Therapy in Hypertension: Position of Fixed Combination.

Harun Rasyid Lubis.

Departemen Ilmu penyakit Dalam FK-USU Medan.

HYPERTENSION
DEFINITION:

WHO-ISH: Because blood pressure is characterized by large spontaneous

variations the diagnosis of hypertension should be based on multiple blood pressure measurements, taken on several separate occasions.

JNC VII: .. Is based on two or more properly measured, seated BP

readings on each of two or more office visits.

INDONESIA: Konsensus: beberapa kali pengukuran dalam beberapa

kali kunjungan

HYPERTENSION DEFINITION: ESH-ESC 2007:

Blood pressure is characterized by large spontaneous variations both during the day and between the days, months, and seasons. Therefore the diagnosis of hypertension should be based on multiple blood pressure measurements, taken on everal occasions over a period of time.

J Hypertens 2007 25:1113.

Routine steps for accurate measurement of blood pressure

Rest the patient (seated) for at least 5 mins in a quiet comfortable room . Use a calibrated aneroid device (a validated and recently calibrated electronic device may also be used . Choose cuff with appropriate width of bladder . Record with cuff at heart level . Deflate cuff at 2 mmHg/sec . First sound = systolic reading, disappearance = diastolic reading . Repeat measurement at least x2 (first visit: x3) & take average value . Take BP in both arms at least once; record which arm is used; patient position ( seated, supine, standing) & pulse rate. . Measure BP at + 1 & 5 mins after standing ( especially in older patients and those with diabetes).

BP Measurement Techniques
Method In-office Brief Description Two readings, 5 minutes apart, sitting in chair. Confirm elevated reading in contralateral arm.

Ambulatory BP monitoring Indicated for evaluation of white-coat HTN. Absence of 1020% BP decrease during sleep may indicate increased CVD risk. Self-measurement Provides information on response to therapy. May help improve adherence to therapy and evaluate white-coat HTN. JNC 7 2003

Office BP Measurement
Use auscultatory method with a properly calibrated and validated instrument. Patient should be seated quietly for 5 minutes in a chair (not on an exam table), feet on the floor, and arm supported at heart level. Appropriate-sized cuff should be used to ensure accuracy. At least two measurements should be made. Clinicians should provide to patients, verbally and in writing, specific BP numbers and2003 JNC 7 BP goals.

How to measure blood pressure accurately

sphygmomanometer Patient should be seated and relaxed, preferably for several minutes prior to to the measurement and in a quiet room. Appropriate cuff size. Average the readings. If the first two readings differ by more than 10 mmHg systolic or 6 mmHg diastolic or if the initial readings are high, take several readings after five minutes of quiet rest, until consecutive readings do not vary by greater than these amounts. Australia, Ideally, patients should not take caffeine- 2004

Burden of Hypertension in Asia.

45% 40% 35% 30% 25% 20% 15% 10% 5% 0%
a Pa ki st an K on g K on g Sr iL an ka na al ng ap or e In di a K or ea ys i al a Ja pa N ep C hi n

45%

34% 26% 20% 27% 24% 23% 29% 25% 20%

Sharma D et al: IHJ Feb 2006, Pakistan Med Research Council Wolf-Meir et.al JAMA .2003 , WHO bulletin , Gu et al 35-74 yrs,China, Jo et.al Korea 18-92 yrs J Hyper 2001

Si

Prevalence of Hypertension in AFRICA

0 0 0 0 0 0 0 0 0 0 0
WHO Global Infobase 2003 Cappuccio et al: Hypertension 2004

Prevalence of hypertension (%)

Egypt

Algeria

SA

SubSahara (Ghana)

Age- and sex-adjusted Hypertension defined as BP 140/90 mmHg or on treatment

HYPERTENSION
If blood pressure is only slightly elevated, repeated measurements should be obtained over a period of several month to define the patients usual blood pressure as accurately as possible. On the other hand if the patient has a more marked blood pressure elevation, evidence of hypertensionrelated target organ damage or a high or very high cardiovascular risk profile, repeated measurements should be obtained over shorter period of time (weeks or days).

