1 Avalide ® (irbesartan/hydrochlorothiazide) NDA 20-758 S-037 For Initial Treatment of Severe...

1

AvalideAvalide®®

(irbesartan/hydrochlorothiazide)(irbesartan/hydrochlorothiazide)NDA 20-758NDA 20-758

S-037S-037For Initial Treatment of Severe HypertensionFor Initial Treatment of Severe Hypertension

Cardiovascular and Renal Drugs Advisory Committee MeetingCardiovascular and Renal Drugs Advisory Committee Meeting

18 April 200718 April 2007

2

Reconsider the criteria for approval of Reconsider the criteria for approval of combination products for first-line use in combination products for first-line use in hypertensionhypertension

Review the data supporting first-line use of Review the data supporting first-line use of Avalide as a basis for developing this new Avalide as a basis for developing this new paradigmparadigm

Input regarding appropriate labeling: Input regarding appropriate labeling: combination products for initial use combination products for initial use

Meeting BackgroundMeeting Background

3

AvalideAvalide

Fixed-dose combination of irbesartan and Fixed-dose combination of irbesartan and hydrochlorothiazidehydrochlorothiazide

Approved in 1997 for hypertension Approved in 1997 for hypertension – 10 million patient-years of exposure10 million patient-years of exposure

150mg/12.5mg, 300mg/12.5mg, 300mg/25mg150mg/12.5mg, 300mg/12.5mg, 300mg/25mg

Current labeling precludes use of the combination Current labeling precludes use of the combination until after titration with one component has not until after titration with one component has not provided adequate BP controlprovided adequate BP control

4

Regulatory Practice and ImplicationsRegulatory Practice and Implications

Start with a single drugStart with a single drug– titrate full dose rangetitrate full dose range– avoid side effects from second drug unless avoid side effects from second drug unless

neededneeded

ImplicationsImplications– may delay BP controlmay delay BP control– more effective initial therapiesmore effective initial therapies

• greater reductions are difficult to matchgreater reductions are difficult to match• differences persistdifferences persist

5

Approvals Allowing Initial Use ofApprovals Allowing Initial Use ofCombination TherapyCombination Therapy

Capozide (captopril / HCTZ) 1991Capozide (captopril / HCTZ) 1991– more convenient dosingmore convenient dosing

Ziac (bisoprolol / HCTZ) 1993Ziac (bisoprolol / HCTZ) 1993– better safety with similar efficacybetter safety with similar efficacy

Hyzaar (losartan / HCTZ) 2003Hyzaar (losartan / HCTZ) 2003– large proportion very unlikely to be controlled large proportion very unlikely to be controlled

on monotherapyon monotherapy

6

Proposed IndicationProposed Indication

Avalide is indicated as initial Avalide is indicated as initial treatment of severe hypertensiontreatment of severe hypertension

7

JNC Guidelines: Combination TherapyJNC Guidelines: Combination Therapy

Severe HypertensionSevere Hypertension– SBP SBP ≥≥ 180 mmHg or DBP 180 mmHg or DBP ≥≥ 110 mmHg 110 mmHg

Moderate HypertensionModerate Hypertension– SBP 160–180 mmHg or DBP 100–110 mmHgSBP 160–180 mmHg or DBP 100–110 mmHg

Merged Moderate / Severe: “Stage 2 Hypertension”Merged Moderate / Severe: “Stage 2 Hypertension”– start with a combinationstart with a combination

– one drug should be a thiazide diureticone drug should be a thiazide diuretic

Initiation of therapy with more than one drug Initiation of therapy with more than one drug increases likelihood of achieving BP goal promptlyincreases likelihood of achieving BP goal promptly

Chobanian et al. Hypertension 2003;42:1221Chobanian et al. Hypertension 2003;42:1221

JNC VI

JNC 7

8

Avalide Clinical ProgramAvalide Clinical Program

Pivotal study compared Avalide to irbesartan Pivotal study compared Avalide to irbesartan monotherapy in severe hypertensionmonotherapy in severe hypertension

Supportive study compared Avalide to irbesartan Supportive study compared Avalide to irbesartan and HCTZ monotherapies in moderate and HCTZ monotherapies in moderate hypertensionhypertension

Intent: Determine the effect of Avalide in patients Intent: Determine the effect of Avalide in patients “very unlikely” to be controlled with irbesartan“very unlikely” to be controlled with irbesartan

– very unlikely: ≤ 10% achieve DBP <90 mmHgvery unlikely: ≤ 10% achieve DBP <90 mmHg

9

Outcome of the Pivotal StudyOutcome of the Pivotal Study

Irbesartan:Irbesartan: 33% achieved DBP < 90 mmHg33% achieved DBP < 90 mmHg

Avalide: Avalide: 47% achieved DBP < 90 mmHg47% achieved DBP < 90 mmHg(p = 0.0005)(p = 0.0005)

Avalide: 35% <140/90 mmHg; Irbesartan: 19% Avalide: 35% <140/90 mmHg; Irbesartan: 19%

Favorable safety and tolerability profile with Favorable safety and tolerability profile with AvalideAvalide

FDA issued approvable letter proposing an FDA issued approvable letter proposing an alternative criterion for approvalalternative criterion for approval

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Considering Additional Criteria for Approval of Considering Additional Criteria for Approval of First-line Combination TherapiesFirst-line Combination Therapies

Current guidelines recommend first-line Current guidelines recommend first-line combination therapy for severe hypertensioncombination therapy for severe hypertension

Criterion based on Hyzaar precedent has limited Criterion based on Hyzaar precedent has limited usefulnessusefulness– results dependent on study design, patient results dependent on study design, patient

population, endpointpopulation, endpoint

Alternative criteriaAlternative criteria– establish a significant efficacy advantage with establish a significant efficacy advantage with

an acceptable tolerability profilean acceptable tolerability profile

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Presentation OverviewPresentation Overview

Unmet Need inUnmet Need inSevere HypertensionSevere Hypertension

William Weintraub, MDWilliam Weintraub, MDJohn H. Ammon Chair of CardiologyJohn H. Ammon Chair of Cardiologyand Director of the Christiana Care Center and Director of the Christiana Care Center for Outcomes Researchfor Outcomes Research

Avalide Registrational Avalide Registrational ProgramProgram

Pablo Lapuerta, MDPablo Lapuerta, MDExecutive Director, Global Medical AffairsExecutive Director, Global Medical AffairsBristol-Myers SquibbBristol-Myers Squibb

Benefit / Risk ProfileBenefit / Risk Profile Michael Weber, MDMichael Weber, MDProfessor of Medicine, SUNY Downstate Professor of Medicine, SUNY Downstate Medical Center College of MedicineMedical Center College of MedicineBrooklyn, New YorkBrooklyn, New York

ConclusionConclusion Anthony Waclawski, PhDAnthony Waclawski, PhDVice President, Global Regulatory SciencesVice President, Global Regulatory SciencesBristol-Myers SquibbBristol-Myers Squibb

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Unmet Need In Severe HypertensionUnmet Need In Severe Hypertension

William Weintraub, MDWilliam Weintraub, MD

John H. Ammon Chair of CardiologyJohn H. Ammon Chair of Cardiologyand Director of the Christiana Care Center and Director of the Christiana Care Center for Outcomes Researchfor Outcomes Research

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Severe Hypertension: an Important ProblemSevere Hypertension: an Important Problem

Defined as SBP ≥ 180 mmHg or DBP ≥ 110 mmHgDefined as SBP ≥ 180 mmHg or DBP ≥ 110 mmHg

2.4 million people in the U.S.2.4 million people in the U.S.

– 40% untreated40% untreated

NHANES 2003-2004 Sample, Data on File at Bristol-Myers Squibb, 2007.NHANES 2003-2004 Sample, Data on File at Bristol-Myers Squibb, 2007.

