dr. esperanza cabral module

7/30/2019 Dr. Esperanza Cabral Module

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In Search of an Ideal Drug:

Emerging Roles ofLOSARTAN inCardiovascular Diseases


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9.5

3.3 2.45

23.5

2.1

45.4

21.3

12.4

6.2

9.9

7.3

13.9

6.3

22.7

0

10

20

30

40

50

Men Women Men Women Men Women Men Women

Normotensive

Hypertensive

Risk Ratio 2.0 2.2 3.8 2.6 2.0 3.7 4.0 3.0

Excess Risk 22.7 11.8 9.1 3.8 4.9 5.3 10.4 4.2

Coronary Disease Stroke Peripheral Artery

Disease Cardiac Failure

Bienn

ialAge-A

djus

tedRa

teper

1000

Kannel WB JAMA 1996;275(24):1571-1576.

Risk of CV Events by Hypertensive StatusFramingham Heart StudyPatients Aged 35-64 Years; 36-Year Follow-Up


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Hypertension Treatment SignificantlyReduced Mortality and Morbidity

Estimated Cumulative Incidence of AllMorbid Events Over 5 Years

Veterans Administration Cooperative Study Group on antihypertensive agents JAMA 1970;213(7):1143-1152.

0

10

20

30

40

50

60

0 1 2 3 4 5

Years

EstimatedCumulative

Incid

enceofAllMorbidE

vents(%)

Control - Placebo

Active Treatment Groups -

Diuretic-based regimen

and hydralazine


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* SciSearch Medline-Current Contents Database (Institute for Scientific Information) Updated

9//02

AII Antagonist Scientific/ClinicalPublications

0

1000

2000

3000

4000

5000

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

Losartan

Candesartan

Irbesartan

Valsartan

Eprosartan

Telmisartan

Cumulative Total

4948

797

494

464

147

121

Cumul

ativeTotalPublications*


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Classical "circulating" system (RAAS):

Renin-Angiotensin Systems (I)

Angiotensin II

Angiotensin I

Angiotensinogen

Aldosterone

Na+-retentionK+-loss

glomerular zone

ACE

Renin

Blood pressure

Na+

Sympathetic

system

Renin

maculadensa

adrenalglands

adapt. from Dominiak & Unger (eds.) in Ang II-AT1-Receptor Antagonists, Steinkopff (1997)


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t-PA = tissue plasminogen activatorCAGE = chymostatin-sensitiveangiotensin generating enzyme

Local "tissue-bound" system (RAS):

Renin-Angiotensin Systems (II)

AT1 AT2

Bradykinin

inactive fragments

B2B1

Angiotensin II

Angiotensin I

Angiotensinogen

ACE

Renin

specific cellular response

ChymasesCathepsin G

CAGE

t-PACathepsin G

Tonin

specific cellular response

adapt. from Dominiak & Unger (eds.) in Ang II-AT1-Receptor Antagonists, Steinkopff (1997)


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Distribution of ACE:

Renin-Angiotensin Systems (III)

mod. from Dzau V, Arch Intern Med 153 (1993)

R A S

circulating (plasma) local (tissue)

10 % 90 %

Acute and short-term effectscardiovascular/

renal homeostasis

Long-term effectslocal "organ adaptation"

renal-independent activation


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Angiotensin II generating systems/organs:

Local Renin-Angiotensin-Systems

Tissue/Compartment

HeartBrain

KidneyBlood vessels

atherosclerotic plaquesTestisUterus

Adrenal gland

Cell systems (e.g.)

MyocytesNeurons

Mesangium,TubuleEndothelium

Macrophages?Smooth muscle?Glomerulosa cells

mod. from Dzau V, Arch Intern Med 153 (1993)


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Growth factors: TGF, PDGF, CTGFCytokines: IL-6, TNFa

Chemokines: MCP-1, RANTES, OPN

Other: PA1, Metalloproteinases

ECM production and degradation

ECM accumulationProteinuria Cell proliferation Inflammation

Activation and recruitment of

inflammatory cells

Renal Cells

(mesangial, tubuloepithelial

interstitial fibroblasts)

Ang Il

ChemotaxisInflammatory Cells

Chemokines

- MCP-1, RANTES

Adhesion molecules

- VCAM-1Cytokines, growth factors

Ang II Induced Renal Fibrosis

Renal FibrosisMezzano, S.A. Hypertension 2001; 38(2) 635-638.


