
22 Chobanian et al. JAMA. 2003;289:2560–2572.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
ESH/ESC: Treatment Algorithm of Hypertension
Consider: BP level before treatment /absence or presence
of target organ damage and risk factors
- 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 two-drug combination
Not at BP goal
Full dose of
single agent
Switch to
different agent
at low dose
Full dose of
two-drug
combination
Add a
third drug
at low dose
Not at BP goal
Two/three-drug
combination
at full dose
Full-dose
single agent
Full doses of
two/three-drug combination
23 Mancia et al. Eur Heart J. 2007;28:1462–1536.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
NICE: Treatment Algorithm of Hypertension
Step 1
< 55 y
 55 y or Black
patients at any age
ACE-I (or ARB*)
CCB or thiazidetype diuretic
Step 2
ACE-I (or ARB*) + CCB or
ACE-I (or ARB*) + thiazide-type diuretic
Step 3
ACE-I (or ARB*) + CCB + thiazide-type diuretic
Step 4
Add further diuretic therapy, or α-blocker or βB.
Consider seeking specialist advice
* If ACE-I not tolerated
24 http://www.nice.org.uk/download.aspx?o=CG034fullguideline (accessed January 2010).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Combination Therapy in Patients With Hypertension is Increasing in Community Practice
70
60
60
50
48
40
30
20
10
0
1993
2004
RAS-I combinations
lead the way
Antihypertensive
drug visits (%)*
Antihypertensive
drug visits (%)*
Increase in combination therapy
prescription from 1993 to 2004
1993
30
27
2004
20
17
15
10
6
16
9
8
10
0
βB–
RAS-I
CCBRAS-I
Diuretics– Diuretics–
βB
RAS-I
• 1993: 29.8 million (weighted number) of ambulatory visits by adults having
uncomplicated essential hypertension; antihypertensive prescriptions occurred in
74% of those visits
• 2004: 39.6 million adults were diagnosed with uncomplicated essential
hypertension; 70% of those received a prescription for antihypertensive therapy
* Antihypertensive drug visits defined as: hypertension visits during which prescription of a generic or
brand-named antihypertensive drug was mentioned.
25 Ma et al. Hypertension. 2006;48:846–852.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Considerations of (Single-Pill) Combination
Therapy
Benefits
• BP goal may be achieved more rapidly than with monotherapy1-4
• Greater reductions in BP1,2 and higher BP response and control rates3,4
vs monotherapy
• Reduced AEs due to lower doses of individual agents (lower doses
effective due to complementary mode of action3,4
• Fixed-dose, single-pill combinations reduce pill burden,1,2 improved
compliance and treatment adherence,3,4 and may cost less than
individual components prescribed
Patients
• Most hypertensive patients will require two or more agents to achieve
target BP1,2
Combinations
• Drugs should have a complimentary mechanism of action2
• Evidence that BP reduction with combination therapy is greater than
that of each individual component alone2
Limitations
• Loss of flexibility with single-pill combinations2
1. Chobanian et al. Hypertension. 2003;42:1206–1252; 2. Mancia et al. Eur Heart J. 2007:28:1462–1536;
26 3. Tedesco et al. J Clin Hypertens. 2006;8:634–641; 4. Wald et al. Am J Med. 2009;122:290–300.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Single-Pill Combinations Improve
Treatment Compliance
Relative reduction in
non-compliance* (%)
30
RR 0.74
95% CI 0.69 to 0.80
p < 0.0001
26
RR 0.76
95% CI 0.71 to 0.81
p < 0.0001
24
20
10
0
Chronic disease
(9 studies)
Hypertension
(4 studies)
* With single-pill combination therapy vs free-drug regimens
27 Bangalore et al. Am J Med. 2007;120:713–719.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Single-Pill Combinations of ACE-I and CCB
Improve Treatment Compliance
Single-pill combination
(ACE-I/CCB)
(n = 2,839)
88.0%
p < 0.0001
Free combination
(ACE-I + CCB)
(n = 3,367)
69.0%
0
20
40
60
80
100
Medication possession ratio (%)*
* Defined
as the total number of days of therapy for medication dispensed/365 days of study follow-up
28 Gerbino, Shoheiber. Am J Health System Pharm. 2007;64:1279–1283.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Single-Pill Combinations Reduce
Resource Utilization
p < 0.0001
Healthcare costs (US$)
6000
Single-pill combinations (n = 2,336)
Component therapy (n = 3,368)
5000
5,236
4000
3,179
3000
p < 0.0001
p < 0.0001
p < 0.0001
1,952
2000
1,646
NS
1,229
1,120
1,322
1000
334
410
402
0
Hospital
Other
Ambulatory
Drug
NS = not significant
29 Dickson, Plauschinat. Am J Cardiovasc Drugs. 2008;8:45–50.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Total
The Simplified Treatment Intervention To
Control Hypertension (STITCH) Trial
STITCH-care algorithm
CHEP guidelines algorithm*
Lifestyle modification
therapy
Initial therapy with a low dose ACE-I/diuretic or
ARB/diuretic combination
IS BLOOD PRESSURE CONTROLLED?
Thiazide
diuretic
ACE-I
ARB
Longacting
CCB
βblocker†
Yes
Continue with
current therapy
No
Up-titration of
combination therapy
successively to
the highest dose
Consider:
• Non-adherence?
Dual
combination
• Secondary HTN?
• Interfering drugs or
lifestyle?
• White coat effect?
Yes
No
Continue with
current therapy
Triple or
quadruple
therapy
Add CCB and
up-titrate
Yes
Continue with
current therapy
* Treatment of systolic/diastolic hypertension without other compelling indications
† Not indicated as first line therapy for patients > 60 y
30 Khan et al. Can J Cardiol. 2007;23:539–550; Feldman et al. Hypertension. 2009;53:646–653.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
No
Add α-blocker
or β-blocker or
spironolactone
The Simplified Treatment Intervention To
Control Hypertension (STITCH) Trial
Secondary outcome:
Combination drug prescriptions
Primary outcome:
Proportion of practices at BP
target
Absolute difference in BP control rate = 12%
p = 0.026
60
100
64,7
85,0
52,7
Patients (%)
Practices (%)
70
50
40
30
20
80
40
20
10
0
p < 0.001
60
15,5
0
CHEP
guideline
care
STITCH
care
CHEP
guideline
care
Target BP: SBP < 140 mmHg and DBP < 90 mmHg; or
SBP < 130 mmHg and DBP < 80 mmHg for diabetic patients
31 Feldman et al. Hypertension. 2009;53:646–653.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
STITCH
care
ARBs have the Best Treatment Adherence
of all Antihypertensive Classes
Diuretics
1.83
βB
1.64
α-blockers
1.23
CCBs
1.08
ACE-Is
1.00
ARBs
0.92
-
0.5
1.0
+
Cause-specific HR (95% CI) for discontinuation*
* Relative to ACE-I after 1 y of treatment
32 Corrrao et al. J Hypertens. 2008;26:819–824.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
2.0
Table of Contents
• Unmet needs in the treatment of hypertension
• Hypertension – a major CV risk factor
• Why is combination therapy needed?