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Morbidity and MortalityMorbidity and Mortality

Hypertensive emergencies Hypertensive emergencies

– hypertensive retinopathy, nephropathy, heart hypertensive retinopathy, nephropathy, heart failure, cerebral hemorrhagefailure, cerebral hemorrhage

Cardiovascular eventsCardiovascular events

– myocardial infarction, stroke, CV deathmyocardial infarction, stroke, CV death

Risks increase exponentially with increasing Risks increase exponentially with increasing levels of blood pressurelevels of blood pressure

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Incidence of CV EventsIncidence of CV Events

Blood Pressure (mmHg)Blood Pressure (mmHg)

7070 8080 9090 100100 110110 120120 140140 160160 180180 200200

DBPDBP SBPSBP

11 Anderson TW: Re-examination of some of the Framingham blood-pressure data. Lancet 1978;2:1139 –1141. Anderson TW: Re-examination of some of the Framingham blood-pressure data. Lancet 1978;2:1139 –1141.

10001000

30003000

40004000

50005000

60006000

20002000

CV Event rates in the Framingham study.CV Event rates in the Framingham study.11C

V E

ven

ts /

100

,000

pat

ien

t-ye

ars

CV

Eve

nts

/ 1

00,0

00 p

atie

nt-

year

s

16

Christiana Care Health System: Study CohortChristiana Care Health System: Study Cohort

16,719 patients seen from 1998-200716,719 patients seen from 1998-2007

– 2025 severe hypertension2025 severe hypertension

Primary care practicePrimary care practice

Electronic medical recordsElectronic medical records

HTN category & index date based on maximum BPHTN category & index date based on maximum BP

Outcomes included ER visits, hospitalizationsOutcomes included ER visits, hospitalizations

– ICD9 codes for CV eventsICD9 codes for CV events

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Christiana Care Health System: Population Christiana Care Health System: Population Characteristics*Characteristics*

Total N = 16,719

Maximum BP Stage

Normal(< 140/90)n = 7472

Mild and Moderate(< 180/110)

n = 7222

Severe(≥ 180/110)

n = 2025 p-value

Age, mean ± SD, (years) 36.7 ± 14.8 50.3 ± 16.6 58.0 ± 15.9 < 0.001

Gender, n (%) female 4870 (65.2) 3988 (55.2) 1312 (64.8) < 0.001

Race, n (%) black 1671 (22.4) 2279 (31.6) 1037 (51.2) < 0.001

Diabetes, n (%) 374 (5.0) 1260 (17.4) 654 (32.3) < 0.001

BMI 26.3 ± 5.9 31.0 ± 7.6 32.4 ± 8.9 < 0.001

*16,719 patients followed in primary care offices with at least 2 blood pressure measurements*16,719 patients followed in primary care offices with at least 2 blood pressure measurements

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Severe Hypertension in Actual PracticeSevere Hypertension in Actual PracticeCumulative Cardiovascular Event Rates*

by Severity of Hypertension

Normal

Mild–Moderate

Severe

0

100

200

300

400

0 1 2 3 4 5 6 7 8

Years

Eve

nts

/ 1

000

Pat

ien

ts

N = 16,719N = 16,719* Events include ER & Inpatient Admissions and Deaths* Events include ER & Inpatient Admissions and Deaths

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Christiana Care Health System: OutcomesChristiana Care Health System: Outcomes

Event rate per 1000 patientsEvent rate per 1000 patientsover a mean of 3.8 yearsover a mean of 3.8 years

EventEvent NormalNormalMild and Mild and ModerateModerate SevereSevere

All CV EventsAll CV Events 45.945.9 160.7160.7 388.9388.9

HTN (ER and Inpatient Admissions) 1.7 14.3 95.7

Heart FailureHeart Failure 13.213.2 51.151.1 95.795.7

CerebrovascularCerebrovascular 5.95.9 25.125.1 68.968.9

DysrhythmiasDysrhythmias 11.511.5 24.624.6 40.940.9

Ischemic HD Ischemic HD (excluding AMI)(excluding AMI) 7.77.7 21.721.7 37.337.3

AMIAMI 3.23.2 16.616.6 35.435.4

Hospital CV MortalityHospital CV Mortality 6.76.7 10.910.9 21.921.9

Peripheral VascularPeripheral Vascular 2.72.7 7.27.2 14.914.9

Unadjusted Disease-Specific Event Rates by Hypertensive Unadjusted Disease-Specific Event Rates by Hypertensive Stage for ER & Inpatient Admissions and DeathsStage for ER & Inpatient Admissions and Deaths

N = 16,719N = 16,719

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Severe Hypertension: Inadequate TitrationSevere Hypertension: Inadequate Titration

HTN CategoryHTN Categoryat Visit at Visit

Probability ofProbability ofHTN Rx IncreaseHTN Rx Increase

at Visitat VisitMedian Days to Median Days to

Next VisitNext Visit

MildMild 20%20% 6666

Personal communication Dan Berlowitz, MD, VA Medical SystemPersonal communication Dan Berlowitz, MD, VA Medical SystemBased on 59,207 patients seen in VA ClinicsBased on 59,207 patients seen in VA Clinics

ModerateModerate 32%32% 5555

SevereSevere 40%40% 4242

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Side effects of older medicationsSide effects of older medications

– ClonidineClonidine

– NifedipineNifedipine

Limited data on newer medicationsLimited data on newer medications

– dose & titrationdose & titration

– side effects (hypotension, syncope)side effects (hypotension, syncope)

Treatment of Severe Hypertension: ChallengesTreatment of Severe Hypertension: Challenges

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Unmet Need ConclusionsUnmet Need Conclusions

Severe hypertension is an important problemSevere hypertension is an important problem

Leads to morbidity and mortalityLeads to morbidity and mortality

Current treatment is inadequateCurrent treatment is inadequate

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Avalide Clinical Program for Initial Avalide Clinical Program for Initial Treatment of Severe HypertensionTreatment of Severe Hypertension

Pablo Lapuerta, MDPablo Lapuerta, MD

Executive DirectorExecutive DirectorGlobal Medical AffairsGlobal Medical AffairsPharmaceutical Research InstitutePharmaceutical Research InstituteBristol-Myers SquibbBristol-Myers Squibb

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Avalide Clinical ProgramAvalide Clinical Program

Pivotal study in severe hypertensionPivotal study in severe hypertension CV131-176CV131-176

Supportive study in moderate hypertensionSupportive study in moderate hypertension CV131-185CV131-185 Provides additional safety dataProvides additional safety data

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Pivotal Study (176)Pivotal Study (176)

Avalide as initial therapy in severe hypertensionAvalide as initial therapy in severe hypertension

Evaluate safety and efficacyEvaluate safety and efficacy

N = 695 *N = 695 *

2:1 randomization2:1 randomization

* 2 additional patients were randomized to monotherapy, but never received drug* 2 additional patients were randomized to monotherapy, but never received drug

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Pivotal Study (176): DesignPivotal Study (176): Design

150 mg150 mg

Forced titrationForced titrationto 300 mgto 300 mg

PlaceboPlacebolead-inlead-in

150/12.5 mg150/12.5 mg

Forced titrationForced titrationto 300/25 mgto 300/25 mg

Week 3Week 3 Week 5Week 5Week 1Week 1

11° ° endpointendpoint

Week 7Week 7

Avalide

Irbesartanmonotherapy

R 2:1R 2:1

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176: Enrollment and Randomization Criteria176: Enrollment and Randomization Criteria

Adults with severe hypertensionAdults with severe hypertension

– untreated with DBP ≥untreated with DBP ≥ 110 mmHg or110 mmHg or

– treated (monotherapy) with DBP ≥treated (monotherapy) with DBP ≥ 100 mmHg100 mmHg

Subjects randomized if DBP ≥Subjects randomized if DBP ≥ 110 mmHg at two 110 mmHg at two consecutive visits during placebo lead-inconsecutive visits during placebo lead-in

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176: Efficacy Endpoints176: Efficacy Endpoints

PrimaryPrimary

% with DBP <% with DBP < 90 mmHg at Week 590 mmHg at Week 5

SecondarySecondary

% with DBP <% with DBP < 90 mmHg at Weeks 1, 3, 790 mmHg at Weeks 1, 3, 7

% with BP control (<% with BP control (< 140/90 mmHg) at 140/90 mmHg) at Weeks 1, 3, 5, 7Weeks 1, 3, 5, 7

Change from baseline in SBP and DBP at Change from baseline in SBP and DBP at Weeks 1, 3, 5, 7Weeks 1, 3, 5, 7

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176: Safety Endpoints176: Safety Endpoints

Overall frequency of Adverse Events (AEs)Overall frequency of Adverse Events (AEs)

