chlorthalidone-telmisartan the new renaissance

8/10/2019 Chlorthalidone-Telmisartan the New Renaissance

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Chlorthalidone:The Renaissance


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0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20Riskofhypertension(%

)

Residual lifetime risk of developing hypertensionamong people with blood pressure


3/127


4/127

0

10

20

30

40

50

60


5/127

0

1

2

3

4

Relativeriskof

CHDmortality

He J, et at. Am Heart J. 1999;138:211-219.Copyright 1999, Mosby Inc.

98

(lowest 10%) (highest 10%)SBP (mmHg)

DBP (mmHg)

Systolic blood pressure (SBP)

Diastolic blood pressure (DBP)

CHD=coronary heart disease


6/127

0

1

2

3

4

5

6

7

8

9

Relativeriskof

strok

edeath

98

(lowest 10%) (highest 10%)SBP (mmHg)

DBP (mmHg)

Systolic blood pressure (SBP)

Diastolic blood pressure (DBP)

He J, et at. Am Heart J. 1999;138:211-219.Copyright 1999, Mosby Inc.


7/127

0

20

40

60

80

100

Age-adjusted

annualCVD

eventrateper1000

Wilking SV et al. JAMA. 1988;260:3451-3455.

Men Women

Isolated Systolic Hypertensionand CVD Risk in Framingham

ISH BP 160/


8/127

Landmark Clinical TrialsHypertension Treatment and Cardiovascular Disease Outcomes

1967VA Cooperative Study on DBP 115-1291970VA Cooperative Study on DBP 90-114

1979HDFP

1980Australian Trial, Oslo Trial

1985MRC I, EWPHE1991SHEP, STOP-Hypertension

1992MRC II in the elderly

1997Syst-Eur

2002LIFE

2002ALLHAT


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Pharmacologic Treatment in JNC 7

Excellent clinical trial outcome data prove that lowering BP

with several classes of drugs, including ACE inhibitors,

angiotensin receptor blockers (ARBs), b-blockers, calcium

channel blockers (CCBs) and thiazide-type diuretics, will all

reduce the complications of hypertension.


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JNC 7 Recommendation forInitial Drug Therapy

Thiazide-type diuretics should be used as initial therapy for

most patients with hypertension, either alone or in combination

with one of the other classes (ACEIs, ARBs, BBs, CCBs)

demonstrated to be beneficial in randomized controlled outcome

trials.


11/127

Without CompellingIndications

(SBP >160 or DBP >100 mmHg)

2-drug combination for most (usuallythiazide-type diuretic and ACEI, or ARB, or

BB, or CCB)

Initial Drug Choices

Stage 2 Hypertension

JNC 7 Algorithm forTreatment of Hypertension


12/127

Inadequate Management of BP in a VAHypertensive Population: Clinical Inertia

800 hypertensive men @ 5 VAs in New England over a 2 yr period in

early 1990s. >6 HTN-related visits/yr; ave age: 65.5 years.

BP control:

40% had BP >160/90 mm Hg

Only 25% had BP


13/127

Classification and Managementof BP for adults in JNC 7

BPClassification

Initial drug therapy

Without compelling indication With compellingindications

Normal

Prehypertension No antihypertensive drug indicated Drug(s) for compellingindications

Stage 1 Hypertension Thiazide-type diuretics for most.

May consider ACEI, ARB, BB, CCB, orcombination

Drug(s) for the compellingindications.

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

Stage 2 Hypertension Two-drug combination for most(usually thiazide-type diuretic and

ACEI or ARB or BB or CCB)

JNC 7. JAMA.2003;289:2560-2572.


14/127


BPClassification



Normal








JNC 7. JAMA.2003;289:2560-2572.


15/127


BPClassification



Normal








JNC 7. JAMA.2003;289:2560-2572.


16/127


BPClassification



Normal








JNC 7. JAMA.2003;289:2560-2572.


17/127


BPClassification



Normal






Stage 2 Hypertension Two-drug combination for most(usually thiazide-type diureticand


JNC 7. JAMA.2003;289:2560-2572.


18/127


19/127

JNC 7 Algorithm for Treatment of Hypertension

Without CompellingIndications

(SBP 140159 or DBP 9099 mmHg)

Thiazide-type diuretics for most.

May consider ACEI, ARB, BB, CCB,or combination.

