Hypertension

combination therapy
(EXFORGE)
between Guidelines & Practice
By
SOLIMAN GHAREEB MD.
Professor of cardiovascular medicine Cairo university
founding and member of Egyptian hypertension society
member of European society of hypertension
 AGENDA
• Value of Control of Hypertension
• Value of combination therapy between
Guidelines & Practice(Advantages of
Multiple-mechanism)
• Value of Single pill combination(SPC).
• Is the matter of timing between ACEIs
& ARBs!!
• Clinical data of Exforge
 Hypertension in Egypt
– prevalence rate of 26.3% among adult population
(>25 years).
– Hypertension is poorly managed in Egyptians.
– low rates of awareness, treatment and control are
Only
– 8% reaching the goals
- 92% not reaching the goal.

3
 Approximately 70% of Patients* Who Receive Treatment
Do Not Reach BP Goal in Europe

Patients (%) BP goal achieved BP goal not achieved

100
60 79 70 81 72
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
 Rule of Halves
 1/2 of HTN patients are not detected.
 1/2 of detected patients are not treated.
 1/2 of treated patients are not controlled.

Therefore
87.5% of HTN patients are not controlled.

5
 Blood Pressure Reduction of 2 mmHg Decreases 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 ischemic
heart disease
2 mmHg mortality
decrease in
mean SBP 10% reduction
in risk of stroke
mortality

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

 Most Patients With Hypertension Have
Additional Risk Factors
No. of risk factors in patients

0
with hypertension

0 5 10 15 20 25 30 35 40
Patients (%)
Mancia et al. J Hypertens 2004;22:517
 Blood Pressure (BP) is Closely Associated with the
Risk of CV Mortality
Ischaemic heart disease
Ischaemic heart disease mortality
(floating absolute risk and 95%
mortality
CI) Age at risk: (floating absolute risk and
Age at risk:
256 80–89 years
256 95% CI) 80–89 years

128 70–79 years 128 70–79 years

64 60–69 years 64 60–69 years

32 50–59 years 32 50–59 years

16 16

8 8

4 4

2 2

1 1
120 140 160 180 70 80 90 100 110
0 Usual systolic BP 0 Usual diastolic BP
(SBP), mmHg (DBP), mmHg
CI = confidence interval Lewington et al. Lancet 2002;360:1903–13
 Blood Pressure and Stroke Mortality

Lewington S, ClarQizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61
prospective studies. Prospective Studies Collaboration. Lancet. 2002; 360: 1903–1913
 Multiple Antihypertensive Agents are Often Needed
to Get Patients to Target BP Goals
Target BP (mmHg)

Appropriate Blood Pressure Control in Diabetes

ABCD (n = 470) <75 diastolic

African American Study of Kidney Disease and Hypertension <92 MAP

AASK (n = 1094)

Anglo-Scandinavian Cardiac Outcomes Trial

<140/90 without diabetes
ASCOT-BPLA Blood Pressure Lowering Arm (n = 19,257) <130/80 with diabetes

United Kingdom Prospective Diabetes Study

<85 diastolic
UKPDS (n = 4209)

Hypertension Optimal Treatment

HOT (n = 18,790) <80 diastolic

0 1 2 3 4
Average no. of antihypertensive agents used

Despite the use of multiple antihypertensive therapies,

many patients in these trials did not achieve BP goals
MAP = mean arterial pressure

Bakris et al. Am J Kidney Dis 2000;36:64661

Sica. Drugs 2002;62:44362
•‘Controlling blood pressure with
medication is unquestionably
• one of the most cost-effective methods
of reducing premature CV morbidity and
mortality’

From Elliott. J Clin Hypertens 2003;5(Suppl. 2):313

Copyright © 2003, with permission from Blackwell Publishing
What the Treatment Guidelines
say?
Current Guidelines Acknowledge that Combination Therapy is required by
the Majority of Patients to Reach BP Goal

• JNC 7 guidelines state1:

“Although effective BP control can be
achieved in most patients who are
hypertensive, the majority will require
two or more antihypertensive drugs.”