Frequency of discontinuations due to AEsFrequency of discontinuations due to AEs

AEs and laboratory abnormalities of special AEs and laboratory abnormalities of special interest:interest:

– dizziness, hypotension, syncope, headache, dizziness, hypotension, syncope, headache, and abnormalities of serum potassiumand abnormalities of serum potassium

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176: Baseline Characteristics176: Baseline Characteristics

AvalideAvaliden = 468n = 468

IrbesartanIrbesartanMonotherapyMonotherapy

n = 229n = 229

Age (years)Age (years) 52.252.2 52.952.9

GenderGender

male (%)male (%) 59.259.2 54.154.1

RaceRace

white (%)white (%) 84.484.4 83.883.8

black (%)black (%) 14.314.3 14.814.8

Diabetes (%)Diabetes (%) 11.111.1 13.113.1

BMI BMI ≥ 30 (%)≥ 30 (%) 47.047.0 54.654.6

Weight (kg)Weight (kg) 89.789.7 91.891.8

Baseline BP (mmHg)Baseline BP (mmHg) 171/113171/113 172/113172/113

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Efficacy ResultsEfficacy Results Study 176 (Severe) Study 176 (Severe)

32

176: Primary Endpoint176: Primary Endpoint

47%

33%

0%

10%

20%

30%

40%

50%**

* Significant difference; Week 5: * Significant difference; Week 5: PP=0.0005=0.0005

Achievement of DBP <Achievement of DBP < 90 mmHg at Week 590 mmHg at Week 5S

ub

ject

s (%

)S

ub

ject

s (%

)

AvalideAvalide IrbesartanIrbesartanMonotherapyMonotherapy

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176: Percent of Subjects with BP Control176: Percent of Subjects with BP Control

0%

10%

20%

30%

40%

Week 1 Week 3 Week 5 Week 7

Avalide

Irbesartan Monotherapy

**

****

**

* Significant difference; Week 1: * Significant difference; Week 1: PP=0.023; Weeks 3, 5, & 7: =0.023; Weeks 3, 5, & 7: PP<0.0001<0.0001

BP <BP < 140/90 mmHg140/90 mmHgS

ub

ject

s (%

)S

ub

ject

s (%

)

34

-35

-30

-25

-20

-15

-10

-5

0


Avalide


176: Change in DBP from Baseline176: Change in DBP from Baseline

* Significant difference; all * Significant difference; all PP<0.001<0.001

Mea

n C

han

ge

fro

m B

asel

ine

(mm

Hg

)M

ean

Ch

ang

e fr

om

Bas

elin

e (m

mH

g)

ΔΔ 4.7 mmHg4.7 mmHg** *

*

35

-35

-30

-25

-20

-15

-10

-5

0


Avalide


176: Change in SBP from Baseline176: Change in SBP from Baseline

* Significant difference; all * Significant difference; all PP<0.0001<0.0001

ΔΔ 9.7 mmHg 9.7 mmHg*

* *

*

Mea

n C

han

ge

fro

m B

asel

ine

(mm

Hg

)M

ean

Ch

ang

e fr

om

Bas

elin

e (m

mH

g)

36

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Controlled Mild Moderate Severe

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Controlled Mild Moderate Severe

176: Blood Pressure Distributions at Week 5176: Blood Pressure Distributions at Week 5

††

**

Su

bje

cts

(%)

Su

bje

cts

(%)

* P=0.0003† P<0.0001

Post-hoc analysis: LOCFPost-hoc analysis: LOCF

BP < 140/90BP < 140/90 SBP 140-159SBP 140-159oror

DBP 90-99DBP 90-99

SBP 160-179SBP 160-179oror

DBP 100-110DBP 100-110

SBP ≥ 180SBP ≥ 180oror

DBP ≥ 110DBP ≥ 110


Avalide

37%

21%

42%

36%

16%

30%

5%

14%

††

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176: Patients with DBP < 90 mmHg at Week 5176: Patients with DBP < 90 mmHg at Week 5by Raceby Race

40.3

48.4

14.7

36.4

0

10

20

30

40

50

60

Black Non-Black

Race

% o

f P

atie

nts

Avalide


n = 67 34 401 195

38

176: BP Control in Diabetic Subjects at Week 5 176: BP Control in Diabetic Subjects at Week 5

5.8

32.7

0.0

23.3

0

10

20

30

40

< 130/80 < 140/90

BP Goal

% o

f P

atie

nts

Avalide


n = 52 30 52 30

39

0

20

40

60

80

100

150 160 170 180 190 200

0

20

40

60

80

100

110 115 120

176: Influence of Baseline Blood Pressure176: Influence of Baseline Blood Pressure

Probability of Achieving Probability of Achieving SBP <140 mmHg at Week 5 SBP <140 mmHg at Week 5

% o

f P

atie

nts

% o

f P

atie

nts

Baseline DBP (mmHg)Baseline DBP (mmHg)Baseline SBP (mmHg)Baseline SBP (mmHg)

AvalideAvalide


AvalideAvalide


Probability of Achieving Probability of Achieving DBP <90 mmHg at Week 5 DBP <90 mmHg at Week 5

40

176: Efficacy Summary176: Efficacy Summary

Avalide showed better efficacy than irbesartan Avalide showed better efficacy than irbesartan monotherapymonotherapy

– more patients achieved < 90 mmHg more patients achieved < 90 mmHg (47% vs 33%)(47% vs 33%)

– more patients achieved < 140/90 mmHgmore patients achieved < 140/90 mmHg(35% vs 19%)(35% vs 19%)

– greater blood pressure reductions at each greater blood pressure reductions at each timepoint (Δ 9.7 / 4.7 mmHg at Week 5)timepoint (Δ 9.7 / 4.7 mmHg at Week 5)

– fewer severe blood pressure elevationsfewer severe blood pressure elevations

41

176: Study Design Comparison with Hyzaar176: Study Design Comparison with HyzaarStudy 176Study 176 HyzaarHyzaar

ComparisonComparison Avalide 150/12.5 mg Avalide 150/12.5 mg titrated to 300/25 mg titrated to 300/25 mg

vsvsIrbesartan 150 mg Irbesartan 150 mg titrated to 300 mgtitrated to 300 mg

Hyzaar 50/12.5 mgHyzaar 50/12.5 mgtitrated to 100/25 mg titrated to 100/25 mg

vs vs Losartan 50 mgLosartan 50 mg

titrated to 100 mgtitrated to 100 mg

Randomization criteriaRandomization criteria DBP > 110 mmHgDBP > 110 mmHg(twice)(twice)

DBP > 110 mmHgDBP > 110 mmHg(twice)(twice)

Baseline DBPBaseline DBP 113 mmHg 113 mmHg 113 mmHg113 mmHg

Baseline SBPBaseline SBP 172 mmHg172 mmHg 171 mmHg171 mmHg

% titrated to highest % titrated to highest dose of monotherapydose of monotherapy

100%100% 86%86%

No. of previous anti-HTN No. of previous anti-HTN medications allowedmedications allowed

11 33

Salerno. Salerno. J Clin HypertensJ Clin Hypertens. 2004;6:614–620.. 2004;6:614–620.Salerno. Salerno. J Clin HypertensJ Clin Hypertens. 2004;6:614–620.. 2004;6:614–620.

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176: Efficacy Differences Resulting from176: Efficacy Differences Resulting fromStudy DesignStudy Design

Study 176Study 176 HyzaarHyzaar

% achieving DBP < 90 mmHg% achieving DBP < 90 mmHg AvalideAvalide 47%47%

IrbesartanIrbesartan 33%33%

HyzaarHyzaar 20%20%

LosartanLosartan 10%10%

Change from baseline DBPChange from baseline DBP AvalideAvalide -24 mmHg-24 mmHg

IrbesartanIrbesartan -19 mmHg-19 mmHg

HyzaarHyzaar -14 mmHg-14 mmHg

LosartanLosartan -10 mmHg-10 mmHg

Change from baseline SBPChange from baseline SBP AvalideAvalide -31 mmHg-31 mmHg

IrbesartanIrbesartan -21 mmHg-21 mmHg

HyzaarHyzaar -18 mmHg-18 mmHg

LosartanLosartan -12 mmHg-12 mmHg

Salerno. Salerno. J Clin HypertensJ Clin Hypertens. 2004;6:614–620.. 2004;6:614–620.Salerno. Salerno. J Clin HypertensJ Clin Hypertens. 2004;6:614–620.. 2004;6:614–620.

