HypertensionRole of New Combination Therapy

Aziz-ur-RehmanServices Institute of Medical Sciences

Lahore

Hypertension is very prevalent

Hypertension is one of the easiest condition to diagnosis

Uncontrolled hypertension may be asymptomatic but has lot of CV

morbidity & mortality

End-stageRenal Disease

CoronaryHeart Disease

Stroke

Heart failure

Left VentricularHypertrophy

Atherosclerosis

PersistentlyElevated BP

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

CV Mortality Risk Doubles with Each 20/10 mmHg Increment in BP*

Cardiovascular mortality risk

0

2

4

8

115/75 135/85 155/95 175/105

6

Systolic BP/Diastolic BP (mmHg)

*Individuals aged 40–69 years

2X risk

4X risk

8X risk

1X risk

Treatment of Hypertension reduces CV morbidity & mortality

Benefits of Blood Pressure Reduction

• Meta-analysis of 61 prospective, observational studies

• 1 million adults• 12.7 years

2 mmHg decrease in mean SBP 10% reduction in risk

of stroke mortality

7% reduction in risk of ischemic heart disease mortality

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

Treatment of hypertension is very cost-effective

Majority of the patients are either not diagnosed or not treated

adequately

Law of 50%

Pakistan< 3%

Hypertension is a multifactorial disease

HTN

SNS

RAAS

Vessels

Psy

Na + W

Blockage of one pathway tends to stimulate others

Limitations of Agents with a Single Mechanism of Action (MoA)

• Inadequate in 4060% of hypertensive patients1

• In majority two or more antihypertensive agents are required to achieve the recommended target BP of <130/80 mmHg2

• Multiple channels are needed to be blocked3

1Materson et al. N Engl J Med 1993;328:914212Bakris et al. Am J Kidney Dis 2000;36:64661

3Milani. Am J Manag Care 2005;11:S2207

• Components of multiple-mechanism therapy can add the desirable effects but not the undesirable ones1,2

• Neutralize adverse events.1,2

– Hyperkalaemia of ACEIs & ARBs neutralised by diuretics

– RAAS blockers may attenuate the oedema that is caused by CCBs

1Sica. Drugs 2002;62:443622Quan et al. Am J Cardiovasc Drugs 2006;6:10313

Advantages of Multiple-mechanism Therapy: Safety/Tolerability

Multiple-mechanism therapy may have an improved tolerability profile compared with its single-mechanism components1,2

Current Guidelines Recommend Combination Therapy

• JNC 7 guidelines state1:“When BP is more than 20/10 mmHg above goal, consideration should be given to initiate therapy with 2 drugs...”

• 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 when CV risk is high.”

1Chobanian et al. Hypertension 2003;42:1206–52 2Mancia et al. J Hypertens 2007:25:110587

ESH = European Society of HypertensionESC = European Society of CardiologyJNC = Joint National Committee

Amlodipine has a Wealth of CV Outcomes Data

1Pitt et al. Circulation 2000;102:1503–10; 2Nissen et al. JAMA 2004;292:2217–26; 3Dahlof et al. Lancet 2005;366:895–906 4Williams et al. Circulation 2006;113:1213–25; 5Leenen et al. Hypertension 2006;48:374–84

PREVENT1

825 CAD patients (≥30%):

35% hospitalization for heart failure + angina43% revascularization procedures

CAMELOT2

1,991 CAD patients (>20%):

42% hospitalization for angina27% coronary revascularization

ASCOT-BPLA/CAFE3,4

19,257 HTN patients

16% total CV events and procedures30% new-onset diabetes23% stroke11% all-cause mortality

ALLHAT5

18,102 HTN patients

6% combined CVD23% stroke

Valsartan has a Wealth of CV Outcomes Data

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;40:970–55Cohn et al. N Engl J Med 2001;345:1667–7; 6Mochizuki et al. Lancet 2007;369:1431–9

VALUE1 15,245 patients: HTN 23% new-onset diabetes

VALIANT2 14,703 patients: Post-MI(valsartan is as effective as standard of care)

Val-HeFT3–5

5,010 patients: Heart failure II–IV patients

13% morbidity and mortality (primary)

left ventricular remodeling

37% atrial fibrillation occurrence

heart failure signs/symptoms28% heart failure hospitalization

JIKEI HEART6

3,081 Japanese patients: HTN plus other risk factors

39% composite CV mortality and morbidity

40% Stroke/transient ischemic attack

47% Hospitalization for heart failure

65% Hospitalization for angina

Valsartan also has a Wealth of CV Protection Data

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

MARVAL1

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

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

Val-MARC2

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

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 (marker of inflammation) vs. valsartan/HCTZ

ARB (Val)• ↓ RAS ↓ SNS• Arterio- and venodilation• Effective in high-renin patients• Congestive heart failure and renal benefits• Attenuates peripheral edema• No effect on cardiac ischemia

