Hypertension Slides

HYPERTENSION/ RAAS BLOCKADE
Contents
 An overview of hypertension 4
 The burden of uncontrolled blood pressure 21
 Management of hypertension: guideline recommendations for
combining therapies 30
 Compliance with antihypertensive medications: clinical
and economic impact 35
 Benefits of single-pill combination therapy 48
 Rationale for a CCBARB combination 60
 Rationale for CCBARB therapy with Amlodipine/Valsartan 72
 Therapeutic value of Amlodipine/Valsartan 87
 Amlodipine/Valsartan: health-economic models 139
 Triple HCTZ therapy 150
3
EXFORGE® (Amlodipine/Valsartan) core value dossier
 Amlodipine/Valsartan and the triple combination

Amlodipine/Valsartan/ HCTZ (Exforge HCT®) are indicated for
the treatment of essential hypertension (HTN)
 This slide set follows the core dossier and presents the ways in
which Amlodipine/Valsartan as well as the triple combination
Amlodipine/Valsartan/ HCTZ (Exforge HCT®) add value to the
current management of HTN, both clinically and economically
 This slide set also contains the clinical evidence upon which the
value messages are built and evidence for economic arguments
to help in reimbursement settings
An overview of hypertension
Classification of hypertension and target blood pressure (BP) goals
Prevalence and risk of hypertension
Relationship between BP levels and cardiovascular (CV) disease
Classification of hypertension and target BP goals
6
Classification of blood pressure in US adults:
JNC VII guidelines
BP category Systolic (mmHg) Diastolic (mmHg)

Normal <120 and <80
Pre-hypertension 120–139 or 80–89
Hypertension, stage 1 140–159 or 90–99
Hypertension, stage 2 160 or 100
Chobanian et al. JAMA 2003;289:256072

7
Classification of blood pressure in European adults:
ESHESC guidelines
BP category Systolic (mmHg) Diastolic (mmHg)

Optimal <120 and <80
Normal 120–129 and 80–84
High normal 130–139 or 85–89
Hypertension
Grade 1 (mild) 140–159 or 90–99
Grade 2 (moderate) 160–179 or 100–109
Grade 3 (severe) 180 or 110
Guidelines Committee. J Hypertens 2003;21:101153

8
JNC VII and ESHESC summary: target blood
pressure goals
Type of hypertension BP goal (mmHg)

Uncomplicated <140/90
Complicated
Diabetes mellitus <130/80
Kidney disease <130/80
Chobanian et al. JAMA 2003;289:256072

Guidelines Committee. J Hypertens 2003;21:101153
Prevalence and risk of hypertension
10
Hypertension is a prevalent disease affecting 1 billion
people today
60
55
49
50 47
Prevalence* of HTN (%)
42
40 38 38
30 27 28
20
10
0
Canada USA Italy Sweden England Spain Finland Germany
*Among persons aged 35–64 years old; age and sex adjusted
HTN = BP 140/90 mmHg or on treatment Wolf-Maier et al. JAMA 2003;289:2363–9
11
The number of adults with hypertension is estimated to
increase 60% by the year 2025
Prevalence* of HTN (%)

50
2000 Predicted 2025 42
40 37.3
29.2
30 26.4
20
10
0
Worldwide Economically developed
countries
*Among people aged 20 years and older Kearney et al. Lancet 2005;365:21723
12
Prevalence of hypertension by age and gender
Prevalence of HTN (%)

100
Men Women 80.3
80 71.2
60.3 61.3
60
44.8 42.0
40 32.6
21.2 23.3
20 14.4
9.9
6.2
0
2029 3039 4049 5059 6069 70
Data for established market economies (US, Canada, Spain,

England, Germany, Greece, Italy, Sweden, Australia, Japan) Kearney et al. Lancet 2005;365:21723
13
Prevalence of hypertension increases with age

80
70 65.2
60
50
40
29.1
30
20
10 6.7
0
2039 4059 60
SBP/DBP (mmHg)
SBP = systolic BP; DBP = diastolic BP
Estimated non-institutionalised US adults, 19992002
From Centers for Disease Control and Prevention Brown. BMJ 2006;332:8336
14
Race/Ethnicity influences risk of hypertension

50
40.5
40
30 27.4
25.1
20
10
0
White non-Hispanic Black non-Hispanic Mexican American
Ethnic group
Estimated non-institutionalised US adults, 19992002

From Centers for Disease Control and Prevention Brown. BMJ 2006;332:8336
15
People without hypertension aged 55 have a 90%
lifetime risk of developing hypertension
Risk of HTN, % (95% CI)
Women, Age (years) Men, Age (years)

Time (years) 55 (n=709) 65 (n=549) 55 (n=589) 65 (n=438)
10 52 (4658) 64 (6069) 56 (4963) 72 (6778)
15 72 (6876) 81 (7784) 78 (7482) 85 (8189)
20 83 (8086) 89 (8692) 88 (8591) 90 (8793)
25 91 (8993) 93 (9195)
Lifetime risk of developing HTN is 25 years for 55-year-old subjects and 20 years for people aged 65
years
Vasan et al. JAMA 2002;287:1003–10
Relationship between blood pressure levels and
cardiovascular disease
17
Hypertension within the cardiovascular continuum
 The CV continuum describes a series of pathophysiological events

linking CV risk factors to a chain of clinical manifestations of disease
 The CV continuum is a useful tool for describing the transition from CV

risk factors through to death in terms of CV health
Dzau et al. Am Heart J 1991;121:244–63

18
High–normal BP increases the risk of cardiovascular
disease
Cumulative incidence
of CV events (%) mmHg
High–normal 130–139
14
12
Normal 121–129
10
8
6 Optimal <120
4
2
0
0 2 4 6 8 10 12 14
Time (years)
Vasan et al. N Engl J Med 2001;345:1291–7

19
Cardiovascular mortality risk doubles with each
20/10 mmHg increment*
CV mortality risk
8
8x
6
4
4x
2
2x
1x
0
115/75 135/85 155/95 175/105
SBP/DBP (mmHg)
*Individuals aged 40–69 years Lewington et al. Lancet 2002;360:1903–13

20
Blood pressure reduction of 2 mmHg reduces the risk of
cardiovascular events by 7–10%
 Meta-analysis of 61 prospective, observational studies
 1 million adults
 12.7 million person-years
7% reduction in
risk of ischaemic
heart disease
2 mmHg mortality
decrease in
mean SBP 10% reduction in
risk of stroke
mortality
Lewington et al. Lancet 2002;360:1903–13

The burden of uncontrolled blood pressure
Not all patients with hypertension are treated
The majority of patients do not achieve BP goal
Health burden of uncontrolled BP
Economic burden of CV disease and hypertension
22
Awareness, treatment and control rates for hypertension
are low across all age groups in the US
Estimated size of population

(in millions)
20 18.5 Age 25–44 years
16.0 Age 45–64 years
15 Age ≥65
10
7.5 6.9
5.8
4.4 4.2 4.5
5 2.9
3.5
2.8 2.3
1.9 1.7
0.9
0
Total no. No. with HTN, No. with No. with No. with
with HTN but unaware acknowledged treated and treated and
of it untreated uncontrolled controlled
HTN HTN HTN
NHANES III data Hyman and Pavlik. N Engl J Med 2001;345:479–86
23
Approximately 73% of European patients with
hypertension remain untreated
Patients (%) Treated Untreated

100
75 74 74 73 68
80
60
40
20
0
England Sweden Germany Spain Italy
Wolf-Maier et al. Hypertension 2004;43:10–17

24
Approximately 70% of treated patients* in Europe do not
reach blood pressure goal
Patients (%) BP goal achieved BP goal not achieved

100
60 79 71 81 71
80
60
40
20
0
England Sweden Germany Spain Italy
*Treated for hypertension

BP goal is <140/90 mmHg Wolf-Maier et al. Hypertension 2004;43:10–17
25
Uncontrolled blood pressure results in major
cardiovascular events (US population)
Events/year
50,000
40,000
DBP/SBP
uncontrolled
30,000
DBP uncontrolled
20,000
10,000 SBP uncontrolled
Medicated Unmedicated Total
Flack et al. Managed Care Interface 2002;15:28–36

26
Global health burden of uncontrolled blood pressure

Events attributable to non-optimal BP control
(mean SBP >115 mmHg) (%)
80 76
62
60
49
40
20 14
0
Stroke Ischaemic heart Hypertensive Other CVD
disease disease*
 Worldwide this equates to approximately 7.1 million deaths (12.8% of total deaths)
and 64.3 million disability-adjusted life years (4.4% of the total)
*Hypertensive disease includes essential HTN, hypertensive heart
disease and hypertensive renal disease Lawes et al. J Hypertens 2006;24:423–30
27
Direct and indirect costs of major cardiovascular
diseases and stroke in the US in 2006
Estimated costs ($ billions)
160
142.5
120
80
63.5
57.9
40 29.6
0
CHD Stroke Hypertensive Heart failure
disease
Estimated total costs of CV diseases and stroke in the US in 2006:
$403.1 billion
American Heart Association. Heart Disease and Stroke Statistics
CHD = coronary heart disease 2006 Update. Dallas, TX
28
Suboptimal treatment of hypertension imposes an
enormous economic burden on society
Estimated costs ($ billions)

30
24.4
25
20
15
11
10 7.7 8.3
6.2
4.2
5 1.7
0
Hospital Nursing Physicians Medical Home Morbidity Mortality
home durables h/care
Estimated total costs of hypertension in the US in 2006: $63.5

billion
American Heart Association. Heart Disease and Stroke
Statistics 2006 Update. Dallas, TX
29
Economic burden of hypertension
 64.3 million disability-adjusted life years (DALYs) [4.4% of the

global total] were estimated to be due to non-optimal BP1
 HTN is ranked third as a cause of DALYs
 Untreated HTN causes an average loss of 5.5 workdays per

person annually2
 HTN represents one of the three leading causes of visits to

primary healthcare centres3
 In France, Germany, Italy, Sweden and the UK, failure to

achieve BP targets result in 281,000 avoidable major CV
events, costing health systems €1.26 billion each year4
1
Lawes et al. J Hypertens 2006;24:423–30; 2Rizzo et al. Health Econ 1996;5:249–65; 3Pardell et
al. Drugs 2000;59:13–20; 4Hansson et al. Blood Pressure 2002;11:35 –45
Management of hypertension: guideline
recommendations for combining therapies
Multiple antihypertensive agents are needed to achieve BP goals
European and US guidelines for combining antihypertensive
therapies
31
There is a need for multiple agents to achieve target
systolic blood pressure goals
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
Number of medications
Bakris et al. Am J Med 2004;116(5A):30S–8
Dahlöf et al. Lancet 2005;366:895–906
32
ESH–ESC: algorithm for treatment of hypertension
Consider: BP level before treatment

Absence or presence of TOD and risk factors
Choose between:
Single agent at low dose 2-drug combination at low dose
If goal BP not achieved

Previous agent Switch to Previous Add a
at full dose different agent combination third drug
at low dose at full dose at low dose
If goal BP not achieved
2–3 drug Full-dose 3-drug combination

combination monotherapy at effective doses
TOD = target organ damage ESH–ESC Guidelines. J Hypertens 2003;21:1779–86

33
Updated UK NICE guidelines for the treatment of newly
diagnosed hypertension
55 years or black

<55 years
at any age
CCB or thiazide-
Step 1 ACEI (or ARB*)
type diuretic
ACEI (or ARB*) + CCB or

Step 2
ACEI (or ARB*) + thiazide diuretic
Step 3 ACEI (or ARB*) + CCB + diuretic
Add further diuretic therapy, α-blocker, or β-blocker.