43

Safety ResultsSafety ResultsStudy 176 (Severe)Study 176 (Severe)

44

176: Overall Adverse Events176: Overall Adverse Events

% of Subjects% of Subjects



n = 227n = 227

Adverse EventAdverse Event 29.929.9 36.136.1

Treatment-related AETreatment-related AE 11.311.3 10.110.1

Serious AEsSerious AEs 0.20.2 0.40.4

DiscontinuationsDiscontinuationsdue to AEdue to AE 1.91.9 2.22.2

DeathsDeaths 00 00

45

176: Adverse Events of Special Interest176: Adverse Events of Special Interest



IrbesartanIrbesartanMonotherapMonotherap

yyn = 227n = 227

AEs of Special Interest*AEs of Special Interest* 8.88.8 11.511.5

DizzinessDizziness 3.63.6 4.04.0

HeadacheHeadache 4.34.3 6.66.6

HyperkalemiaHyperkalemia 0.20.2 00

HypokalemiaHypokalemia 0.60.6 0.40.4

HypotensionHypotension 0.60.6 00

SyncopeSyncope 00 00* Investigator reported* Investigator reported

46

PIDPID

Blood Pressure (mmHg)Blood Pressure (mmHg)

Reported AE Reported AE

(Verbatim text)(Verbatim text)Pre-randPre-rand Week 1Week 1 Week 3Week 3 Week 5Week 5 Week 7Week 7

248-1248-132/F32/F

140/111140/111 133/86133/86 133/83133/83 136/96136/96StBP:StBP:

125/92125/92

NANA Hypotension (onset Hypotension (onset DayDay 30, mild intensity, 30, mild intensity, resolved Day 36)resolved Day 36)

288-4288-462/F62/F

156/113156/113 153/105153/105 131/79131/79StBP:StBP:

124/76124/76

133/81133/81 133/78133/78 Dizziness, orthostatic Dizziness, orthostatic hypotension (onset hypotension (onset DayDay 19, moderate 19, moderate intensity, resolved intensity, resolved Day 19)Day 19)

293-2293-238/F38/F

190/125190/125 145/109145/109 133/97133/97StBP:StBP:

136/104136/104

142/103142/103 134/96134/96 Hypotension Hypotension symptomatic (onset symptomatic (onset Day 16, mild intensity, Day 16, mild intensity, resolved Day 24)resolved Day 24)

176: Hypotension Adverse Events176: Hypotension Adverse Events

47

176: Most Common Treatment-related AEs176: Most Common Treatment-related AEs




n = 227n = 227

Treatment-related AETreatment-related AE 11.311.3 10.110.1

DizzinessDizziness 2.62.6 3.13.1

HeadacheHeadache 1.31.3 2.22.2

Erectile DysfunctionErectile Dysfunction 1.1*1.1* 00

FatigueFatigue 1.11.1 0.40.4

Nausea Nausea 0.60.6 1.31.3

* 1.9% of males* 1.9% of males

48

176: Study Discontinuations176: Study Discontinuations




yyn = 229*n = 229*

Total Subjects DiscontinuedTotal Subjects Discontinued 10.310.3 12.212.2

Adverse EventAdverse Event 1.91.9 2.22.2

Lack of EfficacyLack of Efficacy 3.23.2 5.25.2

OtherOther 5.25.2 4.84.8

* 2 subjects discontinued prior to receiving drug* 2 subjects discontinued prior to receiving drug

49

176: Subjects with SBP < 110 mmHg176: Subjects with SBP < 110 mmHg

9 subjects on Avalide (1.9%)9 subjects on Avalide (1.9%)

All < 65 years of ageAll < 65 years of age

No cases at Week 1No cases at Week 1

6 had BP < 140/90 at Week 16 had BP < 140/90 at Week 1

3 had dizziness (2 mild and 1 moderate)3 had dizziness (2 mild and 1 moderate)

50

176: Subjects with DBP < 60 mmHg176: Subjects with DBP < 60 mmHg

1 subject on Avalide (0.2%)1 subject on Avalide (0.2%)

< 65 years of age< 65 years of age

Week 1 BP 121/73 mmHgWeek 1 BP 121/73 mmHg

BP 103/56 mmHg at Week 7BP 103/56 mmHg at Week 7

No adverse eventsNo adverse events

51

176: Safety Results in Elderly176: Safety Results in Elderly

Avalide was well tolerated in subjects Avalide was well tolerated in subjects ≥ 65 years of age (n = 92)≥ 65 years of age (n = 92)

No hypotensionNo hypotension

No syncopeNo syncope

Dizziness in 1.9% of those ≥ 65 years of age Dizziness in 1.9% of those ≥ 65 years of age vs 3.9% in those < 65vs 3.9% in those < 65

Overall AEs 26.4% in those ≥ 65 years of age Overall AEs 26.4% in those ≥ 65 years of age vs 30.4% in those < 65vs 30.4% in those < 65

52

176: Avalide Safety Conclusions176: Avalide Safety Conclusions

Comparable safety to irbesartanComparable safety to irbesartan

No increase in dizzinessNo increase in dizziness

Hypotension was uncommonHypotension was uncommon

– occurred at a frequency consistent with occurred at a frequency consistent with the labelthe label


Well tolerated in elderlyWell tolerated in elderly

53

Efficacy Results Efficacy Results Study 185 (Moderate) Study 185 (Moderate)

54

185: Study Context185: Study Context

Supportive Safety Data for Study 176 (Severe)Supportive Safety Data for Study 176 (Severe)

– hypotensionhypotension

– syncopesyncope

Examine efficacy of HCTZ and irbesartan Examine efficacy of HCTZ and irbesartan monotherapymonotherapy

55

185: Study Design185: Study Design

Placebolead-in

Week 4Week 4 Week 8Week 8Week 2Week 2 Week 12Week 12

HCTZ12.5 mg12.5 mg

Forced titration to 300 mgForced titration to 300 mg

Forced titration to 300/25 mgForced titration to 300/25 mgAvalide

R3:1:1

11° ° endpointendpoint

Irbesartanmonotherapy

Forced titration to 25 mgForced titration to 25 mg

150 mg150 mg

150/12.5 mg150/12.5 mg

56

185: Efficacy Endpoints185: Efficacy Endpoints

PrimaryPrimary

Compare the change from baseline in SBP between Compare the change from baseline in SBP between treatment arms at Week 8treatment arms at Week 8

SecondarySecondary

Change from baseline in DBP between treatment Change from baseline in DBP between treatment arms at Weeks 8, 12arms at Weeks 8, 12

Change from baseline in SBP between treatment Change from baseline in SBP between treatment arms at Week 12arms at Week 12

% with SBP < 140 mmHg and DBP < 90 mmHg % with SBP < 140 mmHg and DBP < 90 mmHg between treatment arms at Weeks 8, 12between treatment arms at Weeks 8, 12

57

185: Safety Endpoints185: Safety Endpoints

Overall frequency of AEsOverall frequency of AEs

Frequency of discontinuations due to AEsFrequency of discontinuations due to AEs

AEs and laboratory abnormalities of special AEs and laboratory abnormalities of special interest after 12 weeks of therapy:interest after 12 weeks of therapy:

– hypotension, dizziness, syncope, headaches, hypotension, dizziness, syncope, headaches, hypokalemia, and hyperkalemiahypokalemia, and hyperkalemia

58

185: Baseline Characteristics185: Baseline Characteristics



n = 106n = 106HCTZHCTZ

n = 104n = 104

Age (years)Age (years) 55.155.1 55.355.3 56.056.0

GenderGender

male (%)male (%) 55.255.2 46.246.2 59.659.6

RaceRace

white (%)white (%) 82.682.6 89.689.6 82.782.7

black (%)black (%) 15.215.2 8.58.5 14.414.4

Diabetes (%)Diabetes (%) 14.314.3 13.213.2 12.512.5

BMI BMI ≥ 30 (%)≥ 30 (%) 47.947.9 49.149.1 45.245.2

Weight (kg)Weight (kg) 87.687.6 88.288.2 88.488.4

Baseline BP (mmHg)Baseline BP (mmHg) 162/98162/98 161/98161/98 162/98162/98

59

185: Primary Endpoint185: Primary EndpointM

ean

Ch

ang

e fr

om

Mea

n C

han

ge

fro

mB

asel

ine

(mm

Hg

)B

asel

ine

(mm

Hg

)

