Pr Roland Asmar Protecting patients with hypertension How to maximize patient benefit ? Pr Roland...

Protecting patients with hypertensionHow to maximize patient benefit ?

Pr Roland AsmarPr Roland Asmar

1How to maximize patient benefit

Goals of Goals of Antihypertensive TreatmentAntihypertensive Treatment

ESH/ESC 2007ESH/ESC 2007


< 140/90mmHg

< 130/80mmHg

Hypertensive patients

Diabetes

Patient at high risk

USA53.1

Canada41.0

Mexico21.8

Turkey19.8 Germany

33.6

Spain38.8

Greece49.5

England29.2

Egypt33.5

South Africa47.6 Italy

37.5

Worldwide Blood Pressure Control in Worldwide Blood Pressure Control in Treated Hypertensive PatientsTreated Hypertensive Patients

Kearney et al. J Hypertens 2004; 22: 11Kearney et al. J Hypertens 2004; 22: 11

Japan55.7

China28.8

Taiwan

18.0


HOT: HOT: Need for Combination TherapyNeed for Combination Therapy

Hansson et al., Lancet 1998, 351: 1755-62 4How to maximize patient benefit

7030

6584

6866

6841

5145

6693

3546

4970

3433

47100

0 20 40 60 80 100

CONVINCEINSIGHT

LIFERENAAL

IDNTSyts-China

HOTSyst-EurMRC II

SHEPSTOP-1COOPEEWPHE

HAPPHYMAPHY

IPPPHMRC-1ANBPS

HDFPVA

7030

6584

6866

6841

5145

6693

3546

4970

3433

47100

0 20 40 60 80 100

CONVINCEINSIGHT

LIFERENAAL

IDNTSyts-China

HOTSyst-EurMRC II

SHEPSTOP-1COOPEEWPHE

HAPPHYMAPHY

IPPPHMRC-1ANBPS

HDFPVA

%%

Percentage of Patients with Combination Treatment in Clinical Trials


ESH/ESC Guidelines - 2007ESH/ESC Guidelines - 2007

Pharmacological RationalePharmacological Rationalefor Combination Therapyfor Combination Therapy


Rationale for Combination TherapyRationale for Combination Therapy


•Increase EfficacyIncrease Efficacy• Synergistic & additive effects on BPSynergistic & additive effects on BP• Effects on several patho-physiological mechanisms Effects on several patho-physiological mechanisms

of HTof HT• Inhibition of the contra-regulation mechanismsInhibition of the contra-regulation mechanisms

•Decrease Side effectsDecrease Side effects• Inhibition of the contra-regulationInhibition of the contra-regulation• Low doseLow dose Decrease dose-dependent Decrease dose-dependent

side effectsside effects

Advantages of Combination TherapyAdvantages of Combination Therapy

Efficacy


Sympathetic nervous systemRenin-angiotensin systemTotal body sodium

Sympathetic nervous systemRenin-angiotensin systemTotal body sodium

Patient A Patient A Patient BPatient B Patient CPatient CPatient A Patient A Patient BPatient B Patient CPatient C

Rationale of Combination TherapyRationale of Combination Therapy

Waeber B. 2004Waeber B. 2004

Pathogenetic Mechanisms in Hypertension


-3,2

-8,5-9

-8

-7

-6

-5

-4

-3

-2

-1

0

HTZ 6.26 - HTZ 25 HTZ 6.25 + B10

mm

Hg

Titration vs. CombinationTitration vs. CombinationDiastolic BPDiastolic BP

Frishman WH et al,Arch Intern Med 1994;154:1461

-1,5

-3,1-3,5

-3

-2,5

-2

-1,5

-1

-0,5

0

B10 - B40 B10 + HTZ6.25

mm

Hg


Efficacy: Up-titration vs CombinationEfficacy: Up-titration vs Combination

-6,9 -6,9-8,2 -8,2

-15,2 -15,2

-12,2

-18,8

-12,6

-16,8 -16,4

-20,4

-25

-20

-15

-10

-5

0

Ch

ang

e in

SB

P (

mm

Hg

)

T40 T80 T40T40

HCT12.5 V80 V80V160V80

HCT12.5 Ol20 Ol40 Ol20O20

HCT12.5


Value of combination treatment: analysis of Value of combination treatment: analysis of 354 randomised placebo controlled trials354 randomised placebo controlled trials

Law MR BMJ 2003

Effects of two different drugs on BP separately and in combination (results from 119 trials)