• Why combine a RAS-I and a CCB?
– BP regulation
– Synergies and complementary clinical benefits
– Clinical evidence and guidelines
• Why telmisartan plus amlodipine?
• For which patients?
• What about other single-pill combinations?
• Conclusions
33
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
The Two Key Components of BP Regulation
34 Grassi. J Hypertens. 2001;19:1713–1716; modified.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
The RAS: Pharmacological Action of ARBs
Non-ACE
pathways
Angiotensin II
escape
(e.g. chymase, tPA,
cathepsin)
Angiotensinogen
Angiotensin I
ARB
AT1 receptor
ACE
Bradykinin
ACE
Angiotensin II
Inactive fragment
Aldosterone
Sodium/water
retention
35
Vasoconstriction
Cell growth
Sodium/water retention
Sympathetic activation
AT2 receptor
Vasodilation
Antiproliferation
Tissue regeneration
Natriuresis
Adapted with permission from Dzau. J Hypertens Suppl. 2005;23(1):S9–S17.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Effects of ARB on BP Regulation
• Release of renin catalyzes conversion of angiotensinogen into
angiotensin I, which is converted by ACE to angiotensin II →
– Vasoconstriction, increased aldosterone and sodium/water retention,
and SNS activation
• ARBs block the effects of angiotensin II by binding to AT1
receptors →
– Arterial and venous dilation
– Reduced SNS activity
– Reduced secretion of aldosterone and increased secretion of sodium
and water
36 Mistry et al. Expert Opin Pharmacother. 2006;7:575–581.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Amlodipine (DHP-CCB): Mode of Action
• Inhibits the transmembrane influx of calcium ions into vascular
smooth muscle and cardiac muscle
– Inhibition is selective, with a greater effect on vascular smooth muscle
cells
• Binds to both DHP- and non-DHP-binding sites
• Is a peripheral arterial vasodilator
• Acts directly on vascular smooth muscle leading to a reduction
in peripheral vascular resistance and a subsequent reduction
in BP
37 Murdoch, Heel. Drugs. 1991;41:478–505.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Effects of CCB on BP Regulation
SNS activity →
– NA binds to α1-adrenergic receptors on vascular smooth muscle →
vasoconstriction1
• SNS also stimulates renin secretion from the kidney, thereby
activating the RAS1
• CCBs inhibit SNS-induced vasoconstriction by blocking influx
of calcium ions (needed for contraction) through voltage-gated
calcium channels →
– Vasodilation2,3
• Other effects: natriuresis; inhibition of aldosterone release;
interference with angiotensin II-mediated vasoconstriction3
38
1. Mancia et al. J Hypertens Suppl. 2006;24(1):S51–S56; 2. Robertson and Robertson. In: Hardman JG, Limbard JG, eds-in-chief. Goodman
& Gilman’s The Pharmacological Basis of Therapeutics. 9th ed. 1996. p759–779; 3. Prisant. In: Oparil S, Weber MA,
eds. Hypertension: Companion to Brenner & Rector’s The Kidney. 2nd ed. 2005. p683–704.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
CCB + ARB:
The Synergies of Counter-Regulation (1)
CCB
 Arteriodilation
 Peripheral oedema
 Effective in low-renin patients
 Reduces cardiac ischaemia
BP
Synergistic
BP reduction
Complementary
clinical benefits
CCB
 RAS activation
 No renal or CHF
benefits
Mistry et al. Expert Opin Pharmacother. 2006;7:575–581;
39 Sica. Drugs. 2002;62:443–462; Quan et al. Am J Cardiovasc Drugs. 2006;6:103113.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
CCB + ARB:
The Synergies of Counter-Regulation (2)
CCB
 Arteriodilation
 Peripheral oedema
 Effective in low-renin patients
 Reduces cardiac ischaemia
ARB
 Venodilation
 Attenuates peripheral oedema
 Effective in high-renin patients
 No effect on cardiac ischaemia
BP
Synergistic
BP reduction
Complementary
clinical benefits
ARB
 RAS blockade
 CHF and renal
benefits
CCB
 RAS activation
 No renal or CHF
benefits
Mistry et al. Expert Opin Pharmacother. 2006;7:575–581; Sica. Drugs. 2002;62:443–462;
40 Quan et al. Am J Cardiovasc Drugs. 2006;6:103113.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Venous Fluid Leakage Induced by CCBs …
Fluid leakage
Arterial
dilation
(CCBs)
No
venous
dilation
Fluid leakage
Capillary bed
Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:42–73; White et al. Clin Pharmacol Ther.
