How to Achieve BP Goal

and Reducing CV Risk?

 Prevalence of HTN in Indonesia
(Basic Health Research 2007)
Recruited 19,114 persons across 438 districts

%
31.3% 31.9% 31.7%

Male Female All

(Indonesia Ministry of Health Affair 2007)
 Hypertension is inadequately managed
70 Hypertension Hypertension Blood-pressure
awareness treatment control
60
Proportion of population (%)

50

40

30

20

10

0
USA Canada Italy Sweden Spain Germany UK
Age adjusted; 140/90mmHg threshold

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

 Hypertension
Hypertensionis
isaaMajor
MajorRisk
RiskFactor
Factorfor
forCV
CVDisease
Disease

Coronary Peripheral artery Heart

disease Stroke disease failure
Biennial 50
age-
adjusted
rate 40
Normotensive
per 1000
Hypertensive
patients 30

20

10

0
Men Women Men Women Men Women Men Women
Risk ratio: 2.0 2.2 3.8 2.6 2.0 3.7 4.0 3.0
Kannel WB. JAMA. 1996;275:1571-1576.
Cumulative incidence of end-stage renal disease due to any cause,
according to blood-pressure category
in 332,544 men screened for MRFIT

Endstagerenaldiseaseduetoanycause(%)
4
Optimal
Normalbutnotoptimal
Highnormal
3 Stage1hypertension
Stage2hypertension
Stage3hypertension
Stage4hypertension
2

0
0 2 4 6 8 10 12 14 16 18 20
Yearssincescreening
Risk of CVD According to SBP Control by Treatment
40 CHF Prior MI Diabetes Prior Renal Age
Stroke / TIA Impairment

No Yes No Yes No Yes No Yes No Yes 70 > 70

30
30.2
* 29.8
24.6
24.1

21.0 * 20.3
20 18.7 18.9
17.4

* 14.8
12.4*
13.5 13.6 14.0
12.4
11.9 11.9
10.8

10 7.4 7.4
7.9
6.4 6.7
5.1

0
140 mmHg
* P < 0.001; P = 0.03; P = 0.04
< 140 mmHg
Pepine, et al. J Am Coll Cardiol 2006
 Global
GlobalMortality
Mortality2000:
2000:
Impact
Impactof
ofHypertension
Hypertensionand
andOther
OtherHealth
HealthRisk
RiskFactors
Factors
High blood pressure

Tobacco

High cholesterol

Underweight

Unsafe sex

High BMI

Physical inactivity
High mortality, developing region
Alcohol Lower mortality, developing region
Developed region
Indoor smoke from solid fuels

Iron deficiency

0 1000 2000 3000 4000 5000 6000 7000 8000

Attributable Mortality (In thousands; total 55,861,000)

Ezzati et al. Lancet 2002; 360:1347-1360

5119 M
 Framingham Heart Study (1983) 703
8-Year Probability Per 1,000
700
600 CV Risk Gradient Profile
500 459
400
326
300
210
200
100 46
Systolic BP: 105 >>> 185 105 >>> 185 105 >>> 185 105 >>> 185 105 >>> 185
Cholesterol: 185 335 335 335 335
Glucose Intol: 0 0 + + +
Cigarettes: 0 0 0 + +
ECG-LVH: 0 0 0 0 + Kannel 1983.
 Goals of Treatment
European Society of Hypertension/European Society of Cardiology
2007 Guidelines

In hypertensive patients, the primary goal of treatment is to

achieve maximum reduction in the long-term total risk of
cardiovascular disease
This requires treatment of the raised BP as well as of all
associated reversible risk factors
BP should be reduced to at least below 140/90 mmHg
(systolic/diastolic) and to lower values, if tolerated, in all
hypertensive patients
J Hypertens 2007;25:1105-1187.
Guidelines Recognize Growing Treatment Complexities and
Recommend Tighter Control
For individuals with hypertension and: BP goal:

JNC 7
Without diabetes or renal disease <140/90 mm Hg
With diabetes or renal disease <130/80 mm Hg

ESH/ESC
Without diabetes <140/90 mm Hg
With diabetes <130/80 mm Hg

WHO/ISH <140/90 mm Hg
Without diabetes <130/80 mm Hg
With diabetes

Chobanian AV et al. JAMA. 2003;289:2560-2572. Guidelines Committee. J Hypertens. 2003; 21: 1011-1053. Guidelines
Subcommittee. J Hypertens. 1999; 17: 151-183. World Health Organization, International Society
of Hypertension Writing Group. J Hypertens. 2003; 21: 1983-1992.
 Algorithm for Treatment of Hypertension
Lifestyle Modifications