ESH = European Society of 1Chobanian et al. Hypertension

Hypertension 2003;42:1206–52
ESC = European Society of 2Mancia et al. J Hypertens
• ESH/ESC guidelines state2:
“Regardless of the drug employed,
monotherapy allows to achieve BP target
in only a limited number of hypertensive
patients. Use of more than one agent is
necessary to achieve target BP in the
majority of patients.”
 Current Guidelines Recommend Initiating Combination
Therapy
Early in Patients with Stage 2 Hypertension or High
Cardiovascular Risk
• JNC 7 guidelines state1:
“When BP is
more than 20 mmHg above systolic goal
or 10 mmHg above diastolic goal,
consideration should be given to initiate
therapy with 2 drugs...”
“
ESH = European Society of Hypertension
ESC = European Society of Cardiology
JNC = Joint National Committee 1Chobanian et al. Hypertension 2003;42:1206–52
2Mancia et al. J Hypertens 2007:25:110587
 EFFICACY & AVOID SIDE EFFECTS
• ESH/ESC guidelines state2:
• A combination of two drugs at low
doses should be preferred as first step
treatment when initial BP is in the grade
2 or 3 range or total cardiovascular risk
is high or very high.”

1Chobanian et al. Hypertension 2003;42:1206–52

2Mancia et al. J Hypertens 2007:25:110587
 Recommendations for Multiple-mechanism Therapy:
What the Treatment Guidelines Say?
ESH–ESC

• More than one agent is necessary to achieve

target BP in the majority of patients

• Treatment can be initiated with monotherapy

or a combination of two drugs at low doses
–Drug dose or number of drugs may be
increased if necessary

Task Force of ESH/ESC. J Hypertens 2007;25:1105–87

• A combination of two drugs at low doses
preferred 1st step when
– Initial BP in grade 2–3 range
– Total CV risk high/very high

• Fixed combinations of two drugs

simplify treatment/favour compliance
 Advantages
of Multiple-mechanism
Therapy: Efficacy
Multiple-mechanism therapy results in a greater BP
reduction than seen with its single-mechanism
components1,2
• Components with a different mechanism of action
interact on complementary pathways of BP control1
• Each component can potentially neutralize 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
• Multiple-mechanism therapy may result in BP
reductions that are additive2

1Sica. Drugs 2002;62:44362

2Quan et al. Am J Cardiovasc Drugs 2006;6:10313
 Multiple-mechanism therapy may have an
improved tolerability profile compared with its
single-mechanism components1,2

• Components of multiple-mechanism therapy can be

given at lower dosages to achieve BP goal than those
required as monotherapy therefore better
tolerated1,2
• Compound-specific adverse events can be attenuated,
e.g.,1,2
– RAS blockers may attenuate the edema that is
caused by CCBs

1Sica. Drugs 2002;62:44362

2Quan et al. Am J Cardiovasc Drugs 2006;6:10313
 Increased Persistence( patients remaining on treatment
for a duration of 12 months) with Single pill combination
Combinations Compared with Individual Component-based
Therapy

Fixed-dose combination
(Valsartan/HCTZ)
(n=8,150) 54%

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

Improved Compliance with Single-pill Combination
Therapy Compared with Free-combination Therapy
Gerbino & Shoheiber. Am J Health System Pharm 2007;64:1279–83

Single-pill combination
(Amlodipine/RAAS b) 88.0%
(n=2,839)

p<0.0001
Free combination
(RAAS b + CCB) 69.0%
(n=3,367)

0% 20% 40% 60% 80% 100%

Medication possession ratio (MPR)†
Complianc†
Defined as the total number of days of therapy for
medication dispensed/365 days of study follow-up
RAAS Blockade With ARBs Can Be Considered a
Foundation of Antihypertensive and CV Preventive Therapy

Alpha Beta
CCB Diuretics Other
blockers blockers

RAS blockade
The Foundation
Just a matter of timing
Between ACEi & ARBs
RAAS Blockers Have Been Studied
Extensively in Outcomes Trials

Myocardial
Hypertension High Risk
infarction
• LIFE • HOPE • OPTIMAAL
• SCOPE • ONTARGET • VALIANT
• STOP 2 • TRANSCEND • CONSENSUS II
• VALUE • JIKEI HEART • ISIS-4
• KYOTO HEART • KYOTO HEART • GISSI-3
• CAPPP • SMILE
• ALLHAT • SAVE
• ANBP2 • AIRE
Diabetes – Renal • TRACE

• RENAAL
Heart failure • IDNT
• ABCD
• ELITE II
• Val-HeFT Coronary Artery
• CHARM
• CONSENSUS I
Disease
• SOLVD
• V-HeFT II
Pre-diabetes • EUROPA
• PEP-CHF • PEACE
• NAVIGATOR
• IMAGINE
• DREAM
Better stroke protection with ARBs than with
ACEIs