Step 4
Consider seeking specialist advice
http://www.nice.org.uk/download.aspx?o=CG034fullguideline.
*If ACE inhibitor (ACEI) not tolerated Accessed June 2006
34
JNC VII: algorithm for treatment of hypertension

Lifestyle modifications
Not at goal BP*
HTN without compelling HTN with compelling

indications indications
Drug(s) for the compelling

Stage 1 Stage 2
indications
Thiazide-type diuretics for Two-drug combination for
Other antihypertensive
most. May consider ACE most (usually including
drugs (diuretics, ACE
inhibitor, ARB, β-blocker, thiazide-type diuretic)
inhibitor, ARB, β-blocker,
CCB, or combination
CCB) as needed
If not at goal, optimise dosages or add additional drugs until goal BP is achieved.
Consider consultation with hypertension specialist
*BP goal <140/90 mmHg or <130/80 mmHg for those
with diabetes or chronic kidney disease Chobanian et al. JAMA 2003;289:2560–72
Compliance with antihypertensive
medications: clinical and economic impact
Non-compliance and persistence: extent of the problem
Reasons for non-compliance
Improved compliance with antihypertensive therapy improves
clinical and economic outcomes
36
Fifty per cent of patients remain on antihypertensive therapy
after 12 months and 50% are compliant with therapy
 Not persistent: 29–58%

 Persistence defined as patients remaining on treatment for a
duration of 12 months
 Not compliant: 24–51%

 Compliance defined as drugs available >80% of days in a year
Gerth. Curr Hypertens Rep 2002;4:424–33

37
Among patients still on therapy after the first year,
50% stop therapy within the next two years
Retrospective, cohort study of the

100 Netherlands community pharmacy records
Continuous antihypertensive
90 (N=2,325)
80
70
users (%)
60
50
Men
40 Women
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10
Years after first prescription
Van Wijk et al. J Hypertens 2005;23:2101–7

38
Reasons for non-compliance
 Financial constraints
 Doubts over treatment benefits
 Patient characteristics
 Unwelcome side effects or drug tolerability issues
 Need for more than one agent or complex treatment regimens
 A lack of understanding of instructions provided by physicians
Poor compliance is estimated to cost the US $100 billion annually*
DiMatteo et al. Med Care 2002;794–811; Greenberg. Clin Ther 1984;6:592–9; Dezii. Man
Care 2000;9(Suppl):2–6; Taylor & Shoheiber. Congest Heart Fail 2003;9:324– 32; Rudd. Am
J Manag Care 1998;4:957–66; Degli et al. J Clin Hypertens 2004;6:76–84
*Task Force for Noncompliance. Baltimore, Md: Task Force for Noncompliance, 1994
39
As the Number of Concomitant Drugs Increases, Compliance Gap
Between Single-Pill Combination (SPC) and Dual Agent Increases
US pharmacy claims data (n=6,206)
100
FDC Dual agent
89.6 90.2
88.8
90 87.3 86.5
87.7
85.9
80
73.7 73.6
72.1
70.1 69.7
70 67.2
65.6
60
50
Number of concomitant drugs

*p<0.0001 Gerbino PP, Shoheiber O. Am J Health System Pharm 2007;64:1279–83
40
Mean MPR is Greater With Fewer Pills in Multiple Combination

Antihypertensive Pharmacotherapy in a Large US Database
Valsartan + Amlodpine
Valsartan/HCTZ + Amlodipine
Valsartan + HCTZ + Amlodipine
80
Persistency (mean MPR[%])
76
72
68
64
60
80% 120% 160%
Gap days supply
MPR = medication possession ratio Jackson K et al, et al. Clinical Therapeutics 2008;30:1558-1563
HCTZ = hydrochlorothiazide
41
Compliance with Antihypertensive Therapy Results in More Patients
Achieving Blood Pressure (BP) Goal (<140/90 mmHg)
Observational, cross-sectional study (n=1,000)

80
p<0.005
70
60
50
Patients
40
(%)
30
20
10
0
Compliant Non-compliant
Yiannakopoulou EC, et al. Eur J Cardiovasc Prev Rehabil 2005;12:243–9

42
Increased compliance and persistence to antihypertensive
therapy reduces risk of adverse cardiovascular outcomes
Men Women
0
of adverse CV outcomes
-5
Predicted relative risk
–4.6
-10 –8.4
Compliant †
-15
Persistent ‡
–16.4
-20
-25
–26.6
-30
Medication-possession ratio ≥80%

†
Halpern et al. J Hypertens 2006;24(Suppl 4):S154
Remaining on therapy for 12 months
‡
Halpern et al. J Hypertens 2006;24(Suppl 4):S182
43
Highly compliant patients are more likely to achieve
blood pressure control
Patients with BP control* (%)

Odds ratio = 1.45
p=0.026 (controlling for age, gender and comorbidities)
50
43
40
34 33
30
20
10
0
High Medium Low
(≥80%) (50–79%) (<50%)
Compliance (measured using MPR)
*<140/90 mmHg (or <130/85 in patients with diabetes)
Bramley et al. J Manag Care Pharm 2006;12:239–45
MPR = medication possession ratio
44
Persistent use of antihypertensive therapy leads to reduced
risk of hospitalisations for myocardial infarction (MI)/stroke
RR adj = 0.88; 95% CI: 0.82–0.94
0.88
–1 0 1
Persistent Non-persistent
Association stronger in the low/intermediate risk group than in the high-risk group
RR adj = 0.85; 95% CI: 0.79–0.92
Breekveldt-Postina et al. Value Health Suppl 2006;9:A339

45
Better compliance with antihypertensive drugs leads to a
decreased risk of hospitalisation
50
44*
*
All-cause hospitalisation
39 *
40 36
*
30
risk (%)
30 27
20
10
0
1–19 20–39 40–59 60–79 80–100
(n=350) (n=344) (n=562) (n=921) (n=5,804)
Level of compliance (%)
*p<0.05 vs 80–100% compliant group Sokol et al. Med Care 2005;43:521–30

46
Improved compliance leads to a decrease in medical
costs
Costs ($, thousands)

12 All-cause medical costs
* 10.3 Hypertension-related medical costs
10 *
8.8 *
8.4
7.7
8
*
6.0
6.6
6 4.8 5.1 5.0
4.4
4
2
0
1–19 20–39 40–59 60–79 80–100
Compliance (%)
*p<0.05 vs 80–100% compliant group Sokol et al. Med Care 2005;43:52130

47
Improved compliance reduces outpatient resource use
Retrospective US database analysis (N=982)
8 7.3
7
*
Number of visits/calls
6.3 6.1 ≥80% compliant

6 * <80% compliant
5
5
4
* 3.2
3 2.5
2
1
0
Outpatient visits Visits with BP Telephone calls
readings
*p<0.005 vs <80% compliant Halpern et al. Value Health 2005;8:A104

Benefits of single-pill combination
therapy
Rationale for single-pill combinations (SPCs): efficacy; tolerability;
compliance and persistence
Beneficial impact of SPCs on compliance and persistence, and
costs
49
Rationale for the use of single-pill combinations: efficacy
SPC therapy results in more complete BP reduction than seen

with its single-mechanism components1,2
 Two or more different and complementary pathways of BP
control are blocked/interfered with1
 Each component can potentially neutralise counter-regulatory

mechanisms, e.g.
 Diuretics reduce plasma volume, which in turn stimulates the renin
angiotensin system (RAS) and thus increases BP; addition of a
RAS blocker attenuates this effect1,2
 SPC therapy often results in BP reductions that are additive2
1
Sica. Drugs 2002;62:44362
2
Quan et al.Am J Cardiovasc Drugs 2006;6:10313
50
Rationale for the use of single-pill combinations:
tolerability
SPC therapy may have an improved tolerability profile compared

with its single-mechanism components1,2
 Low doses of two agents often result in fewer adverse events

than high doses of one agent1,2
 Physicians may accept less than optimal BP control to minimise
adverse events
 Compound-specific adverse events can be attenuated, e.g.1,2

 RAS blockers effectively blunt the metabolic effects of diuretics
 RAS blockers may attenuate the oedema that is caused by
calcium channel blockers (CCBs)
1
Sica. Drugs 2002;62:44362
Quan et al. Am J Cardiovasc Drugs 2006;6:10313
2
51
Rationale for the use of single-pill combinations:
compliance and persistence
 A single, once-daily pill simplifies the treatment regimen

compared with agents given as separate pills
 Increases convenience for patients
 Reduces the pill burden
 Increased convenience and lower pill burden likely to improve

compliance to and persistence with antihypertensive
medications
 Overcomes a major barrier to effective BP control
 Likely to cost less than the individual components prescribed

separately
Neutel. In: Oparil and Weber, eds. Hypertension. Companion to Brenner & Rector’s
The Kidney. 2nd ed. Philadelphia: Elsevier Saunders, 2005. p. 5229
52
Single-pill combination therapy increases persistence by
19% compared with free combination
Persistence with single-pill combination therapy vs concurrent
two-pill therapy in patients with HTN
Patients persistent (%)