Initial Drug Choices

Stage 1 Hypertension


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Chlorthalidone:Relationship

with Blood Pressure andCardiovascular Disease Risk reduction


21/127

Thiazide diuretics in the

management of Hypertension

T d d


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Thiazide diuretics

Thiazide diuretics became available in the late 1950s and werethe first

effective oral antihypertensive agents with an acceptable side-effectprofile.

These agents reduce blood pressure when administeredas monotherapy,

enhance the efficacy of other antihypertensive agents, and reduce

hypertension-related morbidity and mortality.

Thiazide-type diuretics, especially HCTZ, have been used as a cornerstone ofantihypertensive treatment for years.

There is substantial evidence that low doses of Chlorthalidone (25 mg daily) are effective

reducing CVD morbidity and mortality.

Recent outcome trials showing CVD benefits with thiazide-type diuretics haveprimarily used chlorthalidone or indapamide

(Lancet. 1985;1:1349-1354.,BMJ. 1992;304:405-


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24/127


25/127

Major Diuretic Trials

VA Coop (1967) HCTZ 50-100 mg

PHS trial (1977) Chlorothiazide 500-1000 mgHDFP (1982) Chlorthalidone 25-100 mg

MRFIT (1990) HCTZ 50-100 mg (BID) or

Chlorthalidone 50-100 mg

EWPHE (1985) HCTZ 25-50 mgMRC (1992) HCTZ 25-50 mg

SHEP (1991) Chlorthalidone 12.5-25 mg

TOMHS (1993) Chlorthalidone 15-30 mg

ALLHAT (2002) Chlorthalidone 12.5-25 mg

ACCOMPLISH (2008) HCTZ 12.5-25 mg

Chlorthalidone has been the preferred diuretic in NHLBI


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Data Source: IMS NPA - 72 months ending January 2007

Diuretics by Molecule

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

Feb-01

May

-01

Aug-01

Nov-01

Feb-02

May

-02

Aug-02

Nov-02

Feb-03

May

-03

Aug-03

Nov-03

Feb-04

May

-04

Aug-04

Nov-04

Feb-05

May

-05

Aug-05

Nov-05

Feb-06

May

-06

Aug-06

Nov-06

TRx(000s)

BENDROFLUMETH

CHLOROTHIAZIDE

CHLORTHALIDONE

HYDROCHLOROTH

HYDROFLUMETHIA

INDAPAMIDE

METHYCLOTHIAZID

METOLAZONE

POLYTHIAZIDE

QUINETHAZONE

TRICHLORMETHIAZ

IMS Health NDTI, 2001-06.

Chlorthalidone has been the preferred diuretic in NHLBI

hypertension trials but is infrequently used.

ABPM Differences


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ABPM Differences

ChangeinAmb

ulatorySystolic

BloodPress

ure(mmHg)

Week8

Week0

Ernst ME, et al. Hypertension. 2006;47:352-358,

-30

-26

-22

-18

-14

-10

-6

-2

2

6

Hours 6am 8am 10am 12pm 2pm 4pm 6pm 8pm 10pm 12am 2am 4am

Hydrochlorothiazide 50 mg daily

Chlorthalidone 25 mg daily

OfficeBlood

Pressure*

7.6 2.817.4 2.9

p= 0.069

9.3 3.219.6 3.4p= 0.109

10.8 3.517.1 3.7p= 0.842

Week 2 Week 4 Week 6 Week 8

*All values are expressed as means the standard deviation. Thepvaluesreported are Bonferroni adjustedpvalues (unadjustedpvalue 4 tests).

4.5 2.115.7 2.2p= 0.001


28/127

(Hypertension. 2006;47:352-358.)

Hydrochlorothiazide Vs Chlorthalidone

BP lowering effect of Hydrochlorothiazide and Chlorthalidone

SBP reduction P value

Chlorthalidone

25mg/day15.7 2.2 mm

P=.001

HCTZ 50mg/day 4.5 2.1 mm Hg


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Diuretics and CVD Events

5 trials have demonstrated the benefit of chlorthalidone-basedregimen in reducing CVD events. No comparator has provensuperior.

Some trials of HCTZ-based regimens have shown benefit;they used 25-50 mg/day

2 trials of low-dose (12.5-25 mg/day) HCTZ regimens(ACCOMPLISH, ANBP-2) were found not as effective inreducing CVD events as the comparator.