In general a diagnosis of hypertension should be based on at least 2 blood pressure measurements per visit on at least 2 to 3 visit, although in parrticularly severe cases the diagnosis can be based on measurement taken at a single visit.

J Hypertens 2007 25:1113-4.

Threshold for intervention initial blood pressure (mmHg)

>180/110

160/179 100-109

140/159 90-99

130/139 85-89

<130/85

*
180/110 140/159 90-99

<140/90

Target organ damage or cardiovascular complications or diabetes or 10 year risk of cardiovascular disease 20% Treat Treat Treat

No target organ damage and no cardiovascular complications and no diabetes and 10 year risk of cardiovascular disease <20% Observe, reassess risk of cardiovascular disease yearly Reassess yearly Reassess in 5 years

* Unless malignant phase of hypertensive emergency confirm over 1-2 weeks then treat.
If cardiovascular complications, target organ damage, or diabetes is present, confirm over 3-4 weeks then treat, if absent remeasure weekly treat if blood pressure persists at these levels over 4-12 weeks. If cardiovascular complications, target organ damage, or diabetes is present, confirm over 12 weeks then treat, if absent remeasure monthly and treat if these levels are maintained and estimated 10 year cardiovascular disease risk is 20%. Assessed with risk chart for cardiovascular disease.

HYPERTENSION
If blood pressure is only slightly elevated, repeated measurements should be obtained over a period of several month to define the patients usual blood pressure as accurately as possible. On the other hand if the patient has a more marked blood pressure elevation, evidence of hypertensionrelated target organ damage or a high or very high cardiovascular risk profile, repeated measurements should be obtained over shorter period of time (weeks or days).

In general a diagnosis of hypertension should be based on at least 2 blood pressure measurements per visit on at least 2 to 3 visit, although in parrticularly severe cases the diagnosis can be based on measurement taken at a single visit.

J Hypertens 2007 25:1113-4.

JNC VII: Algorithm for Treatment of Hypertension

Lifestyle modifications Not at goal blood pressure (BP)* Hypertension without compelling indications Hypertension with compelling indications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACE inhibitor, ARB, -blocker, CCB) as needed

Stage 1 Thiazide-type diuretics for most. May consider ACE inhibitor, ARB, -blocker, CCB, or combination

Stage 2 Two-drug combination for most (usually including thiazide-type diuretic)

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;289:256072

Recommendations for healthy lifestyle

Recommended for healthy lifestyle
Lifestyle parameter
Diet

Health recommendation
Eat more whole grain products/fiber Eat more-fresh fruits & vegetarian Use low-fat milk products Use low-fat meat & alternatives Reduce saturated fat content Reduce salt content (6 g per day max. 1 teaspoon 30-60 min of endurance activities x 4-7 days per week (e.g. brisk walking, jogging, cycling)

Exercise Body weight Alcohol comsumption

Maintain BMI*@ 20-25

Limit to 0-2 standard drinks per day People with elevated triglyceride levels should eliminate alcohol completely Smokers should be advised to quit ( cessation programs, nicotine replacement/drug therapy) Encourage young people not to start

Smoking cessation

*BMI = weigth(kg/height2(m) (Normal : 20-25; overweight ; 25-30; obese : >30)

Controlling blood pressure with medication is unquestionably one of the most cost-effective methods of reducing premature CV morbidity and mortality

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

The major classes of anti-hypertensive drugs

1. Diuretics . Loop . K+-sparing . Thiazide . Thiazide-like 2. Adrenergic inhibitors . Alpha-1 blockers . Beta-blockers . Combine 3. RAS inhibitots . ACE-inhibitors . ARB 4. Ca-channel blockers (CCB) . Dihydropyridin . Non-dihydropyridine 5. Imidazoline receptor agonist 6. Vasodilatation

furosemide, bumetanide amiloride, spironolactone hydrochlorothiazide, bendrofluazide chlorthalodone, indapamide Doxazosin, Prazosin Atenolon, Metoprolol, Bioprolol, Carvedilol Labetalol Captopril, Enalapril, Perindopril etc Losartan, Valsartan, Candesartan etc Nifedipin, Amlodipin Diltiazem, Verapamil monoxidine, nilmenidine hidralazine, minoxidil