Lisinopril/HCTZ (single pill)
100
Lisinopril + diuretic (two pills)
90
80
70
68.7%
18.8%
60 difference
57.8%
50
0 1 2 3 4 5 6 7 8 9 10 11 12
Month
HCTZ = hydrochlorothiazide
Lisinopril/HCTZ (n=1,644); lisinopril + diuretic (two pills; n=624)
Statistical significance (p<0.05) seen at Months 6 and 12 Dezii. Manag Care 2000;9(Suppl):2–6
53
Patients on single-pill combination therapy have greater
persistence than those on individual component-based therapy
Single-pill combination
(Valsartan/HCTZ) 54%
(n=8,150)
p<0.0001
Free combination
(Valsartan + HCTZ) 19%
(n=561)
0% 20% 40% 60% 80%
Persistence (defined as patients remaining on treatment

for a duration of 12 months)
Jackson et al. Value Health Suppl 2006;9:A363

54
21% more patients are fully compliant with single-pill
combination therapy than with free-combination therapy
Cohort study of
general practice research data (N=755)
100
Patients fully compliant (%)
Single-pill combination therapy

80 Co-administration of two pills
60
40
20 17%
21%
0
0 3 6 9 12 15 18 21 24 27
Months since start of therapy
Patients on free combination had a higher odds ratio (OR) of being

non-compliant than patients on SPC: OR 2.09 (95% CI: 1.69, 2.59)
Sturkenboom et al. J Hypertens 2005;23(Suppl 2):S236
55
Patients on single-pill combination therapy have greater
compliance than those on individual component-based therapy
Single-pill combination
(amlodipine/benazepril) 87.9 *
(n=2,839)
Free combination
(ACEI + DHP-CCB) 69.2
(n=3,367)
0 20 40 60 80 100
Medication possession ratio† (%)

*p<0.0001
†
MPR is an indicator of compliance measured by the proportion of days in the year when the
patient is supplied with the medication
DHP = dihydropyridine Wanovich et al. Am J Hypertens 2004;17:223A
56
SPCs improve compliance regardless of concomitant
medications
SPC amlodipine/benazepril vs dual agent ACE inhibitor + DHP-CCB
100 Fixed-dose (n=2,839) Dual agent (n=3,367)
90.2
Medication possession
88.8 89.6
90 87.3 86.5 87.7
85.9
ratio (%)
80
* * *
73.7 73.6 *
72.1
70.1 * *
69.7 *
70 67.2
65.6
60
50
1 2 3 4 5 6 >6
Number of concomitant drugs
p<0.0001 Wanovich et al. Am J Hypertens 2004;17:223A

57
SPC Therapy Demonstrates Improved Compliance in
Hypertensive Patients
Risk ratio
(95% CI) % Weight
Taylor, et al. 0.74 (0.67, 0.81) 25.2
Dezii 0.74 (0.65, 0.84) 18.4
NDC dataset 0.81 (0.77, 0.86) 37.8
Dezii 0.71 (0.62, 0.80) 18.5
Overall (95% CI) 0.76 (0.71, 0.81) p<0.0001
0.1 1 10
Risk ratio
Favours SPC agent Favours individual
agents given separately
CI = confidence interval
SPC = single-pill combination Bangalore S, et al. Am J Med 2007;120:713–9
58
Patients on Single-Pill Combinations (SPC) Use Less
Resource Compared with Patients on Free Combinations
8,000
FDC (n=2,336)
Component therapy (n=3,368)
6,000
Healthcare costs (US $)
5,236
4,000
3,179
1,952
2,000 1,646
1,322
1,120 1,229
334 410 402
0
Total Ambulatory Drug Hospital Other
Dickson M, Plauschinat CA. Am J Cardiovasc Drugs 2008;8:45–50
59
Average total annual cost per patient is lower with single-pill
combinations than with free combinations
Severity score SPC ($) Separate pills ($) p value
0 538 879 <0.001

1 781 1,029 0.038
2 723 1,016 0.013
3 952 1,953 0.001
4 1,581 2,370 0.204
5 908 3,767 0.026
≥6 3,180 6,289 0.086
Total 726 1,600 <0.001
Severity score based on the Charlson index.
Taylor et al. Congest Heart Fail 2003;9:32432

Rationale for a CCBARB combination:
tolerability and efficacy
The calcium channel blocker (CCB)angiotensin receptor blocker

(ARB) reduces BP by targeting two key BP effector pathways
61
The CCBARB targets two key BP effector
pathways (1)
Sympathetic nervous system (SNS)

 SNS activity → noradrenaline binds to α1-adrenergic receptors on
vascular smooth muscle → vasoconstriction1
 SNS also stimulates renin secretion from the kidney, thereby
activating the RAS2
 CCBs inhibit SNS-induced vasoconstriction by blocking influx of
calcium ions (needed for contraction) through voltage-gated calcium
channels → vasodilation3,4
 Other effects of CCBs: natriuresis; inhibition of aldosterone release;
interference with angiotensin II-mediated vasoconstriction4
Grassi. J Hypertens 2001;19:1713–16; 2Mancia and Grassi.
1
http://www.sns-web.org/pages/advances/11/article.asp; 3Robertson and Robertson. In: Hardman JG,

Limbard JG, editors-in chief. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 9th ed.
1996. p. 759–79
4
Prisant. In: Oparil S, Weber MA, editors. Hypertension:
Companion to Brenner & Rector’s The Kidney. 2nd ed. 2005. p. 683–704
62
The CCBARB targets two key BP effector
pathways (2)
Renin angiotensin system (RAS)
 Release of renin catalyses conversion of angiotensinogen into

angiotensin I, which is converted by ACE to angiotensin II →
 Vasoconstriction; increased aldosterone and sodium/water
retention; 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
Mistry et al. Expert Opin Pharmacother 2006:7:575–81

63
Neutralising counter-regulatory mechanisms to minimise
elevations in BP
 CCBs will variably activate the SNS; the SNS, in turn activates
the RAS1,2
 Overall effect is to blunt BP-lowering efficacy
 Through the effects of RAS blockade, ARBs can counteract such
effects, thereby maintaining potent BP-lowering effects of CCBs
 In addition, CCBs possess diuretic and natriuretic properties

and thereby induce a state of negative sodium balance1,2
 This further reinforces the antihypertensive effect of the ARB
1
Sica. Drugs 2002;62:443–62
2
64
Rationale for a CCB–ARB combination
Hypertension =
Peripheral vasoconstriction  in peripheral vascular resistance =
effective BP lowering with combination
therapy
CCBs
ARBs
 in BP triggers ARBs block the

the stimulation of the SNS action of Ang II
Peripheral vasodilation level at the AT1
resulting in lower BP and RAS
receptor
 Aldosterone  Ang II
levels levels

Mistry et al. Expert Opin Pharmacother 2006;7:57581
65
Low-dose CCBARB therapy is efficacious in getting
patients to BP goal (<140/90 mmHg)
Patients achieving BP goal (%) N=137

70
*
60
50
40
30
20
10
0
CCB ARB CCB + ARB
*p<0.05 vs CCB and ARB alone Andreadis et al. J Hum Hypertens 2005;19:491–6
66
Significantly smoother BP variation and higher trough-to-peak
ratio with low-dose CCBARB
BP (mmHg) variability
150
148 CCBs ARBs CCB + ARB
146
144
142
140
138
136 0.950* 0.936
134 0.935
132
130
8:00 10:00 12:00 2:00 4:00 6:00 8:00 10:00 12:00 2:00 4:00 6:00
AM AM PM PM PM PM PM PM AM AM AM AM
*p<0.05 vs CCB and ARB alone

Values in boxes represent trough-to-peak ratio Andreadis et al. J Hum Hypertens 2005;19:491–6
67
Peripheral oedema associated with CCBs
Fluid leakage
Arterial No venous
dilation 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 1986;39:438
Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl 1):S12131
68
Oedema-dependent adverse events with increasing doses
of amlodipine
Oedema-dependent AE (%) N=168

15 14.3%
10 The incidence of oedema increases

as the dose of amlopidine
increases, which may limit its
therapeutic utility
5
3.6%
2.4%
0%
0
Valsartan Valsartan 80 mg/ Amlodipine Amlodipine
80 mg Amlodipine 5 mg 5 mg 10 mg
Study population: mild-to-moderate HTN

12-week study
Corea et al. Clin Pharmacol Ther 1996;60:341–6
AE = adverse event
69
Complementary effects of a CCB/ARB: reduction of
CCB-associated oedema
Arterial Venous
dilation dilation
(CCB and (ARB)
ARB)
Capillary bed
Opie. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273
White et al. Clin Pharmacol Ther 1986;39:438; Gustaffson. J Cardiovasc Pharmacol
1987;10(Suppl. 1):S12131; Messerli et al. Am J Cardiol 2000;86:11827
70
Tolerability and risk factor modification: CCB-induced
peripheral oedema minimised by the ARB
CCB dilates ARB dilates

arteries Veins remain arteries and veins
constricted
Capillary overload Reduces

forces fluid into CCB-induced
surrounding tissue peripheral
oedema
Single mode of action of the Dual mode of action of the

CCB CCBARB
Illustration modified from www.lotrel.com
Opie. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273
White et al. Clin Pharmacol Ther 1986;39:438; Gustaffson. J Cardiovasc Pharmacol
1987;10(Suppl. 1):S12131; Messerli et al. Am J Cardiol 2000;86:11827
71
Addition of amlodipine to valsartan provides similar efficacy
but superior tolerability to doubling of amlodipine
Additional amlodipine Additional amlodipine

5 mg in patients 5 mg in patients
Valsartan uncontrolled Amlodipine uncontrolled
80 mg at 8 weeks 5 mg at 8 weeks
0
n=84 n=24 n=84 n=28
−5
−10
−15
8 weeks 12 weeks 8 weeks 12 weeks
−20
Change from baseline in sitting diastolic BP (mmHg)
AEs = 7.1% 4.2% 9.5% 14.3%

Corea et al. Clin Pharmacol Ther 1996;60:341–6
Rationale for CCBARB therapy: with
Amlodipine/Valsartan
73
Amlodipine: the chemistry
 Amlodipine is a dihydropyridine, long-acting CCB
 Chemical name: 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy)

methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-
pyridinedicarboxylate, monobenzenesulphonate
 Empirical formula: C20H25CIN2O5•C6H6O3S

