amlodipine/valsartan (exforge -...

Amlodipine/Valsartan(Exforge®)

Changing the Landscapeof BP Management

Bum-Kee Hong

Yongdong Severance HospitalYonsei University College of Medicine

� Inadequacy of agents with a single mechanism of action

� Advantages of multiple-mechanism therapy

� Recommendations for multiple agent therapy

� Benefits of fixed-dose combinations vs. free combinations

Rationale for Multiple-Mechanism Therapy

� Angiotensin-converting enzyme (ACE) inhibitor and CCB� Benazepril + amlodipine (Lotrel)

� Trandolapril + verapamil (Tarka)

� Ramipril + felodipine (Unimax)

� ACE inhibitor and diuretic� Benazepril + HCTZ (Lotensin HCTZ)

� Captopril + HCTZ (Capozide)

� ARB and diuretic� Valsartan + HCTZ (Diovan HCTZ/Co-Diovan)

� Candesartan + HCTZ (Atacand plus)

� Losartan + HCTZ (Cozaar plus)

� ββββ-blocker and diuretic� Atenolol + chlorthalidone (Tenoretic)

� Metoprolol + HCTZ (Lopressor HCT)

� ββββ-blocker and CCB� Metoprolol + felodipine (Logimax)

� Atenolol + nifedipine (Nif-Ten)

Notable absentee

Fixed Combinations of Antihypertensives“Notable Absentee”

Sympathetic Nervous System (SNS)

Renin Angiotensin System (RAS)

“Mutually reinforcing actions combine to regulate BP”

Two Key Systems in BP Regulation

Grassi. J Hypertens 2001;19:1713–6

� Adrenergic receptors on vascular smooth muscle > Vasoconstriction1

� SNS also stimulates renin secretion from the kidney, thereby activating the renin angiotensin system2

� CCBs inhibit SNS-induced vasoconstriction by blocking influx of Ca++

(needed for contraction) through voltage-gated Ca++ channels > Vasodilation3,4

� Other effects of CCBs: natriuresis; Inhibition of aldosterone release; interference with angiotensin II-mediated vasoconstriction4

1Grassi. J Hypertens 2001;19:1713–162Mancia and Grassi. http://www.sns-web.org/pages/advances/11/article.asp3Robertson & Robertson. In: Hardman JG, Limbard JG. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 9th ed. 1996. : Oparil S, Weber MA, editors. Hypertension: Companion to Brenner & Rector’s The Kidney. 2nd ed. 2005. p. 683–704

CCB-ARB: 2 Key BP Effector PathwaysOn Sympathetic Nervous System

CCB-ARB: 2 Key BP Effector PathwaysOn Renin-Angiotensin-Aldosterone System

� Release of renin catalyzes conversion of angiotensinogen into angiotensin I, which is converted by ACE to angiotensin II:

� Vasoconstriction: ↑Aldosterone and Na+/water retention > ↑SNS

� ARBs block the effects of angiotensin II by binding to AT1 receptors

� Arterial and venous dilation

� ↓SNS activity

� ↓Secretion of aldosterone and ↑secretion of Na+/ water

Mistry et al. Expert Opin Pharmacother 2006;7:575–81

� 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

1Sica. Drugs 2002;62:443–62 2Quan et al. Am J Cardiovasc Drugs 2006;6:103−13

Neutralizing Counter-regulatory Mechanismsto Minimize Elevations in Blood Pressure

SynergisticBP reduction

ComplementaryClinical Benefits

CCB• Arteriodilation• Peripheral edema• Effective in low-renin patients• Reduces cardiac ischemia

CCB• RAS activation• No renal or CHF benefits

ARB• Venodilation• Attenuates peripheral edema• Effective in high-renin patients• No effect on cardiac ischemia

ARB• RAS blockade• CHF and renal benefits

BP

CCB-ARB: Synergy of Counter-regulation

Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:42−73White et al. Clin Pharmacol Ther 1986;39:43−8Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl 1):S121−31

Arterialdilation

No venousdilation

Fluid leakage

Fluid leakage

Capillary bed

Peripheral Edema Associated with CCBs

Complementary Effects of CCB/ARBReduction of CCB-associated Edema

Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:42−73White et al. Clin Pharmacol Ther 1986;39:43−8Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl 1):S121−31

Arterial dilation

(CCB & ARB)

Venousdilation(ARB)

Capillary bed

2.4

3.6

0

2

4

6

8

10

12

14

16

Valsartan 80mg (n=84)

Amlodipine 5mg (n=84)

Ed

em

a-d

ep

en

den

t A

E (

%)

0

14.3

0

2

4

6

8

10

12

14

16

Valsartan 80mg/amlo 5 mg

(n=24)