Blood pressure treatment thresholds

Recommended blood pressure targets
Organisation Uncomplicatied hypertension American Kidney Association (2001) British Hypertension Society (1999) Canadian Hypertension Society (1999) European Hypertension Society (2003) JNC-VII (2003) National Kidney Foundation US (2000) WHO-ISH (1999) < 140/85 < 140/90 < 140/90 < 140/90 < 140/90 < 140/90 Patient group + DM or Renal disease <130/80 < 140/80 < 130/80 < 130/80 < 130/80 < 130/80 < 130/80 + RF with proteinuria* <125/75 <125/75 <125/75 <125/75 <125/75 <125/75 <125/75

*Proteinuria : > 1 gram per 24 hours

AUSTRALIA 2003

Stroke and Ischemic Heart Disease (IHD) Mortality Rate in Each Decade of Age, Versus Usual Systolic BP at the Start of that Decade
Stroke
256 128 64 Age at risk 8089 y 7079 y 6069 y 5059 y

IHD
256 128 64 32 16 8 4 2 1

Age at risk 8089 y 7079 y 6069 y 5059 y 4049 y

Mortality*

32 16 8 4 2 1

0 120

140

160

180

120

140

160

180

Usual SBP (mmHg)

Usual SBP (mmHg)

*Floating absolute risk and 95% CI

Lewington et al. Lancet 2002;360:190313

Cardiovascular Mortality Risk Doubles with Each 20/10 mmHg Increment in Systolic/Diastolic Blood Pressure*
CV mortality risk 8 6 4 2 0
1X risk

8X risk

4X risk 2X risk

115/75

135/85

155/95

175/105

Systolic BP/Diastolic BP (mmHg)

*Individuals aged 4069 years Lewington et al. Lancet 2002;360:190313

Blood Pressure Reduction of 2 mmHg Decreases the Risk of Cardiovascular Events by 710%
Meta-analysis of 61 prospective, observational studies 1 million adults 12.7 million person-years
7% reduction in risk of ischaemic heart disease mortality 10% reduction in risk of stroke mortality

2 mmHg decrease in mean SBP

Lewington et al. Lancet 2002;360:190313

ASCOT Trial Design

19,342 randomized to antihypertensive therapy 85 excluded before end of study due to irregularities 19,257 randomized 9,639 assigned and received amlodipine + perindopril 9,618 assigned and received atenolol + thiazide

Systolic and diastolic blood pressure

180 160 140 120 100 80 60 Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Last visit

164.1 SBP 163.9

atenolol thiazide amlodipine perindopril Mean difference 2.7

137.7 136.1

mm Hg

94.8 94.5

DBP

Mean difference 1.9

79.2 77.4

Time (years)

CV mortality
%
3.5 3.0
atenolol thiazide (No. of events 342)

24%

Cumulative Events

2.5 2.0 1.5 1.0 0.5 0.0

amlodipine perindopril (No. of events 263)

HR = 0.76 (0.65-0.90) p = 0.0010

0.0 1.0 2.0 3.0 4.0 5.0

Years

Number at risk amlodipine perindopril 9639 atenolol thiazide 9618

9544 9532

9441 9415

9322 9261

9167 9085

8078 7975

Fatal and non-fatal stroke

%
Cumulative Events
5.0

4.0

atenolol thiazide (No. of events 422)

23%

3.0

amlodipine perindopril (No. of events 327)

2.0

1.0

HR = 0.77 (0.66-0.89) p = 0.0003

0.0 1.0 2.0 3.0 4.0 5.0

0.0

Years

Number at risk amlodipine perindopril atenolol thiazide

9639 9618

9483 9461

9331 9274

9156 9059

8972 8843

7863 7720

Total CV events and procedures

%
Cumulative Events
18.0 16.0 14.0 12.0 10.0 8.0 6.0 4.0 2.0 0.0 1.0 2.0

atenolol thiazide (No. of events 1602)

16%

amlodipine perindopril (No. of events 1362)