CCB (Aml)• ↑ SNS ↑ RAS• Arteriodilation• Effective in low-renin patients• No renal or congestive heart failure benefits• Peripheral edema• Reduces cardiac ischemia

negative sodium balance

reinforces the effects of the

ARB

Vasodilation Arterial +Venous

CCBs and ARBs compliment each other’s functions

Natriuresis

Arterial

SNS = sympathetic nervous system; RAS = renin-angiotensin system

Amlodipine/Valsartan Provides Powerful BP Reductions

¶DBP 9099 mmHg, SBP 140159 mmHg‡DBP ≥100 mmHg, SBP ≥160 mmHgBP = blood pressure; DBP = diastolic BP; SBP = systolic BP; MSSBP = mean sitting SBP

1Smith et al. J Clin Hypertens 2007;9:355–64 (Dose 10/160 mg)2Poldermans et al. Clin Ther 2007;29:279–89 (Dose 5–10/160 mg)

Mild HTN1¶

Mea

n ch

ange

in M

SSBP

from

bas

elin

e (m

mH

g)

0

–10

–20

–30

–40

–50

n=69 n=140 n=15

–20

–43

–30

Moderate HTN1‡Baseline SBP≥180 mmHg2

10/160 (aml+val)

Amlodipine/Valsartan vs. Amlodipine

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

p=0.1

−20

−10

0

Amlodipine/Valsartan10/160 mg

Amlodipine10 mg

p=0.0018

−40

−30

N=55

−31.7

N=46

–40.1

LSM=least square meanMSSBP=mean sitting systolic blood pressure

EX-EFFeCTS1

Patients with Stage 2 Hypertension

−20

−10

0N=42

Amlodipine/Valsartan10/160–320 mg

Amlodipine10 mg

–43.5

−40

−30

−50

−37.2

N=38

EX-STAND2

Black Patients with Stage 2 Hypertension

1.Destro et al. J Am Soc Hypertens 2008;2:294–3022.Flack et al. J Hum Hypertens 2009 (E-pub ahead of print).

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

Amlodipine 10 mg

DiabetesElderly

(65 yrs)

Mea

n ch

ange

in M

SSBP

at W

eek

4 (m

mH

g)

86 89 78 98 46 55 134 145 34 36

*p<0.05 amlodipine/valsartan vs. amlodipine monotherapy

Amlodipine/Valsartan: Superior BP Across Diverse Patient Populations (EX-EFFECTS)

ISH†Severe

(180 mmHg) Obese‡

**

*

* *–29.7

–21.7

–30.2

–22.0

–40.1

–31.7

–27.2

–22.9

–29.5

–22.7

Amlodipine/valsartan 10/160 mg

MSSBP = mean sitting systolic BP†ISH = isolated systolic hypertension (140 and <90 mmHg)‡Obese defined as body mass index 30 kg/m2

–5

–10

–15

–20

–25

–30

–35

–40

–45

Destro et al. J Am Soc Hypertens 2008;2:294–302

Amlodipine/Valsartan Reduces Albuminuria Versus Amlodipine in Black Patients with Stage 2 Hypertension (EX-STAND)

Chan

ge fr

om b

asel

ine

in U

ACR

(%)

Amlodipine5+5 mg

Amlodipine/Valsartan5+160 mg

n=157

n=160

Post-hoc analysis (Week 12 data)UACR = urinary albumin-to-creatinine ratio

–30

101510

50

–5–10–15–20–25–30–35

Flack et al. J Hum Hypertens 2009 (E-pub ahead of print)

Complementary Effects of a CCB/ARB Reduction of CCB-associated Edema

I.

II.

III.

Edema

Arterial hypertension

Constricted blood vessels, high resistance

CCBs BP reduction due to arterial vasodilation Tendency towards edema due to absent venodilation BP reduction stimulates RAAS & causes venoconstriction

CCBs + RAS inhibitors* Blockade of RAAS inhibits effects of angiotensin II,

giving rise to additional BP reduction Additional venodilation by RAS inhibitors reduces

edema

Edema

*Angiotensin receptor blockers or angiotensin-converting enzyme inhibitors

Messerli. Am J Hypertens 2001;14:978–9

Amlodipine/Valsartan: Fewer Patients Experience Peripheral Oedema*

Prop

ortio

n of

pati

ents

exp

erie

ncin

g pe

riphe

ral e

dem

a (%

)

p<0.00140

30

20

10

0

Amlodipine/Valsartan 5/160 mg

Amlodipine10 mg

31%

7%

n=184/591n=39/592

Schrader et al. J Int Clin Pract 2009;63:217225*Week 8 data

SUMMARY- CCB/ARB COMBO

• Amlodipine/Valsartan provides powerful BP reductions

–across hypertension severities• Up to 43 mmHg systolic BP (SBP) drop

– in diverse patient types• Elderly (≥65 years), ISH, obese and diabetics

– in patients uncontrolled with monotherapy• ~21 mmHg SBP drops

–with fewer patients experience peripheral edema

Single-pill combinations of Amlodipine and Valsartan approved as first-line treatments for HTN

• Approvals consistent with current treatment guidelines

• Up to 80% of patients may need multiple medications

• Single-pill combinations offer effective, convenient medications

• Single pill combination improves compliance

Amlodipine + Valsartan Combo

Make use of this powerful tool to control the menace of

hypertension

Combination is Better

Thank youAziz-ur-Rehman