Not at Goal Blood Pressure (<140/90 mmHg)

(<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Without Compelling With Compelling

Indications Indications

Stage 1 Hypertension Stage 2 Hypertension Drug(s) for the compelling indications

(SBP 140159 or DBP 9099 mmHg) (SBP >160 or DBP >100 mmHg) Other antihypertensive drugs (diuretics,
Thiazide-type diuretics for most. 2-drug combination for most (usually ACEI, ARB, BB, CCB)
May consider ACEI, ARB, BB, CCB, thiazide-type diuretic and as needed.
or combination. ACEI, or ARB, or BB, or CCB)

Not at Goal
Blood Pressure

Optimize dosages or add additional drugs

until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
The Seventh Report of the Joint National Committee onPrevention, Detection,
Evaluation, and Treatment of High Blood Pressure (JNC 7)
NICE
(National Institute for Health and Clinical
Excellence) GUIDELINE
CCBs: Most preferred partner in two-drug combination therapy, across all
antihypertensive classes
Diuretics

-blockers ARBs

Preferred
combinations in the
general HTN
population shown
by solid lines
1-blockers CCBs

ACEI Mancia G, et al. J Hypertens 2007;25:1105-1187.

Evidence-based treatment of HTN:

Trials shaping practice

 INSIGHT:

Atherosclerosis
Carotid IMT:
Significantly greater
progression with
co-amilozide vs Co-
Female
amilozide
nifedipine Nifedipine
(p=0.001)1
Coronary calcification
(TCS): Significantly
greater with co-
amilozide vs
nifedipine (p=0.02)2

IMT, intima-media thickness; TCS, total calcium 1. Simon A, et al. Circulation 2001;103;2949-2954.
score 2. Motro M, Shemesh J. Hypertension
2001;37;1410-1413.
 INSIGHT : Nifedipine Blocks IMT Progression
Nifedipine
HCTZ + amiloride
0.008
**
Intima media thickness
progression (mm/year)

** **
0.006

0.004
*

0.002

0.002

Year 2 Year 3 Year 4 Study end

Simon A, et al. Circulation 2001 *p<0.01, **p<0.001 vs zero within treatment group
 INSIGHT: Fewer Metabolic Disturbances
with Nifedipine GITS
10 Nifedipine OROS
9 Diuretic combination
8
7 7.7 7.6
% of patients

6 6.4
5 5.6 5.9
4
3
2
1 1.3
0
Hyperglycemia Hypercholesterolemia Hyperuricemia
p<0.01 p<0.01 p<0.01
Brown M, et al. Lancet 2000. * Reported by investigator
 INSIGHT: Emergence of New Diseases*
Nifedipine OROS
Diuretic
6 Combination

5.3 5.6
% of Patients

4 4.3
3.0
2
2.1
1.3
0
Gout1 Peripheral Diabetes2
Vascular Disorder1
p < 0.01 p < 0.01 p = 0.01
*or Recurrence; 1 Reported by investigator; 2 WHO definition of random glucose measurement >11.0 mmol/L or use of anti-
diabetic drugs. Brown M, et al. Lancet 2000.
 6VALUE: Fatal and non-fatal stroke
5 Valsartan-based regimen
Proportion of Patients With

Amlodipine-based regimen
4
First Event (%)

3 CCB group received

earlier onset of
2 treatment effect

1
HR = 1.15; 95% CI = 0.981.35; p=0.08
0

0 6 12 18 24 30 36 42 48 54 60 66
Number at risk Time (months)
Valsartan 7649 7494 7448 7312 7170 7022 6877 6692 6515 6093 3859 1516
Amlodipine 7596 7499 7455 7334 7195 7055 6918 6744 6587 6163 3846 1532
Julius S et al. Lancet 2004;363.
 ACTION: Significant reduction in new overt
5
heart failure vs placebo
Proportion having an event (%)