Amlo 5 mg +additionalamlo 5 mg

(n=28)

Corea et al. Clin Pharmacol Ther 1996;60:341–6

After 8 weeks of therapy, amlodipine 5 mg added to initial therapy in patients not at goal (sitting DBP >95 mmHg)

At Week 8 At Week 12

Edema-dependent Adverse Eventswith Increasing Doses of Amlodipine

Primary outcome: No difference in composite of fatal CHD + non-fatal MI vs. lisinopril

6% � combined CVD

23% � stroke

ALLHAT5

18,102 HTN patients: Randomized, prospective study vs. lisinopril

Primary outcome: 10% � in non-fatal MI & fatal CHD

16% � total CV events and procedures

30% � new-onset diabetes

27% � stroke

11% � all-cause mortality

� central aortic pressure by 4.3 mmHg

ASCOT-BPLA/CAFE3,4

19,257 HTN patients: Multicenter, randomized, prospective study vs. atenolol

Primary outcome: 31% � in CV events vs. placebo

41% � hospitalization for angina

27% � coronary revascularization

CAMELOT2

1,991 CAD patients (>20%): Double-blind, randomized study vs. placebo and enalapril 20 mg

Primary outcome: No difference in mean 3 yr coronary angiographic changes vs. placebo

35% � hospitalization for heart failure + angina

33% � revascularization procedures

PREVENT1

825 CAD patients (≥30%): Multicenter, randomized, placebo controlled

Amlodipine: Wealth of CV Outcome Data

1Pitt et al. Circulation 2000;102:1503–10; 2Nissen et al. JAMA 2004;292:2217–26; 3Dahlof et al. Lancet 2005;366:895–9064Williams et al. Circulation 2006;113:1213 –25; 5Leenen et al. Hypertension 2006;48:374–84

1Julius et al. Lancet 2004;363:2022–31; 2Pfeffer et al. N Engl J Med 2003;349:1893–9063Maggioni et al. Am Heart J 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

Primary endpoints: Mortality and combined endpoint of mortality and morbidity13% � mortality and morbidity

� left ventricular remodeling37% � atrial fibrillation occurrence

� heart failure signs/symptoms28% � heart failure hospitalization

Val-HeFT3–5

5,010 heart failure II–IV patients:Double-blind, randomized study vs placebo

Primary outcome: No difference vs. captopril in all-cause mortality

(Valsartan is as effective as standard of care)

VALIANT2

14,703 post-myocardial infarction patients: Double-blind, randomized study vs. captopril and vs captopril + valsartan

Primary outcome: No difference in composite of cardiac mortality and morbidity

23% � new-onset diabetes

VALUE1

15,245 high-risk HTN patients: Double-blind, randomized, active-controlled study vs. amlodipine

Valsartan: Wealth of CV Outcomes Data

Valsartan: Wealth of CV Protection Data

1Viberti et al. Circulation 2002;106:672–82Ridker et al. Hypertension 2006;48:73–9

Primary endpoints: change in systolic BP and in high-sensitivity C-reactive protein (hsCRP) between randomization and Week 6

Drop in systolic BP was greater with the combination

13% � hsCRP vs. valsartan/HCTZ

Val-MARC2

1,668 stage 2 HTN patients: Multicenter, open-label, randomized study vs valsartan/HCTZ

Primary endpoint: % change in urinary albumin excretion rate (UAER) over 6 months

44% � in UAER vs. baseline with valsartan vs. 8% with amlodipine

15.4% between-group difference favoring valsartan in patients returning to normoalbuminuria

MARVAL1

332 patients with T2D + microalbuminuria ± HTN: Multicenter, randomized, double-blind, active-controlled study vs. amlodipine

� Notable absentee of available dual-mechanism therapies

� Complementary mode of action

� CCB-induced edema is minimized by ARB

� Wealth of CV Outcomes Data for Amlodipine and Valsartan

Rationale for CCB/ARB Therapy

Clinical Evidence with Amlodipine/Valsartan

� BP-lowering Efficacy and Get to Goal Rates

� Efficacy in Non-responders to Monotherapy

� Efficacy in Non-responders to Combination Therapy

� Efficacy Across Different Grades of Hypertension

� Safety and Tolerability

Amlodipine/ValsartanBP-lowering efficacy and get to goal rates

Superior BP-lowering efficacy compared with monotherapiesin patients with mild-to-moderate hypertension

−25

0

−5

−10

−15

−20

Change from baseline in systolic BP (mmHg)

Amlodipine10 mg

Valsartan160 mg

Amlodipine/Valsartan10/160 mg

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

*p<0.01 vs. monotherapiesMild-to-moderate hypertension = diastolic BP >90 and <110 mmHgN=80