Change in SBP from Baseline to Week 8Change in SBP from Baseline to Week 8

**PP<0.0001 vs HCTZ; <0.0001 vs HCTZ; PP=0.0016 vs irbesartan=0.0016 vs irbesartan

-27.1

-22.1

-15.7

-30

-25

-20

-15

-10

-5

0Avalide

IrbesartanMonotherapy HCTZ

**

60

185: Change in SBP from Baseline185: Change in SBP from Baseline

-30

-25

-20

-15

-10

-5

0


Avalide Irbesartan Monotherapy HCTZ

*

**

*

**PP<0.0001 vs HCTZ; <0.0001 vs HCTZ; PP≤≤0.0044 vs irbesartan0.0044 vs irbesartan

Mea

n C

han

ge

fro

mM

ean

Ch

ang

e fr

om

Bas

elin

e (m

mH

g)

Bas

elin

e (m

mH

g)

61

185: Change in DBP from Baseline185: Change in DBP from Baseline

-20

-15

-10

-5

0



*

**

*Mea

n C

han

ge

fro

mM

ean

Ch

ang

e fr

om

Bas

elin

e (m

mH

g)

Bas

elin

e (m

mH

g)

**PP<0.0001 vs HCTZ; <0.0001 vs HCTZ; PP≤≤0.0147 vs irbesartan0.0147 vs irbesartan

62

Safety Results Safety Results Study 185 (Moderate) Study 185 (Moderate)

63

185: Adverse Events185: Adverse Events





n = 104n = 104

Adverse EventAdverse Event 47.047.0 45.345.3 39.439.4

Treatment-Related AETreatment-Related AE 14.314.3 11.311.3 7.77.7

Serious AEsSerious AEs 1.81.8 00 2.92.9

DiscontinuationsDiscontinuationsdue to AEdue to AE 6.76.7 3.83.8 4.84.8

DeathsDeaths 00 00 00

64

185: SAE of “Symptomatic Hypokalemia”185: SAE of “Symptomatic Hypokalemia”

50-year-old woman with chest pain50-year-old woman with chest pain

On AvalideOn Avalide

Ruled out for myocardial infarctionRuled out for myocardial infarction

KK++ 3.2 mEq/L on one occasion 3.2 mEq/L on one occasion

Cardiac catheterization results normalCardiac catheterization results normal

Investigator felt “probable” relation to study drugInvestigator felt “probable” relation to study drug

65

185: AEs of Special Interest185: AEs of Special Interest





n = 104n = 104

AEs of Special InterestAEs of Special Interest 10.710.7 6.66.6 6.76.7

DizzinessDizziness 3.03.0 3.83.8 1.01.0

HeadacheHeadache 5.55.5 3.83.8 4.84.8

HyperkalemiaHyperkalemia 1.21.2 00 1.01.0

HypokalemiaHypokalemia 0.90.9 00 00

HypotensionHypotension 0.90.9 00 00

SyncopeSyncope 00 00 1.01.0

66

185: Study Discontinuations185: Study Discontinuations

2.1% of patients discontinued Avalide due to dizziness 2.1% of patients discontinued Avalide due to dizziness or hypotensionor hypotension




yyn = 106n = 106

HCTZHCTZn = 104n = 104

Total Subjects Total Subjects DiscontinuedDiscontinued

12.512.5 11.311.3 12.512.5

Adverse EventAdverse Event 6.76.7 3.83.8 4.84.8

Lack of EfficacyLack of Efficacy 0.30.3 0.90.9 1.01.0

OtherOther 5.45.4 6.66.6 6.76.7

67

185: Safety Results in Elderly185: Safety Results in Elderly

Avalide was well tolerated in subjects Avalide was well tolerated in subjects ≥ 65 years of age (n = 68)≥ 65 years of age (n = 68)

No hypotensionNo hypotension


Dizziness in 2.9% of those ≥ 65 years of age Dizziness in 2.9% of those ≥ 65 years of age vs 3.1% of those < 65vs 3.1% of those < 65

Overall AEs 47.1% in those ≥ 65 years of age Overall AEs 47.1% in those ≥ 65 years of age vs 46.9% of those < 65vs 46.9% of those < 65

68

185: Avalide Conclusions185: Avalide Conclusions

Avalide showed better efficacy than irbesartan Avalide showed better efficacy than irbesartan monotherapy and HCTZ monotherapymonotherapy and HCTZ monotherapy

Safety comparable to monotherapySafety comparable to monotherapy

Dizziness and hypotension were consistent Dizziness and hypotension were consistent with the current labelwith the current label

2.1% of patients discontinued due to dizziness 2.1% of patients discontinued due to dizziness or hypotensionor hypotension

Well tolerated in elderlyWell tolerated in elderly

69

Original NDA Matrix Study: Original NDA Matrix Study: Dose-Dependent SBP LoweringDose-Dependent SBP Lowering

-25

-20

-15

-10

-5

0

Placebo

37.5mg

100mg

300mg

Placebo 6.25mg 12.5mg 25mg Irbes

arta

n dose

HCTZ dose

Kochar M et al. Kochar M et al. Am J HypertensAm J Hypertens. 1999;12:797-805.. 1999;12:797-805.

Mea

n c

han

ge

fro

m b

asel

ine

at W

eek

8 (m

m H

g)

70

Matrix Study: Serum Potassium ChangesMatrix Study: Serum Potassium Changes

Kochar M et al. Kochar M et al. Am J HypertensAm J Hypertens. 1999;12:797-805.. 1999;12:797-805.

-0.35

-0.25

-0.15

-0.05

0.05

Placebo

37.5mg

100mg

300mg

Placebo 6.25mg 12.5mg 25mg

HCTZ dose

Ad

just

ed M

ean

Ch

ang

e fr

om

Bas

elin

e (m

Eq

/L)

Irbes

arta

n dose

71

Original NDA: Original NDA: Comparison of Avalide vs. Control – AEsComparison of Avalide vs. Control – AEs

Avalide Compared toAvalide Compared to Adjusted RRAdjusted RR

Approximate 95% Approximate 95% CI for Adjusted CI for Adjusted

RRRR

Irbesartan Irbesartan MonotherapyMonotherapy 1.021.02 (0.91, 1.15)(0.91, 1.15)

HCTZHCTZ 1.041.04 (0.94, 1.16)(0.94, 1.16)

PlaceboPlacebo 1.031.03 (0.90, 1.18)(0.90, 1.18)

Subjects reporting at least one AE

Includes protocols CV131-037, -038, -039, -040

72

Post-marketing Spontaneous Reports:Post-marketing Spontaneous Reports:Avalide vs. IrbesartanAvalide vs. Irbesartan

Over 10 million patient-years of dataOver 10 million patient-years of data

Thorough review of eventsThorough review of events

Rates of events were lowRates of events were low

No safety concernsNo safety concerns

Detail: BMS Briefing Book – Table 4, p. 42

73

Overall Safety of AvalideOverall Safety of Avalide

Low incidence of dose-dependent side effectsLow incidence of dose-dependent side effects Pivotal Study 176Pivotal Study 176 Supportive Study 185Supportive Study 185

No signal of dose-independent side effectsNo signal of dose-independent side effects Original NDAOriginal NDA Post-marketing surveillancePost-marketing surveillance

74

Benefit / RiskBenefit / Risk

Michael Weber, MDMichael Weber, MD

Professor of MedicineProfessor of MedicineSUNY Downstate Medical Center SUNY Downstate Medical Center College of MedicineCollege of MedicineBrooklyn, New YorkBrooklyn, New York

75

Benefit / Risk Profile of Benefit / Risk Profile of Initial Combination TherapyInitial Combination Therapy

1.1. Overall rationaleOverall rationale

2.2. RisksRisks

3.3. BenefitsBenefits

– avoiding severe blood pressure elevationsavoiding severe blood pressure elevations

– long-term blood pressure advantageslong-term blood pressure advantages

– preventing cardiovascular eventspreventing cardiovascular events

76

Rationale for Initial Combination TherapyRationale for Initial Combination Therapy

Why consider an ARB/Thiazide combination as initial treatment?