HR = 0.84 (0.78-0.90) p < 0.0001

0.0 3.0 4.0 5.0

Years

Number at risk amlodipine perindopril atenolol thiazide

9639 9618

9277 9210

8957 8848

8646 8465

8353 8121

7207 6977

New-onset diabetes mellitus

%
Cumulative Events
10.0

8.0

atenolol thiazide (No. of events = 799)

6.0

30%
amlodipine perindopril (No. of events = 567)

4.0

2.0

HR = 0.70 (0.63-0.78) p < 0.0001

0.0 1.0 2.0 3.0 4.0 5.0

0.0

Years

Number at risk amlodipine perindopril atenolol thiazide

9639 9618

9383 9295

9165 9014

8966 8735

8726 8455

7618 7319

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

Materson et al. observed that antihypertensive agents with a single MoA were inadequate to achieve a diastolic BP <95 mmHg in 4060% of hypertensive patients1 In patients with hypertension and diabetes, more than 65% will require two or more antihypertensive agents to achieve the recommended target BP of <130/80 mmHg2 Because hypertension is a multifactorial disease, in most cases at least two antihypertensive agents are needed for patients to achieve BP goal3

Materson et al. N Engl J Med 1993;328:914 21 2 Bakris et al. Am J Kidney Dis 2000;36:646 61 3 Milani. Am J Manag Care 2005;11:S220 7

Multiple Antihypertensive Agents are Needed to Reach BP Goal

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

Average no. of antihypertensive medications

Bakris et al. Am J Med 2004;116(5A):30S8 Dahlf et al. Lancet 2005;366:895906

Rationale for Multiple-mechanism Therapy in Hypertension

Advantages of multiple-mechanism therapy

Back to section content

Blood Pressure has Multiple Regulatory Pathways

Patient 1 Patient 2 Patient 3

Sympathetic nervous system Renin-angiotensin system Total body sodium

B. Waeber, March 2007, with permission

Advantages of Multiple-mechanism Therapy

Enhanced antihypertensive efficacy Potential for attenuation of certain class-specific adverse events May improve patient compliance (multiple-mechanism agent in a single pill versus free combination therapy) Potentially cost effective Recommended by treatment guidelines

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

2

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

1

Efficacy: Blood Pressure Reduction with Valsartan/HCTZ Compared with Valsartan Monotherapy in Mild-to-Moderate Hypertension
Change in BP from baseline (mmHg) Diastolic BP 0
n=663 n=665 n=657 n=663

Systolic BP

n=665

n=657

-5

-10

-10.8
-15

-12.8

*
Valsartan 160 mg

-14.2

**,

-15.7 -19.4

-20

Valsartan/HCTZ 12.5 mg -25

-21.7

Valsartan/HCTZ 25 mg

**,

Patients with mild-to-moderate hypertension not adequately controlled by monotherapy Mallion et al. Blood Press 2003;12(Suppl 1):3643

*p0.01 vs valsartan 160 mg; **p0.01 vs valsartan/HCTZ 12.5 mg p<0.001 vs valsartan 160 mg

Additive Reduction in Blood Pressure with Initial Dual ACE Inhibitor/CCB Therapy
Ramipril/felodipine ER Ramipril 2.5 mg Felodipine ER 2.5 mg 2.5/2.5 mg (n=51) (n=51) (n=47)

0 2 4 6 8 10 12 14 16 Mean BP reduction (mmHg) over 4-week treatment period

** ***

Systolic BP Diastolic BP

*p<0.0001 vs ramipril and vs felodipine ER **p=0.0002 vs ramipril; ***p=0.0038 vs felodipine ER

Scholze et al. Int J Clin Pract 2006;60:265 74

Advantages of Multiple-mechanism Therapy: Safety/Tolerability

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

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

1

Complementary Effects of a CCB/RAS Inhibitor: Reduction of CCB-associated Edema

I.
Arterial hypertension
Constricted blood vessels, high resistance

II.

Edema

CCBs
BP reduction due to arterial vasodilation Tendency towards edema due to absent venodilation BP reduction stimulates RAS and increases angiotensin II level

Edema

III.