BP differences between groups were similar in ACCOMPLISH study


30/127

MRFIT

The Multiple Risk Factor Intervention Tria

Hypertension. 2011;57:689694.


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MRFIT

Men ages 35-57 years, upper 10%-15% of CHD

risk, randomization to Special Intervention (SI)or Usual Care (UC), stratified by clinical center

Choice of diuretic allowed to initiate treatment

in SI group; some clinics predominantly usedHCTZ (50 or 100 mg) while others usedpredominantly chlorthalidone (50 or 100 mg)

Multiple Risk Factor Intervention Trial Research Group. Circulation.1990;82:1616-1628.


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MRFIT: H and C Clinics

H Clinics C ClinicsNo. Clinics 9 6

No. Participants 5,466 3,193

% Hypertensive at entry 62.2 % 66.1%

No. SI 1725 1046

No. UC 1674 1066

Baseline BP

SBP (mm Hg) 141.5 142.0DBP (mm Hg) 95.5 95.8

H- Hydrochlorothiazide C- Chlorthalidone


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MRFIT

Four years into the study the DSMBrequested all SI participants on HCTZ beconverted to chlorthalidone.

MRFIT


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Probability of event-free cardiovascular events with thiazide-type diuret

Hypertension. 2011;57:689694.

In a retrospective cohort analysis, significantly fewer CV events were

noted with chlorthalidone compared with HCTZ (P=.0016)

Conclusion: Chlorthalidone is the preferred thiazide-type diuretic for

treating those patients with hypertension who are at high risk for CV even

MRFIT


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MRFIT

Leading up to protocol change

H clinics: 44% more CHD, 16% more dea(vs UC patients)

C clinics: 58% less CHD, 41% less death(vs UC patients; majority of diuretic use in

UC remained HCTZ) After switch to C

H clinics: 28% less CHD, 26% less death vUC (P= 0.04, 0.06)

Multiple Risk Factor Intervention Trial Research Group. Circulation.1990;82:1616-1628.

Bartsch G et al. Circulation.1984;70(suppl II):II-1438.


36/127

ALLHAT

ALLHAT: Antihypertensive and Lipid-Lowering Treatment to prevent Heart

Attack Trial

Heart Attack Trial. JAMA2002;288:298197.


37/127

PurposeTo determine whether, in hypertensive patients, the calcium channel

blocker amlodipine or the angiotensin converting enzyme inhibitor

lisinopril reduces coronary heart disease and other cardiovascular

disease compared with the thiazide diuretic chlorthalidone

The ALLHAT Officers and Coordinators for the ALLHAT

Collaborative Research Group.

Heart Attack Trial.JAMA2002;288:298197.

ALLHAT

ALLHAT Study Design


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ALLHAT Study Design

n=13,8542,235 (16.1%)stopped drug

Chlorthalidonen=15,255

Amlodipinen=9,048

Randomizedn=42,418

n=15,255339 (2.2%) lost to follow-up80 (0.5%) refused follow-up

n=9,048200 (2.2%) lost to follow-up58 (0.6%) refused follow-up

n=6,2101,873 (30.2%)stopped drug

n=9,054218 (2.4%) lost to follow-u58 (0.6%) refused follow-u

n=8,215

1,357 (16.5%)stopped drug

n=3,7691,052 (27.9%)stopped drug

YEAR 1n=8,158

1,842 (22.6%)stopped drug

n=3,6051,399 (38.8%)stopped drug

Lisinopriln=9,054

YEAR 5

ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.org

Intent-to-Treat

Analysis

Doxazosinn=9,062

Discontinued

early at 3.3 yrs

ALLHAT Endpoints


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ALLHAT Endpoints

Primary endpoint Composite of fatal coronary heart disease (CHD) or nonfatal

myocardial infarction (MI)

Other predefined endpoints

all-cause mortality

stroke combined CHD nonfatal MI, CHD death, coronary

revascularization, hospitalized angina

combined cardiovascular disease combined CHD, stroke,lower extremity revascularization, treated angina, fatal/hospitalized/treated congestive heart failure, hospitalized or

outpatient peripheral arterial disease other renal

ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.org

ALLHAT Mean Systolic and Diastolic Blood


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70

75

80

85

90

130

135

140

145

150

ALLHAT Mean Systolic and Diastolic BloodPressure During Follow-up

SystolicBP(mmHg)

Follow-up, yrs0 1 2 3 4 5 6 0 1 2 3 4 5 6

DiastolicB

P(mmHg)

ChlorthalidoneAmlodipine

Lisinopril


Lisinopril

ALLHAT Research Group. JAMA. 2002;288:2981-2997.Copyright 2002, American Medical Association. www.hypertensiononline.org

SBP=systolic blood pressure DBP=diastolic blood pressure

Compared to chlorthalidone:

DBP significantly lower inamlodipine group (~1 mmHg).