Combination vs. ARB alone:Combination vs. ARB alone:– equal safetyequal safety– greater efficacygreater efficacy

Combination vs. HCTZ alone:Combination vs. HCTZ alone:– greater safetygreater safety– greater efficacygreater efficacy

77

Effects of Low-Dose Combination Therapy: MetaEffects of Low-Dose Combination Therapy: Meta Analysis of 50 Studies Analysis of 50 Studies (Treatment vs. Placebo)(Treatment vs. Placebo)

-8.1

-14.6

-4.1 -4.6

-8.6

-7.0

-17

-15

-13

-11

-9

-7

-5

-3

-1

One combinationcomponent

Other combinationcomponent

Combination therapy(actual)

Systolic BP

Diastolic BP

Mea

n d

ecre

ase

in B

P v

s p

lace

bo

(m

m H

g)

Law et al. Law et al. BMJBMJ 2003; 326:1-8. 2003; 326:1-8.

78

Meta-analysis: Value of Combination TherapyMeta-analysis: Value of Combination Therapy

Benefit/Risk Analysis of Law and ColleaguesBenefit/Risk Analysis of Law and Colleagues

Minimal metabolic effects of low-dose diuretics in Minimal metabolic effects of low-dose diuretics in combinations did not compromise safetycombinations did not compromise safety

Incremental benefits projected to prevent CVDIncremental benefits projected to prevent CVD

Law et al. Law et al. BMJBMJ 2003; 326:1-8. 2003; 326:1-8.

79

ARB/Thiazide Potential Risk: HypotensionARB/Thiazide Potential Risk: Hypotension

Is there a serious risk of hypotension with 1st-line combination therapy?

Study 176 (severe)Study 176 (severe)– hypotension 0.6% on Avalidehypotension 0.6% on Avalide– 3/3 on maximum dose3/3 on maximum dose

Study 185 (moderate)Study 185 (moderate)– hypotension 0.9% on Avalidehypotension 0.9% on Avalide– 2/3 on maximum dose2/3 on maximum dose

80

Why Is Starting Treatment with HCTZ Why Is Starting Treatment with HCTZ Possibly a Greater Risk than Starting with Possibly a Greater Risk than Starting with Combination Treatment?Combination Treatment?

HCTZ in monotherapy doses that are efficacious HCTZ in monotherapy doses that are efficacious causes metabolic changescauses metabolic changes

After HCTZ is established, adding an ARB can After HCTZ is established, adding an ARB can produce hypotensionproduce hypotension

81

Risk of Hypotension with Diuretic MonotherapyRisk of Hypotension with Diuretic Monotherapy

WARNINGWARNING

““Initiation of antihypertensive therapy may cause Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with symptomatic hypotension in patients with intravascular volume or sodium depletion…such intravascular volume or sodium depletion…such volume depletion should be corrected prior to volume depletion should be corrected prior to administration of Avapro”administration of Avapro”

From Avapro Package InsertFrom Avapro Package Insert(Similar to all other ARBs, ACE inhibitors and renin inhibitors)(Similar to all other ARBs, ACE inhibitors and renin inhibitors)

82

Benefits of Initial AvalideBenefits of Initial Avalide

Avoiding severe blood pressure elevationsAvoiding severe blood pressure elevations

– Study 176 (severe)Study 176 (severe)

Sustained blood pressure reduction with Sustained blood pressure reduction with potential cardiovascular protectionpotential cardiovascular protection

– Study 176 (severe)Study 176 (severe)

– Study 185 (moderate)Study 185 (moderate)

83

176: Reducing Severe Blood Pressure Levels 176: Reducing Severe Blood Pressure Levels (Baseline BP = 172/113 mmHg)(Baseline BP = 172/113 mmHg)

Mean BP difference = 10/5 mmHgMean BP difference = 10/5 mmHg

% of Patients% of Patients

BP category at Week 5BP category at Week 5 AvalideAvalideIrbesartan Irbesartan

MonotherapyMonotherapy p-valuep-value

SevereSevere(SBP ≥ 180 or DBP ≥ 110)(SBP ≥ 180 or DBP ≥ 110) 55 1414 0.00030.0003

ModerateModerate(SBP 160-179 or DBP 100-110)(SBP 160-179 or DBP 100-110) 1616 3030 <0.0001<0.0001

JNC 7 Stage 2 JNC 7 Stage 2 (moderate & severe)(moderate & severe) 2121 4444

84

StudyNumber on

PlaceboFollow-Up Time

(Years)Excess Events

on Placebo

Excess Riskof Events*

(per patient-yr)

VA Study I 1967 70 1.3 25 27%

VA Study II 1972 110 3.3 37 11%

NHLBI, 1966 42 2 13 14%

Risk of HTN Emergencies inRisk of HTN Emergencies inSevere HypertensionSevere Hypertension

Active treatment yielded immediate benefitsActive treatment yielded immediate benefits

* Compared with active treatment* Compared with active treatment

VA Cooperative Study Group. VA Cooperative Study Group. JAMAJAMA. 1967;202:1028-1034. 1967;202:1028-1034..VA Cooperative Study Group. Circulation 1972; 45:991-1004.VA Cooperative Study Group. Circulation 1972; 45:991-1004.Wolff and Lindeman. Wolff and Lindeman. J Chronic DisJ Chronic Dis. 1966;19:227-240. 1966;19:227-240..

85

Sustained BP ReductionSustained BP Reduction

Initial Avalide provides additional BP reduction Initial Avalide provides additional BP reduction

– Study 176 (severe):Study 176 (severe): 10/510/5 vs irbesartanvs irbesartan

– Study 185 (moderate):Study 185 (moderate): 5/35/3 vs irbesartanvs irbesartan11/711/7 vs HCTZvs HCTZ

Clinical trialsClinical trials

– BP reduction persists long-termBP reduction persists long-term

Epidemiology studiesEpidemiology studies

– lower BP associated with lower CV risklower BP associated with lower CV risk

86

CI, confidence interval; IHD, ischemic heart disease

Systolic Blood PressureSystolic Blood Pressure

40-49 years

50-59 years

60-69 years

70-79 years

80-89 yearsAge at risk:

CHD mortality(floating

absolute risk and 95% CI)

256

128

64

32

16

8

4

2

1

120 140 160 180Usual SBP (mm Hg)

Diastolic Blood PressureDiastolic Blood Pressure

256

128

64

32

16

8

4

2

1

70 80 90 100 110

Usual DBP (mm Hg)

Age at risk:

40-49 years

50-59 years

60-69 years

70-79 years

80-89 years

Lewington S et al. Lancet. 2002;360(9349):1903-1913Lewington S et al. Lancet. 2002;360(9349):1903-1913

Coronary Heart Disease Rates byCoronary Heart Disease Rates bySBP, DBP, and AgeSBP, DBP, and Age

87

Initial Efficacy Is Related to Long-term Initial Efficacy Is Related to Long-term OutcomesOutcomes

Early, inadequate blood pressure responses are Early, inadequate blood pressure responses are never fully corrected (ASCOT, VALUE, ALLHAT)never fully corrected (ASCOT, VALUE, ALLHAT)

1st-line combination therapy associated with the 1st-line combination therapy associated with the best BP control ever reported in a large best BP control ever reported in a large hypertension outcomes study (ACCOMPLISH)hypertension outcomes study (ACCOMPLISH)

– 73% patients <140/90 by 6 months*73% patients <140/90 by 6 months*

*Jamerson K et al, ASH Abstract, 2007*Jamerson K et al, ASH Abstract, 2007

88

Patients on Monotherapy Do Not Catch Up with Patients on Monotherapy Do Not Catch Up with Those Starting on a CombinationThose Starting on a Combination Follow-up visits are inadequateFollow-up visits are inadequate

– can be costly and inconvenient for patientscan be costly and inconvenient for patients

– some health plans encourage prescription refills, but some health plans encourage prescription refills, but do not incentivize doctor visits do not incentivize doctor visits

– practitioners renewing prescriptions in multi-doctor practitioners renewing prescriptions in multi-doctor settings may not be aware of the original treatment settings may not be aware of the original treatment goalgoal