41 1986;39:43–48; Gustaffson. J Cardiovasc Pharmacol. 1987;10:S121–S131.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
… Gets Reduced by Co-administration of ARBs
Arterial
dilation
(CCB and
ARB)
Venous
dilation
(ARB)
Capillary bed
Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:42–73; White et al. Clin Pharmacol Ther. 1986;39:43–48;
42 Gustaffson. J Cardiovasc Pharmacol. 1987;10:S121–S131; Messerli et al. Am J Cardiol. 2000;86:11821187.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Renal Hyperfiltration Induced by
Amlodipine is Reduced by Telmisartan
Amlodipine
L-type Ca
channels
Amlodipine + Telmisartan
L-type Ca
channels
Increased
Decreased
Glomerular pressure
and filtration
Glomerular pressure
and filtration
43 Peti-Peterdi; Abstract ESC 2010 (submitted).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
In ASCOT CCB ± ACE-I Lowers BP as
Effectively as β-Blocker ± Diuretic
BP reduction
Study design
Patients with treated
hypertension
SBP > 140 mmHg and/or
DBP > 90 mmHg
Plus three CV
risk factors
Randomized
Assigned CCB adding
ACE-I as required to
reach BP goal*
(n = 9,639)
Assigned βB adding
diuretic as required to
reach BP goal*
(n = 9,618)
Mean BP reduction (mmHg)
Patients with untreated
hypertension
SBP > 160 mmHg and/or
DBP > 100 mmHg
βB ± diuretic CCB ± ACE-I
0
-10
–15.6
-20
-30
–25.7
–17.7
–27.5
5.5 y median follow-up
* BP goal defined as < 140/90 mmHg in patients without diabetes and < 130/80 mmHg in patients with diabetes
44 Dählof et al. Lancet. 2005;266:895–906.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
But CCB ± RAS-I Lowers Central Aortic Pressure More
Effectively Than βB ± Diuretic (ASCOT-CAFÉ)
45 Williams et al. Circulation. 2006;113:1213–1225.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
ACCOMPLISH: Similar BP in Both Treatment Arms
46 Jamerson et al. N Engl J Med. 2008;359:2417–2428.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
But RAS-I/CCB Reduces CV Morbidity/Mortality
Significantly More Than RAS-I/HCTZ (ACCOMPLISH)
552 (9.6%) patients with events in the benazepril-amlodipine group vs 679 (11.8%) in the benazeprilHCTZ group (RR 20%; HR 0.80; 95% CI 0.72 to 0.90; p < 0.001)
47 Jamerson et al. N Engl J Med. 2008;359:2417–2428.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
HRs of Adjudicated Primary Endpoints
(ACCOMPLISH)
48 Jamerson et al. N Engl J Med. 2008;359:2417–2428.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan is the Most Studied Amongst ARBs in
Mortality and Morbidity Endpoint Trials
Number of patients
60,000
51,878
50,000
44,264
40,000
30,000
19,335
20,000
12,565
10,000
1,405
0
Eprosartan
MOSES1
4,449
Olmesartan
ROADMAP2
6,405
Irbesartan
Losartan
Valsartan
Telmisartan
IRMA II3
SCOPE6
RENAAL8
Val-HeFT12
TRANSCEND®16
IDNT4
CHARM7
ELITE II9
NAVIGATOR13
PRoFESS®16
OPTIMAAL10
VALIANT14
ONTARGET®16
LIFE11
VALUE15
I-Preserve5
49
Candesartan
1. Schrader et al. Stroke. 2005;36:1218–1226; 2. http://www.roadmapstudy.org/resident.aspx; 3. Parving et al. N Engl J Med. 2001;345:870–878; 4. Lewis et al. N Engl J Med. 2001;345:851–860; 5.
Carson et al. J Card Fail. 2005;11:576–585; 6. Papademetriou et al. J Am Coll Cardiol. 2004;44:1175–1180; 7. www.atacand.com; 8. Brenner et al. N Engl J Med. 2001;345:861–869; 9. Pitt et al.
Lancet. 2000;355:1582–1587; 10. Dickstein et al. Lancet. 2002;360:752–760; 11. Dahlof et al. Lancet. 2002;359:955–1003; 12. Cohn et al. N Engl J Med. 2001;345:1667–1675; 13.
www.novartis.com; 14. Pfeffer et al. N Engl J Med. 2003;349:1893–1906; 15. Julius et al. Lancet. 2004;363:2022–2031; 15. www.ontarget-micardis.com.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Reappraisal of ESH/ESC Guidelines Suggests Four
Preferred Antihypertensive Drug Classes
2009
2007
Diuretics
Diuretics
βB
ARB
ARB
ONTARGET®
ACCOMPLISH
HYVET
CCB
CCB
α-blockers
ACE-I
ACE-I
Most rational combinations
Combinations used as necessary
Mancia et al. Eur Heart J. 2007;28:1462–1536;
50 Mancia et al. J Hypertens. 2009;27:2121–2158.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
ARBs and DHP-CCBs are Recommended for
Complementary Indications (ESC/ESH Guidelines)
ARBs
DHP-CCBs
• Essential hypertension
• Isolated systolic hypertension
• Heart failure
• CAD
• Post-MI
• Angina pectoris
• Diabetic nephropathy
• Hypertension in Blacks
• Proteinuria/microalbuminuria
• (Pregnancy)
• Atrial fibrillation
• LVH
• Metabolic syndrome
• ACE-I-induced cough
• LVH
51 Mancia et al. Eur Heart J 2007;28:1462–1536.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Table of Contents
•
•
•
•
•
Unmet needs in the treatment of hypertension
Hypertension – a major CV risk factor
Why is combination therapy needed?
Why combine a RAS-I and a CCB?
Why telmisartan plus amlodipine?
– Unique pharmacology
– Phase III/IV clinical trials programme
– Efficacy/safety as initial therapy
• Including 24-h ABPM
– Efficacy/safety in patients not at goal with amlodipine
monotherapy
– CV protection evidence of the respective components
• For which patients?
• What about other ARB/CCB single-pill combinations?
• Conclusions
52
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Plasma elimination half-life (h)
Amlodipine has the Longest Plasma
Elimination Half-life in its Class (CCB)
35
> 30
30
25
19
20
16
14
15
12
9
10
7
5
5
0
Lercanidipine
Nifedipine
Nimodipine
Nisoldipine
Nicardipine
Felodipine
Lacidipine
53 Based on available online product information.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Amlodipine
Plasma half-life (h)
Longest plasma half-life
24
24
18
15
15
12
12
7
8
9
6
0
Epro- LoVal- Cande- Olme- Irbe- Telmisartan sartan sartan sartan sartan sartan sartan
Receptor dissociation
half-life (min)
Telmisartan has a Unique Pharmacology
Profile in its Class (ARB)
Highest receptor affinity
213
200
166
150
133
100
81
70
50
0
Losartan
Valsartan
Candesartan
Olmesartan
Telmisartan
500
Most lipophilic
(high tissue penetration)
Highest selective PPARγ activation
†
93
100
80
60
34
40
20
9
13
17
17
0
Cande- Epro- Val- Olme- LoIrbe- Telmisartan sartan sartan sartan sartan sartan sartan
54
PPARy fold activation
Volume of distribution (L)
500
Active metabolite of losartan
30
27
25
20
15
10
4
5
1
1
2
2
2
0
Epro- Olme- EXP Cande- ValIrbe- Telmisartan sartan 3174† sartan sartan sartan sartan
Burnier, Brunner. Lancet. 2000;355:637–645; Brunner. J Hum Hypertens. 2002;16(Suppl 2):S13–S16; Kakuta et al. Int J Clin Pharmacol Res. 2005;25:
41–46; Wienen et al. Br J Pharmacol. 1993;110:245–252; Song, White. Formulary. 2001;36:487–499; Asmar. Int J Clin Pract.