CH3
 Molecular weight: 567.1 CI O

O
H3 C O
O
H3 C NH
O
C5H5O3S
NH2
http://www.pfizer.com/pfizer/download/uspi_norvasc.pdf
74
Mechanism of action of amlodipine
 Amlodipine 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
 It binds to both dihydropyridine and non-dihydropyridine binding

sites
 Amlodipine is also a peripheral arterial vasodilator

 Acts directly on vascular smooth muscle to cause a reduction in
peripheral vascular resistance and a reduction in BP
http://www.pfizer.com/pfizer/download/uspi_norvasc.pdf
75
Amlodipine: wealth of CV outcome data

Primary outcome: No difference in mean 3 yr
PREVENT1 coronary angiographic changes vs. placebo
825 CAD patients (≥30%): Multicenter, 35%  hospitalization for heart failure + angina
randomized, placebo controlled
33%  revascularization procedures
Primary outcome: 31%  in CV events vs. placebo

CAMELOT2 41%  hospitalization for angina
1,991 CAD patients (>20%): Double-blind,
27%  coronary revascularization
randomized study vs. placebo and enalapril 20 mg
Primary outcome: 10%  in non-fatal MI & fatal CHD

ASCOT-BPLA/CAFE3,4 16%  total CV events and procedures
19,257 HTN patients: Multicenter, randomized,
30%  new-onset diabetes
prospective study vs. atenolol
27%  stroke
11%  all-cause mortality
 central aortic pressure by 4.3 mmHg
Primary outcome: No difference in composite of fatal

ALLHAT5 CHD + non-fatal MI vs. lisinopril
18,102 HTN patients: Randomized, prospective 6%  combined CVD
study vs. lisinopril
23%  stroke
Pitt et al. Circulation 2000;102:1503–10; 2Nissen et al. JAMA 2004;292:2217–26; 3Dahlof et al. Lancet 2005;366:895–906
1
4
Williams et al. Circulation 2006;113:1213 –25; 5Leenen et al. Hypertension 2006;48:374–84
76
Valsartan: the chemistry
 Valsartan is a non-peptide, orally active and specific angiotensin II

type 1 (AT1) receptor antagonist
 Chemical name: N-(1-oxopentyl)-N-((2′-(1H-tetrazol-5-yl)

(1,1′-biphenyl)-4-yl)methyl)-L-valine
H3 C CH3
 Empirical formula: C24H29N5O3 O (S)
H3C
 Molecular weight: 435.5 N COOH
N
N
NH
N
http://www.pharma.us.novartis.com/product/pi/pdf/diovan.pdf
77
Mechanism of action of valsartan

Non-ACE Vasoconstriction
pathways Cell growth
(e.g. chymase)
Sodium/water retention
Angiotensinogen
Sympathetic activation
Angiotensin I
Valsartan AT1 receptor
Angiotensin-converting enzyme
Angiotensin II
AT2 receptor
Aldosterone
Vasodilation
Antiproliferation
Sodium/water
retention
78
Valsartan: wealth of CV outcomes data

Primary outcome: No difference in composite
VALUE1 of cardiac mortality and morbidity
15,245 high-risk HTN patients: Double-blind,
23%  new-onset diabetes
randomized, active-controlled study vs.
amlodipine
Primary outcome: No difference vs. captopril

VALIANT2 in all-cause mortality
14,703 post-myocardial infarction patients:
(Valsartan is as effective as standard of care)
Double-blind, randomized study vs. captopril
and vs captopril + valsartan
Primary endpoints: Mortality and combined

Val-HeFT3–5 endpoint of mortality and morbidity
5,010 heart failure II–IV patients:
13%  mortality and morbidity
Double-blind, randomized study vs placebo
 left ventricular remodeling
37%  atrial fibrillation occurrence
 heart failure signs/symptoms
28%  heart failure hospitalization
Julius et al. Lancet 2004;363:2022–31; 2Pfeffer et al. N Engl J Med 2003;349:1893–906; 3Maggioni et al. Am Heart J
1
2005;149:548–57; 4Wong et al. J Am Coll Cardiol 2002;40:970–5; 5Cohn et al. N Engl J Med 2001;345:1667–75
79
Valsartan: wealth of CV protection data
MARVAL1 Primary endpoint: % change in urinary

albumin excretion rate (UAER) over 6 months
332 patients with T2D + microalbuminuria ±
44%  in UAER vs. baseline with valsartan
HTN: Multicenter, randomized, double-blind,
vs. 8% with amlodipine
active-controlled study vs. amlodipine
52%  patients returning to
normoalbuminuria vs. amlodipine
Primary endpoints: change in systolic BP and

Val-MARC2 in high-sensitivity C-reactive protein (hsCRP)
1,668 stage 2 HTN patients: Multicenter, between randomization and Week 6
open-label, randomized study vs
Drop in systolic BP was greater with the
valsartan/hydrochlorothiazide (HCTZ)
combination
13%  hsCRP (marker of inflammation) vs.
valsartan/HCTZ
1
Viberti et al. Circulation 2002;106:672–8
2
Ridker et al. Hypertension 2006;48:73–9
80
ACCOMPLISH: first study to compare effect on CV morbidity and mortality of two

ACE inhibitor-based anti-hypertensive drug combinations
ACCOMPLISH1,2
11,506 ‘high-risk’ patients Primary endpoint: time to first event
randomised into two treatment arms of a composite of CV morbidity and
(5,744 to benazepril-amlodipine, mortality in the two treatment groups
5,762 to benazapril- 73% Achieved Systolic BP<140
hydrochlorothiazide) across the US mmHg in 6 months
(n=8110) and Europe (n=3,353)1
only 26% of patients were receiving
(Weber et al. 2007).
add-on treatment at month six
1
Weber et al. Blood Pressure 2007; 16:13-19
2
Jamerson et al. 2008 NEJM; 359(23)2417-2428
Early BP Results: MSSBP at 6 months was significantly 81
reduced compared with baseline (p<0.001 for all groups)
Mean Diastolic BP Mean Systolic BP
100 160
M ean dias tolic BP (m m Hg)
M ean systolic BP (m m H g)
150
90 145.5
140
80.2
132.5
80
130
74.3
70 120
Baseline At 6 months Baseline At 6 months
Jamerson et al. 2007. Blood Pressure 2007; 16:80-86

82
Early BP Control Results, 73% Achieved Systolic
BP<140 mmHg in 6 months
Change in Systolic BP after 6 months of Treatment

with RAAS Blocker-Based Fixed Dose
80
Combination Therapy
% of Study Population
70
61.1
60
50
40
28.4 27
30 26.1
19.8
18.5
20 12.4
6.6
10
0
<120 <130 <140 >140
BP Range (mmHg) Baseline
At 6 months
Jamerson et al. 2007. Blood Pressure 2007; 16:80-86

Final ACCOMPLISH results demonstrate unprecedented 83
BP control with early treatment with high-dose RAAS

inhibitor-based SPC
Jamerson et al. 2008 NEJM; 359(23)2417-2428

84
Target patient population for Amlodipine/Valsartan
 Patients with high BP not adequately controlled with either

amlodipine or valsartan alone (monotherapy)
85
Amlodipine/Valsartan tablets  Europe
5/80 mg 5/160 mg 10/160 mg
Size mm: 8 14 x 5.5 14 x 5.5

Weight: 175 mg 341 mg 347 mg
86
Amlodipine/Valsartan tablets  US
5/80 mg 5/160 mg 10/160 mg 5/320 mg 10/320 mg
Size mm: 8 14 x 5.5 14 x 5.5 19 x 7.5 19 x 7.5

Weight: 175 mg 341 mg 347 mg 945 mg 945 mg
Therapeutic value of Amlodipine/Valsartan
Introduction to Amlodipine/Valsartan
Support for the Amlodipine/Valsartan combination
Overview of completed Amlodipine/Valsartan registration trials
Registration trial results: efficacy and safety/tolerability
Completed Phase IV programme: ExPress-C
Support for Amlodipine/Valsartan
89
Additional BP-lowering effect of amlodipine, chlorthalidone
and benazepril when combined with valsartan monotherapy
Systolic BP Diastolic BP
0
−5
−6.3
−8.6 *
−10
* −9.9 −9.5
# * # *
−15 −13.5 N=64
−15.2 # *
Valsartan + amlodipine
# *
−20 Valsartan + chlorthalidone
BP decline (mmHg) Valsartan + benazepril
*p<0.001 vs valsartan monotherapy

#
p<0.05 vs valsartan-benazepril Stergiou et al. J Hypertens 2005;23:883–9
90
Amlodipine/Valsartan has superior BP-lowering efficacy compared
with monotherapies in patients with mild-to-moderate hypertension
Amlodipine Valsartan Amlodipine/Valsartan

10 mg 160 mg 10/160 mg
0
−5
−10
−15
−16.5
−20 −17.8
N=42
−25 −23.5
Change from baseline in systolic BP (mmHg) *
*p<0.001 vs monotherapies
Mild-to-moderate HTN = DBP >95 and <110 mmHg Fogari et al. J Hypertens 2006;24(Suppl 4):S34
91
Incremental blood pressure lowering effectiveness when
amlodipine is added to valsartan in a real-life setting
 Add-on therapy with amlodipine

 Reduced BP by 13.3/6.1 mmHg in patients receiving valsartan
 Reduced BP by 30.7/11.2 mmHg in patients with baseline SBP ≥160 mmHg receiving
valsartan
Overall Baseline SBP ≥160 mmHg

DBP SBP DBP SBP
0 0
n=155 n=64
-5 -5
Change from index

Change from index
-6.1 -10
date* (mmHg)
date* (mmHg)
-10
-15 -15 -11.2
-13.3
-20 -20
-25 -25
-30 -30
-35 -30.7
-35
*The start of amlodipine add-on therapy was Weycker et al. Presented at International Society of
designated the index date Hypertension, October 2006, Japan. Poster P3-29
92
Amlodipine/Valsartan demonstrates superior tolerability
compared with amlodipine monotherapy
Ankle-foot volume increase (%) N=42

20 17.9
15
*
10 8.3
0
Amlodipine 10 mg Amlodipine/Valsartan
10/160 mg
*p<0.05 vs amlodipine
Crossover design Fogari et al. J Hypertens 2006;24(Suppl 4):S34
93
Amlodipine/Valsartan prevents recurrence of atrial fibrillation more
effectively than atenolol/valsartan during a 1-year follow-up
Patients with at least one symptomatic or non-symptomatic