4
Hazard ratio 0.71
95% CI 0.540.94
3 p=0.015 Placebo 29%

Nifedipine
1 GITS/OROS

0
0 1 2 3 4 5 6
Time in study (years) Poole-Wilson PA, et al. Lancet 2004;364:849-857.
 ENCORE: Influence of Nifedipine on Coronary
Endothelial Function in Patients with CAD
25 All patients Patients enrolled
after restart
% change in lumen diameter

20 P=0.0007 P<0.0001

18.3 17.5
15
during Ach

10

5 6.9

(n=108) (n=113) (n=41) (n=76)

0

Placebo
-5
-0.95
Schellekens S, Verheught FWA. ESC Hotline sessions 2004. Nifedipine GITS
INSIGHT: Nifedipine Preserves Renal Function

80 Nifedipine GITS
HCTZ + amiloride
filtration rate (mL/min)
Estimated glomerular

75

70 *
*p<0.05
65

60

Baseline Year 1 Year 2 Year 3 Study end

Brown M, et al. Lancet 2000. De Leeuw PW, et al. Arch Intern Med 2004.
CCBs as an antihypertensive
combination therapy partner
 Hypertension management guidelines recommend CCBs
and ARBs as preferred combination therapy partners

2007 ESH/ESC Guidelines1 2009 ESH/ESC Reappraisal2

Diuretics Diuretics

-blockers ARBs ARBs

1-blockers CCBs CCBs

ACE inhibitors ACE inhibitors

Continuous lines show two-drug combinations that have been
found to be well tolerated and effective for BP lowering

. Mancia G. Eur Heart J 2007;28:1462536. by permission of Oxford University Press 2007*

. Mancia G, et al. J Hypertens 2009;27:212158.*
uidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the Europeans
ociety of Hypertension (ESH) and of the European Society of Cardiology (ESC).
24
 Potential clinical advantages of combining an ARB with
a CCB for the management of hypertension

DHP CCB ARB

Arteriodilation RAAS blockade
Risk of peripheral oedema Reduces risk of CHF and
Effective in low-renin patients BP has renal benefits
Reduces cardiac ischaemia

ARB DHP CCB

Venodilation RAAS activation
Synergistic
Attenuates peripheral oedema No renal or CHF benefits
BP reduction
Effective in high-renin patients
No effect on cardiac ischaemia Complementary
clinical benefits

CHF, congestive HF; DHP, dihydropyridine

Destro M, et al. Vasc Health Risk Manage 2010;6:25360.
25
 ACCOMPLISH shows that combination therapy with CCB/RAAS
blockade reduces the risk of
CV events
0.1
mean follow-up of 39 months

6
Cumulative event* rate after

0.1 20% CCB/ACE inhibitor

4 reduced CV morbidity
0.1 and mortality by 20%
2
compared with the
0.1 diuretic/ACE inhibitor
0
despite achieving
0.0
8 p=0.0002 similar BP control
0.0 Diuretic/ CCB/
6 ACE inhibitor ACE inhibitor
0.0
4 41.4% 43.8% patients achieved BP control
between baseline 30 months follow-up
0.0
*First CV morbidity/mortality (primary endpoint)

<140/90mmHg 2
ACCOMPLISH, Avoiding Cardiovascular
0 Events Through Combination Therapy in Patients Living with Systolic
Hypertension; RAAS, renin-angiotensin-aldosterone system; HR, hazard ratio
Jamerson K, et al; ACCOMPLISH Trial Investigators. American College of Cardiology Scientific 26
Sessions; March 31, 2008; Chicago, IL.
 Nifedipine CR/ARB combination reduced BP to a significantly greater extent
than an amlodipine/ARB combination in hypertensive patients

Nifedipine CR** + valsartan (n=245)

Washout Double blind treatment
180 Amlodipine + valsartan (n=260)
SBP
160 *

BP SD (mmHg)

*
140 * * * * 27mmHg
p<0.05
*
* *
34mmHg
*
120

DBP
100 *
*

* * * 16mmHg
* p<0.05
80 *
* * * 20mmHg

60 *p<0.05 vs baseline

p<0.05 between
Pulse rate SD (bpm)

treatment groups
90
* * * * +2bpm
p=n.s.
70 * *
+1bpm

50 2 0 4 8 12 16 End of treatment
Time (weeks)
bpm, beats per minute; SD, standard deviation
**Study conducted in Japan
Reprinted with permission from Macmillan Publishers Ltd. Hypertens Res. 2006 Oct;29(10):789-96. copyright
28
2006
 Target BP was achieved in significantly more hypertensive
patients receiving nifedipine CR/ARB combination than
amlodipine/ARB combination