Treatment SBP DBPObserved“First” drug alone 7.0 (0.4) 4.1 (0.3)“Second” drug alone 8.1 (0.3) 4.6 (0.3)Both drugs together 14.6 (0.5) 8.6 (0.4)ExpectedSum of first and second drugs alone 15.1 8.7Difference between observed andexpected (95% CI)

-0.5 (-1.4 to 0.4) -0.1 (-1.0 to 0.8)


Advantages of Combination Advantages of Combination TherapyTherapy

SideEffects


-0,4

-0,3

-0,2

-0,1

0

0,1

0,2

HCTZ dose (mg/d)

ARB dose(mg/d)

0 6.25 12.5 250

37.5

100

300

Adjusted mean

from baseline at 8 weeks (mEq/L)

Effect of ARB and HCTZ on Serum Effect of ARB and HCTZ on Serum PotassiumPotassium

Kochar M, et al. Am J Hypertens. 1999;12:797 16How to maximize patient benefit

BMJ 2003;326:1427

Drug related symptoms: comparison Drug related symptoms: comparison between monotherapy & combinationbetween monotherapy & combination

SYMPTOMS

Single drugs 5.2% (3. To 6.6)

Two drugs 7.5% (5.8 to 9.3)

Expected adding2 drugs

10.4%

50 trials testing drugs of two different categories separately and in combination,



Convenience


Fixed-dose Combination Therapy Fixed-dose Combination Therapy Increases Compliance to TreatmentIncreases Compliance to Treatment

Dezii CMDezii CM. Manag Care 2000; 9 : s2. Manag Care 2000; 9 : s2

Persistence rates of one pill of lisinopril/HCTZ in fixed-combination vs two separate pills of lisinopril and HCTZ

100100 9595 9090 8585 8080 7575 7070 6565 6060 5555 5050

0 1 2 3 4 5 6 7 8 9 10 11 120 1 2 3 4 5 6 7 8 9 10 11 12MonthsMonths

68.768.7

57.857.8

18.8%18.8%

Lisinopril/HCTZ (1 pill)Lisinopril/HCTZ (1 pill)

Lisinopril and HCTZ (2 pills)Lisinopril and HCTZ (2 pills)


Equal efficacy?


Blood pressure control with ARBs and in Fixed Dose Combination

®

Protocol Endpoints

Primary endpoint■ Changes from baseline in SBP during

last 6 hours of dosing interval using ABPM

Secondary endpointsChanges from:

■ Baseline in DBP during the last6 hours of dosing interval

■ Baseline in pulse pressure during the last 6 hours of dosing interval

■ Baseline in the 24-hour mean SBP and DBP

n=294 n=297n=160

Neutel JM, et al. Hypertens Res 2005;28:555

ABPM Comparison of Telmisartan HCTZ & Losartan HCTZ

Parallel Group Comparison after 6 weeks Therapy

Neutel et al. Hypertens Res. 2005;28:555

Time after dosing (h)Time after dosing (h)

-6

2 6 10 14 18 22

-10

-12

-14

-8

-16

-8

2 6 10 14 18 22

-16

-20

-24

Cha

nge

from

bas

elin

e (m

mH

g) Telmisartan 80mg + HCTZ 12.5mg

Losartan 50mg + HCTZ 12.5mg -12 Telmisartan 40mg + HCTZ 12.5mg

Systolic BP Diastolic BP


®

Protocol Endpoints

Study of telMisartan On Obese/overweight Type2 diabetics with Hypertension



Secondary endpoints■ Changes in other ABPM-derived

parameters■ Changes in trough cuff SBP and

DBP■ Metabolic blood markers

(e.g.cholesterol)■ Urine markers (e.g. proteinuria)

Sharma AM, et al. Cardiovascular Diabetology. 2007;6:28

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

00 4 8 12 16 20 24

Time post dose (hours)

Valsartan 160 mg + HCTZ

Telmisartan 80 mg + HCTZ

SB

P c

hang

e fr

om b

asel

ine

(mm

Hg)

***p < 0.001 T + H vs V + H 24-hour and last 6-hour mean SBP

***

Sharma et al. Hypertension 2005;46:898

Telmisartan + HCTZ vsValsartan + HCTZTelmisartan + HCTZ vsValsartan + HCTZPowerful 24 hr SBP reductionsPowerful 24 hr SBP reductions


How to maximize patient benefitFogari & al Current Therapeutic Research; 2008; 69

Telmisartan 80mg/HCTZ 12.5 mg vs Olmesartan 20mg/HCTZ12.5 mg

Systolic BP

Diastolic BP

25

n=497 n=503

A comparison of Telmisartan plus HCTZ with amlodipine plus HCTZ in Olderpatients with predominantly Systolic hypertension

Protocol Endpoints



Secondary endpointsChanges from:

■ Baseline in DBP during the last6 hours of dosing interval

■ Baseline in pulse pressure during the last 6 hours of dosing interval

■ Baseline in the 24-hour mean SBP and DBP

®

Neldam S, et al. AJGC 2006;15:151-60.