– simple regimens preferred by patients and doctorssimple regimens preferred by patients and doctors

BP varies between visitsBP varies between visits

– physicians wait before taking action*physicians wait before taking action*

– physicians intensify treatment at only 40% of visits physicians intensify treatment at only 40% of visits even when hypertension severe*even when hypertension severe*

* Berlowitz et al, NEJM 1998; 339:1957, and personal communication* Berlowitz et al, NEJM 1998; 339:1957, and personal communication

89

132

134

136

138

140

142

144

146

148

0 1 2 3 4 5Year

mm

Hg

Lisinopril

Chlorthalidone

ALLHAT: Early BP Differences PersistedALLHAT: Early BP Differences Persisted

Systolic Blood Pressure

ALLHAT Collaborative Research Group. JAMA. 2000; 283: 1967-75

90

Early BP Differences Associated with OutcomesEarly BP Differences Associated with Outcomes

ALLHATALLHAT11: 15% : 15% stroke (p=0.02) stroke (p=0.02)– chlorthalidone vs lisinoprilchlorthalidone vs lisinopril

Syst-EurSyst-Eur22: 28% : 28% stroke (p=0.01) stroke (p=0.01)– early vs late treatment with CCBearly vs late treatment with CCB

SCOPESCOPE33: 28% : 28% stroke (p=0.04) stroke (p=0.04)– candesartan vs controlcandesartan vs control

ASCOTASCOT44: 23% : 23% stroke (p=0.0003) stroke (p=0.0003)– amlodipine-based regimenamlodipine-based regimen

1. ALLHAT Collaborative Research Group. JAMA. 2000; 283: 1967-75. 2. Staessen et al. Lancet. 1997;350(9080):757-64. 3. Lithell et al. J Hypertens. 2003;21:875-886. 4. Dahlöf et al. Lancet. 2005;366:895–906.

91Julius S et al. Julius S et al. LancetLancet. June 2004;363.. June 2004;363.

0

1.0

2.0

3.0

4.0

1 24 48

mm

Hg

2 3 4 6 12 18 30 36 42 54 60 66

Months(or final visit)

5.0

Difference in SBP Between Valsartan and Amlodipine

–1.0

VALUE: Early Difference in BP PersistedVALUE: Early Difference in BP Persisted

92Julius S et al. Lancet. June 2004;363.

Odds Ratios and 95% CIs

Favors valsartan Favors amlodipine

1.0 2.00.5

Time Interval(months)

Overall study

36–4824–3612–246–12

0–3

Study end

SBP(mmHg)

1.41.61.82.0

3.8

1.7

2.2

3–6 2.3

0.25 4.0

STROKE

VALUE: Outcome and SBP Differencesat Specific Time Periods: Stroke

93

Summarizing Overall Risks & BenefitsSummarizing Overall Risks & Benefits

94

Overall RiskOverall Risk

Avalide safety adequately demonstratedAvalide safety adequately demonstrated

– Study 176, Study 185, Original NDA,Study 176, Study 185, Original NDA,Post-marketing surveillancePost-marketing surveillance

Meta-analyses have shown low-dose combinations Meta-analyses have shown low-dose combinations do not compromise safetydo not compromise safety

Initial Avalide safety may be better than with HCTZ Initial Avalide safety may be better than with HCTZ monotherapy monotherapy

– fewer metabolic effects (lower HCTZ doses, fewer metabolic effects (lower HCTZ doses, compensating effects of ARB)compensating effects of ARB)

– lower risk of hypotension than if ARB added to lower risk of hypotension than if ARB added to therapeutic dose of diuretictherapeutic dose of diuretic

95

Overall BenefitOverall Benefit

Initial Avalide provides additional BP reduction Initial Avalide provides additional BP reduction

– Study 176 (severe):Study 176 (severe): 10/510/5 vs irbesartanvs irbesartan

– Study 185 (moderate):Study 185 (moderate): 5/35/3 vs irbesartanvs irbesartan11/711/7 vs HCTZvs HCTZ

Short-term 2–3 mmHg additional BP lowering Short-term 2–3 mmHg additional BP lowering considered clinically meaningfulconsidered clinically meaningful

Early advantages in BP reduction persist and are Early advantages in BP reduction persist and are associated with better long-term outcomesassociated with better long-term outcomes

96

Benefit / Risk ConclusionBenefit / Risk Conclusion

Initial use of Avalide can provide greater efficacy Initial use of Avalide can provide greater efficacy without compromising safetywithout compromising safety

Patients with severe hypertensionPatients with severe hypertension

Patients 20/10 away from goalPatients 20/10 away from goal

Patients at increased CV risk (diabetes, CKD, CHD)Patients at increased CV risk (diabetes, CKD, CHD)

97

ConclusionsConclusions

Anthony Waclawski, PhDAnthony Waclawski, PhD

Vice PresidentVice PresidentGlobal Regulatory SciencesGlobal Regulatory SciencesResearch and Development Research and Development Bristol-Myers SquibbBristol-Myers Squibb

98

Safety and Efficacy Conclusions Safety and Efficacy Conclusions

Avalide, compared to irbesartan monotherapy…Avalide, compared to irbesartan monotherapy… Lowered blood pressure Lowered blood pressure

– furtherfurther– more rapidlymore rapidly– in a higher proportion of patientsin a higher proportion of patientswith a similar safety and tolerability profilewith a similar safety and tolerability profile

Hypotension was infrequent and not severe Hypotension was infrequent and not severe

Risk of HCTZ-related hypokalemia is decreased by Risk of HCTZ-related hypokalemia is decreased by irbesartanirbesartan

Dose-independent side effects are very rare: Dose-independent side effects are very rare: in post-marketing data, published meta-analysisin post-marketing data, published meta-analysis

99

Proposed Labeling RevisionProposed Labeling Revision

Add an indication: Add an indication: Initial use in severe hypertensionInitial use in severe hypertension

Remove restriction requiring titration with a Remove restriction requiring titration with a component before using Avalide component before using Avalide

Provide guidance to physiciansProvide guidance to physicians

0

20

40

60

80

100

150 160 170 180 190 200

0

20

40

60

80

100

110 115 120

% o

f P

atie

nts

% o

f P

atie

nts

Baseline DBP (mmHg)Baseline DBP (mmHg)Baseline SBP (mmHg)Baseline SBP (mmHg)

AvalideAvalide


AvalideAvalide


% o

f P

atie

nts

% o

f P

atie

nts

Probability of Achieving SBP <140 mmHg at Week 5 Probability of Achieving SBP <140 mmHg at Week 5 Probability of Achieving DBP <90 mmHg at Week 5 Probability of Achieving DBP <90 mmHg at Week 5

100

Overall ConclusionsOverall Conclusions

Appropriate labeling of Avalide will result in:Appropriate labeling of Avalide will result in:

Reduced exposure to severe hypertensionReduced exposure to severe hypertension

– potential for fewer hypertensive emergenciespotential for fewer hypertensive emergencies

Lower overall BPLower overall BP

– potential for fewer CV eventspotential for fewer CV events

101

ADDITIONAL SLIDESADDITIONAL SLIDES

102

Risk of First CV Event: Christiana CareRisk of First CV Event: Christiana Care

100.0080.0060.0040.0020.000.00

0.10

0.08

0.06

0.04

0.02

0.00

Cu

mu

lati

ve H

azar

d f

or

CV

Eve

nt

Time to CV Event (months)

Adjusted Risk of Cardiovascular EventsAdjusted Risk of Cardiovascular Eventsby Severity of Hypertensionby Severity of Hypertension

Severe (n = 2025)Severe (n = 2025)

Mild and ModerateMild and Moderate

NormalNormal

Total N = 16,719Total N = 16,719

Personal communication Bill Weintraub, MDPersonal communication Bill Weintraub, MD 63 - 1

103

Awareness, Treatment, and Control of Awareness, Treatment, and Control of Hypertension in the USHypertension in the US

51

69 68 69 71

31

52 5258 61

10

25 2331 34

0

10

20

30

40

50

60

70

80

NHANES II1976-1980

NHANES III(Phase 1)1988-1991

NHANES III(Phase 2)1991-1994

NHANES1999-2000

NHANES2001-2002

Awareness

Treatment

Control

Hyp

erte

nsi

ve A

du

lts

(%)