Suggests AT2-receptor
mediated
cerebroprotection
• Spansk studie ARB less severe strokes

The multiple regression analysis showed that

Previous treatment with ARB was independently
associated with reduced stroke severity:
OR: 0.40; 95% CI 0.24—0.65, p<0.001
and against poor outcome:
OR: 0.41; 95%CI 0.23-0.78, p=0.003
 Effects of RAS blockade on stroke: meta-
analysis of ARBs and ACE inhibitors

MI

Cardiovascular mortality

All-cause mortality

Stroke

0.8 0.9 1 Favours

Favours ARB ACE inhibitor
Studies (N=63,409 ): ELITE; ELITE-II; OPTIMAAL; DETAIL; VALIANT; ONTARGET
Reboldi et al. J Hypertension 2008;26:1282–1289
Conditions favoring use of some antihypertensive drugs
versus others:
ESHESC Recommendations for Combining BP-lowering
Drugs and Availability as Fixed-dose Combinations
Diuretics

Angiotensin
b-blockers receptor blockers
(ARBs)

Calcium channel
a-blockers
blockers (CCBs)

Angiotensin-converting enzyme (ACE) inhibitors

Available as a fixed-dose combination

Less frequently used/combination used as necessary
Task Force for ESH–ESC. J Hypertens 2007;25:1105–87
Summary
• BP-lowering efficacy: ARB > ACE-inhibitor
and longer duration of action
• Clinical outcomes: ARB = ACE-inhibitor:
• High risk hypertension: ON-TARGET
• Heart Failure: Val-Heft
• Myocardial Infarction: VALIANT
• Renoprotection: MARVAL
• Adverse Effects: ARB better tolerated than
ACE-inhibitor: Less cough, less angioedema
 Interaction of Amlodipine and Valsartan
on Vascular and Renal Function, SNS and RAS
Activity

Natriuresis

Vasodilation
Arterial Arterial +
Venous

Amlodipine Valsartan

↑ RAS RAS ↓
↑ SNS SNS ↓
 Exforge
Clinical data
 Amlodipine/Valsartan: BP Reductions Across All
Grades of Hypertension - (Exzellent Trial1)
0
n=
syst.BP reduction (mmHg)

-10 1800
n=
-20 2293
-19
-30 n=
890
-32
-40

-50
-49
-60
Mild (Grade 1) HTN Moderate (Grade 2) Severe (Grade 3)
HTN HTN
DBP ↓ (mmHg) -11 -15 -19

1Schrader J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June
2008.
Amlodipine/Valsartan FDC: BP Reductions for Patients
with Diabetes– (Exzellent Trial1)

0
n=
syst.BP reduction (mmHg)

-10 639
n=
-20 795 n=
-19
295
-30

-40 -32

-50
-48
-60
Mild (Grade 1) HTN Moderate (Grade 2) Severe (Grade 3)
HTN HTN
DBP ↓ (mmHg) –11 –15 –18

1Schrader J et al. PS38 Late Breaking Abstracts Session. ESH/ISH Congress, 14 June 2008.
Amlodipine/Valsartan: Powerful SBP Drops of Over 40
mmHg in Patients with Baseline MSSBP ≥180 mmHg

EX-EFFeCTS1 EX-STAND2
Patients with Stage 2 Hypertension Black Patients with Stage 2 Hypertension

Amlodipine/Valsartan Amlodipine Amlodipine/Valsartan Amlodipine

10/160 mg 10 mg 10/160–320 mg 10 mg
0 0
N=46 N=55 N=38 N=42

−10 −10

−20 −20

−30 −30
−31.7
−40 −40 −37.2
–40.1
–43.5
p=0.0018 −50
p=0.1

LSM Change in MSSBP from baseline (mmHg) LSM Change in MSSBP from baseline (mmHg)

LSM=least square mean 1.Destro et al. J Am Soc Hypertens 2008;2:294–302

MSSBP=mean sitting systolic blood 2.Flack et al. J Hum Hypertens 2009 (E-pub
pressure
 Amlodipine/Valsartan:
Up to 9 Out of 10
Patients Reach BP Goal <140/90 mmHg
All patients Non-diabetic patients Diabetic patients
100
84.4 85.2
77.1 78.4 80
80
69.7
Patients (%)

60 n=375
n=440 n=369 n=71 n=449 n=74
40

20

0
Amlodipine/Valsartan 5/160 mg Amlodipine/Valsartan 10/160 mg

Diabetic patients with BP <130/80 mmHg at Week 8 were 47.0% and 49.2%
for 5/160 mg and 10/160 mg doses, respectively