ECG-documented episode of atrial fibrillation (% incidence) N=220
40
33
30
20 *
13
10
0
Amlodipine/Valsartan Amlodipine/atenolol
10/160 mg† 10/100 mg†
*p<0.01 vs amlodipine/atenolol
†
Titration to maximum dose of amlodipine Mugellini et al. J Hypertens 2006;24(Suppl 4):S5
Amlodipine/Valsartan registration trials:
efficacy and safety/tolerability
Amlodipine/Valsartan registration trials: overview
96
Double-blind, randomised studies supporting the efficacy
and safety of Amlodipine/Valsartan
Design Study Duration Randomised Patient population and treatment

number (weeks) (N)
Placebo- 2201 8 1,911 Mild-to-moderate HTN;

controlled 2201Ea 52 amlodipine/valsartan vs monotherapy
and placebo
2307 8 1,250 Mild-to-moderate HTN;
2307Ea 54 amlodipine/valsartan vs monotherapy
and placebo
Active- 2305 8 947 Mild-to-moderate HTN (non-responder
controlled to valsartan 160 mg); amlodipine/
valsartan vs valsartan 160 mg alone
2306 8 944 Mild-to-moderate HTN (non-responder

to amlodipine 10 mg); amlodipine/
valsartan vs amlodipine 10 mg alone
Single-pill 2308 6 130 Severe HTN; amlodipine/valsartan vs

dose lisinopril/HCTZ
a
Open-label, long-term extension study
Amlodipine/Valsartan registration trials: efficacy
98
Amlodipine/Valsartan provides superior blood pressure lowering
versus amlodipine or valsartan monotherapy (Study A2201*)
Valsartan (mg) 0 40 80 160 320

Amlo (mg) 0 2.5 5 0 2.5 5 0 2.5 5 0 2.5 5 0 2.5 5
-5
-10
p p
p
-15 p p
pva p
pva pa
pa
-20 pva pva
pva
N=1,911 pva
-25
Change from baseline in MSSBP (mmHg) at endpoint
p = p<0.05 vs placebo; v = p<0.05 vs valsartan; a = p<0.05 vs amlodipine

MSSBP = mean sitting systolic BP
*Randomised, double-blind, placebo-controlled, multifactorial trial

Smith et al. J Clin Hypertens 2007;9(5):355-364
99
Amlodipine/Valsartan provides superior responder rates
Responder rate† N=1,911

100% pva
pva pva pv
pva pa
80% p pa p
p
p p p p
60%
40%
20%
Amlo (mg) 0 2.5 5 0 2.5 5 0 2.5 5 0 2.5 5 0 2.5 5

Valsartan (mg) 0 40 80 160 320

†
Responder rate defined as mean sitting diastolic BP (MSDBP) <90 mmHg or
≥10 mmHg decrease vs baseline
*Randomised, double-blind, placebo-controlled, multifactorial trial Smith et al. J Clin Hypertens 2007;9(5):355-364
100
Amlodipine/Valsartan provides superior blood pressure control
Control rate† N=1,911

100%
pva
80% pv pv pva pv p pa
p pva
p
60% p
p p
p
40%
20%
Amlo (mg) 0 2.5 5 0 2.5 5 0 2.5 5 0 2.5 5 0 2.5 5

Valsartan (mg) 0 40 80 160 320
†
Control rate defined as MSDBP <90 mmHg
101
Amlodipine/Valsartan provides superior blood pressure lowering
Valsartan (mg) 0 160 320 0 160 320

Amlo (mg) 0 10 0 10 0 10 0 10 0 10 0 10
-5
-10 8.8
-15 13.3 13.3 12.9

15.6 p p
-20 p 17.6
pva 18.7 20.2 19.8
pva p
-25 24.1
N=1,250 p
27.8
-30 28.4
pva
pva
-35
DBP SBP
Change from baseline in BP (mmHg) at endpoint
102
Amlodipine/Valsartan provides superior responder rates
Responder rate† N=1,250

100% p pv pv
86.9% 88.5% 87.5%
p p
80% 74.9% 72.0%
60% 49.3%
40%
20%
Amlo (mg) 0 10 0 10 0 10
Val (mg) 0 160 320

†
Responder rate defined as MSDBP <90 mmHg or ≥10 mmHg decrease vs baseline
Smith et al. J Clin Hypertens 2007;9(5):355-
103
Amlodipine/Valsartan provides superior control rates versus
amlodipine or valsartan monotherapy (Study A2307*)
 Control rate at endpoint is competitive

Control rate† N=1,250
100% pv pv
p 84.1%
80.1% 81.8%
p
80% 70.5% p
63.8%
60%
42.6%
40%
20%
Amlo (mg) 0 10 0 10 0 10
Val (mg) 0 160 320
†
104
Blood pressure reductions with Amlodipine/Valsartan in
valsartan non-responders meet regulatory criteria (Study A2305*)
Amlo/Val Amlo/Val
Val Val
160 5/160 10/160 160 5/160 10/160
0
n=308 n=322 n=317 n=308 n=322 n=317
-5
-6.6
-8.2
-10 -9.6
v -11.4
v, av -12.0
-15 v -13.9
N=947 v, av*
-20 DBP SBP

Change from baseline in BP (mmHg) at endpoint
= p<0.0001 vs valsartan
v = p<0.001, av* = p<0.02 vs Amlodipine/Valsartan 5/160 mg Novartis data on file
*Randomised, double-blind, active-controlled trial
105
Amlodipine/Valsartan offers greater responder rates in patients
uncontrolled on valsartan monotherapy (Study A2305*)
Responder rate† N=947

100% v, av
81.0%
v
80% 68.0%
56.8%
60%
40%
20%
n=308 n=322 n=316
Val 5/160 10/160

160 Amlo/Val
v = p<0.05 vs valsartan; av = p<0.05 vs Amlodipine/Valsartan 5/160 mg
†
Responder rate defined as MSDBP <90 mmHg or ≥10 mmHg decrease vs baseline
*Randomised, double-blind, active-controlled trial Novartis data on file
106
Amlodipine/Valsartan offers greater control rates in patients
uncontrolled on valsartan monotherapy (Study A2305*)
Control rate†
N=947
100% v, av
75.3%
80% v
62.4%
52.6%
60%
40%
20%
n=308 n=322 n=316
Val 5/160 10/160

160 Amlo/Val
v = p<0.05 vs valsartan; †p<0.05 vs Amlo/Val 5/160 mg
†
107
Blood pressure reductions with Amlodipine/Valsartan in
amlodipine non-responders meet regulatory criteria (Study A2306*)
Amlo Amlo/Val Amlo Amlo/Val

10 mg 10/160 mg 10 mg 10/160 mg
0
n=471 n=473 n=471 n=473
Change from baseline in
BP (mmHg) at endpoint
−5
−10 -10.0
-10.8
-11.8
-12.7
−15 a
a
N=944
−20 DBP SBP
a = p<0.0001 vs amlodipine
108
Amlodipine/Valsartan results in superior responder rates
versus amlodipine monotherapy (Study A2306*)
Responder rate† (%) N=944

100% a
79.0%
80% 70.1%
60%
40%
20%
n=471 n=473
0
Amlo Amlo/Val
10 mg 10/160 mg
a = p=0.0011 vs amlodipine
†
Responder rate defined as MSDBP <90 mmHg or ≥10 mmHg decrease vs baseline Novartis data on file
*Randomised, double-blind, active-controlled trial
109
Amlodipine/Valsartan results in superior blood pressure
control versus amlodipine monotherapy (Study A2306*)
Patients controlled† (%) N=944

100%
a
77.8%
80%
66.5%
60%
40%
20%
n=471 n=473
0
Amlo Amlo/Val
10 mg 10/160 mg
a = p<0.0001 vs amlodipine
†
110
Amlodipine/Valsartan is highly effective at reducing blood pressure
in patients with stage 2 hypertension (Study A2308*)
Endpoint BP MSSBP MSDBP

(mean mmHg) 135.0 138.7 83.6 85.2
0
−10
−20
−30 −28.6 −27.6

−31.8
−35.8 Amlodipine (5–10 mg) +
−40
valsartan (160 mg) (n=64)
Change from baseline (mmHg) Lisinopril (10–20 mg) +
HCTZ (12.5 mg) (n=66)
ITT population
*Randomised, double-blind, active-controlled trial Poldermans et al.Clin Ther 2007;29(2):279-289.
111
Amlodipine/Valsartan results in a 43 mmHg drop in MSSBP in
patients with MSSBP 180 mmHg (Study A2308*)
Endpoint BP MSSBP MSDBP

(mean mmHg) 145.4 157.4 86.4 92.5
0
−10
−20
−21.7
−30 −26.1
−31.2
−40
−43.0 Amlodipine (5–10 mg) +
−50 valsartan (160 mg) (n=15)
Change from baseline (mmHg) Lisinopril (10–20 mg) +
HCTZ (12.5 mg) (n=11)
ITT population
*Randomised, double-blind, active-controlled trial Poldermans et al.Clin Ther 2007;29(2):279-289.
112
100% of patients treated with Amlodipine/Valsartan respond to therapy
and 80% achieve BP control (DBP <90 mmHg) (Study A2308*)
Amlodipine (5–10 mg) +

Patients (%) valsartan (160 mg) (n=64)
100
100 95.5 Lisinopril (10–20 mg) +
90 HCTZ (12.5 mg) (n=66)
79.7
80 77.3
70
60
50
40
Responders Achieved BP control
(MSDBP <90 mmHg or (MSDBP <90 mmHg
≥10 mmHg reduction at endpoint)
from baseline)
*Randomised, double-blind, active-controlled trial Poldermans et al. Clin Ther 2007;29(2):279-289.
113
Amlodipine/Valsartan: appropriate BP reductions across
all grades of hypertension
Mean change in mean sitting SBP from baseline (mmHg)