−−−−22.9 *

−−−−14.5−−−−16.9


BP-lowering efficacy in patients with stage 2 hypertension

−40

0

−10

−20

−30

Change from baseline (mmHg)

Mean sitting systolic BP Mean sitting diastolic BP

−−−−35.8

−−−−31.8−−−−28.6

−−−−27.6

Amlodipine (5–10 mg) +valsartan (160 mg) (n=64)

Lisinopril (10–20 mg) +HCTZ (12.5 mg) (n=66)

135.0 138.7 83.6 85.2

Endpoint BP(mean mmHg)

Poldermans et al. J Clin Hypertens 2006;8(5, Suppl. A)Poldermans et al. J Hypertens 2006;24(Suppl. 4):S20


↓↓↓↓43 mmHg in MSSBP in patients with baseline MSSBP ≥≥≥≥180 mmHg

−50

0

−10

−20

−30

−40

Change from baseline (mmHg)

−−−−43.0

−−−−31.2−−−−26.1

−−−−21.7



145.4 157.4 86.4 92.5

Endpoint BP(mean mmHg)

Poldermans et al. J Clin Hypertens 2006;8(5, Suppl. A):A96Poldermans et al. J Hypertens 2006;24(Suppl. 4):S20

Mean sitting systolic BP Mean sitting diastolic BP

Baseline MSSBP/MSDBP 188/113 mmHg


Responder & control rates in patients with stage 2 hypertension

40

100

80

70

60

50

90

Poldermans et al. J Clin Hypertens 2006;8(5, Suppl A):A96 (poster)Poldermans et al. J Hypertens 2006;24(Suppl 4):S20 (poster)

Patients (%)

Responders(MSDBP <90 mmHg or≥≥≥≥10 mmHg reduction

from baseline)

100 95.5

79.7 77.3



Achieved BP control(MSDBP <90 mmHg

at endpoint)


Response rates in mild-to-moderate hypertensionR

esp

on

der

rate

20%

40%

60%

80%

100%

*

74.9%

*†

88.5%

N=1,250

Valsartan 160 mg Amlodipine/Valsartan 10/160 mg

*p<0.05 vs placebo; †p<0.05 vs valsartan

Mean sitting diastolic BP ≥95 mmHg and <110 mmHg at study entry or randomization

Response rate = MSDBP <90 mmHg or ≥10 mmHg decrease vs baseline

Amlodipine/ValsartanEfficacy on Non-Responders to Monotherapy

Antihypertensive efficacy of Exforge® in patients previouslyuncontrolled on monotherapy

Overall b-Blocker CCB ARB ACEi Diuretic

Antihypertensive class prior to randomization into the trial

Ch

an

ge i

n S

BP

fro

m b

aseli

ne t

o W

eek

16

-18

-21

-17

-23

-19

-24

-18

-20 -19 -20

-16

-18

-25

-20

-15

-10

-5

0

5/160

(N=440)

10/160

(N=449) (N=76) (N=55) (N=53) (N=70) (N=175) (N=175) (N=92) (N=105) (N=41) (N=39)

5/160 10/160 5/160 10/160 5/160 10/160 5/160 10/160 5/160 10/160Exforge dose (mg):

Presented in 2007 ASH


BP Control Rates at Week 8* according to Prior BP Medication

7480 77

82

7375 75

79

71

83

69

81

0

10

20

30

40

50

60

70

80

90

100

Overall b-Blocker CCB ARB ACEi Diuretic

Antihypertensive class prior to randomization into the trial

5/160

(N=423)

10/160

(N=410) (N=70) (N=50) (N=51) (N=67) (N=174) (N=158) (N=89) (N=94) (N=36) (N=36)

5/160 10/160 5/160 10/160 5/160 10/160 5/160 10/160 5/160 10/160Exforge dose (mg):


Control rate defined as BP <140/90 mmHg for non-diabetic and <130/80 mmHg for diabetic patients* No HCTZ add-on was allowed until after week 8

%


% Patients achieving BP <140/90 mmHg at Week 16 by DM Status

Non-Diabetics

All Patients

Diabetic Patients

# Diabetic Patients with BP<130/80 at Week 16 were 45.9% & 40.7% for 5/160 & 10/160 mg doses, respectively.

5/160 mg 10/160 mg

Amlodipine/Valsartan Dose

N= 406 345 61 378 319 59

81.387.6

81.786.8

78.7

91.5

%


Amlodipine/ValsartanEfficacy on Non-Responders to Combination Therapy “ExPress-C”

Systolic/diastolic responder rates with amlodipine/valsartan10/160 mg among non-responders to ramipril/felodipine 5/5 mg