Compared to chlorthalidone:

SBP significantly higher in

amlodipine (~1 mmHg) and

lisinopril (~2 mmHg) groups.

ALLHAT BP Controlled


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0

10

20

30

40

50

60

70

Baseline Year 1 Year 2 Year 3 Year 4 Year 5

ALLHAT BP Controlledto


42/127

Years after randomization

Cumulativeevent rate

(%)

0

0

1 2 3 4 5 6 7

4

12

8

16

20

Fatal CHD and nonfatal MI

ALLHAT Officers and Coordinators. JAMA 2002; 288:2981 97.

Chlorthalidone

Amlodipine

Lisinopril

yby Treatment Group

ALLHAT Combined CV Disease


43/127

Relative Risk

(95% CI)

Relative Risk

(95% CI)

TOTAL1.04

(0.99-1.09)

1.10

(1.05-1.16)

Age


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Relative Risk

(95% CI)

Relative Risk

(95% CI)

TOTAL0.93

(0.82-1.06)

1.15

(1.02-1.30)

Age


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0

3

6

9

12

15

by Treatment Group

0 1 2 3 4 5 6

1525590489054

7No. at Risk


Lisinopril

1452885358496

1389881858096

1322478017689

1151167856698

636937753789

301617801837

384210313

Cumulativeeventrate(%

)Chlorthalidone

Amlodipine

Lisinopril

Time to event, yrs

www.hypertensiononline.org

P


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ALLHAT ConclusionsALLHAT


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ALLHAT Conclusions

Better control of systolic BP was achieved withchlorthalidone than with amlodipine or lisinopril

There were no differences in risk for CHDdeath/nonfatal MI between chlorthalidone andamlodipine or lisinopril

In secondary endpoints, chlorthalidone wasassociated with lower risk for

stroke, combined CVD, and HF compared with

lisinopril HF compared with amlodipine

MI=myocardial infarction CHD=coronary heart disease HF=heart failure

www.hypertensiononline.orgALLHAT Research Group. JAMA. 2002;288:2981-2997.

ALLHAT

ALLHAT ImplicationsALLHAT


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ALLHAT Implications

Unless contraindicated, or unless specific indications

are present that would favor use of another drugclass, diuretics should be the initial drug of choice inantihypertensive regimens

Only 30 percent of patients achieve both systolic BP


49/127

The Systolic Hypertension

in the Elderly Program, 1991 (SHEP)

The Systolic Hypertension in


50/127

the Elderly Program, 1991

SHEP Research Group. JAMA. 1991;265:3255-3264.

Cohort 4,736; 43% menAge 60 yrs old; mean 71.6 yrs old

EligibilitySystolic BP 160219 mmHg andDiastolic BP


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65

70

75

80

140

150

160

170

180

Changein

BP(mmHg)

Years

Change in Blood Pressure

Placebo (n=2,371)

Active Rx (n=2,365)

Years0 1 2 3 4 5 0 1 2 3 4 5

Systolic BP Diastolic BP

SHEP Research Group. JAMA. 1991;265:3255-3264.Copyright 1991, American Medical Association.

BP=blood pressureSHEP=Systolic Hypertension in the Elderly Program

Placebo (n=2,371)

Active Rx (n=2,36

SHEP


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Bloodpressure(mmHg)

0 12 36 60Months of follow-up

Average Blood Pressure During Follow-up

24 48

50

65

80

95

110

125

140

155

170

185

200

0

SHEP=Systolic Hypertension in the Elderly ProgramSHEP Research Group. JAMA. 1991;265:3255-3264.Copyright 1991, American Medical Association.

SHEPl i k


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0

1

2

3

4

5

6

7

8

9

10

Cumulativ

estrokerate

per100persons

0 12 36 60Months of follow-up

Cumulative Stroke Rate

24 48 72

P=0.0003

Placebo(n=2,371)

Active Rx(n=2,365)

SHEP=Systolic Hypertension in the Elderly ProgramSHEP Research Group. JAMA. 1991;265:3255-3264.Copyright 1991, American Medical Association.