2006;60:315–320; Israili. J Hum Hypertens. 2000;14(Suppl 1):S73–S86; Benson et al. Hypertension. 2004;43:993–1002.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine Phase III/IV
Clinical Trials Programme
Study
Objective
Phase III
• 4x4 factorial design1,2
Combinations of T20–80 mg and A2.5–10 mg vs respective monotherapies in patients with
stage 1 or 2 hypertension
• TEAMSTA-53
T40–80/A5 single-pill combinations vs A5–A10 monotherapy in hypertensive patients not
sufficiently controlled with A5 (DBP ≥ 90 mmHg)
• TEAMSTA-5 follow-up
6-month follow-up of TEAMSTA-5 (long-term safety and efficacy)
• TEAMSTA-104
T40–80/A10 single-pill combinations vs A10 monotherapy in hypertensive patients not
sufficiently controlled with A10 (DBP ≥ 90 mmHg)
• TEAMSTA-10 follow-up
6-month follow-up of TEAMSTA-10 (long term safety and efficacy)
Phase IIIb/IV
• TEAMSTA Severe HTN5
T80/A10 single-pill combination vs T80 and A10 monotherapy in patients with severe
hypertension (SBP ≥ 180 mmHg and DBP ≥ 95 mmHg)
• TEAMSTA Diabetes
T80/A10 single-pill combination vs A10 monotherapy in hypertensive diabetics
• TEAMSTA Switch
Switch of RAS-I non-responders to telmisartan/amlodipine single-pill combinations
• TEAMSTA Protect
Telmisartan/amlodipine vs olmesartan/HCTZ on endothelial dysfunction beyond BP
55
1. Littlejohn et al. J Clin Hypertens. 2009;11:207–213; 2. Littlejohn et al. Postgrad Med. 2009;121:5–14; 3. Neldam S, Lang M.
J Clin Hypertens. 2009;11(Suppl s1):114 (P279); 4. Neldam S, Edwards C. Poster presentation ESH 2009 (P911);
5. Neutel et al. J Clin Hypertens. 2010: In press.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine …
… as Initial Therapy
56
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine Provides Consistent
BP Reductions Across HTN Severities
Moderate HTN
Baseline SBP = 160 – < 1701
(n = 31)
Severe HTN
170 – < 1801
180 – < 1902
190 – < 2002
(n = 13)
(n = 305)
(n = 71)
Mean SBP reductions from
baseline (mmHg)
0
-10
-20
-30
-40
-50
-60
57
-33,7
-36,9
-47,5
T80/A10 (n = 1361; n = 3792)
1. Littlejohn et al. J Clin Hypertens. 2009;11:207–213; 2. Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010
poster presentation (LB-PO-10) & data on file
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
-48,9
Telmisartan Plus Amlodipine Provides BP
Reductions of Almost 50 mmHg
Severe HTN*
Baseline SBP = 180 – < 185
(n = 195)
185 – < 190
190 – < 195
195 – < 200
(n = 110)
(n = 57)
(n = 14)
-48.3
-48.7
-49.5
Mean SBP reductions from
baseline (mmHg)
0
-10
-20
-30
-40
-50
-60
-47.0
T80/A10 (n = 379)
* SBP ≥ 180 – < 200 mmHg; mean baseline BP = 185.4/103.2 mmHg
58 Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine Provides BP Reductions of
≥ 50 mmHg in Almost 50% of Patients With Severe HTN*
50
A10
46.3
T80/A10
Patients (%)
40
31.7
29.6
30
18.0
20
15.4
9.8
10
0
(n = 65)
(n = 183)
(n = 37)
(n = 117)
(n = 20)
(n = 61)
≥ 55 mmHg
≥ 60 mmHg
≥ 50 mmHg
Mean SBP reductions from baseline*
* Mean baseline BP = 185.4/103.2 mmHg
59 Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine Provides Consistently High
BP Reductions in Hypertensive at-Risk Patients
Diabetic1
Obese
BMI ≥ 30kg/m1
(n = 62)
(n = 175)
-46.8
Elderly
≥ 65 y1
Black1
Severe HTN
≥ 180/95 mmHg2
(n = 36)
(n = 100)
(n = 30)
(n = 379)
-44.2
-46.6
-46.1
-47.5
Metabolic
syndrome1*
Mean SBP reductions from
baseline (mmHg)
0
-10
-20
-30
-40
-50
-43.2
T80/A10
-60
Mean baseline BP = 185.4/103.2 mmHg
* Diabetes, obesity (BMI  30kg/m2), and HTN
1. TEAMSTA Severe HTN study (data on file; Boehringer Ingelheim Pharmaceuticals, Inc);
60 2. Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
0
2
SBP
DBP
Week
Week
4
6
8
-10
-20
-30
p=
0.0077
-40
-50
p=
0.0001
p=
0.0001
p=
0.0001
p=
0.0002
T80/A5–A10* (n = 379)
0
Mean change from baseline (mmHg)
Mean change from baseline (mmHg)
Telmisartan/Amlodipine Provides Significant BP
Reductions (> 31 mmHg SBP) Already After 1 Week
2
4
6
8
-5
-10
p=
0.0301
p=
0.0089
-15
p=
0.0001
-20
A5–A10* (n = 195)
* A5 and T80/A5 for the first 2 weeks, then forced-titration to A10 and T80/A10, respectively;
baseline BP = 185.4/103.2 mmHg
61 Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
p=
0.0002
p=
0.0006
Telmisartan/Amlodipine Provides 80% of its
Maximum Effect After Just 2 Weeks of Treatment
Mean SBP reduction (mmHg)
T80/A5
T80/A10
(n = 405)
(n =379)
Mean SBP (mmHg)
185.4
Baseline
80%*
147.7
–37.9 mmHg
Week 2
–47.5 mmHg