How to maximize patient benefit Neldam S, et al. AJGC 2006;15:151-60. 27

Telmisartan Telmisartan in combinationin combination

HCTZ 25 mgHCTZ 25 mg

How to maximize patient benefit 28

Change in clinic trough BP from baseline after 8 weeks therapy

Comparison of Telmisartan HCTZ & Valsartan HCTZ

White et al. J Hypertens Suppl. 2003;21:S9-15.

Telmisartan-HCTZ 80/25mg (n=467)Valsartan-HCTZ 160/25mg (n=479)Placebo (n=120)-25

-20

-15

-10

-5

0Systolic BP Diastolic BP

-2.8 (-4.6, -1.0) p<0.004

Cha

nge

from

bas

elin

e (m

mH

g)

-1.8 (-3.0, - 0.6) p<0.02


How to maximize patient benefit

Comparison of Telmisartan HCTZ & Valsartan HCTZ


White W & al BP Monitoring 2008, 13:21 30

AIIA + CCBAIIA + CCB


Composed end-point comparing a fixed combination of a CCB +ACEI vs a thiazide+ACEI

Jamerson K et al. NEJM; 2008; 359:2417

Time for events

Inci

den

ce o

f e

ven

tos

HR: 0,80; IC 95%: 0,72 – 0,90

ACCOMPLISH Trial


ASCOT - Summary of all end pointsASCOT - Summary of all end points

The area of the blue square is proportional to the amount of statistical informationAmlodipine perindopril better Atenolol thiazide better

0.50 0.70 1.00 1.45

Primary

Non-fatal MI (incl silent) + fatal CHDSecondaryNon-fatal MI (exc. Silent) +fatal CHDTotal coronary end pointTotal CV event and proceduresAll-cause mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal heart failureTertiary Silent MIUnstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset diabetes mellitusNew-onset renal impairment

Post hoc Primary end point + coronary revasc procs

CV death + MI + stroke2.00

Unadjusted Hazard ratio (95% CI)

0.90 (0.79-1.02)

0.87 (0.76-1.00)0.87 (0.79-0.96)0.84 (0.78-0.90)0.89 (0.81-0.99)0.76 (0.65-0.90)0.77 (0.66-0.89)0.84 (0.66-1.05)

1.27 (0.80-2.00)0.68 (0.51-0.92)0.98 (0.81-1.19)0.65 (0.52-0.81)1.07 (0.62-1.85)0.70 (0.63-.078)0.85 (0.75-0.97)

0.86 (0.77-0.96)0.84 (0.76-0.92)


Chemical structuresChemical structures

N

N CO2H

CI

NN

N

NH

N

N COOH

C

OH

CH3H3C

NN

N

NH

O

N

N

NN

N

NH

N

O

CO2H

NN

N

NH

N

N OCH2CH3

NN

N

NH

COOH

Candesartan(active form)

Losartan (active form)

Valsartan Irbesartan Olmesartan (active form)

Telmisartan

N

N

N

N

CH3

CH3

CH3

O OH

Telmisartan and other angiotensin II antagonists


Kakuta et al. Int J Clin Pharmacol Res. 2005;25:41-6.

Dissociation Half-Lives of ARB’sfrom Human AT1 Receptors

0 50 100 150 200 250

Losartan

Telmisartan

Olmesartan

Candesartan

Valsartan

EXP3174

202-226 min

151-184 min

121-149 min

60-83 min

73-91 min

60-77 min

95% CI

Dissociation half-life (min)


Peroxisome Proliferator-Activated Receptor Gamma (PPAR ) interaction

Selective Nuclear HormoneSelective Nuclear HormoneReceptor ModulationReceptor Modulation

Rosiglitazone

Pioglitazone

PPAR

Full Agonists

Insulin SensitivityNO Weight Gain

NO Oedema

Insulin Sensitivity

Weight Gain

Oedema

Telmisartan

Selective ModulationSelective Peroxisome Proliferator-ActivatedReceptor Gamma Modulators (SPPARMS)


150

100

50

0

Fol

d A

ctiv

atio

n

Full Agonists

PartialAgonist

Difference between Thiazolodinediones & ARBsin the Interaction with PPARReceptor

rosiglitazone pioglitazone telmisartan irbesartan eprosartan

Benson et al. Hypertension. 2004;43:993 37How to maximize patient benefit

Telmisartan was the only ARB that activated PPAR at concentrations (1-5 mol/l) attained in plasma with

conventional oral dosing

Benson et al. Hypertension. 2004;43:993.