Mild HTN1 Moderate HTN1 Stage 2 HTN2
(DBP 95–100 mmHg (DBP 100–110 mmHg (DBP ≥110 mmHg <120 Systolic BP
SBP 140–160 mmHg) SBP 160–180 mmHg) mmHg) ≥180 mmHg2
0
n=69 n=140 n=64 n=15
−10
−20
−20
−30
−30
−40 −36
−43
−50
Dose: 10/160 mg Dose: 510/160 mg
DBP
reduction –17 –18 –29 –26
(mmHg)
Poldermans et al. Clin Ther 2007;29(2):279-289.
1
2
Data from Poldermans et al. J Hypertens 2006;24(Suppl 4):S20 (poster)
114
Open-label extension results (studies A2201E and
A2307E)
 Antihypertensive efficacy of Amlodipine/Valsartan was

maintained for 1 year
 No tachyphylaxis was observed
 Amlodipine/Valsartan treatment was well tolerated

 No significant new adverse events compared with
short-term treatment
Novartis data on file

115
Completed Phase IV clinical trials assessing SPC therapy
Amlodipine/Valsartan (A2401, A2402, A2403, A2404).
 Study 2401, EX-FAST: (Alleman et al. J Clin Hyperten 2008; 10(3): 185-194)
Efficacy and safety in patients not controlled on any monotherapy
 Study 2402, EX-STAND: (Flack J et al., ASH - J Clin Hypertens 2008)
Efficacy and safety in black patients with stage 2 systolic hypertension
 Study 2403, EX-EFFeCTS: (Flack J et al., ASH - J Clin Hypertens 2008)
Efficacy and safety in patients with stage 2 systolic hypertension
 Study 2404: (Schrader J et al., ESH 2008)
Treatment strategies in patients not controlled on amlodipine 5 mg

116
Study A2401: EX-FAST: Non-responders to
monotherapy
 Primary objective: overall BP control rate (<140/90 mmHg or <130/80 mmHg for
patients with diabetes) at the end of the study
 Population: mild-to-moderate hypertensives, non-responder to any monotherapy
 First patient/first visit February 2006; last patient/last visit November 2006
 Planned enrollment: 926
+ HCTZ 25 mg
+ HCTZ 12.5 mg
Screening/
direct switch Amlodipine/Valsartan 5/160 mg
12 weeks Amlodipine/Valsartan 10/160 mg

+ HCTZ 12.5 mg
+ HCTZ 25 mg
Randomization Weeks 8 12 16
HCTZ=hydrochlorothiazide Allemann et al. J Clin Hypertens 2008;10:185–94
Study A2401: EX-FAST: Incremental MSSBP reduction 117
after direct switch
Antihypertensive class prior to randomization in the trial
Overall -blocker CCB ARB ACEI Diuretic

N= 440 449 76 55 53 70 175 175 92 105 41 39
0
Change in MSSBP from baseline
–5
to Week 8 (mmHg)
–10
–15
−17.6 −17.7 −17.4 −17.5 −17.6

−18.4
–20 −19.5 −20.0
−21.0 −21.3
−22.1
–25 −24.3
Amlodipine/Valsartan 5/160 mg
Randomized, double-blind, multinational,
parallel-group, 16-week study
BL (under treatment) 150/91 mmHg Allemann et al. J Clin Hypertens 2008;10:185–94
118
Study A2402, EX-STAND: Black patients with stage 2
hypertension
 Primary objective: superior BP-lowering efficacy of an Amlodipine/Valsartan-based
treatment strategy vs. an amlodipine-based treatment strategy
 Secondary objective: BP control rate (<140/90 mmHg)
 Population: African American/Black stage-2 hypertensive patients
 First patient/first visit June 2006; last patient/last visit April 2007
+ HCTZ 12.5 mg
Screening/
Wash-out Amlo/Val 5/160 Amlodipine/Valsartan 10/160 mg
1 week Amlo 5 mg Amlodipine 10 mg

+ HCTZ 12.5 mg
Randomization 2 4 8 12 Wks
HCTZ=hydrochlorothiazide Flack J et al., ASH - J Clin Hypertens 2008
119
Study A2403, EX-EFFeCTS: Patients with stage 2
hypertension
 Primary objective: superior BP-lowering efficacy of an Amlodipine/Valsartan-based
treatment strategy vs. an amlodipine-based treatment strategy
 Secondary objective: BP control rate (<140/90 mmHg)
 Population: stage-2 hypertensive patients – MSSBP ≥160 mmHg and MSSBP <200 mmHg
 First patient/first visit June 2006; last patient/last visit March 2007
+ HCTZ 12.5 mg
Screening Amlo/Val 5/160 Amlodipine/Valsartan 10/160 mg
1 week Amlo 5 mg Amlodipine 10 mg

+ HCTZ 12.5 mg
Randomization 2 4 8 Wks
HCTZ=hydrochlorothiazide Source: Study CVAA489A2403; accepted in JASH
120
Studies A2402/A2403: EX-EFFeCTS and EX-STAND:
MSSBP measurements by week
2403: EX-EFFeCTS 2402: EX-STAND
175
Systolic Blood Pressure (mm Hg)
170
165
160
155
150
145
140
135
130
0 2 4 6 8 0 2 4 8 12
Week Week
Amlodipine/Valsartan 10/160 mg Amlodipine 10 mg
MSSBP=mean sitting systolic blood pressure Source: Study CVAA489A2403 and 2402
121
Studies A2402/A2403: EX-EFFeCTS and EX-STAND:
MSSBP changes for patients receiving HCTZ
2403: EX-EFFeCTS 2402: EX-STAND
Amlo/Val Amlo Amlo/Val Amlo

10/160 mg 10 mg 10/160–320 mg 10 mg
0 0
N=133 N=206 N=146 N=183
− 2.5 − 2.5
−3.1
− 5.0 − 5.0
−4.6
−7.5 −7.5
–6.9
−10.0 –8.5
−10.0
Δ = –3.82
p=0.0012 Δ = –3.85
p=0.0124
LSM Change in MSSBP from Week 4 to Week 8 LSM Change in MSSBP from Week 8 to Week 12
HCTZ=hydrochlorothiazide Source: Study CVAA489A2403 and 2402

122
Study 2404: Patients not controlled on amlodipine 5 mg

 Population:
 Hypertensive patients not adequately controlled on amlodipine 5 mg (MSSBP >130mmHg)
 Primary objectives:
 To confirm that the combination of Amlodipine/Valsartan 5/160 mg is non-inferior to amlodipine10mg
when comparing the reduction of MSSBP from baseline to Week 8 (Visit 4)
 To confirm that the combination of Amlodipine/Valsartan 5/160 mg induces less peripheral edema
compared to amlodipine10mg alone up to Visit 4 (Week 8) quantified as AE reported peripheral edema
Amlo/Val 5/160 mg
Amlo 5 mg
Amlo 10 mg Amlo/Val 5/160 mg
Weeks –4 Randomizatio 4 8 12
n
Period 1 Period 2
AE=adverse event Source: Study CVAA489A2404 Schrader J et al., ESH 2008
123
Study A2404: Proportion of patients experiencing peripheral

oedema at Week 8
p <0.001
35 31.1% Number of discontinuations

(n=184) between randomization and
30 Week 8
25 • Amlo/Val: 5.1% (30/592)

• Amlo: 18.1% (107/591)
20
%
15
10 6.6%
(n=39)
5
N=592 N=591
0
Amlo/Val 5/160 mg Amlo 10 mg
Source: Study CVAA489A2404 Schrader J et al., ESH 2008

124
Study A2404: Change in MSSBP at Week 8

Amlo/Val 5/160 mg Amlo 10 mg
0
N=570 N=521
-1
Change in MSSBP (mmHg)
-2
-3
-4
-5
-6
-7 –6.3
-8
–8.01
-9
Δ = –1.72
p <0.001
p-value for non-inferiority (non-inferiority margin 3 mmHg); CI for difference [–3.00; –0.44]
LSM change in MSSBP from baseline: BL Amlodipine/Valsartan:143/83 mmHg; BL amlodipine: 144/84 mmHg
Source: Study CVAA489A2404 Schrader J et al., ESH 2008
125
Phase IV Program focuses on efficacy in special patient
populations & special conditions
Gaps Action
Limited superiority data vs. existing Existing data and ongoing Phase IV studies
therapies (non-controlled with current Rx) in uncontrolled hypertensive patients
Importance of intensive reduction in SBP: Phase IV studies (EXCEED and EXAMIN)

time to BP control; diastolic fx and LV Mass ongoing
Greater understanding of effects of Phase IV Central BP (eXPLoR) Study

valsartan/amlodipine on central BP ongoing
Limited data examining 24 hr BP lowering Phase IV ABPM study ongoing

effects – BP morning surge & BP variability
Restricted data in specific patient groups Maximize BP lowering efficacy & control
(ISH-Elderly, T2D, African-American) rate in African American patients
Renal effects of valsartan/amlodipine in Data available from recently completed

patients with type 2 diabetes study in African American patients
126
Phase IIIb/IV Trials
Ongoing Studies
 VAA489AUS01 – EXCEED – Evaluate the effects of systolic

blood pressure lowering to different targets (<130 mmHg vs.
<140 mmHg) on diastolic function (N=214)
 VAA489AUS02 – EXTRA - Evaluate the effect of
valsartan/amlodipine (160-320/10 mg) in patients not
adequately controlled on an ARB (N=400)
 VAA489ADE02 – EXAMIN LVH - Evaluate the effect of
valsartan/amlodipine (160/10 mg) as compared to
losartan/HCTZ (100/25 mg) on the regression of LVH (N=100)
 VAA489AFR02 – eXPloR – Evaluate the effect of valsartan
/amlodipine (160/10 mg) as compared to atenolol/amlodipine
(100/10 mg) on central aortic blood pressure (N=424)
Amlodipine/Valsartan registration trials: safety
128
Safety and tolerability of Amlodipine/Valsartan
 Safety evaluated in 5,175 patients

 Five large phase III double-blind, controlled trials
 Two long-term, open-label extension trials
 One short-term, open-label trial
 One short-term, sub-population analysis of a double-blind trial
 Trial participation, withdrawals and AEs studied in three combined

datasets
Dataset A Dataset B Dataset C

Double-blind, active- or Double-blind, placebo- Long-term
placebo-controlled safety controlled safety safety
populations* population population
*A2201, *A2307, A2305, A2306, #A2308 *Smith et al. J Clin Hypertens 2007;9(5):355-364
# Poldermans et al. Clin Ther 2007;29(2):279-289
129
Safety and tolerability of Amlodipine/Valsartan (cont.)
 Majority of AEs were mild or moderate in severity