137.9
Week 8
* Percentage of effect achieved after 2 weeks of treatment compared with
end of study (Week 8)
A5 and T80/A5 for the first 2 weeks, then forced-titration to A10 and T80/A10, respectively;
baseline BP = 185.4/103.2 mmHg
62 Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine Provides BP Goal Rates
(< 140/90 mmHg) in > 50% of Patients With Severe HTN*
BP goal rate after 8 weeks (%)
60
50,4
50
40
35,6
30
20
10
0
A10
T80/A10
(n = 205)
(n = 395)
* ≥ 180/95 mmHg; A5 and T80/A5 for the first 2 weeks, then forced-titration to A10 and T80/A10, respectively
63 Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan/Amlodipine Provides High BP Goal
Rates (< 140/90 mmHg) in HTN at-Risk Patients
T80/A10
BP goal rate after 8 weeks (%)
100
87,0
81.7
84.6
80
83.3
72.7
72.7
60
50.4
40
20
0
(n = 23)
Diabetes1
(n = 71)
(n = 13)
1
Obese
Metabolic
BMI ≥ 30kg/m2 syndrome1*
(n = 22)
Elderly1
≥ 65 y
* Presence of diabetes, obesity (BMI  30kg/m2), and HTN
(n = 24)
Black1
(n = 44)
(n = 395)
Moderate-severe Severe HTN2
HTN1
≥ 180mmHg
≥ 160mmHg
1. Factorial design study (data on file; Boehringer Ingelheim Pharmaceuticals, Inc);
64 2. Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine Provides BP
Response Rates* in up to 99.7% of Patients
SBP response*
No SBP response
99.7%
* SBP < 140 mmHg or ≥ 10 mmHg reduction; T80/A10 (n = 395)
65 Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine …
… 24-h ABPM
66
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine Provides
Consistent 24-h ABPM Dose Response
24-h mean SBP reduction
(mmHg)
***†††
25
***†††
***†††
***†††
***†††
20
15
10
5
0
24-h mean DBP reduction
(mmHg)
10
80
40
0
Telmisartan (mg)
0
5
16
14
12
10
8
6
4
2
0
***†††
**†††
***†††
10
80
40
0
Telmisartan (mg)
0
5
** p < 0.001; *** p < 0.0001 vs Telmisartan alone; ††† p < 0.0001 vs Amlodipine alone; n = 562
67 Littlejohn et al. J Hypertens. 2008;26(suppl 1):S494; White et al. Blood Press Monit. 2010: In press.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Placebo
150
A5
T40
T40/A5
140
130
120
110
1
3
5
7
9
Mean SBP (mmHg)
Mean SBP (mmHg)
Telmisartan Plus Amlodipine Provides
Superior 24-h ABPM Profiles
Placebo
150
A5
T40
120
110
1
3
T40/A5
80
70
60
3
5
7
9
5
7
9
11 13 15 17 19 21 23
Time after dosing (h)
90
1
T40/A10
130
11 13 15 17 19 21 23
11 13 15 17 19 21 23
Time after dosing (h)
Mean DBP (mmHg)
Mean DBP (mmHg)
Placebo
T40
140
Time after dosing (h)
100
A10
Placebo
100
A10
T40
T40/A10
90
80
70
60
1
3
5
7
9
11 13 15 17 19 21 23
Time after dosing (h)
AHA criteria: recommended 24-h BP goal: < 130/80 mmHg
68 Littlejohn et al. J Hypertens. 2008;26(suppl 1):S494; White et al. Blood Press Monit. 2010: In press.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Placebo
150
A5
T80
T80/A5
140
130
120
110
1
3
5
7
9
Mean SBP (mmHg)
Mean SBP (mmHg)
Telmisartan Plus Amlodipine Provides
Superior 24-h ABPM Profiles
Placebo
150
A5
T80
120
110
1
3
T80/A5
80
70
60
3
5
7
9
5
7
9
11 13 15 17 19 21 23
Time after dosing (h)
90
1
T80/A10
130
11 13 15 17 19 21 23
11 13 15 17 19 21 23
Time after dosing (h)
Mean DBP (mmHg)
Mean DBP (mmHg)
Placebo
T80
140
Time after dosing (h)
100
A10
Placebo
100
A10
T80
T80/A10
90
80
70
60
1
3
5
7
9
11 13 15 17 19 21 23
Time after dosing (h)
AHA criteria: recommended 24-h BP goal: < 130/80 mmHg
69 Littlejohn et al. J Hypertens. 2008;26(suppl 1):S494; White et al. Blood Press Monit. 2010: In press.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine Provides Superior 24-h ABPM Goal
Rate Achievement (< 130/80 mmHg*) in > 82% of Patients
p < 0.0001
100
Patients achieving 24-h
ABPM goal* (%)
82.7
80
60
37.9
40
20
0
A10
T80/A10
(n = 58)
(n = 52)
* AHA criteria for 24-h BP goal
70 Littlejohn et al. J Hypertens. 2008;26(suppl 1):S494; White et al. Blood Press Monit. 2010: In press.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine …
… Safety and Tolerability
71
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine Has a Safety
and Tolerability Profile Similar to Placebo
12
Patients with
AEs > 1% incidence (%)
10.9
10
Placebo (n = 46)
A mono (n = 319)
T/A (n = 789)
7.8
8
6.0
6
4.8
4.7
4.3
4.3
4
3.0
2.2 2.2 2.2
1.9
2
1.3
0
1.1
0.9 1.1
0.9 1.1
0
1.8
1.4
1.1
1.3
1.3
0.6
0
0
0
0
0
Fatigue Oedema Sinusitis
NasoUpper Influenza
pharyn- respiratory
gitis
tract
infection
Back
pain
Dizziness
72 Littlejohn et al. J Clin Hypertens. 2009;11:207–213.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Headache Peripheral