Data shown are at Week 8 Adapted from Allemann et al. J Clin Hypertens 2008;10:185–94
No hydrochlorothiazide add-on was permitted until after Week 8
Randomized, double-blind, multinational, parallel-group, 16-week study
Amlodipine/Valsartan Reduces Urinary Albumin
Excretion Compared with Amlodipine in Black Patients with
Stage 2 Hypertension: EX-STAND Study
Amlodipine/Valsartan 10/160 mg Amlodipine 10 mg
Change from baseline in UACR (%)

15
10
10
5 N=160
0
N=157
–5
–10
–15
–20
–25
–30
–35 –30*
*p=0.0003; UACR = urinary albumin-to-creatinine ratio
12 weeks .

Flack et al. J Hum Hypertens 2009;23:479–89

 EXFORGE® Significantly Reduces Fluid Retention
Vs Amlodipine Monotherapy

25
23.0 n=80
Ankle-foot volume increase (%)

20
70%
difference
15

10 *
6.8

0
Amlodipine 10 mg EXFORGE®
*p<0.01 vs. amlodipine 10/160 mg

Fogari et al. J Hum Hypertens 2007;21:220-4

Additional Reduction in BP with Amlodipine/Valsartan in
Non-responders to Ramipril/Felodipine
n=133 100
180 14.3 mmHg
–

– 30.7 mmHg

Mean diastolic BP (mmHg)

Mean systolic BP (mmHg)

96.6
–15.4 mmHg –7.0 mmHg
166.7 p<0.0001 p<0.0001
160

90
151.4
89.3
140

136

82.3
120 80
Week 0 5 10
Week 0 5 10
After Ram After Amlo/Val
After Ram 5 + After Amlo/Val 5 + Fel 5 10/160
Fel 5 10/160
Open, sequential, non-responder 10-
week study Trenkwalder et al. Blood Press Suppl 2008;2:13–21.
 Summary
• Strong support for the use of RAS-blockade as a foundation
for antihypertensive therapy

• ARB at least the same efficacy as ACEI but better

tolerability/safety and potentially a stroke benefit

• Every molecule is unique and there is no common class-

effect that explains all of the effects of a molecule
• Valsartan provides the most comprehensive documentation
for control of BP and reduction of CV mortality and morbidity
• Valsartan can preferably be combined with Amlodipine,
HCTZ and Aliskiren SPC to a majority
Take home
messages

Invest in Health
Instead of
Paying for disease
Amlodipine/Valsartan Single-Pill Combination: A
Prospective, Observational Evaluation of
the Real-Life Safety and Effectiveness in the
Routine Treatment of Hypertension

October 27, 2011

Amlodipine/Valsartan Single-Pill Combination: prospective,
multinational, open-label, observational, postmarketing, surveillance study

Study purpose: To evaluate its efficacy and safety in a real-life practice setting

Target population: Patients with arterial hypertension (systolic BP >140 mmHg and/or
diastolic BP >90 mmHg). Overall, mean baseline BP was 165.0/99.3 mmHg.
After enrolment in the study, patients did not undergo any special change in dietary habits, medication,
lifestyle, or exercise schedule.(Real-Life Practice)

Amlodipine/Valsartan 5/80 qd

n=8336* Amlodipine/Valsartan 5/160qd

Amlodipine/Valsartan 10/160 qd

12weeks
BP=blood pressure; qd= once daily.
*A total of 8336 patients completed all study visits and were included in the efficacy analysis.
Y. Karpov et al. Adv Ther (2011); on press
 Mean SBP and DBP during treatment with
single-pill combination
amlodipine/valsartan.**
Mean BP (mmHg)

SBP= systolic blood pressure, DBP= diastolic blood pressure

*p<0.0001vs baseline, **amlodipine/valsartan used with 3 dosing regimen 5/80 qd, 5/160qd, and10/160 qd
Y.Karpov et al. Adv Ther (2011); on press
 Subgroup analysis of mean BP-reduction at 12 weeks in
patients with grade 3 hypertension receiving
amlodipine/valsartan** single pill combination

BL SBP DBP SBP DBP SBP DBP

mmHg 189.1 105.7 199.5 109.2 208.9 112.3
Mean BP reduction at 12 weeks (mmHg)