 Lower overall incidence of severe AEs in the
Amlodipine/Valsartan, amlodipine monotherapy or valsartan
monotherapy groups vs placebo
 Dataset B had an overall lower incidence of severe AEs in the
amlodipine and valsartan groups vs placebo
 Severe AEs were reported in 9% of patients in A2201E and 2.5%
of patients in A2307E
 Most frequent serious AEs

 Cardiac disorders (7 total, 0.1% of all patients)
 Musculoskeletal and connective tissue disorders (6 total, 0.1%
of all patients in dataset A)
130
Amlodipine/Valsartan reduces the incidence of
amlodipine-associated peripheral oedema
Peripheral oedema (%)

10
8.7
*
6 5.4
4
3
2.1
2
0
Placebo Valsartan Amlodipine Amlodipine/Valsartan
(n=337) (n=921) (n=460) (n=1,437)
*p=0.0138 vs amlodipine
Novartis data on file
Completed phase IV programme:
ExPress-C study
132
Amlodipine/Valsartan gets 9 of 10 patients whose BP is not
normalised by ramipril/felodipine to goal: ExPress-C study
Normalization rate in patients on Amlodipine/Valsartan 86%

Mean sitting SBP <140 mmHg or mean sitting DBP <90 mmHg
Responder rates in patients receiving Amlodipine/Valsartan

Patients with mean sitting SBP <140 or decrease ≥20 mmHg 83%
Patients with mean sitting DBP <90 or decrease ≥10 mmHg 82%
ExPress-C = Exforge in patients not controlled by other antihypertensives – Combination therapy with
ACE inhibitor plus CCB
Trenkwalder et al. 2007. J Hypertens 2007;25(Suppl. 2):S228 (abstract P24.261).

133
Systolic blood pressure reduction of 31 mmHg in patients
with moderate hypertension: ExPress-C study
180 100
N=133 –14.3 mmHg
–30.7 mmHg
Systolic BP (mmHg)
96.6
Diastolic BP (mmHg)
166.7 –15.4 mmHg
160 p<0.0001 –7.0 mmHg
p<0.0001
151.4
90
89.3
140
136
82.3
120 80
Week 0 5 10 Week 0 5 10
Ram/fel 5/5
Amlo/val 10/160 Amlo/val 10/160
Ram/fel 5/5
Trenkwalder et al. J Hypertens 2007;25(Suppl. 2):S228 (abstract P24.261).

134
Even greater BP reductions with Amlodipine/Valsartan in
patients with higher BP at Week 5: ExPress-C study
Additional BP reduction depending on the BP level at Week 5
SBP at Week 5 SBP reduction by Amlodipine/

(after ramipril/felodipine 5/5 mg) Valsartan 10/160 mg
>140 mmHg and <160 mmHg –14.3 mmHg
≥160 mmHg and <170 mmHg –16.6 mmHg
≥170 mmHg and <180 mmHg –25.0 mmHg

135
Additional BP reduction in elderly patients:
ExPress-C study
Additional BP reduction depending on age group
Age (years) Additional SBP reduction by

<65 –15 mmHg
≥65 –16 mmHg

136
ExPress-M study
 Open-label, single-arm trial evaluating the efficacy and tolerability of

the combination of Amlodipine/Valsartan in patients not responding
adequately to treatment with amlodipine or felodipine alone.
 Patients (n=214) aged >=18 years with moderate essential HTN
(MSSBP >=160 and <180mmHg) were treated with amlodipine 5mg or
felodipine 5mg for 4 weeks
 Of the 214 patients treated for the 4 weeks, 181 failed to achieve
MSSBP<140mmHg. Non-responders were treated for an additional 4
weeks with Amlodipine/Valsartan 5/180 mg.
 The additional 4 weeks’ treatment with Amlodipine/Valsartan provided
statistically highly significant and clinically relevant additional BP
reductions in patients not controlled by amlodipine or felodipine
therapy (p<0.0001 for both SBP and DBP).
Brachmann et al. Adv Ther. 2088;25(5):399-411..

137
ExPRESS-M: BP reduction with amlodipine/valsartan 5/160 mg in
hypertensive patients not controlled by CCB monotherapy
N=214 pts Brachmann et al. Adv Ther. 2088;25(5):399-411

138
EXPRESS-M: Effect of amlodipine/valsartan 5/160 mg
in patients uncontrolled on amlodipine 5 mg
Brachmann et al. Adv Ther. 2008;25(5):399-411

Amlodipine/Valsartan: health-economic
models
Cost minimisation and budget impact models
Model demonstrations
140
Cost minimisation and budget impact models
 The cost minimisation and budget impact models have been

developed to allow flexibility in support of European and US
needs
 The cost minimisation model demonstrates cost savings as

more patients move to EXFORGE rather than free-combination
use
 The budget impact model, in addition to the cost minimisation

model, demonstrates cost savings as patients move from other
generic amlodipine/ARB combinations
141
Cost minimisation and budget impact models: choices
 Settings can be customised to present user-selected outputs

over a user-selected timeframe (1, 3 or 5 years) based on
country/payer/setting-specific inputs
 Individual users can conduct sensitivity analyses to evaluate

specific conditions using their input data
142
Cost minimisation and budget impact models: model
settings
For demonstration purposes only. Data may not reflect the current situation
143
Cost minimisation and budget impact model: introduction
144
Cost minimisation and budget impact model: inputs –
population characteristics
145
market share and growth
146
regimen costs
147
Cost minimisation and budget impact model:
sample cost minimization results (tabular)
148
Cost minimisation and budget impact model: results
(graphics)
149
Cost minimisation and budget impact model: data needs
and decisions
 Country/payer/setting-specific data may be needed for

 Eligibility flow (percent eligible for SPC therapy)
 Market projections
 penetration of SPC into a market of free combination of amlodipine +
valsartan only (cost minimization analysis) and into a market of other
free combination therapy regimens (budget impact analysis)
 Market growth projections
 number of patients newly eligible for SPC therapy each year
 Pricing data
 drug prices and co-pay data for all drugs to be considered in the
market basket, in addition to projected price of SPC and generic
amlodipine (for longer timeframes)
Amlodipine/Valsartan/HCTZ
“Triple Combination” Clinical Evidence

151
Contents
 Rationale for Valsartan / Amlodipine / HCTZ

 Physiology
 Guidelines
 Wealth of Experience with Respective Monotherapies and SPCs
 Clinical Evidence for Valsartan / Amlodipine / HCTZ

Exforge Program
 EXFAST – CVAA489 A2401 (see slides 116, 117)
 EXSTAND – CVAA489 A2402 (see slides 118, 120, 121)
 EX-EFFECTS – CVAA489 A2403 (see slides 119, 120, 120)
Exforge HCT Program
 CVEA489A2302 – Pivotal US Registration Study
152
Different Classes of Drugs have Different Sites of Action
BP
=
Total
Cardiac
X peripheral
output
resistance
=
Stroke Arterial Venous
Heart rate X
volume pressure pressure
β-blockers Diuretics CCBs ARBs ACEIs
Different, but complementary mechanism of action

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin Beevers, et al. BMJ 2001;322:912–6;
Type II receptor blocker; CCB = calcium channel blocker McGhee, et al. Crit Care Nurse 2002;22:60–4;
Goodman & Gilman’s Pharmacological Basis of Therapeutics. 9 th ed. 1995.
153
There are many possible combinations of hypertension drugs

Diuretics  ESH-ESC
recommendations
include
-blockers ARBs  ARB + diuretic
 ARB + CCB
 CCB + diuretic
 NICE guidelines for

triple therapy
-blockers CCBs recommend
 ACEI or ARB +
CCB + thiazide
diuretic (Step 3)
ACEIs
Preferred combinations
Less frequently used/combination used as necessary Task Force for ESH–ESC.
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin J Hypertens 2007;25:1105–87;
Type II receptor blocker; CCB = calcium channel blocker NICE hypertension guidelines 2006
154
Triple Therapy: VEA 2302 Pivotal Triple Combination
Study
 8 week, multicentre, randomized trial comparing the efficacy and safety of

the triple combination of valsartan/HCTZ/amlodipine to each of its dual
components
 Valsartan/HCTZ
 Amlodipine/valsartan
 Amlodipine/HCTZ
 Inclusion
 Moderate–severe hypertension
 MSDBP ≥100 –<120 mmHg
 MSSBP ≥145–< 200 mmHg
 Plasma drug levels were assessed to examine the potential for

pharmacokinetic drug-drug interactions
 The primary efficacy variables were change from baseline to endpoint

(LOCF) in MSDBP and in MSSBP
Data on file. Study CVEA489A2302. Novartis Pharmaceuticals Corporation.

155
Study VEA A2302
Secondary Variables
 Overall BP control rates (MSSBP/MSDBP <140/90 mmHg)
 DBP control rate (MSDBP <90 mmHg)
 SBP control rate (MSSBP <140 mmHg)
 Responder rates in MSDBP (<90 mmHg and/or ≥10 mmHg

reduction from baseline) and in MSSBP (<140 mmHg and/or
≥15 mmHg reduction from baseline)
 Decrease in 24-hour ABPM: DBP and SBP
 Safety and tolerability

156
Patient Demographics
 273 centers in 15 countries worldwide
 2271 patients randomized

 Average age 53.2 years
 Caucasian 71.6%, Blacks 17.1%
 Baseline SBP/DBP 169.9/106.5 mm Hg
 Ambulatory blood pressure monitoring (ABPM) substudy was conducted in
673 randomized patients in selected study centers. 506 patients are expected
to complete the ABPM substudy.