oedema
Combinations With Telmisartan 40mg and 80mg plus
Amlodipine Have a Similar Safety & Tolerability Profile
T40/A5 (n = 976)1,2
T80/A5 (n = 397)1,2
n (%)
Patients
per 100
patientyears
n (%)
Patients
per 100
patientyears
n (%)
Patients
per 100
patientyears
n (%)
Patients
per 100
patientyears
381 (39.0)
94.5
201 (50.6)
96.7
102 (12.2)
50.2
157 (25.7)
46.3
Patients with severe
AE
17 (1.7)
4.2
9 (2.3)
4.3
5 (0.6)
2.5
6 (1.0)
1.8
Patients with drugrelated AE
51 (5.2)
12.6
30 (7.6)
14.4
28 (3.3)
13.8
38 (6.2)
11.2
23 (2.4)
–
5.7
–
11 (2.8)
6 (1.5)
5.3
2.9
16 (1.9)
–
7.9
–
24 (3.9)
–
7.1
–
Patients with AEs
leading to
discontinuation
12 (1.2)
3.0
4 (1.0)
1.9
6 (0.7)
3.0
9 (1.5)
2.7
Patients with
serious AEs
22 (2.3)
5.5
6 (1.5)
2.9
4 (0.5)
2.0
13 (2.1)
3.8
Patients with any
AE
T40/A10 (n = 838)3,4
T80/A10 (n = 611)3,4
Treatment-related
AEs with incidence
> 1%
Peripheral oedema
Dizziness
73
1. Neldam et al. ESH 2010 poster presentation (P-95); 2. TEAMSTA-5 Follow-Up (data on file; Boehringer Ingelheim Pharmaceuticals, Inc);
3. Neldam et al. ESH 2010 poster presentation (P-90); 4. TEAMSTA-10 Follow-Up (data on file; Boehringer Ingelheim Pharmaceuticals, Inc).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine is Associated With Less
Peripheral Oedema Compared With Amlodipine 10 mg
p < 0.0001
p < 0.0001
20
Patients with peripheral
oedema (%)
17.8
15
–90%
–71%
10
5.2
5
1.7
0
A10
T40–80+A5
T40–80+A5–A10
(n = 124)
(n = 264)
(n = 543)
74 Littlejohn et al. J Clin Hypertens. 2009;11:207–213.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine …
… in Patients not at BP Goal With
Amlodipine Monotherapy
75
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine Provides Significant Additional
BP Lowering in Patients not at BP Goal With Amlodipine 5 mg
Mean SBP reduction (mmHg)
A5
Mean SBP (mmHg)
157.0
Run-in baseline
–8.4 mmHg
A10
T80/A5
(n = 261)
(n = 271)
–11.1 mmHg
Randomization baseline
(after 6 weeks)
138.4
–15.0 mmHg
134.5
p < 0.0001
76 Neldam, Lang. J Clin Hypertens. 2009;11(Suppl s1):114 (P279).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
After 14 weeks
Telmisartan Plus Amlodipine is Superior in Reducing BP
in Patients not at BP Goal With Amlodipine 10 mg
Mean SBP reduction (mmHg)
A10
Mean SBP (mmHg)
160.1
Run-in baseline
–12.5 mmHg
A10
T80/A10
(n = 305)
(n = 310)
–7.4 mmHg
140.2
Randomization baseline
(after 6 weeks)
–11.3 mmHg
136.2
p < 0.0001
Neldam, Edwards. ESH 2009 poster presentation (P911); TEAMSTA-10
77 (data on file; Boehringer Ingelheim).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
After 14 weeks
Telmisartan Plus Amlodipine is Better Tolerated Than
Amlodipine 10 mg in Patients not at Goal With Amlodipine 5 mg
p < 0.0001
Incidence of peripheral
oedema (%)
30
27.2
25
20
–87%
15
10
3.6
5
0
A10
T80/A5
(n = 276)
(n = 277)
78 Neldam, Lang. J Clin Hypertens. 2009;11(Suppl s1):114 (P279).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan Plus Amlodipine is Better Tolerated Than
Amlodipine 5 mg in Patients not at Goal With Amlodipine 5 mg
p = 0.0028
p = 0.0053
p = 0.0613
Incidence of oedema (%)
10
8.6
–41%
8
6
–58%
–50%
5.1
4.4
3.6
4
2
0
A5
T40/A5
T80/A5
T40–80/A5
(n=267)
(n=277)
(n=277)
(n=554)
79 Neldam, Lang. J Clin Hypertens. 2009;11(Suppl s1):114 (P279).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan + Amlodipine Data Conclusion
• Fast and superior BP reductions of > 31 mmHg (SBP) already after 1 week of
treatment1
• Up to 80% of maximum effect already after 2 weeks of treatment1
• Consistent and strong BP reductions of up to 49.5 mmHg (SBP) across
hypertension severities and a wide range of hypertensive at-risk (complex)
patients1
• SBP reduction of ≥ 50 mmHg in almost 50% of patients with baseline
SBP ≥ 180 mmHg1
• High BP response rates of up to 99.7% of patients1
• Superior and dose dependent 24-h ABPM reductions
• Superior 24-h ABPM goal rate achievement (< 130/80 mmHg) of > 82%2,3
• Superior efficacy and safety in patients not at goal with amlodipine4
• A safety and tolerability profile similar to placebo, with up to 90% lower oedema
rates compared with A10 monotherapy5
80
1. Neutel et al. J Clin Hypertens. 2010: In press; 2. White et al. Blood Press Monit. 2010: In press; 3. Littlejohn et al. J Hypertens.
2008;26(suppl 1):S494; 4. Neldam, Lang. J Clin Hypertens. 2009;11(Suppl s1):114 (P279); 5. Littlejohn et al.