SHEPCardiovascular Disease Endpoints


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0.20

0.40

0.600.80

1.00

1.20

1.40

1.60

Relativer

isk(95%CI

)

Stroke CHD

Active Therapy vs. Placebo

CHF Death

0.63

0.46

0.68

0.87

CVD

0.75

Cardiovascular Disease Endpoints


SHEP=Systolic Hypertension in the Elderly Program

CHD=coronary heart disease; CHF=congestive heart failure; CVD=cardiovascular disease

SHEPC l i


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Conclusions

SHEP was the first clinical trial to demonstrate thatreduction of blood pressure in patients with isolatedsystolic hypertension reduced cardiovascular (CV)mortality

The relative risk of stroke was reduced by 36% withchlorthalidone compared to placebo (P=0.0003)

The 5-year absolute benefits were a reduction in 30strokes and 55 major CV disease events per 1,000

persons


SHEP=Systolic Hypertension in the Elderly Program


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The Australian National

Blood Pressure (ANBP) Study, 1980

The Australian NationalBl d P St d 1980


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Blood Pressure Study, 1980

The Australian Study Committee. Lancet. 1980;1:1261-1267.

Cohort 3,427; 80% men

Age 3069 yrs old

Eligibility Diastolic BP 95109 mmHg

Design Single blind; placebo controlTherapy Chlorothiazide (methyldopa, beta blocker)

Duration 4 yrs

BPdifference -6 mmHg

The Australian StudyM Di t li Bl d P


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80

84

88

92

96

100

104

At Screening During Trial

Placebo Active

Mean Diastolic Blood Pressure

Diastolicblood

pressure

(mmHg)


The Australian StudyIncidence of Trial Endpoints (TEP)*


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Incidence of Trial Endpoints (TEP)*

Intention-to-treat

Placebo (n=1,706) Active (n=1,721)

No. Rate No. Rate

Total Fatal TEP 35 5.1 25 3.6

Cardiovascular 18 2.6 8 1.1

Non-cardiovascular 17 2.5 17 2.4

Non-fatal TEP 133 19.4 113 16.2

All TEP 168 24.5 138 19.7

*Rates per 1,000 person-years exposure to risk.P


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Intention-to-Treat Trial Endpoints

No. of events

Placebon=1,706

Activen=1,721Ischemic heart disease

Fatal 11 5

Nonfatal myocardial infarction 22 28

Nonfatal other 76 65

Cerebrovascular eventsFatal 6 3

Nonfatal

Hemorrhage or thrombosis 16 10

Transient cerebral ischemic attacks 9 4

Other fatal 18 17Other nonfatal 10 6


The Australian StudyOn Treatment Trial Endpoints (TEP)


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0

20

40

60

80

100

120

140

On-Treatment Trial Endpoints (TEP)

Numberoftrialendpoints

Days in trial

200016001200600400

All TEPP


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Conclusions

The actively treated compared to placebogroup experienced 30 fewer trial endpointsendpoints (P


63/127

systolic hypertension and long-term survival

22 years of follow-up after chlorthalidone stepped-caretherapy for 4.5 years in the SHEP trial.

Study Design: A national death index ascertainment ofdeath in the long-term follow up of SHEP trial of patient

aged 60 years or older with isolated systolic hypertension

Main outcome measures:cardiovascular death and all-cause mortality

JAMA. 2011;306(23):2588-2593.

Association between chlorthalidone treatment osystolic hypertension and long-term survival


64/127

Results: Blood pressure

systolic hypertension and long term survival

Active treatment group Placebo

Reduction in SBP from baseline

(mmHg)-26 -15

Reduction in DBP from baseline(mmHg) -9 -4

Lowering in mean SBP (mmHg) - 11-14 -

Lowering in mean DBP (mmHg) - 3-4 -

Goal BP achievement(%) 65-72 32-40



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Results: Life expectancy at 22 years


Active treatment

groupP-value

Life expectancy gain from Cardio-vascular

death158 d P=.009

Life expectancy gain from All-cause mortality 105 d P=.07

Life expectancy free of cardiovascular death

If controlled at first year 215.2 d

If controlled at the second year 130.7 d

If controlled at the end of study 215.3 dLife expectancy free of all-cause mortality

If controlled at first year 195.6 d



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Conclusion:

The active treatment group was associated withhigher survival free from cardiovascular deathcompared with the placebo group


The gain in life expectancy free from cardiovascular death

corresponds with approximately 1 day gained for each month of

treatment.