157
Valsartan/Amlodipine/HCTZ Therapy: Pivotal Study Design (VEA 2302)
This was a 8 week, multicentre, randomized trial where primary objective was to investigate whether triple
combination is superior to respective dual-combinations at lowering either: MSDBP or MSSBP. Inclusion
criteria was moderate-to-severe hypertension (MSDBP ≥100 –<120 mmHg, MSSBP ≥145–< 200 mmHg).
Randomization
12.5/5 mg 25/10 mg
HCTZ/amlodipine HCTZ/amlodipine
160/12.5 mg 320/25 mg
Single-blind Valsartan/HCTZ Valsartan/HCTZ
placebo
run-in 5/160 mg 10/320 mg
Amlodipine/Valsartan Amlodipine/Valsartan
160/12.5 mg 160/12.5/5 mg
320/25/10 mg
Valsartan/HCTZ/
Valsartan/HCTZ amlodipine Valsartan/HCTZ/amlodipine
4 weeks 1 week 1 week 6 weeks

MSSBP = mean sitting systolic BP
MSDBP = mean sitting diastolic BP Data on file. Study CVEA489A2302. Novartis Pharmaceuticals Corporation
158
Study VEA 2302: Triple Therapy Superior to All Dual Regimens
Mean Change from Baseline in MSSBP (mmHg) at Endpoint
Intent-to-Treat Population (N=2,271)
Amlodipine/
Valsartan/ Valsartan/ Amlodipine/ HCTZ/
HCTZ HCTZ Valsartan amlodipine
10/320/25 mg 320/25 mg 10/320 mg 25/10 mg
0 n=583 n=559 n=568 n=561
LSM change in MSSBP
from baseline (mmHg)
–10
–20
–30
–32.0 –33.5 –31.5
–40
–39.7*
Δ 7.6 mmHg
Δ 6.2 mmHg
Δ 8.2 mmHg
*p<0.0001 versus all other combinations

LSM=least squares mean;
MSSBP = mean sitting systolic BP Data on file. Study VEA489A2302. Novartis Pharmaceuticals Corporation.
159
Study VEA 2302 – Rapid Onset of Action change from Baseline in
MSSBP after 2 Weeks of Therapy (post hoc analysis)
Amlodipine/
5/160/12.5 mg 160/12.5 mg 5/160 mg 12.5/5 mg
0 n=583 n=559 n=568 n=561
Mean change in MSSBP
–10
–20 –23.6
–24.6
–26.3
–30 –29.6* Δ 5.0 mmHg
Δ 3.4 mmHg
Δ 6.0 mmHg
* p<0.0001 versus all other combinations

Post hoc analysis. Data on file. Study VEA489A2302.
MSSBP = mean sitting systolic BP Novartis Pharmaceuticals Corporation
160
Study VEA 2302: Triple Therapy Superior to All Dual Regimens
Mean Change from Baseline in MSDBP (mmHg) at Endpoint
Amlodipine/
10/320/25 mg 320/25 mg 10/320 mg 25/10 mg
0 n=583 n=559 n=568 n=561
LSM change in MSDBP
–10
–20 –19.7 –19.5

–21.5
–24.7*
–30 Δ 5.1 mmHg
Δ 3.3 mmHg
Δ 5.3 mmHg
*p<0.0001 versus all other combinations

LSM=least squares mean;
MSDBP = mean sitting diastolic BP Data on file. Study VEA489A2302. Novartis Pharmaceuticals Corporation.
161
Study VEA 2302 - Triple Therapy is Superior to All Two-
drug Combinations in Patients with Severe Hypertension‡
post-hoc analysis
Amlodipine/
10/320/25 mg 320/25 mg 10/320 mg 25/10 mg
0 n=168 n=155 n=155 n=168
LSM Reduction in MSSBP
–10
(mmHg)
–20
–30
–40
–39.9
–43.6 –42.5
–50
–49.6*
Δ 9.7 mmHg
Δ 6.0 mmHg
Δ 7.2 mmHg
*p=0.0019 versus all other combinations #

LSM=least squares mean; MSDBP = mean sitting systolic BP
Data on file. Study VEA489A2302.
‡
Defined as SBP ≥180 mmHg at baseline
#
Hochberg Adjusted Novartis Pharmaceuticals Corporation.
162
Study VEA A2302 – Triple Therapy Gets More Patients to BP Goal
Control Rate (%) of MSSBP/MSDBP (<140/90 mmHg) at Endpoint
Control Rate (%) of MSSBP/MSDBP
80
70.8*
(<140/90 mmHg) at Endpoint
70
60 54.1
48.3
50 44.8
40
30
20
10 n=583 n=559 n=568 n=561
Valsartan/ 0 Valsartan/
Valsartan/ HCTZ/
HCTZ/
HCTZ amlodipine amlodipine
amlodipine
320 / 25 / 10 320 / 25 320 / 10 25 /10
At each assessment (double-blind phase), significantly more patients receiving triple therapy
achieved overall BP control versus those receiving dual therapies
Data on file. Study CVEA489A2302.
* p<0.0001 versus all other combinations Novartis Pharmaceuticals Corporation.
163
Study VEA 2302: ABPM

Mean ambulatory systolic blood pressure at endpoint
by hour and treatment (ABPM population)
Amlo/Val/HCTZ 25/320/10 mg Val/HCTZ 320/25 mg

Amlo/Val 320/10 mg Amlo/HCTZ 10/25 mg Amlo/ Dual LSM Difference
Val/HCTZ in ∆ change from
Baseline versus
140 Triple
ASBP (mm Hg)
24-hr Ambulatory SBP

130
–30.3 Val/HCTZ
120 –23.9 –6.4*
Amlo/Val
110 –24.1 –6.2*
100 Amlo/HCTZ
–18.8 –11.5*
0 4 8 12 16 20 24
Hours after dosing
 At all time points, greater reductions in ambulatory SBP were observed with the triple
therapy combination compared to each of the dual combinations
 The MASBP was maintained below 130 mmHg for all time points following the first post
dose hour measurement for the triple therapy
Data on file. Study VEA489A2302. Novartis Pharmaceuticals
Corporation.
164
Study VEA 2302: Triple Combination Therapy was
Generally Well Tolerated Compared with Dual Therapy
Amlodipine/ Valsartan/ Amlodipine/ HCTZ/

AEs, %
Valsartan/HCTZ HCTZ Valsartan amlodipine
All 45.2 45.3 44.9 48.3
Dizziness 7.7 7.0 2.3 3.9
Peripheral Oedema 4.5 0.9 8.5 8.9
Headache 4.3 5.4 4.9 7.0
Dyspepsia 2.2 0.9 1.1 0.4
Fatigue 2.2 2.7 2.1 1.4
Muscle spasms 2.2 1.3 1.2 0.9
Back pain 2.1 2.3 0.9 2.1
Nasopharyngitis 2.1 2.3 2.3 2.1
Nausea 2.1 1.3 1.8 2.1
SAEs 0.9 1.3 0.7 0.9
AEs leading to drug
4.0 2.9 1.6 3.4
discontinuation
AEs were as expected for this population and classes of drug Data on file. Study VEA489A2302. Novartis
Mostly mild and transient, with no indication of target organ toxicity Pharmaceuticals Corporation.
165
Study VEA 2302
Selected Adverse Events Potentially Related to Low BP
Val/HCTZ/Amlo Val/HCTZ Val/Amlo HCTZ/Amlo

Dizziness 7.7 7.0 2.3 3.9
Hypotension 1.5 1.4 0.4 0.0
Syncope 0.5 0.9 0.4 0.0
Postural dizziness 0.3 0.4 0.2 0.2
Orthostatic 0.2 0.4 0.0 0.2
hypotension
Exertional 0.2 0.0 0.0 0.0
dizziness

166
Study VEA A2302
Conclusions
Triple therapy with valsartan/HCTZ/amlodipine was efficacious and
produced:
Superior reductions in both MSDBP and MSSBP (p<0.0001) compared to all
dual therapies, in patients with moderate–severe hypertension
Up to -50mmHg reductions in patients with severe systolic hypertension

(post hoc)
Significantly greater BP control rates (overall, systolic, and diastolic) vs dual

therapies
Superior reductions in 24-hr mean diastolic and systolic BP compared to

each dual therapy
Triple therapy was generally well-tolerated
Data on file. Study CVEA489A2302. Novartis Pharmaceuticals

Corporation.

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HYPERTENSION/ RAAS BLOCKADE

EXFORGE® (Amlodipine/Valsartan) core value dossier

 Amlodipine/Valsartan and the triple combination

BP category Systolic (mmHg) Diastolic (mmHg)

Chobanian et al. JAMA 2003;289:256072

BP category Systolic (mmHg) Diastolic (mmHg)

Guidelines Committee. J Hypertens 2003;21:101153

Type of hypertension BP goal (mmHg)

Chobanian et al. JAMA 2003;289:256072

Prevalence* of HTN (%)

Prevalence of hypertension by age and gender

Prevalence of HTN (%)

Data for established market economies (US, Canada, Spain,

Prevalence of hypertension increases with age

Prevalence of HTN (%)

Race/Ethnicity influences risk of hypertension

Prevalence of HTN (%)

Estimated non-institutionalised US adults, 19992002

Risk of HTN, % (95% CI)

Women, Age (years) Men, Age (years)

10 52 (4658) 64 (6069) 56 (4963) 72 (6778)

15 72 (6876) 81 (7784) 78 (7482) 85 (8189)

20 83 (8086) 89 (8692) 88 (8591) 90 (8793)

Hypertension within the cardiovascular continuum

 The CV continuum describes a series of pathophysiological events

 The CV continuum is a useful tool for describing the transition from CV

Dzau et al. Am Heart J 1991;121:244–63

Vasan et al. N Engl J Med 2001;345:1291–7

*Individuals aged 40–69 years Lewington et al. Lancet 2002;360:1903–13

 12.7 million person-years

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

Estimated size of population

Patients (%) Treated Untreated

Wolf-Maier et al. Hypertension 2004;43:10–17

Patients (%) BP goal achieved BP goal not achieved

*Treated for hypertension

10,000 SBP uncontrolled

Medicated Unmedicated Total

Flack et al. Managed Care Interface 2002;15:28–36

Global health burden of uncontrolled blood pressure

Estimated costs ($ billions)

Estimated total costs of hypertension in the US in 2006: $63.5

Economic burden of hypertension

 64.3 million disability-adjusted life years (DALYs) [4.4% of the

 Untreated HTN causes an average loss of 5.5 workdays per

 HTN represents one of the three leading causes of visits to

 In France, Germany, Italy, Sweden and the UK, failure to

ASCOT-BPLA (136.9 mmHg)

ESH–ESC: algorithm for treatment of hypertension

Consider: BP level before treatment

Single agent at low dose 2-drug combination at low dose

If goal BP not achieved

If goal BP not achieved

2–3 drug Full-dose 3-drug combination

TOD = target organ damage ESH–ESC Guidelines. J Hypertens 2003;21:1779–86

55 years or black

ACEI (or ARB*) + CCB or

Step 3 ACEI (or ARB*) + CCB + diuretic

Add further diuretic therapy, α-blocker, or β-blocker.