J Clin Hypertens 2009:11:207–213.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Proven CV Protection
… of the Single Components
81
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Amlodipine has Shown CV Protective
Efficacy in Landmark Studies
PREVENT1
825 CAD patients (≥ 30%); multicentre,
randomized, placebo-controlled
CAMELOT2
1,991 CAD patients (≥ 20%); double-blind,
randomized study vs placebo and enalapril
20 mg
ASCOT-BPLA/CAFE3,4
19,257 HTN patients; multicentre,
randomized, prospective study vs atenolol
ALLHAT5
18,102 HTN patients; multicentre,
randomized, prospective study vs lisinopril
Primary outcome: no difference in mean 3-y coronary
angiographic changes vs placebo
35% ↓hospitalization for heart failure + angina
33% ↓revascularization procedures
Primary outcome: 30%↓in CV events vs placebo
41% ↓hospitalization for angina
27% ↓coronary revascularization
Primary outcome: 10%↓in non-fatal MI and fatal CHD
16% ↓total CV events and procedures
30% ↓new-onset diabetes
27% ↓stroke
11% ↓all-cause mortality
4.3 mmHg ↓central aortic pressure
Primary outcome: no difference in composite of fatal
CHD and non-fatal MI vs lisinopril
6% ↓combined CVD
23% ↓stroke
1. Pitt et al. Circulation. 2000;102:1503–1510; 2. Nissen et al. JAMA. 2004;292:2217–2226; 3. Dahlof et al. Lancet.
82 2005;366:895–906; 4. Williams et al. Circulation. 2006;113:1213 –1225; 5. Leenen et al. Hypertension.2006;48:374–384.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Clinical Evidence With ARBs BEFORE
ONTARGET®
CV high risk
Heart failure
Hypertension
MI and
stroke
LIFE
VALUE
Microalbuminuria
Atherosclerosis
and LVH
Endothelial
dysfunction
VALIANT
CHARM
Val-HeFT
ELITE II
Remodelling
Ventricular dilation/
cognitive dysfunction
Macroproteinuria
Nephrotic
proteinuria
Risk factors:
hypertension, diabetes,
obesity, smoking, age
CHF/
secondary stroke
ESRD
Dzau et al. Circulation. 2006;114:2850–2870; Dzau, Braunwald. Am Heart J. 1991;121:1244–1263;
83 Yusuf et al. Lancet. 2004;364:937–952.
Telmisartan plus Amlodipine Medical Education Slide Ressource: FINAL Version 1.0 (30-June-2010)
Cardio/
cerebrovascular
death
Telmisartan is similarly effective to Ramipril
in Prevention of CV Events in CV High-risk Patients
Telmisartan
Ramipril
‡
Composite
endpoint *
Secondary
composite: HOPE
primary endpoint †
* Composite CV endpoint =
CV mortality, non-fatal MI,
hospitalization for CHF,
non-fatal stroke
† Primary
outcome in the HOPE
trial (death from CV causes + MI
+ stroke)
0.8
‡
‡p
< 0.01 vs
non-inferiority margin (1.13)
0.9
Telmisartan
better
1.0
1.1
Ramipril
better
84 The ONTARGET Investigators. N Engl J Med. 2008;358:1547–1559.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
1.2
Clinical Evidence With ARBs AFTER
ONTARGET®
CV high risk
ONTARGET® trial programme
Heart failure
Hypertension
MI and
stroke
LIFE
VALUE
Microalbuminuria
Atherosclerosis
and LVH
Endothelial
dysfunction
VALIANT
CHARM
Val-HeFT
ELITE II
Remodelling
Ventricular dilation/
cognitive dysfunction
Macroproteinuria
Nephrotic
proteinuria
Risk factors:
hypertension, diabetes,
obesity, smoking, age
ESRD
Dzau et al. Circulation. 2006;114:2850–2870; Dzau, Braunwald. Am Heart J. 1991;121:1244–1263;
85 Yusuf et al. Lancet. 2004;364:937–952; The ONTARGET Investigators. N Engl J Med. 2008;358:1547–1559.
.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
CHF/
secondary stroke
Cardio/
cerebrovascular
death
Telmisartan is the Only ARB Indicated
for CV Protection in CV High-risk Patients
Based on the Data From The ONTARGET® Trial Program
Hypertension
- Treatment of renal disease
- Prevention of stroke in LVH
Losartan
Eprosartan
Irbesartan
Olmesartan
Valsartan
Candesartan
Telmisartan
✔
✔
✔
✔
✔
✔
✔
✔
✔
✔
✔
CV high risk
• Atherothrombotic CV disease
such as:
✔
- Coronary heart disease
✔
- Peripheral vascular disease
✔
- Stroke
✔
• Type 2 diabetes with target
organ damage
Heart failure or LV
dysfunction
✔
✔
86 Product information provided by EMA (http://www.emea.europa.eu) and eMC (http://emc.medicines.org.uk).
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
✔
CV Protective Effects …
… of the Combination
as Measured by Intermediate Endpoints
87
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan + Amlodipine:
Reduction of Urinary Albumin Excretion
UAER change from baseline (%)
4 weeks
0
40/2.5 40/2.5
48 weeks
40/5 80/2.5
40/7.5 120/2.5
40/10 160/2.5
-20
-25.5 -25.9
-34.1
-40
*
-60
-80
-33.2
-37.1
-46.4
**
-63.8
†
Amlodipine increasing dose (2.5–10 mg)
Telmisartan increasing dose (40–160 mg)
-75.3
‡§
-100
* p < 0.03; ** p < 0.01, change from baseline; † p < 0.01; ‡ p < 0.001, between treatment; §p < 0.05 vs 80/2.5
Hypertensive patients with type 2 diabetes (n = 300); microalbuminuria > 30 – < 300 mg/24 h
88 Fogari et al. Am J Hypertens. 2007;20:417–422.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Table of Contents
• Unmet needs in the treatment of hypertension
• Hypertension – a major CV risk factor
• Why is combination therapy needed?
• Why combine a RAS-I and a CCB?
• Why telmisartan plus amlodipine?
• For which patients?
• What about other single-pill combinations?
