Int Med-hyp

7/31/2019 Int Med-hyp

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Therapy in Hypertension: Position

of FixedCombination.

Harun Rasyid Lubis.

Departemen Ilmu penyakit Dalam FK-USU Medan.


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HYPERTENSION

DEFINITION:

WHO-ISH: Because blood pressure is characterized by large spontaneousvariations 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 BPreadings on each of two or more office visits.

INDONESIA: Konsensus: beberapa kali pengukuran dalam beberapakali kunjungan


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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.


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Routine steps for accurate measurement

of blood pressure

Rest the patient (seated) forat least 5 mins in a quietcomfortable 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 averag

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 afterstanding ( especially in older

patients and those with diabetes).


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BP Measurement TechniquesBP Measurement TechniquesMethod Brief Description

In-office Two readings, 5 minutes apart, sittingin chair. Confirm elevated reading incontralateral arm.

Ambulatory BP monitoring Indicated for evaluation of white-coatHTN. Absence of 1020% BP decreaseduring sleep may indicate increased CVDrisk.

Self-measurement Provides information on response totherapy. May help improve adherence totherapy and evaluate white-coat HTN.

JNC 7 2003


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Office BP MeasurementOffice 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, andarm 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 and BPgoals. JNC 7 2003


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sphygmomanometer

Patient should be seated and relaxed, preferablyfor several minutes

prior to to the measurement and in a quietroom.

Appropriate cuff size.

Average the readings. If the first two readings differ bymore than 10 mmHg systolic or 6 mmHg diastolic or ifthe initial readings are high, take several readings afterfive minutes of quiet rest, until consecutive readings donot vary by greater than these amounts.

Ideally, patients should not take caffeine-

How to measure blood pressure accuratelyHow to measure blood pressure accurately

Australia, 2004


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20%

26%27%

24%23%

29%

20%

25%

34%

45%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Nepal

Sing

apore

China

Malaysia

Pakistan

Kong

Kon

g

SriL

anka

India

Korea

Japa

n

Burden of Hypertension in

Asia.

Sharma D et al: IHJFeb 2006, Pakistan Med Research Council

Wolf-Meiret.al JAMA .2003 , WHO bulletin , Gu et al 35-74 yrs,China, Jo et.al Korea 18-92yrs J Hyper2001


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0

00

00

00

00

00

Prevalence of Hypertension in AFRICA

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

Prevalenceofhypert

ension(%)

EgyptAlgeria

WHO Global Infobase 2003Cappuccio et al: Hypertension 2004

SA

Sub-

Sahara

(Ghana)


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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 hypertension-

related 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 asingle visit.

J Hypertens 2007 25:1113-4.


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Threshold for intervention

initial blood pressure (mmHg)

>180/110160/179

100-109

140/159

90-99


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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 hypertension-

related 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 asingle visit.

J Hypertens 2007 25:1113-4.


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Lifestyle modifications

Chobanian et al. JAMA 2003;289:256072

Not at goal blood pressure (BP)*

Hypertension without

compelling indications

Hypertension with


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

JNC VII: Algorithm for Treatment ofHypertension

Drug(s) for the compelling

indications

Other antihypertensive

drugs (diuretics, ACE


CCB) as needed

*BP goal


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Recommended for healthy lifestyle

Lifestyle parameter Health recommendationDiet 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

Exercise 30-60 min of endurance activities x 4-7 days per week(e.g. brisk walking, jogging, cycling)

Body weight Maintain BMI*@ 20-25

Alcohol comsumption Limit to 0-2 standard drinks per day

People with elevated triglyceride levels should eliminatealcohol completely

Smoking cessation Smokers should be advised to quit ( cessation

programs, nicotine replacement/drug therapy)

Encourage young people not to start

*BMI = weigth(kg/height2

(m) (Normal : 20-25; overweight ; 25-30; obese : >30)

Recommendations for healthy lifestyle


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Elliott. J Clin Hypertens 2003;5(Suppl. 2):313

Controlling blood pressure with

medication is unquestionably one of the

most cost-effective methods of reducing

premature CV morbidity and mortality


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The major classes of anti-hypertensive drugs

1. Diuretics. Loop furosemide, bumetanide

. K+-sparing amiloride, spironolactone

. Thiazide hydrochlorothiazide, bendrofluazide

. Thiazide-like chlorthalodone, indapamide

2. Adrenergic inhibitors

. Alpha-1 blockers Doxazosin, Prazosin

. Beta-blockers Atenolon, Metoprolol, Bioprolol, Carvedilol

. Combine Labetalol

3. RAS inhibitots

. ACE-inhibitors Captopril, Enalapril, Perindopril etc

. ARB Losartan, Valsartan, Candesartan etc

4. Ca-channel blockers (CCB)

. Dihydropyridin Nifedipin, Amlodipin

. Non-dihydropyridine Diltiazem, Verapamil

5. Imidazoline receptor

agonist monoxidine, nilmenidine

6. Vasodilatation hidralazine, minoxidil


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Recommended blood pressure targets