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Angiotensin II and Atherosclerosis

Stimulation of superoxide-production,lipid-peroxidation and inactivation of NO(oxidative stress)

Expression of adhesion molecules (VCAM-1,ICAM-1) and chemoattractant proteins (MCP-

1)

Involvement of Ang II in inflammatory processes:

adapt. from Gibbons GH, Clin Cardiol 20 (1997)

Activation and migration of macrophages


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Angiotensin II and Atherosclerosis

Proliferation, migration and hypertrophyof smooth muscle cells

Stimulation of growth factors, cytokines

and metalloproteinases

Involvement of Ang II in inflammatory processes:

Matrix-expansion and interstitial fibrosis

adapt. from Gibbons GH, Clin Cardiol 20 (1997)


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AII Receptor Blockers

Bridging the Gap for MaximalTarget Organ DamageProtection via AII inhibition

i i l Sh S i i


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Mega-trials CAPPP NORDIL STOP-2

ComparatorTreatments

ACE IVs

B-blockers/Diur

CCBVs

B-blockers/Diur

ACE Is/CCBsVs

B-bockers/DiurNumber of

Patients 10985 10881 6614Number of

PrimaryEnd points

698 803 659

Composite primaryendpoint

MI,

Stroke, CV

Death

MI,

Stroke, CV Death

Fatal MI, Fatal

Stroke, Fatal

CV Disease

Differences onprimary end point

NSP = 0.52

NSP = 0.97

NSP = 0.89

No Hypertension Trial Has Shown Superiorityon Combined CV Morbidity and Mortality vs.Active comparator

These data were from 3 independent, non-comparative studies.

Hansson L et al, Lancet1999;353:611-616; Hannson L et al Lancet2000;356:359-365; Hannson L et al,Lancet1999;354(9192):1751-1756.


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m


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Clin Ther. 1995 Sep-Oct;17(5):911-23.Efficacy and tolerability of losartan versus enalaprilalone or in combination with hydrochlorothiazide inpatients with essential hypertension.

Townsend R, Haggert B, Liss C, Edelman JM.

Department of Medicine, Universityof Pennsylvania, Philadelphia,USA.

Am J Hypertens. 1995 Jun;8(6):578-83.Efficacy and tolerabilityof losartan potassium and atenolol in patients with mildto moderate essential hypertension.

Dahlof B, Keller SE, Makris L, Goldberg AI, Sweet CS,Lim NY.

Department of Medicine, University of Goteborg, Ostra Hospital,Sweden.

Losartan Efficacy


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GENERIC BRAND MANUFACTURER T/P RATIO

Losartan COZAAR Merck 65%Valsartan DIOVAN Novartis 54-76%

Temisartan MICARDIS Boehringer

Ingelheim66-100%

Telmisartan PRITOR GSK 66-100%

Candesartan BLOPRES Boie Takeda 76-87%

Irbesartan APROVEL Sanofi 60-70%

Eprosartan TEVETEN Solvay 67%

TROUGH TO PEAK RATIO

Source : Acta Cardiol Sin 2002, 18:1-10


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The Losartan Intervention

For Endpoint Reductionin Hypertension Study

Dahlf B et al Lancet2002;359:995-1003.

Steering Comm ittee

Chair: Co-chair:

B . Dah lf R.B. Devereux


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LIFE: A Landmark Study

RCT of 9193 hypertensive patients with LVH,aged 55-80 years

Mean 4.8-year follow-up

44,119 patient-years of follow-up

945 study sites in 7 countries

1096 patients with primary endpoints



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* Titration encouraged if SiDBP >90 mmHg or SiSBP >140 mmHg but was mandatory if SiBP >160 / 95 mmHg

**Other antihypertensives excluding ACEIs, AII antagonists, beta blockers

HCTZ=hydrochlorothiazide, SiDBP= sitting diastolic blood pressure, SiSBP=sitting systolic blood pressureDahlf B et alAm J Hypertens 1997;10:705713.