CCBs + RAS inhibitors*

Blockade of RAS inhibits effects of angiotensin II, giving rise to additional BP reduction Additional venodilation by RAS inhibitors reduces edema

*Angiotensin receptor blockers or angiotensin-converting enzyme inhibitors

Attenuation of Peripheral Edema with Dual ACE Inhibitor/CCB Therapy Compared with CCB Monotherapy: Stage 2 Hypertension
Patients (%) 30

p=0.0102

20

10
n=182 n=182

Amlodipine 10 mg

Benazepril/amlodipine 20/10 mg
Jamerson et al. Am J Hypertens 2004;17:495 501

Adverse events reported at an incidence of 5% in the safety population

Recommendations for Multiplemechanism Therapy: What the Treatment Guidelines Say

JNC VII1
Most patients with hypertension will require two or more antihypertensive agents to achieve their BP goals 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, either as separate prescriptions or in fixeddose combinations

ESH ESC2
To reach target blood pressures, it is likely that a large proportion of patients will require therapy with more than one agent

Chobanian et al. JAMA 2003;289:256072 ESHESC Guidelines. J Hypertens 2003;21:101153

1

JNC VII: Algorithm for Treatment of Hypertension

Lifestyle modifications Not at goal blood pressure (BP)* Hypertension without compelling indications Hypertension with compelling indications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACE inhibitor, ARB, -blocker, CCB) as needed

Stage 1 Thiazide-type diuretics for most. May consider ACE inhibitor, ARB, -blocker, CCB, or combination

Stage 2 Two-drug combination for most (usually including thiazide-type diuretic)

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;289:256072

ESHESC: 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 at full dose different agent at low dose Previous combination at full dose Add a third drug at low dose

If goal BP not achieved

23 drug combination at full doses Full-dose monotherapy 3-drug combination at full doses
ESHESC Guidelines. J Hypertens 2007;25:1144

TOD = target organ damage

Updated UK NICE Guidelines for the Treatment of Newly Diagnosed Hypertension

<55 years Step 1 ACEI (or ARB*) 55 years or black patients at any age CCB or thiazidetype diuretic

Step 2

ACEI (or ARB*) + CCB or ACEI (or ARB*) + thiazide diuretic ACEI (or ARB*) + CCB + diuretic Add further diuretic therapy, -blocker, or -blocker. Consider seeking specialist advice
http://www.nice.org.uk/download.aspx?o=CG034fullguideline. Accessed June 2006

Step 3

Step 4

*If ACE inhibitor (ACEI) not tolerated

ESH ESC Recommendations for Combining BPlowering Drugs

Thiazide diuretics

-blockers

Angiotensin receptor antagonists

-blockers

Calcium Antagonists

Angiotensin-converting enzyme (ACE) inhibitors

Most rational combinations Combinations used as necessary
ESHESC Guidelines. J Hypertens 2007 25:1144

Improved Compliance with Fixed-dose Combination Therapy Compared with Free-combination Therapy

Fixed-dose combination (amlodipine/benazepril) (n=2,839)

88.0%

p<0.0001
Free combination (ACEI + CCB) (n=3,367)

69.0%

0%

20%

40%

60%

80%

100%

Medication possession ratio (MPR)

Defined as the total number of days of therapy for medication dispensed/365 days of study follow-up

Wanovich et al. Am J Hypertens 2004;17:223A (poster)

Fixed-dose Combination Therapy Supports Compliance in Hypertensive Patients

Risk ratio (95% CI) Taylor et al. Dezii NDC dataset Dezii 0.74 (0.67, 0.81) 0.74 (0.65, 0.84) 0.81 (0.77, 0.86) 0.71 (0.62, 0.80) % Weight 27.1 13.9 46.4 12.6

Overall (95% CI)

0.77 (0.73, 0.80) p<0.0001

0.1
Favors fixed-dose combination agent

Risk ratio Favors individual agents given separately

Bangalore et al. J Clin Hypertens 2006;8(Suppl. A):P-157 (poster)

10

Increased Persistence with Fixed-dose Combination Therapy Compared with Free Combination Therapy
Patients persistent (%)
100 90 80 70 60 50 0 1 2 3 4 5 6 7 8 9 10 11

Lisinopril/HCTZ (single pill) Lisinopril + diuretic (two pills)