Organisation Patient group

Uncomplicatiedhypertension

+ DM or

Renal disease

+ RF withproteinuria*

American Kidney Association(2001)


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Rate in Each Decade of Age, Versus Usual SystolicBP at the Start of that Decade

Mortality

*

Usual SBP (mmHg)

5059 y

6069 y

7079 y

8089 y

Stroke

Age at risk

256

128

64

32

16

8

4

2

1

0 120 140 160 180

IHD

Usual SBP (mmHg)

5059 y

6069 y

7079 y

8089 yAge at risk

4049 y

256

128

64

32

16

8

4

2

1

0 120 140 160 180

*Floating absolute risk and 95% CI Lewington et al. Lancet 2002;360:190313


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Lewington et al. Lancet 2002;360:190313

Each 20/10 mmHg Increment inSystolic/Diastolic Blood Pressure*

CV mortality risk

0

2

4

8

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

6

Systolic BP/Diastolic BP (mmHg)

*Individuals aged 4069 years

2X

risk

4X

risk

8X

risk

1X risk


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Decreases the Risk of CardiovascularEvents by 710%

Meta-analysis of 61 prospective, observational studies

1 million adults

12.7 million person-years

2 mmHg

decrease in

mean SBP 10% reduction inrisk of stroke

mortality

7% reduction in

risk of ischaemic

heart disease

mortality

Lewington et al. Lancet 2002;360:190313


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ASCOT Trial DesignASCOT Trial Design

19,342 randomized to antihypertensive therapy

9,639 assigned andreceived amlodipine

+ perindopril

9,618 assigned andreceived atenolol +

thiazide

85 excluded beforeend of study due to

irregularities


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Systolic and diastolicblood pressure

mmH

g

60

80

100

120

140

160

180

Time (years)

Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5

atenolol thiazideamlodipine perindopril

137.7

136.1

79.2

77.4

Mean difference 1.9

Last

visit

Mean difference 2.7

SBP

DBP

163.9

164.1

94.8

94.5


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Number at risk

amlodipine perindopril 9639 9483 9331 9156 8972 7863atenolol thiazide 9618 9461 9274 9059 8843 7720

0.0 1.0 2.0 3.0 4.0 5.0

0.0

1.0

2.0

3.0

4.0

5.0

amlodipine perindopril

(No. of events 327)

atenolol thiazide

(No. of events 422)

HR = 0.77 (0.66-0.89)

p = 0.0003

23%

%

CumulativeEvents

Fatal and non-fatal stroke

Years


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Number at risk


0.0 1.0 2.0 3.0 4.0 5.0

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

16.0

18.0


(No. of events 1362)

atenolol thiazide

(No. of events 1602)

HR = 0.84 (0.78-0.90)

p< 0.0001

16%%

CumulativeEvents

Total CV events and procedures

Years


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Number at risk


0.0 1.0 2.0 3.0 4.0 5.0

0.0

2.0

4.0

6.0

8.0

10.0


(No. of events = 567)

atenolol thiazide

(No. of events = 799)

HR = 0.70 (0.63-0.78)

p < 0.0001

30%

%

CumulativeEvents

New-onset diabetes mellitus

Years


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Inadequacy of Agents with a SingleMechanism of Action (MoA)

Materson et al. observed that antihypertensive agents with asingle MoA were inadequate to achieve a diastolic BP


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Average no. of antihypertensive medications

1 2 3 4

Multiple Antihypertensive Agents are Needed toReach BP Goal

Trial (SBP achieved)

Bakris et al. Am J Med 2004;116(5A):30S8

Dahlf et al. Lancet 2005;366:895906

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)


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Rationale for Multiple-mechanismTherapy in Hypertension

Advantages of multiple-mechanism therapy

Back to section content


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Sympathetic nervous systemRenin-angiotensin system

Total body sodium

Patient 1 Patient 2 Patient 3

B. Waeber, March 2007, with permission

Blood Pressure has Multiple RegulatoryPathways


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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-mechanismTherapy


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Advantages of Multiple-mechanism Therapy:Efficacy

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 reninangiotensin 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;62:443622Quan et al. Am J Cardiovasc Drugs 2006;6:10313

Multiple-mechanism therapy results in a greater BP reduction thanseen with its single-mechanism components1,2


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Valsartan/HCTZ Compared with ValsartanMonotherapy in Mild-to-Moderate Hypertension