JAMA. 2011;306(23):2588-2593.

Chlorthalidone: Pleiotropic effects


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Reduce epinephrine-mediated platelet aggregation.

Increase transcription of vascular endothelial growthfactor C and transforming growth factor-beta3

Thereby lead to reduced vascular permeability toalbumin and increased angiogenesis

These properties explain the ability of chlorthalidoneto reduce cardiovascular morbidity.

Hypertension. 2010 Sep;56(3):463-70. Epub 2010 Jul 12.

Chlorthalidone


68/127

Head-to-head studies favor chlorthalidone as a more

effective blood pressure lowering agent compared withHCTZ

CTD produce superior 24-hour blood pressure controlcompared with HCTZ

When comparing the 2 drugs, CTD had significantly fewer

CVEs compared with HCTZ.

SHEP trial: Chlorthalidone treatment was associated with

36% reduction in total stroke incidence

27% lower incidence of nonfatal MI and coronary death

32% reduction in all cardiovascular event

Hypertension. 2011; 57: 689-694

Chlorthalidone


69/127

Each month of chlorthalidone therapy associated with an

additional day free from risk of cardiovascular death

CTD displayed significantly lower SBP, total cholesterol,low-density lipoprotein cholesterol, potassium, and higheruric acid compared with HCTZ.

Given the documented irregular intake of antihypertensivedrugs, the prolonged efficacy of chlorthalidone makes thisagent a "forgiving drug" with a definite advantage over

hydrochlorothiazide.

Combining Antihypertensive Drugs


70/127

Most drug classes can be combined safely in most patients.

Diuretic will combine well with any other class.

Non-DHP CCBs and clonidine should not be combined with b-

blockers (DHPs combine well).

b

-blockers add little BP efficacy to ACEIs, ARBs, or other

adrenergic inhibitors except -blockers.

ESH 2003: Possible Combinations of Different Classes ofAntihypertensive Agents


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ESH/ESC Guidelines Committee. J Hypertens. 2003;21:1011-1053.

The most rational combinations are represented as thick lines

b

-blockers

-blockersCalcium

antagonists

AT1-receptor

blockers

Diuretics

ACE inhibitors

Example of an Effective Combination


72/127

Example of an Effective CombinationRegimen:

Diuretic + ACEI or ARB + CCB

Could add reserpine or aldosterone

antagonist

Examples of Combination Regimens


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Diuretic+ACEI (or ARB)+CCB and/orreserpine

Diuretic +b-blocker +DHP CCBand/or -blocker

Diuretic+b-blocker+vasodilator+aldosterone antagonist

For rare patient who cannot take a diuretic:

ACEI (or ARB)+CCB+reserpine


74/127

Angiotensin II


75/127

AT1receptor

Vasoconstriction

Cell growthSodium/water retention

Sympathetic activation

AT2receptor

Vasodilation

Antiproliferation

Tissue regeneration

Natriuresis

Angiotensinogen

Angiotensin I

Angiotensin II

Non-ACE pathways

(e.g. chymase, tPA,

cathepsin)

Aldosterone

Sodium/waterretention

Bradykinin

Inactive fragment

ACE

ACE

Angiotensin II

escape

Adaptedwith permission from Dzau.J Hypertens Suppl. 2005;23(1):S9S17.


76/127


77/127

Blood Pressure = C.O. X Peripheral Resistan

Vasoconstriction

RAAS

SympatheticNerve

Activity

ContractilityHeart RatePreload

RenalSodium

Retention


78/127

Oxidative Stress Inflammation

Endothelial dysfunction Tissue remodelling

Vascular permeability Leucocyte infiltration

Activation of signalling pathways

Production of

inflammatory mediator

Proliferation of VSMC

Matrix deposition

MMP activationPlatelet aggregation

PAI-1 activation

Vasoconstriction

Nitric oxide

LOX-1 expression

LDL peroxidation

Reactive oxygen species

NAD(P)H oxidase activity

Angiotensin II

Schmieder et al. Lancet 2007;369:12081219


79/127

Adapted from

Dzau VJ, et al. Circulation2006;114:28502870; Figure adapted from Dzau V, Braunwald E.