68.7% 18.8% difference 57.8%

12

Month
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):26

Increased Persistence with Fixed-dose Combinations Compared with Individual Component-based Therapy

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

54%
p<0.0001

Free combination (Valsartan + HCTZ) (n=561)

19%

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

Highly Compliant Patients are More Likely to Attain BP Goal

Patients with BP control* (%)

50 40 30 20 10 0

Odds ratio = 1.45 p=0.026 (controlling for age, gender and co-morbidities)

43 34 33

High (80%) (n=629)

Medium (5079%) (n=165)

Low (<50%) (n=46)

Compliance (measured using medication possession ratio)

*<140/90 mmHg or <130/85 mmHg for patients with diabetes Bramley et al. J Manag Care Pharm 2006;12:23945

Rationale for Dual-mechanism Therapy with a CCB/ARB: Amlodipine/Valsartan

A CCB/ARB is a Notable Absentee of Available Dual-mechanism Thera CCB/ARB Complementary Mode of Action CCB-induced Edema is Minimized by the ARB There is a Wealth of CV Outcomes Data for Amlodipine and Valsartan

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Rationale for Dual-mechanism Therapy with a CCB/ARB: Amlodipine/Valsartan

A CCB/ARB is a notable absentee of available dual-mechanism therapies

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ESH ESC Recommendations for Combining BPlowering Drugs and Availability as Fixed-dose Combinations
Diuretics

-blockers

?
-blockers

Angiotensin receptor blockers (ARBs)

Calcium channel blockers (CCBs)

Angiotensin-converting enzyme (ACE) inhibitors

Most rational combinations Combinations used as necessary Available as FDC Adapted from ESHESC Guidelines. J Hypertens 2003;21:101153

A Notable Absentee From Currently Available Dual-Mechanism Agents is the CCB ARB
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)

Notable absentee is a CCB + ARB

ARB and diuretic

Valsartan + HCTZ (Diovan HCTZ/Co-Diovan) Losartan + HCTZ (Hyzaar HCTZ)

-blocker and diuretic

Atenolol + chlorthalidone (Tenoretic) Metoprolol + HCTZ (Lopressor HCT)

-blocker and CCB

Metoprolol + felodipine (Logimax) Atenolol + nifedipine (Nif-Ten)

CCB and diuretic

Rationale for Dual-mechanism Therapy with a CCB/ARB: Amlodipine/Valsartan

CCB-induced edema is minimized by the ARB

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Peripheral Edema Associated with CCBs

Fluid leakage

Arterial dilation

No venous 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

Complementary Effects of a CCB/Angiotensinreceptor Blocker (ARB): Reduction of CCBassociated Edema

Arterial dilation (CCB and ARB)

Venous dilation (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 Gustaffson. J Cardiovasc Pharmacol 8; 1987;10(Suppl. 1):S121 Messerli et al. Am J Cardiol 2000;86:1182 31; 7

Amlodipine/Valsartan: effect on amlodipine-induced peripheral edema

p=0.0138

Incidence of peripheral edema (%)

10 8 6 4 2
n=337

8.7%
38% difference

5.4%

3.0%

n=460

n=1,437

Placebo

Amlodipine

Amlo/Val
Novartis data on file

Pooled data from two trials at doses of Amlodipine/Valsartan up to 10/320 mg and amlodipine up to 10 mg

Clinical Evidence with Amlodipine/Valsartan

Amlodipine/Valsartan: efficacy in non-responders

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Effect of Amlodipine/Valsartan on Response Rates in Mild-to-Moderate Hypertension

N=1,250
* *

100% Responder rate 80% 60% 40% 20%

74.9%

88.5%

Valsartan 160 mg

Amlodipine/Valsartan 10/160 mg

*p<0.05 vs placebo; p<0.05 vs valsartan Mean sitting diastolic BP 95 and <110 mmHg at study entry/randomization Response rate = MSDBP <90 or 10 mmHg decrease vs baseline

Philipp et al. Clin Ther 2007;29:online

Amlodipine/Valsartan: Superior BP-lowering Efficacy Compared with Monotherapies in Patients with Mild-to-Moderate Hypertension
Amlodipine 10 mg Valsartan 160 mg Amlodipine/Valsartan 10/160 mg