Activation of PPARActivation of PPAR by ARB’s by ARB’sF

old

Act

ivat

ion

0

5

10

15

20

25

Telmisartan Candesartan Olmesartan EXP 3174Irbesartan Valsartan Eprosartan


-10

0

-20

-30

FPG

Cha

nge

from

bas

elin

e (%

)

P<0.05

FPI HOMA IR HbA1c

P<0.06

P<0.05

P<0.05

Effects of Telmisartan & Losartan in Effects of Telmisartan & Losartan in Patients with metabolic syndromePatients with metabolic syndrome

Vitale et al. Cardiovasc Diabetol. 2005;15:6.

Telmisartan (n=20)

Losartan (n=20)


FPG TG HOMA IRHbA1c FPIAdiponectin

-16

-14

-12

-10

-8

-6

-4

-2

0

-60

-40

-20

0

20

40

60

80

100

120

% c

hang

e fr

om b

asel

ine

% c

hang

e fr

om b

asel

ine

* p<0.05 & ** p<0.01 vs amlodipine

* ** *

*

n.s.n.s.

Negro et al. JRAA 2006:243-6.

Effects of Telmisartan and AmlodipineEffects of Telmisartan and Amlodipineon Metabolic Parameters on Metabolic Parameters

in Type 2 Diabetic Hypertensivesin Type 2 Diabetic Hypertensives

Telmisartan Amlodipine


Effects of telmisartan on fat distribution in Effects of telmisartan on fat distribution in individuals with metabolic syndromeindividuals with metabolic syndrome

Shimabukuro, J Hypertens 2007;25:841

50

100

150

200

TelmisartanAmlodipine

VF

A c

m²

300

250

+10%p=0.046

-12%p=0.008

90

92

94

96

TelmisartanAmlodipine

Wai

st c

ircu

mfe

renc

e (c

m)

100

98

+3% -5%

Baseline 24 wks treatment

Change in the Visceral Fat Area (VFA) Change in waist circumference


ComparativeComparativeCardio-Metabolic Studies with TelmisartanCardio-Metabolic Studies with Telmisartan

Trial Patients N Duration (weeks)

ComparatorAgent(s)

BP differential

ImprovedInsulin

Sensitivity

Improved Lipid

Profile

Anti-oxidant/ Inflammatory

Action

Derosa 2004a HT, T2DM 119 52 Eprosartan/Placebo No (P yes) No Yes -

Derosa 2004b HT, T2DM 116 52 Nifedipine GITS No No Yes -

Vitale 2005 HT, MS 40 12 Losartan Yes? Yes - -

Miura 2005 HT, T2DM 18 12 Candesartan/Valsartan No Yes Yes Yes

Koulouris 2005 NT, T2DM 40 12 Ramipril No No No Yes

Honjo 2005 HT, T2DM 38 12 Candesartan - Yes - -

Benndorf 2006 HT 37 6 Nisoldipine No? Yes - -

Negro 2006a HT, T2DM 40 16 Amlodipine No Yes Yes -

Negro 2006b HT, obese,IR 46 26 Irbesaratn No Yes Yes -

Bahadir 2007 HT, MS 42 10 Losartan No? Yes? No -

Derosa 2007 HT, T2DM 188 52 Irbesartan No Yes Yes Yes

Sharma 2007 HT, obese 840 10 Valsartan HCTZ Yes No No -


ConclusionsConclusions

Use of Use of more than one agent more than one agent is necessary to achieve is necessary to achieve target BP in the majority of patients. target BP in the majority of patients.

Combination therapy is related with a Combination therapy is related with a higher BP higher BP reduction and CV protectionreduction and CV protection

Fixed combinations of two drugs can simplify Fixed combinations of two drugs can simplify treatment schedule and treatment schedule and improve compliance and improve compliance and tolerabilitytolerability. .