Am Heart J 1991;121:12441263; Yusuf S, et al. Lancet2004;364:937952

Angiotensin II

CV High-Risk

Death

Remodelling

Congestive heart failure/

secondary stroke

Myocardial infarction

and stroke

Hyper-

tension

Atherosclerosisand

left ventricular

hypertrophy

HF

Death

Ventricular dilation/

cognitive dysfunction

Risk factors


80/127


81/127

Angiotensin convertingenzyme inhibitors (ACE)

Captopril,Enalapril,

Lisinopril

RamiprilPerindopril

Angiotensin II receptor

Blockers (ARBs)Losartan

Irbesartan

Olmesartan

Candesartan

ValsartanTelmisartan

Azilsartan


82/127

Bradykinin/NO

Inactive fragments

Angiotensin I

Angiotensin II

ARB

ACE-independentANG II formation

by Chymase, etc.

AT2RECEPTOR

Vasodilation

Natriuresis

Tissue regeneration

Inhibition of inappropriate cell growth

Differentiation

Anti-inflammation

Apoptosis

ACEACE Inhibitor

AT1RECEPTOR

Vasoconstriction

Sodium retention

SNS activation

Inflammation

Growth-promoting effects

Aldosterone

Apoptosis

SNS = sympathetic nervous system

Hanon S, et al. J Renin Angiotensin Aldosterone Syst 2000;1:147150;

Chen R, et al. Hypertension 2003;42:542547; Hurairah H, et al. Int J Clin Pract 2004;58:173183;

Steckelings UM, et al. Peptides 2005;26:14011409


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Percent(%)

P value*


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Telmisartan- The Uniqueness


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Telmisartan is an angiotensin II receptor antagonistthat is highly selective for Type1 angiotensin IIreceptors


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Longest elimination Half-Life


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Burnier M., Lancet 2000;355:637645Brunner HR., J Hum Hypertens 2002;16(Suppl 2):S13S16

Range



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(Index of the Ability of a Drug to Enter Tissues

Throughout the Body)

50

100

150

200

250

300

350

400

Telmisartan

Liters

450

500

Valsartan Olmesartan LosartanLosartan

MetaboliteCandesartan Irbesartan

Telmisartan most potently activates the PPAR-y


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2

Losartan

4

6

8

10

12

14

16

Eprosartan Irbesartan Valsartan Candesartan Telmisartan

Fold activation

Olmesartan

5 micromolar

p y y

Implication of activating PPAR



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Implication of activating PPAR-

Improves insulin sensitivity

Decreases adipocyte cell size

Decrease hepatic fat storage

Decreased serum glucose and serum triglyceride levels, and increased

glucose uptake and GLUT4 protein expression

These effects improve metabolic syndrome and reduce the risk of

atherosclerosis

Hypertension


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Indicated for treatment of hypertension

May be used alone or in combination with other antihypertensive agentsCardiovascular Risk Reduction

Indicated for risk reduction of myocardial infarction, stroke, or death from

cardiovascular causes in patients 55 years of age or older at high risk of developing

major cardiovascular events who are unable to take ACE inhibitors.

High risk for cardiovascular events can be evidenced by a history of coronary artery

disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk

diabetes (insulin-dependent or non-insulin dependent) with evidence of end-organ

damage


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Telmisartan is particularly useful in following groups of

hypertensive patients:

Intolerance to ACE inhibitor

Diabetics

Patients with heart failure.Elderly

Renal impairment


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Baseline

Final Visit

Am

bulatoryDBP

(mmH

G)

90

85

75

70

12:00 PM 4:00 PM 8:00 PM 12:00 AM 4:00 AM 8:00 AM8:00 AM

Time of day

White WB, et al. Blood Press Mon i t . 2005;10:157-163.

80

65

60

n=1628


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BloodPressureRe

duction(mm

HG)

-11.513.2

-7.08.9

-15

-10

-5

0SBP DBP

Change in mean ABPM blood pressure during the first 4hours after awakening2

White WB, et al. Blood Press Moni t .2005;157:157-161.