• Conclusions
89
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
ESH/ESC: Stratification of CV Risk
Other
risk
factors
SBP 120–129 SBP 130–139 SBP 140–159 SBP 160–179 SBP ≥ 180
DBP 80–84
DBP 85–89
DBP 90–99 DBP 100–109 DBP ≥ 110
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,
TOD,
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
None
90 Mancia et al. Eur Heart J 2007;28:1462–1536.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
JNC VII
• Most patients with hypertension will require two
or more antihypertensive medications to achieve
their BP goals
– When BP is > 20/10 mmHg above goal,
consideration should be given to initiating
therapy with two drugs
ESH/ESC
Guidelines Acknowledge That Patients with BP >
20/10 mmHg Above Goal Need Combination Therapy
• Combination treatment should be considered as
first choice when there is high CV risk
– i.e., in individuals in whom BP is markedly above
the hypertension threshold (> 20/10 mmHg), or
associated with multiple risk factors subclinical
organ damage, diabetes, renal or CV disease
91 Chobanian et al. JAMA. 2003;289:2560–2572; Mancia et al. Eur Heart J 2007;28:1462–1536.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
In Hypertensive at-Risk Patients CCB/RAS-I Combination Reduces CV Morbidity/Mortality Significantly
More Than HCTZ/RAS-I Combination (ACCOMPLISH)
Baseline characteristics
Patients, n
Primary endpoint
11,506
Mean age, y
68.4
Male, %
60.5
BP at randomization, mmHg
552 (9.6%) patients with events with RAS-I/CCB vs
679 (11.8%) with RAS-I/HCTZ
(RR 20%; HR 0.80; 95% CI 0.72 to 0.90; p < 0.001)
145/80
Hypertension, %
100
BMI, kg/m2
31.0
Diabetes, %
60.4
Previous MI, %
23.6
Unstable angina, %
11.5
Coronary-artery bypass grafting, %
21.3
Previous stroke, %
13.1
LVH, %
13.3
92 Jamerson et al. N Engl J Med. 2008;359:2417–2428.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Which Patients may Benefit From Telmisartan/
Amlodipine Combination treatment?
Other
risk
factors
None
1−2
≥ 3,
TOD, MS
or
diabetes
CV or
renal
disease
SBP 120–129 SBP 130–139 SBP 140–159 SBP 160–179 SBP ≥180
DBP 80–84
DBP 85–89
DBP 90–99 DBP 100–109 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
93 Mancia et al. Eur Heart J 2007;28:1462–1536.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Table of Contents
• Unmet needs in the treatment of hypertension
• Hypertension – a major CV risk factor
• Why is combination therapy needed?
• Why combine a RAS-I and a CCB?
• Why telmisartan plus amlodipine?
• For which patients?
• What about other ARB/CCB single-pill combinations?
– Valsartan/amlodipine (Exforge)
– Olmesartan/amlodipine (Azor/Sevikar)
• Conclusions
94
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
DISCLAIMER:
The following data are indirect comparisons of
placebo controlled studies. Although all studies
investigated hypertensive patients, the study
designs varied. No statistical conclusions about
superiority or inferiority, of one or the other product,
can be drawn from these indirect comparisons
95
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Telmisartan+Amlodipine vs Valsartan+Amlodipine
Indirect Comparison of BP Reductions at Comparable Baseline BP values*
Agent
Baseline BP
Telmisartan+Amlodipine
(all doses)1
153/102 mmHg
T40/A5
0
T40/A10
T80/A5
T80/A10
0
Baseline BP
Valsartan with:2
5 mg amlodipine
10 mg amlodipine
153/99 mmHg
157/99 mmHg
V160/A5
V160A10
-10
-10.3
-12.0
-15
V320/A10
-13.9
-14.0
-7.6
-10
-15
-9.0
-19.3
-20
-19.6
-22.2
-25
* Indirect
SBP
DBP
-23.9
-25
-9.3
-9.9
-13.2
-15.5
-20
V320/A5
-5
mmHg †
mmHg †
-5
Agent
SBP
DBP
comparisons: study design varied; †Placebo-corrected values
1.TWYNSTA™ [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc, 2009;
96 2. Exforge [prescribing information]. East Hanover, CJ: Novartis Pharmaceuticals Corporation, 2009.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
-16.2
-15.9
Telmisartan+Amlodipine vs Olmesartan+Amlodipine
Indirect Comparison of BP Reductions at Comparable Baseline BP values*
Agent
Baseline BP
Agent
Baseline BP
Telmisartan+Amlodipine
(all doses)1
167/103 mmHg
Olmesartan+Amlodipine
(all doses)2
164/102 mmHg
T40/A5
0
T40/A10
T80/A5
T80/A10
0
-5
O40/A5
O40/A10
-10
-9.8
-12.4
-15
-13.4
-15.3
-20
-22.0
mmHg †
mmHg †
O20/A10
-5
-10
-25
O20/A5
-22.4
-11
-15
-16
-20
-20
-22
-25
-25
-27.6
-30
-35
* Indirect
SBP
-28.9
DBP
-13
-14
-30
-35
SBP
DBP
comparisons: study design varied; †Placebo-corrected values
1. Factorial design study (data on file; Boehringer Ingelheim Pharmaceuticals, Inc);
97 2. Azor [prescribing information]. Parsippany, NJ: Daiichi Sankyo, Inc; 2009.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
-26
Telmisartan+Amlodipine vs Competitors
Incidence of Peripheral Oedema Compared With Amlodipine 10 mg
Patients with peripheral oedema
after 8 weeks of treatment (%)
40
82.7
35
–42%3
30
25
20
21.4
17.8
–71%1
15
–50%2
10
5.2
5.1
5
0
A10
* Indirect
10.3
T40–80/
A5–10
A10
V160–320/
A5–10
A10
comparisons: study design varied; †Placebo-corrected values
1. Littlejohn et al. J Clin Hypertens. 2009:11:207–213; 2. Exforge EU SPC;
98 3. Chrysant et al. Clin Ther. 2008;30:587–604.
Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
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A5–10
Table of Contents
• Unmet needs in the treatment of hypertension
• Hypertension – a major CV risk factor
• Why is combination therapy needed?
• Why combine a RAS-I and a CCB?
• Why telmisartan plus amlodipine?
• For which patients?
• What about other ARB/CCB single-pill combinations?
• Conclusions
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Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)
Conclusions
• Hypertension is a major CV risk factor
• There is still a huge unmet medical need in the treatment of hypertension, with
many patients being uncontrolled
• Most patients need combination therapy to reach their BP goals
• ARB plus CCB combination exhibit complementary and synergistic MoA with high
BP reductions and a good safety and tolerability profile
• RASi plus CCB combinations are favorable in hypertensive patients at-risk
• Telmisartan + Amlodipine provides powerful and consistent BP reductions, as well
as high BP goal and response rates, including in hypertensive at-risk (complex)
patients, combined with an excellent safety and tolerability profile
• Both components have a huge clinical evidence-based database for CV protection,
and Telmisartan is the only ARB with a CV protection indication
• Indirect comparisons reveal a favorable safety and efficacy profile for Telmisartan +
Amlodipine
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Telmisartan Plus Amlodipine Medical Education Slide Resource: FINAL Version 1.1 (13-July-2010)