Trenkwalder et al. DMW 2006;131:S164

Systolic response: SBP <140 mmHg or ≥20 mmHg decrease compared to Visit 4*Diastolic response: DBP <90 mmHg or ≥10 mmHg decrease compared to Visit 4*

0

20

40

60

80

Systolic response rate Diastolic response rate

83% 82%

*Visit 4 occurred at the end of ramipril/felodipine therapy

Amlodipine/ValsartanEfficacy on Non-Responders to Combination Therapy “ExPress-C”

↓↓↓↓31mmHg Systolic BP in patients with moderate hypertension

136

151.4

166.7

120

140

160

180

Mean systolic BP (mmHg)

96.6

89.3

82.380

90

100

Mean

dia

sto

lic B

P (

mm

Hg

)

Week 5 10Week 5 10

–30.7 mmHg

–14.3 mmHg

–15.4 mmHgp<0.0001

–7.0 mmHgp<0.0001

Amlo/Val 10/160

Amlo/val10/160Ram/Fel

5/5

Ram/fel5/5

00

N=133

Trenkwalder et al. DMW 2006;131:S164

Amlodipine/ValsartanEfficacy across Different Grades of Hypertension

BP lowering across all grades of hypertension

−−−−50

0

−−−−10

−−−−20

−−−−30

−−−−40

n=69

−−−−20

Mild HTN1 Severe HTN2

Systolic BP≥≥≥≥180 mmHg2Moderate HTN1

n=140

−−−−30

n=64

−−−−36

n=15

−−−−43

DBP Reduction –17 –18 –29 –26(mmHg)

1Novartis data on file: Dose 10/160 mg2Data from Poldermans et al. J Hypertens 2006;24(Suppl 4):S20 (poster): Dose 5–10/160 mg

Mean change in mean sitting SBP from baseline (mmHg)

Amlodipine/ValsartanEfficacy in All Doses

Amlodipine/ValsartanEfficacy across All Ages

Amlodipine/ValsartanRapid Control of BP: Non-DM vs. DM

Non-Diabetics(N=369)

Diabetics(N=71)

Change from baseline in SBP was -18.5 mmHg for the Non-Diabetics and -14.9 mmHg for Diabetic Patients.*Patients not at BP goal had the option to receive HCTZ add-on starting at 8 weeks

120

125

130

135

140

145

150

155

0 4 8* 12 16 Week

Sy

sto

lic B

loo

d P

ressu

re (

mm

Hg

)


Amlodipine/ValsartanRapid Control of BP across All Ages

Change from baseline to Endpoint in SBP (ITT population) was -17.9 mmHg for Patients<65 y, -18.2 mmHg for Patients >65 y and -19.7 mmHg for Patients >75 y*Patients not at BP goal had the option to receive HCTZ add-on starting at 8 weeks

120

125

130

135

140

145

150

155

0 4 8 12 16 Week

Systo

lic B

loo

d P

ressu

re (

mm

Hg

)

Age <65 y (N=308)

Age ≥≥≥≥65 y (N=132)

Age ≥≥≥≥75 y (N=52)

Amlodipine/ValsartanSafety and Tolerability

↓↓↓↓Fluid retention with amlo/val compared with amlo monotherapy

*p<0.01 vs. amlodipine

0

10

15

20

5

Amlodipine 10 mg Amlodipine/Valsartan10/160 mg

*

23.0

6.8

25

Fogari et al. J Hum Hypertens 20072007;21:220–4

Ankle-foot volume increase (%)


Effect on amlodipine-induced peripheral edema

8

10

6

4

2

0

8.7%

5.4%

p=0.0138

Novartis data on file

3.0%

Placebo Amlodipine Amlo/Val

Pooled data from two trials at doses of Amlo/Val up to 10/320 mg and Amlo up to 10 mg

n=337 n=460 n=1,437Incid

en

ce o

f p

eri

ph

era

led

em

a (

%)


Recurrence of atrial fibrillation with Amlodipine/Valsartancompared with Amlodipine/Atenolol during a 1-year follow-up

0

10

30

40

20

Mugellini et al. J Hypertens 2006;24(Suppl. 4):S5*p<0.01 vs amlodipine/atenolol†Titration to maximum dose of amlodipine

Amlodipine/Valsartan10/160 mg†

Amlodipine/Atenolol10/100 mg†

13%

33%

*

N=220

Patients with at least one symptomatic or non-symptomaticECG-documented episode of atrial fibrillation (% incidence)

Exforge® shows…

� Big SBP reduction

� Superior efficacy across all the grades of HiBP

� Additional BP lowering in any mono uncontrolled

� Additional BP lowering in combination uncontrolled

� Wealth in safety and tolerability evidence

Take-away Messages

Ex(tra)+Forge

“ Big Drop of BP”

Safely

√√√√

amlodipine/valsartan (exforge -...

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