-10.8

-15.7

-12.8

-19.4

-14.2

-21.7

-25

-20

-15

-10

-5

0

Valsartan 160 mgValsartan/HCTZ 12.5 mg

Valsartan/HCTZ 25 mg

Diastolic BP Systolic BP

Mallion et al. Blood Press2003;12(Suppl 1):3643

Change in BP from baseline (mmHg)

n=663 n=665 n=657 n=663 n=665 n=657

*

*

*p0.01 vs valsartan 160 mg; **p0.01 vs valsartan/HCTZ 12.5 mgp


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Additive Reduction in Blood Pressure with InitialDual ACE Inhibitor/CCB Therapy

Scholze et al. Int J Clin Pract 2006;60:26574*p


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

Advantages of Multiple-mechanism Therapy:Safety/Tolerability

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

C l t Eff t f CCB/RAS I hibit


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Complementary Effects of a CCB/RAS Inhibitor: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 RAS and increases

angiotensin II level

CCBs + RAS inhibitors* Blockade of RAS 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


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-h i Th Wh t th


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mechanism Therapy: What theTreatment Guidelines Say

JNC VII1

Most patients with hypertension will require two or moreantihypertensive agents to achieve their BP goals

When BP is more than 20 mmHg above systolic goal or 10 mmHgabove diastolic goal, consideration should be given to initiate

therapywith 2 drugs, either as separate prescriptions or in fixed-dose combinations

ESHESC2

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

1Chobanian et al. JAMA 2003;289:2560722ESHESC Guidelines. J Hypertens 2003;21:101153

JNC VII Al ith f T t t f


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Lifestyle modifications

Chobanian et al. JAMA 2003;289:256072

Not at goal blood pressure (BP)*

Hypertension without


Hypertension with


Stage 1

Thiazide-type diuretics for

most. May consider ACE


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

JNC VII: Algorithm for Treatment ofHypertension

Drug(s) for the compelling

indications

Other antihypertensive

drugs (diuretics, ACE


CCB) as needed

*BP goal


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Consider: BP level before treatment

Absence or presence of TOD and risk factors

2-drug combination at low dose

Choose between:

Single agent at low dose

If goal BP not achieved

Previous agentat full dose

Switch todifferent agent

at low dose

Previouscombinationat full dose

Add athird drug

at low dose

If goal BP not achieved

23 drugcombinationat full doses

3-drug combinationat full doses

ESHESC: Algorithm for Treatment ofHypertension

ESHESC Guidelines. J Hypertens 2007;25:1144

Full-dosemonotherapy

TOD = target organ damage

T t t f N l Di d


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http://www.nice.org.uk/download.aspx?o=CG034fullguideline.Accessed June 2006

Treatment of Newly DiagnosedHypertension

*If ACE inhibitor (ACEI) not tolerated

ACEI (or ARB*) + CCB or

ACEI (or ARB*) + thiazide diuretic


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ESHESC Recommendations for Combining BP-lowering Drugs

ESHESC Guidelines. J Hypertens 2007 25:1144

Thiazide diuretics

Angiotensin

receptor antagonists

Calcium Antagonists

Angiotensin-converting enzyme (ACE) inhibitors

-blockers

-blockers

Most rational combinations

Combinations used as necessary

-Combination Therapy Compared with


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Defined as the total number of days of therapy for

medication dispensed/365 days of study follow-up

Fixed-dose combination

(amlodipine/benazepril)

(n=2,839)

Free combination

(ACEI + CCB)

(n=3,367)

Medication possession ratio (MPR)

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

p


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Supports Compliance in HypertensivePatients

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

Risk ratio0.1 1 10

% Weight

Risk ratio

(95% CI)

0.74 (0.67, 0.81)Taylor et al. 27.1

0.74 (0.65, 0.84)Dezii 13.9

0.81 (0.77, 0.86)NDC dataset 46.4

0.71 (0.62, 0.80)Dezii 12.6

0.77 (0.73, 0.80)Overall (95% CI) p


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Combination Therapy Compared withFree Combination Therapy

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

Lisinopril/HCTZ (single pill)

Lisinopril + diuretic (two pills)

Dezii. Manag Care 2000;9(Suppl):26

68.7%

57.8%

18.8%difference

Patients persistent (%)

Month

Lisinopril/HCTZ (n=1,644); lisinopril + diuretic (two pills; n=624)

Statistical significance (p


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Combinations Compared with IndividualComponent-based Therapy

54%

19%

0% 20% 40% 60% 80%

Fixed-dosecombination

(Valsartan/HCTZ)

(n=8,150)

Free combination(Valsartan + HCTZ)

(n=561)