LIFE: Design/Dosing Titration

Day14 Day7 Day1 Mth1 Mth2 Mth4 Mth6 Yr1 Yr1.5 Yr2 Yr2.5 Yr3 Yr3.5 Yr4 Yr5

* Target BP:


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0

2

4

6

8

10

12

14

16

Prop

ortionofpatients

withfirstevent(%

)

Losartan

Atenolol

LIFE: Primary Composite Endpointof CV death, stroke or MI

Study Month0 6 12 18 24 30 36 42 48 54 60 66

Losartan 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901Atenolol 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876

Adjusted Risk Reduction 13.0%, p=0.021

Unadjusted Risk Reduction 14.6%, p=0.009


Number

at Risk

22


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LIFE: Stroke

Losartan

Atenolol

Adjusted Risk Reduction 24.9%, p=0.001

Unadjusted Risk Reduction 25.8%, p=0.0006

Study

Month

0 6 12 18 24 30 36 42 48 54 60 660

1

2

3

4

5

6

7

8


Losartan 4605 4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 925

Atenolol 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897

Fatal and non-fatal stroke

Proportionofpatientsw

ithfirstevent(%)

Number

at Risk


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Intention-to-Treat

LIFE: New-Onset Diabetes

Losartan

AtenololAtenolol (N=3979)

Losartan (N=4019)

Study Month 0 6 12 18 24 30 36 42 48 54 60 66

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

Adjusted Risk Reduction 25 %, p


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0.5 1 1.5

Hazard Ratio (95% CI

Composite 242

Cardiovascular Death 99

Stroke 116

MI 91

Total Mortality 167

Favors L Favors A

Primary Composite Endpoints and

Components in Patients with Diabetes

L H Lindholm et al. Lancet:2002

Baseline Factor #

Events


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0

5

10

15

20

Discontinuation

due to all AEs

Discontinuation due to

drug-related AE

Discontinuation due to

serious drug-related AE

p


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LIFE: Conclusions

Losartan is the only antihypertensive that hasdemonstrated a superior benefit over another activetreatment, atenolol, in reducing the risk of combined CV

morbidity and death in patients with hypertension andLVH*

The superior benefit of losartan therapy on combined CV

morbidity and death* compared to atenolol was: beyond blood-pressure control only partially explained by superior LVH regression

potentially linked to molecule-specific effects

* Defined as composite of CV death, MI, and stroke


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ELITE II - Evaluation ofLosartan In The Elderly II

Study Design:Multicenter, double-blind, randomized, parallel, captopril-controlled involving 2600 patients(>60 years old) withsymptomatic heart failure(NYHA II-IV)Period of Study: 36 months

Primary Objective:To evaluate the effect of losartan vs captopril on TotalMortality in patients with symptomatic congestive heartfailure

Secondary Objectives:1. Evaluate the effects of losartan vs captopril on compositeendpoint of sudden cardiac death and/or resuscitatedcardiac arrest in patients with symptomatic CHF.2. Investigate safety and tolerability of losartan in patientswith congestive heart failure.


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ELITE - II

Study Design

60 yrs; NYHA II - IV; EF 40 %

ACEI naive or 7 days in 3 months prior to entry

Standard Rx ( Dig / Diuretics ), - blocker stratification

Captopril

50 mg 3 times dailyn = 1574

Losartan

50 mg dailyn = 1578

Event Driven

Targeting 510 deaths

estimate 2 yrs

median follow-up 555 days

Primary Endpoint : All-cause Mortality

Secondary Endpoint : Sudden cardiac death and/or Resuscitated Arrest

Other : All-cause Mortality / Hospitalizations

Safety and Tolerability

Lancet 2000; 355:1582-87


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ELITE IIPrimary Endpoint: All-Cause Mortality

0.0

0.2

0.4

0.6

0.8

1.0

Captopril (n-1574) 250 Events 15.9 % over 1.5 yearsLosartan (n-1578) 280 Events 17.7 % over 1.5 years

p=0.16

Probability

ofS

urvival

Days of Follow-up0 100 200 300 400 500 600 700

Pitt, B. et al, Lancet 2000; 355:1582-87

Average Mean Mortality Rate = 11.0 % per year


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ELITE IIWithdrawal for Adverse Experience ( Excluding Death )

0

5

10

15

20

Any adverse

effect

Drug-related

adverse effect

Cough Heart failure

Losartan

Captopril

*

*

*

* p = 0.001 between groups

Patients who died were excluded from any adverse effect and drug-related adverse effects.