100
Amlodipine/valsartan Nifedipine CR/valsartan
(n=260) (n=245)
*
Patients achieving BP target (%)

80 73.1
*
61.2
*
60 52.5
48.6

40 34.6
24.5

20

0
Age <60 years Age 60+ years Total patients
*p<0.001 versus amlodipine/valsartan

Target BP was <130/85mmHg for age <60 years and <140/90mmHg for age 60+ years
Study conducted in Japan
Reprinted with permission from Macmillan Publishers Ltd. Hypertens Res. 2006 Oct;29(10):789-96.
Copyright 2006 29
 Nifedipine GITS combined with an ARB significantly improved
ambulatory BP control in hypertensive patients compared with
monotherapy with either drug

(n=99)

(n=100)

(n=100)

*
*

*p<0.05 versus nifedipine GITS + losartan

Reprinted with permission from Kuschnir E, et al. J Cardiovasc Pharmacol 2004;43:3005.

Effects of the combination of low-dose nifedipine GITS 20 mg and losartan 50 mg in patients with mild to moderate hypertension
30
 Target BP was achieved in significantly more hypertensive patients receiving nifedipine
CR/ARB combination than
up-titrated ARB monotherapy

Nifedipine CR 20mg/day/candesartan 8mg/day (n=130)

50
Patients achieving target BP* (%)

Up-titrated candesartan 12mg/day (n=128) p=0.0164

40
p=0.0225 40.8
30

20 28.5 27.3

10 17.2

0
SBP DBP
*Target BP was <130/85mmHg for age <60 years, <140/90mmHg for age 6069 years
and <150/90mmHg for age 70+ years
Study conducted in Japan
Reprinted with permission Hasebe N, et al. J Hypertens 2005;23:44553.
Controlled-release nifedipine and candesartan low-dose combination therapy in patients with essential hypertension: the NICE Combi (Nifedipine and
Candesartan Combination) Study. 31
 Initiating antihypertensive therapy with a combination of
nifedipine GITS/telmisartan reduced 24 hour BP within 8 weeks*
compared with starting with monotherapy with either drug
24h SBP (mmHg)

10.0mmHg

Group A (n=164)
24h DBP (mmHg)

Group B (n=89)
Group C (n=74)
4.7mmHg

Group A Nifedipine GITS 20mg + telmisartan 80mg

Nifedipine GITS Nifedipine GITS 20mg + telmisartan
Group B 20mg 80mg
Nifedipine GITS 20mg + telmisartan
Group C Telmisartan 80mg
80mg
*p<0.05 for combination therapy vs telmisartan monotherapy;
p<0.01for combination therapy vs nifedipine GITS monotherapy
Mancia G, et al. Abstract presented at the 20th European Meeting on Hypertension,
1820 June 2010, Oslo, Norway. 32
 Potential benefits of CCB/ARB for the management
of hypertension
Potential benefit
More effective than monotherapy and at least
as effective as free combination of the same
agents
More rapid achievement of target BP compared
with monotherapy
Lower rate of AEs
Less need to modify antihypertensive regimen
Lower overall cost
Additional benefits associated with drug class
Oparil S, Weber M. Postgrad Med 2009;121:2539.
Possible reason(s)
Combination may block more than one
pathophysiological pathway
Greater antihypertensive efficacy
Action of one agent may ameliorate some
AEs of the other
Target BP reached more quickly
Lower prescription costs; fewer physician
visits because lower need for regimen
modifications
ARBs confer stroke and renal protection;
CCBs reduce the risk of stroke and treat
angina and cardiac ischaemia
33
 Summary

Global strategies for detecting and managing HTN should be improved BP control remains
poor and recommended targets are not being achieved
BP control is particularly difficult in patients with additional cardiovascular risk factors
International hypertension guidelines increasingly recommend combination therapy for the
treatment of hypertension in patients with additional CV complications
While being as effective as other antihypertensive treatments in BP lowering, and CV morbidity
& mortality prevention, Nifedipine GITS/OROS has interesting effects beyond BP control:
Endothelial function and kidney function preservation, as well as antiatherosclerotic properties,
which may provide better protection in the long run

In light of results from recent clinical trials, CCBs should be the preferred combination for RAS
blocking agents
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