Persistence (defined as patients remaining on treatment

for a duration of 12 months)

Jackson et al. Value Health Suppl 2006;9:A363

p


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0

10

40

50

30

20

Highly Compliant Patients are More Likely to AttainBP Goal

*


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

A CCB/ARB is a Notable Absentee of Available Dual-mechanism Ther

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

Back to contents


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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


-lowering Drugs and Availability as Fixed dose


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lowering Drugs and Availability as Fixed-doseCombinations

Adapted from ESHESC Guidelines. J Hypertens 2003;21:101153

Diuretics

Angiotensin

receptor blockers

(ARBs)

Calcium channel

blockers (CCBs)

Angiotensin-converting enzyme (ACE) inhibitors

-blockers

-blockers

Most rational combinationsCombinations used as necessary

Available as FDC

??

Available Dual-Mechanism Agents is


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Available Dual Mechanism Agents isthe CCBARB

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)

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

Notable absentee is a

CCB + ARB


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Rationale for Dual-mechanism

Therapy with a CCB/ARB:Amlodipine/Valsartan

CCB-induced edema is minimized by the ARB



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Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273White et al. Clin Pharmacol Ther 1986;39:438

Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl 1):S12131

Arterialdilation No venousdilation

Fluid leakage

Fluid leakage

Capillary bed

Peripheral Edema Associated with CCBs

-receptor Blocker (ARB): Reduction of CCB-


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receptor Blocker (ARB): Reduction of CCBassociated Edema

Opie. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273White et al. Clin Pharmacol Ther 1986;39:438; Gustaffson. J Cardiovasc Pharmacol

1987;10(Suppl. 1):S12131; Messerli et al. Am J Cardiol 2000;86:11827

Arterial

dilation(CCB and

ARB)

Venous

dilation(ARB)

Capillary bed

Amlodipine/Valsartan: effect on


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Amlodipine/Valsartan: effect onamlodipine-induced peripheral edema

Pooled data from two trials at doses of Amlodipine/Valsartan

up to 10/320 mg and amlodipine up to 10 mg

8

10

6

4

2

0

8.7%

5.4%

Inciden

ceofperipheraledema(%)

p=0.0138

3.0%

Placebo Amlodipine Amlo/Val

38% difference

n=337 n=460 n=1,437

Novartis data on file


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Clinical Evidence withAmlodipine/Valsartan

Amlodipine/Valsartan: efficacy in non-responders


Response Rates in Mild-to-Moderate


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Response Rates in Mild to ModerateHypertension

Respond

errate

20%

40%

60%

80%

100%*

74.9%

*

88.5%

Philipp et al. Clin Ther 2007;29:online

N=1,250

Valsartan 160 mg Amlodipine/Valsartan

10/160 mg*p


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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;21:2204

*p90 and


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Efficacy in Patients with Stage 2Hypertension

*p


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50

0

10

20

30

40

MSSBP in Patients with Baseline MSSBP 180 mmHg

Change from

baseline (mmHg)

43.0

*

31.2

26.1

*

21.7

*

Amlodipine (510 mg) +

valsartan (160 mg) (n=15)Lisinopril (1020 mg) +

HCTZ (12.5 mg) (n=11)

145.4 157.4 86.4 92.5Endpoint BP(mean mmHg)

Mean sitting systolic BP Mean sitting diastolic BP

*p


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40

100

80

70

60

50

90

Amlodipine/Valsartan in Patients withStage 2 Hypertension

Patients (%)

Responders

(MSDBP


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mmHg in Patients with ModerateHypertension: ExPress-C

136

151.4

166.7

120

140

160

180

MeansystolicB

P(mmH

96.6

89.3

82.3

80

90

100

MeandiastolicB

P(mmHg)

Week 5 10Week 5 10

30.7 mmHg

14.3 mmHg

15.4 mmHg

p


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Clinical Evidence withAmlodipine/Valsartan

Amlodipine/Valsartan: safety and tolerability


Amlodipine/Valsartan Compared with Amlodipine


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*p


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p / p pMonotherapies and Placebo

*p=0.0138 vs amlodipine

Val/Amlo Val Amlo Placebo Total

Total popln (n) 1,437 921 460 337 3,155

Peripheral edema (%) 5.4* 2.1 8.7 3.0 4.6

Headache (%) 4.3 4.8 7.6 5.9 5.1

Nasopharyngitis (%) 4.3 4.0 3.5 1.8 3.8

Upper RTI (%) 2.9 1.4 2.4 2.1 2.3

Dizziness (%) 2.1 2.4 1.5 0.9 2.0

RTI = respiratory tract infection

Philipp et al. Clin Ther 2007;29:online


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Int Med-hyp