A combination of two drugs should be preferred as A combination of two drugs should be preferred as first step treatment first step treatment when initial BP is in the grade 2 when initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very or 3 range or total cardiovascular risk is high or very highhigh

Are all the combination therapies Are all the combination therapies equipotent equipotent

BackupBackup


Combination TherapyCombination TherapyStudy / Drugs BP Mo- Mort

STOP 2 Old/Recent ≡ ≡

BACRI ARB + HCTZ /ACEI + Verap

≡ NA

INVEST BB + HCTZ /Verap + ACEI

≡ ≡

EXFORGE ARB + CCB /ACEI + HCTZ

≡ ou ≥ NA

ASCOT BB + HCTZ /ACEI + CCB

≡ ≡ ou ≥

LIFE BB + HCTZ /ARB + HCTZ

≡ ≥

ACCOMPLISH ACEI + HCTZ /ACEI + CCB

≡ ≥

ONTARGET ACEI + ARB / ACEI

≥ ≡ Side effects ++


The HOT Study: CV Risk Reduction in Diabetics

Hansson L, et al. Lancet 1998;351:1755–62.

0

5

10

15

20

25

maj

or C

V e

vent

s/10

00 p

atie

nt.y p < 0.005 for trend (n = 1501)

< 90 mmHg85 mmHg

< 85 mmHg83 mmHg

TargetAchieved

< 80 mmHg81 mmHg


Management of BP for adults- Management of BP for adults- JNC VIIJNC VII

BP classificationBP classification SBP* SBP*

mmHgmmHg DBPDBP

mmHgmmHg Lifestyle Lifestyle

modificationmodification

Initial drug therapyInitial drug therapy

Without compelling indication Without compelling indication With compelling With compelling indicationsindications

NormalNormal <120<120 and <80and <80 EncourageEncourage

PrehypertensionPrehypertension 120120––139139 or 80or 80––8989 YesYes No antihypertensive drug No antihypertensive drug indicated.indicated.

Drug(s) for compelling Drug(s) for compelling indications. indications. ‡‡

Stage 1 Stage 1 HypertensionHypertension

140140––159159 or 90or 90––9999 YesYes Thiazide-type diuretics for Thiazide-type diuretics for most. May consider ACEI, most. May consider ACEI, ARB, BB, CCB, or ARB, BB, CCB, or combination.combination.

Drug(s) for the Drug(s) for the compelling compelling indications.indications.‡‡

Other Other antihypertensive antihypertensive drugs (diuretics, ACEI, drugs (diuretics, ACEI, ARB, BB, CCB) as ARB, BB, CCB) as needed. needed.

Stage 2 Stage 2 HypertensionHypertension

>>160160 or or >>100100 YesYes Two-drug combination for Two-drug combination for mostmost†† (usually thiazide-type (usually thiazide-type diuretic and ACEI or ARB or diuretic and ACEI or ARB or BB or CCB).BB or CCB).

†Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.‡Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.


Adverse Events: HCTZ 25 mg vs Adverse Events: HCTZ 25 mg vs ARB + HCTZ 25 mgARB + HCTZ 25 mg

HCTZHCTZ ARB + HCTZARB + HCTZ

PotassiumPotassium

InsulinInsulin

GlucoseGlucose

LipidsLipids

Uric AcidUric Acid

Adverse Adverse eventsevents

ImpotenceImpotence48How to maximize patient benefit

How to maximize patient benefit

Effect of Telmisartan HCTZ 25 mg


Neldam & al J Clin Hypertens 2008; 10:612 49

INVEST: Primary Composite INVEST: Primary Composite Endpoint by Treatment GroupEndpoint by Treatment Group

0

5

10

15

20

25

Cu

mul

ativ

e %

Time, mo

1126711309

No. at Risk CAS NCAS

1092110991

1071610785

1051210536

1000810048

66126604

15681563

3533

393390

37383706

974960

0 6 12 18 24 36 48 5442 6030

Calcium Antagonist Strategy (CAS) (Verap + ACEI)

Non-Calcium Antagonist Strategy (NCAS) (BB + HCTZ)

Log-Rank P=.57

RR = 0.98 (0.90 – 1.06)

Pepine CJ, et al. JAMA. 2003;290:2805

Years of Follow-up

Cu

mu

lative

Ha

za

rd R

ate

s

0.0

0.0

50

.10

0.1

50

.20

0.2

5

0 1 2 3 4

RamiprilTel. & Ram.

# at Risk Yr 1 Yr 2 Yr 3 Yr 4

R 8576 8214 7832 7473 7095T&R 8502 8134 7740 7377 7023

ONTARGET – CombinationONTARGET – CombinationACEI + ARB vs ACEACEI + ARB vs ACE

The ONTARGET Investigators N EJM 2008;358:1547 51How to maximize patient benefit

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