Early-morning BP control:Telmisartan Vs existing therapy


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HCTZ

Additional DBP reductions (mm HG) when telmisartan is added to

patients uncontrolled on current therapy at the end of the dosing period

Telmisartan 40mg 80mg plus current therapyPlacebo plus current therapy

ACE InhibitorsBeta BlockersCCBs

-4.8

n=56

-5.8

n=35

-6.8

n=49

-10.6

n=14

1.9

n=15

-5.2

n=50

-2.3

n=36

-0.2

n=56

Gil-Extremera B, et al. Int J Clin Pract. 2003;57:861-866.


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In Combination with OtherAntihypertensive Agents


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Adjunctive therapy with Telmisartan

calcium channel antagonist

a -blocker

a diuretic agent

Was effective in controlling Blood Pressure

Drugs 2006; 66 (1)


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Comparison of Telmisartan with

other Anti-hypertensive Drugs

Comparison with other ARBs


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Versus Losartan :Telmisartan monotherapy (40 or 80mg OD)

demonstrated superior anti-hypertensive efficacy to Losartanmonotherapy (50mg or 100mg OD)

Versus Valsartan: Telmisartan monotherapy (4080mg OD)demonstratedbetter anti-hypertensive efficacythan Valsartan

monotherapy (80160mg once daily)

Drugs 2006;66(1) 51-83

Parameter Telmisartan Olmesartan

Elimination

Half- life (hr)24 hrs 13 hrs

Comparison with other ARBs


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Trough Peak Ratio 66 -100 % 60 -80%

24 hr control of BP*Complete 24 hr control of

BP covers early morning

Hour

Incomplete 24 hr control

of BP

LipophilicityMore Lipophilic so better

tissue penetration and hence

better inhibition of tissue

RAAS

Less lipophilic so less

inhibition of tissue RAAS.

Elimination1% urine

99% stools

35-50% urine

50% stools

Renal Insufficiency No dosage adjustment20 mg maximum in severe

disease

PPAR Agonistic activity Present therefore Improves

insulin sensitivity and lipidprofile

Absent

Telmisartan Vs Losartan


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Aim: Anti-hypertensive efficacy & tolerability of Telmisartan and

Losartan compared with placebo in a6-week study

Patients: 223patients with mild-to moderate Hypertension

Treatment: Telmisartan 40 mg, telmisartan 80 mg, losartan 50 mg, orplacebo

J Hum Hypertens. 1999 Oct;13(10):657-64.

Telmisartan Vs Losartan


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-10.7/6.8mm Hg-12.2/7.1 mm Hg

-6/3.7 mm Hg

-15

-10

-5

0

ReductioninBlood

Pressure

Telmisartan more effective anti-hypertensive during

18-24 hour peroid after dosing( P


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Patients:533 patients with mild- moderate hypertension

Duration:26-week

Treatment :

- Telmisartan (40 mg titrated to 80 mg titrated to 120 mg)

- Atenolol (50 mg titrated to 100 mg)

- Hydrochlorothiazide (HCTZ) 12.5 or 25 mg was added if needed

Clin Ther. 2001 Jan;23(1):108-23.

Telmisartan more effective than Atenolol in Controlling


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80%

68%

60

70

80

%of

P

atient

showing

Re

duction

o

fSBP>

or=

Telmisartan more effective than Atenolol in Controlling

Systolic Blood Pressure(p=0.003)

Telmisartan

Atenolol

Clin Ther. 2001 Jan;23(1):108-23.

Reduction from baseline in SBP of > or = 10 mm Hg achieved by 80% of

Telmisartan-treated and 68% of Atenolol-treated patients (P = 0.003)


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Versus Calcium Channel Blockers:

Comparison of efficacies duration of action of

Telmisartan and Amlodipine

Patients: 234 patients with hypertension


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Patients:234 patients with hypertension

Treatment:40 mg Telmisartan increased to 80 and 120 mg as necessary for patients

5 mg Amlodipine titrated to 10 mg as necessary for patients

Placebo (n = 81)

12 weeks of double-blind treatment

Both drugs alsosignificantly reduced 24 h mean systolic blood pressures andDBPcompared with placebo(P < 0.0001)

Blood Press Monit. 1998 Oct;3(5):295-302.

Telmisartan effective in controlling Diastolic Blood

pressure

Comparison of efficacies duration of action of

Telmisartan and Amlodipine


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71% 55%

0

20

40

60

80

%p

atientswith

Twentyfour-hour

mean

ABPMD

BP

chlorthalidone-telmisartan the new renaissance

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