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ELITE IIStudy Endpoint Summary

P Value

1.13 (0.95-1.35) P = 0.16 NS

1.25 ( 0.98, 1.60 ) P = 0.08 NS

1.07 ( 0.97, 1.19 ) P = 0.18 NS

228 ( 14.5 ) P = 0.001149 ( 9.4 )

Losartan n = 1578

number ( % )Captopril n = 1574

number ( % )

752 ( 47.7 ) 707 ( 44.9 )

115 ( 7.3 )142 ( 9.0 )

280 ( 17.7 ) 250 ( 15.9 )

Hazards

Ratio ( 95% CI )*

Withdrawal forAdverse

Experiences

Combined total mortalityor hospitalizations

for any reason

Sudden death or/resuscitated cardiac

arrest

All-cause mortality

(primary endpoint)



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Acronym Diagnosis Randomization PrimaryEndpoint Duration

IDNT

N=1715

Type 2 DM withnephropathy

Irbesartan/amlodipine/placebo + AHT*

ESRD2x creatininemortality

2.6 yrs

IRMA 2 Type 2 DM withmicroalbuminuria

Irbesartan (150 mg)/irbesartan (300 mg)/placebo + AHT

Progressionto proteinuria

2 yrs

RENAAL Type 2 DM withnephropathy

Losartan/placebo + AHT

ESRD2x creatinine

mortality

3.4 yrs

MARVAL Type 2 DM withmicroalbuminuria

Valsartan/amlodipine

UAER 6 mos

*AHT=other antihypertensive therapy (excluding ACEIs, ARBs, and CCBs).AHT=other antihypertensive therapy (excluding ACEIs, ARBs, and DHP CCBs).

AHT=other antihypertensive therapy (excluding ACEIs and ARBs).

ARBs and Diabetic Nephropathy

N=590

N=1513

N=332


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0

5

10

15

20

25

30

Losartan Placebo

Doublingofserumcre

atinine

conce

ntration(%o

fpatients)

ARBs in preventing renal disease progression

Brenner et al. N Engl J Med2001;345:861869

Lewis et al. N Engl J Med2001;345:851860

RENAAL IDNTp=0.003

p


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IDNT and RENAAL Trial Results

Doubling of Creat, 16 (P=0.02) 20 (P=0.02) 23 (P=0.006) -4 (P=0.69)

ESRD, or death

Doubling of Creat 25 (P=0.006) 33 (P=0.003) 37 (P


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ARBs and ACE inhibitors areestablished renoprotective therapies

JNC 7. JAMA 2003;289:25602572

The renal protection trials

ARBs are first-line treatment in type 2diabetic patients with nephropathy

ARBs have shown superior efficacycompared with placebo and calciumchannel blockers


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Compelling indications for specific

antihypertensive classes JNC 7

Diabetes Chronic kidney

disease

Diuretic Beta blocker ACE inhibitor ARB CCB Aldosterone

antagonist


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ARBs & ACE Inhibitors: Do theycomplement each others clinical effects?

Maximal inhibition of AII effects not possible

with ACE inhibitors due to non-ACEpathways of AII production

ARBs capable of complete blockade of AII

effects on the AT1 receptor


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ARBs & ACE Inhibitors: Do theycomplement each others clinical effects?

ACE inhibition and AII Receptor Blockade(AT2 receptor) both reduces PAI-1 activity

(

anti-thrombotic effect)

Bradykinin and NO production via ACEinhibition and AII Receptor Blockade (AT2

receptor) improves endothelial function


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OPTIMAALOptimal therapy in post MI

patients withAALosartan


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Relative risk = 1.13 (o.99 to 1.28:p=0.069)

All-cause Mortality

OPTIMAAL


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OPTIMAAL: Summary

Losartan (50 mg/day) compared withcaptopril (150 mg/day) in high risk MIwas associated with:

Non-significant trend in all-cause mortalityin favor of captopril

Higher incidence of CV mortality (p=0.032)

Essentially identical results for:

Re-infarction, stroke, revascularization, all-cause re-hospitalization and NYHA class

Better tolerability with significantly fewerdiscontinuations for adverse effects

ACE I hibit ARB


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Captopril Losartan Hazard pratio value

ACE Inhibitors vs ARBs

in Multicenter Trials

OPTIMAAL 447/2733 499/2744 1.13 .07(post-MI CHF) (0.99, 1.28)

ELITE II 250/1574 280/1578 1.13 .16(Chronic HF) (.95, 1.35)

Dickstein et al. Lancet 2002. 360, 752-760. Pitt et al. Lancet 2000. 355; 1582-87


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New treatment modalities

Are as effective with fewer side effects

Will improve patient compliance Will Target organ protection


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Side Effects of CurrentAntihypertensive Agents

Some patients suffer from troublesome sideeffects that:

Interfere with quality of life

Negatively affect compliance

lead to more frequent visits to the physicianand more frequent lab tests

ultimately increase the cost of medical care


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Efficacy: Adverse Effects Ratio

100%

50%

0%EFFICAY

/ADVERSE

EFFECTS

Gang

lion

bloc

kers

Reserp

in

Hy

dra

laz

ine

Guane

the

dine

Thiaz

ides

a-me

thyl-

dopa

Clon

idine

Proprano

lol

Prac

tolol

Verapam

il

Nife

dipine

Diltiazem

Captopri

l

Ace

Inhibitor

1950 1960 1970 1980 1990 YEAR


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(Adapted from Hollenberg NK, Higginbotham MB. Therapeutic Options to Preserve

Target Organs. Parsippany, NJ: Applied Clinical Communications; Case 3 of 5)

Muscle cramps

Impotence

Gout

Glucose intolerance

Hypokalemia

Hyperuricemia

Hypomagnesemia

Hypercalcemia

DIURETICS

Depression

Sleep disorders

Exerciseintolerance

Dyslipidemia

Glucoseintolerance

Impotence

BBs

Edema

Flushing

Headache

Dizziness

GI disorders

Changes inheart rate

CCBs

Cough

Rash

Hyperkalemia

Angioedema

Altered Taste

ACEIs

Hyperkalemia

Dizziness

Fatigue

ARBs

EVOLUTION OF ADVERSE EVENT

PROFILE


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We may have lofty goals in treating

hypertension, particularly with regard totarget-organ protection and compliance,

but we will never be able to accomplishthem unless our patients are willing totake their medication

Target Organ Protection & Compliance

THE RISK FACTOR


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THE RISK FACTOR

CARDIOVASCULAR

CONTINUUM

Risk Factors

Diabetes

Hypertension

Atherosclerosis

and LVH

Myocardial

Infarction

RemodelingVentricular

Dilation

Congestive

Heart Failure

End-Stage

Heart Disease

and Death

DeathRENAAL

ELITE II

OPTIMAAL

LIFE

LIFE

Adapted from Dzau V, Braunwald E.Am Heart J. 1991;121:1244-1263.

because endpoint mattersLosartan


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BIOEQUIVALENCE STUDY

The bioavailability ofUnilabs Lifezar 50 mg Tabletwas compared to that of the innovatorMSDsCozaar 50 mg Tablet

Eighteen (18) male adult volunteers with normalphysical findings participated in the study.

The clinical phase of the study was done at Dr. Victor R.

Potenciano Medical Center and approved by the MedicalEthics Committee.


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RESULTSLosartan plasma concentrations (ng/mL)

PARAMETERS DRUG A

ULs Lifezar 50 mg

Tablet

DRUG B

MSDs Cozaar 50 mg

Tablet1. Tmax (hour) 0.5 1.5

2. Cmax + S.D.

(ng/mL)

> % of Reference

206.23 + 234.103

120%

171.75 + 112.72

Reference

3. AUC0-36hr + S.D.

(ng-hr/mL)

> % of Reference

526.19 + 151.11

93%

566.37 + 180.22

Reference


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Semilogarithmic plots ofthe mean losartan plasmaconcentration versussampling time of

ULs Losartan and MSDsCozaar 50mg Tablets.

The lower and upper limits ofthe 90% CI for thelogarithmically-transformed datalie within the bioequivalence

criteria of 80-125%.


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