0 5 10 15 20

16.9

14.5

25 Change from baseline in systolic BP (mmHg)

22.9 *

*p<0.01 vs. monotherapies Mild-to-moderate hypertension = diastolic BP >90 and <110 mmHg N=80 Fogari et al. J Hum Hypertens 2007;21:2204

Amlodipine/Valsartan: BP-Lowering Efficacy in Patients with Stage 2 Hypertension

Endpoint BP (mean mmHg) Mean sitting systolic BP 135.0 138.7 Mean sitting diastolic BP 83.6 85.2

10 20 30 40
35.8 * 31.8 * 28.6 * 27.6 *

Change from baseline (mmHg)

Amlodipine (510 mg) + valsartan (160 mg) (n=64)

Lisinopril (1020 mg) + HCTZ (12.5 mg) (n=66)

*p<0.001 vs baseline Baseline MSSBP/MSDBP 171/113 mmHg

Poldermans et al. Clin Ther 2007;29:27989

Amlodipine/Valsartan: 43 mmHg Drop in MSSBP in Patients with Baseline MSSBP 180 mmHg
Endpoint BP (mean mmHg)

Mean sitting systolic BP

145.4 157.4

Mean sitting diastolic BP

86.4 92.5

10 20 30
31.2 26.1 * 21.7 *

40 50 * Change from baseline (mmHg)

43.0

Amlodipine (510 mg) + valsartan (160 mg) (n=15)

Lisinopril (1020 mg) + HCTZ (12.5 mg) (n=11)

*p<0.001; p<0.002 vs baseline Baseline MSSBP/MSDBP 188/113 mmHg

Poldermans et al. Clin Ther 2007;29:27989

Responder and Control Rates with Amlodipine/Valsartan in Patients with Stage 2 Hypertension
Patients (%) Amlodipine (510 mg) + valsartan (160 mg) (n=64)
95.5

100 90 80 70 60 50 40

100

Lisinopril (1020 mg) + HCTZ (12.5 mg) (n=66)

79.7 77.3

Responders (MSDBP <90 mmHg or 10 mmHg reduction from baseline)

Achieved BP control (MSDBP <90 mmHg at endpoint)

Poldermans et al. Clin Ther 2007;29:27989

Systolic Blood Pressure Reduction of 31 mmHg in Patients with Moderate Hypertension: ExPress-C
N=133
180

100
Mean diastolic BP (mmHg)

14.3

mmHg

Mean systolic BP (mmHg)

30.7

mmHg
96.6
7.0 mmHg p<0.0001

160

166.7

15.4 mmHg p<0.0001

90
89.3

151.4 140 136

120

Week

After Ram After Amlo/Val 10/160 5 + Fel 5

10

80 Week

82.3

10

After Ram After Amlo/Val 10/160 5 + Fel 5

Poster presented at DMW 2006. Trenkwalder et al. DMW 2006;131:S164

Clinical Evidence with Amlodipine/Valsartan

Amlodipine/Valsartan: safety and tolerability

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Reduced Fluid Retention with Amlodipine/Valsartan Compared with Amlodipine Monotherapy

Ankle-foot volume increase (%) 25 20 15 10 5 0 *
23.0

70% difference

6.8

Amlodipine 10 mg

*p<0.01 vs. amlodipine N=80

Amlodipine/Valsartan 10/160 mg
Fogari et al. J Hum Hypertens 2007;21:2204

The Five Most Frequently Reported AEs for Amlodipine/Valsartan Compared with Component Monotherapies and Placebo

Val/Amlo Total popln (n) Peripheral edema (%) Headache (%) Nasopharyngitis (%) Upper RTI (%) Dizziness (%)
RTI = respiratory tract infection

Val 921 2.1 4.8 4.0 1.4 2.4

Amlo 460 8.7 7.6 3.5 2.4 1.5

Placebo 337 3.0 5.9 1.8 2.1 0.9

Total 3,155 4.6 5.1 3.8 2.3 2.0

1,437 5.4* 4.3 4.3 2.9 2.1

*p=0.0138 vs amlodipine

Philipp et al. Clin Ther 2007;29:online