BP= blood pressure SBP= systolic blood pressure, DBP= diastolic blood pressure
*p<0.0001vs baseline, , **amlodipine/valsartan used with 3 dosing regimen 5/80 qd, 5/160qd, and10/160 qd
Y.Karpov et al. Adv Ther (2011); on press
 It is a dose dependent
Mean BP-reduction at 12 weeks in patients on stable
doses of single-pill combination amlodipine/valsartan**.
A dose-dependent effect
BL SBP DBP SBP DBP SBP DBP
mmHg 158.0 97.4 163.6 98.3 172.8 102.4
Mean BP reduction at 12 weeks (mmHg

BP= blood pressure SBP= systolic blood pressure, DBP= diastolic blood pressure
*p<0.0001vs baseline, , **amlodipine/valsartan used with 3 dosing regimen 5/80 qd, 5/160qd, and10/160 qd
Y.Karpov et al. Adv Ther (2011); on press
 Mean change in BP from BL with patients received
combination amlodipine/valsartan** single pill combination
plus concomitant hydrochlorothiazide

(n=189)
Duration 12 weeks

BP= blood pressure,BL=baseline, SBP=systolic blood pressure, DBP=diastolic blood pressure

*p<0.0001vs baseline, , **amlodipine/valsartan used with 3 dosing regimen 5/80 qd, 5/160qd, and10/160 qd
Y.Karpov et al. Adv Ther (2011); on press
 Mean BP-reduction at 12 weeks in patients on previous
therapy with two antihypertensive drug safer receiving
amlodipine/valsartan** single pill combination

BP= blood pressure SBP= systolic blood pressure, DBP= diastolic blood pressure, ACEi=angiotensin-converting-enzyme inhibitor;
ARB=angiotensin receptor blocker; BB=beta-blocker; CCB=calcium channel blocker;
, **amlodipine/valsartan used with 3 dosing regimen 5/80 qd, 5/160qd, and10/160 qd
Y.Karpov et al. Adv Ther (2011); on press
JIKEI HEART study)
• JIKEI HEART study)( Japanese
Investigation of Kinetic Evaluation In
Hypertensive Events And Remodelling
Treatment
 Mochizuki et al. Lancet 2007;369:1431–9

Valsartan-based Therapy Provides Risk Reduction for CV

Outcomes When Added to Conventional Therapy
Results from a 3-year# study in 3,081 Japanese patients§ (JIKEI HEART study)( Japanese
Investigation of Kinetic Evaluation In Hypertensive Events And Remodelling Treatment

CV mortality Hospitalization Hospitalization

and morbidity‡ Stroke/TIA for HF for angina
0
Risk reduction (%)

20

40
39%* 40%*
p=0.0002 p=0.0280 47%*
60 p=0.0293

65%*
80 p=0.0001
#Median follow-up = 3.1 years; *Valsartan-based therapy versus non-ARB therapy; §Patients were undergoing treatment for
hypertension and/or coronary heart disease and/or heart failure;
TIA = transient ischemic attack; HF = heart failure; CV = cardiovascular; JIKEI HEART = Japanese Investigation of Kinetic
Evaluation In Hypertensive Events And Remodelling Treatment
The KYOTO HEART Study

An independent clinical trial assessing valsartan

in high-risk hypertensive patients in Japan

Sawada et al. J Hum Hypertens 2009;23:188–95

 Valsartan Add-on Arm Showed Significant Benefit in
Stroke, Angina and New-onset of Diabetes
CV New Onset
morbidity Stroke/TIA Angina Pectoris Diabetes
0
valsartan-based therapy (%)

45%* 45%* 49%* 33%*

Risk reduction with

20

40 p=0.0282

p=0.00001 p=0.0149
60 p=0.0106

80
Sawada et al. Eur Heart J 2009;30:2461–69.

TIA = transient ischaemic attack

*relative risk reduction vs non-ARB therapy;
In patients with or without CKD ,Valsartan add-on
significantly decreased the occurrence of primary endpoint

-39%
CKD+ CKD-
-40%
-41%
-42%
-43%
RRR
-44% -42%
-45%
-46%
-47%
-48%
-47%
The primary endpoint was a composite of defined Cardio- or Cerebro-vascular
events such as : stroke, myocardial infarction, heart failure, angina pectoris.
RRR: relative to non ARB
International Journal of Cardiology (2012)
 Conclusion

• Based on Guidelines and

practice there is great Value
from the use of combination
therapy EXFORGE above
monotherapy AND OTHER
combination therapies

European Heart Journal 31 (SUPPL. 1) 800 ,2010