Hypertension, Awareness, Treatment, and Control: US 1976 to 2002

Cheung et al. J Clin Hypertens. 2006;8:93–98.63 - 14

104

176: BP Medications Prior to Double-blind 176: BP Medications Prior to Double-blind TreatmentTreatment


Drug ClassDrug Class

AvalideAvalide

n = 468n = 468

Irbesartan Irbesartan monotherapymonotherapy

n = 229n = 229

AlphaAlpha11 blocking agent blocking agent 0.20.2 0.40.4

AlphaAlpha22 agonist agonist 1.71.7 0.90.9

Angiotensin Converting Enzyme Angiotensin Converting Enzyme InhibitorInhibitor 17.417.4 22.622.6

Angiotensin Receptor BlockerAngiotensin Receptor Blocker 14.814.8 12.212.2

Beta BlockerBeta Blocker 6.56.5 9.69.6

Calcium Channel BlockerCalcium Channel Blocker 8.58.5 12.512.5

DiureticDiuretic 4.54.5 3.03.0

OtherOther 1.41.4 1.61.6

33 - 11

105

44.5%

53.4%55.8%

40.6%

26.5%

20.8%

29.2%

34.0%

25.0%

20.2%17.3%

14.4%

0%

10%

20%

30%

40%

50%

60%


AvalideIrbesartanHCTZ

Su

bje

cts

(%)

††

**

**

* P<0.0001 vs HCTZ; P<0.05 vs irbesartan. † P<0.0001 vs HCTZ and vs Irbesartan.

185: Percent of Subjects with BP Control185: Percent of Subjects with BP ControlBP <BP < 140/90 mmHg140/90 mmHg

25 - 104

106

Results from 176 and 185 by Baseline SBP: Results from 176 and 185 by Baseline SBP: Combined TargetCombined Target

0102030405060708090

100

150 160 170 180 190 200

% o

f P

atie

nts

% o

f P

atie

nts

Baseline SBP (mmHg)Baseline SBP (mmHg) Baseline SBP (mmHg)Baseline SBP (mmHg)

Probability of Achieving BP <140/90 mmHgProbability of Achieving BP <140/90 mmHg

AvalideIrbesartan Monotherapy

% o

f P

atie

nts

% o

f P

atie

nts

Study 176Study 176Results at Week 5Results at Week 5

Study 185Study 185Results at Week 8Results at Week 8

0102030405060708090

100

140 150 160 170 180

51 - 101

107

176: Model for 130/80176: Model for 130/80

0102030405060708090

100

150 160 170 180 190 200

% o

f P

atie

nts

% o

f P

atie

nts

0102030405060708090

100

110 115 120%

of

Pat

ien

ts%

of

Pat

ien

ts

Baseline SBP (mmHg)Baseline SBP (mmHg) Baseline DBP (mmHg)Baseline DBP (mmHg)


* Using subjects with baseline DBP between 110 and 130 mmHg and SBP < 220 mmHg

Probability of Achieving BP <130/80Probability of Achieving BP <130/80at Week 5at Week 5


51 - 24

108

185: Model for BP 130/80185: Model for BP 130/80

0102030405060708090

100

130 140 150 160 170 180

% o

f P

atie

nts

% o

f P

atie

nts


% o

f P

atie

nts

% o

f P

atie

nts


0102030405060708090

100

90 100 110



51 - 87

109

176: Model Variability176: Model Variability

0102030405060708090

100

150 160 170 180 190 200

0102030405060708090

100

110 115 120

Probability of Achieving DBP <90Probability of Achieving DBP <90at Week 5at Week 5

Probability of Achieving SBP <140Probability of Achieving SBP <140at Week 5at Week 5

% o

f P

atie

nts

% o

f P

atie

nts


AvalideAvalide CI

Irbesartan MonotherapyIrbesartan Monotherapy CI

* Using subjects with baseline DBP between 110 and 130 mmHg and SBP < 220 mmHg 51 - 32

110

Mean BP Change at Week 8Mean BP Change at Week 8by Race by Race Study 185

-21.7

-28.1

-13.9 -14.7-12.4

-22.8

-6.5

-12.2

-30

-20

-10

0

Black Non-Black Black Non-Black

Avalide Irbesartan Monotherapy

Ch

ang

e in

Blo

od

Pre

ssu

re (

mm

Hg

)

Systolic Diastolic

n = 46 7 257 88 46 7 257 88

25 - 59

111

Mean BP Change at Week 8Mean BP Change at Week 8by Race by Race Study 185

-21.7

-28.1

-13.9 -14.7-12.4

-22.8

-6.5

-12.2

-5.8

-17.1

-1.7

-8.0

-30

-20

-10

0



Ch

ang

e in

Blo

od

Pre

ssu

re (

mm

Hg

)

Systolic Diastolic

n = 46 7 12 257 88 83 46 7 12 257 88 83

25 - 136

112

-29.6 -30.9

-36.8

-24.1 -23.8-25.6

-21.8-19.0

-33.1

-18.6 -18.9

-24.9

-40

-30

-20

-10

0


176: Mean BP Change at Week 5 176: Mean BP Change at Week 5 by Stage of Renal Function by Stage of Renal Function

Ch

ang

e in

Blo

od

Pre

ssu

re (

mm

Hg

)

Systolic Diastolic

n = 171 73 225 118 24 15 171 73 225 118 24 15

Stage 1Stage 1 Stage 2Stage 2 Stage 3Stage 3 Stage 1Stage 1 Stage 2Stage 2 Stage 3Stage 3

GFR GFR ≥≥9090 GFR 60-89GFR 60-89 GFR 30-59GFR 30-59 GFR GFR ≥≥9090 GFR 60-89GFR 60-89 GFR 30-59GFR 30-59

25 - 207

113

-25.1-27.4

-10.4

-15.2-16.7

-22.9

-9.7

-12.2

-17.2-15.5

-10.3

-6.8

-30

-20

-10

0

Diabetes No Diabetes Diabetes No Diabetes


Mean BP Change at Week 8 Mean BP Change at Week 8 by Diabetes Statusby Diabetes StatusStudy 185

Ch

ang

e in

Blo

od

Pre

ssu

re (

mm

Hg

)

Systolic Diastolic

n = 41 14 10 262 81 85 41 14 10 262 81 85

25 - 132

114

176: Proportion of Subjects with176: Proportion of Subjects withOrthostatic ChangesOrthostatic Changes* *

AvalideAvalideIrbesartanIrbesartan

MonotherapyMonotherapy

BaselineBaseline 3.33.3 3.13.1

Week 1Week 1 3.13.1 3.23.2

Week 3Week 3 2.02.0 2.72.7

Week 5Week 5 1.41.4 1.01.0

Week 7Week 7 0.90.9 2.52.5

*Either the (SeSBP-StSBP) 20 mmHg or (SeDBP-StDBP) 10 mmHg 35 - 175

115

Mean BP Change at Week 18 with Avalide Mean BP Change at Week 18 with Avalide by Raceby RaceINCLUSIVE Study

-21.5

-10.6

-20.7

-9.7

-30

-20

-10

0

White BlackCh

ang

e in

Blo

od

Pre

ssu

re (

mm

Hg

)

n = 454 157 454 157

After 2 weeks HCTZ, 8 weeks Avalide 150/12.5 mg, and 8 weeks Avalide 300/25 mgBaseline BP: White: 154 / 91; Black: 156 / 94

Systolic Diastolic

25 - 182

116

Risks of Initial Use of Avalide vs. Irbesartan – Risks of Initial Use of Avalide vs. Irbesartan – Pharmetrics Observational Study, 1997-2006Pharmetrics Observational Study, 1997-2006

0.10 1.00 10.00

Hypokalemia

Hypotension

Syncope

Evidence of renal failure

New-onset Diabetes*

Allergic reactions

Gout

Pancreatitis

Lower Risk with Irbesartan Monotherapy

Lower Risk with Avalide Adverse Event

Risk Ratio (95% CI)

*Patients with a history of diabetes were excluded from this analysis 31 - 60

117

Baseline Characteristics of Subjects in the Baseline Characteristics of Subjects in the Pharmetrics StudyPharmetrics Study

Baseline Characteristics Avalide Irbesartan HCTZ

Mean Age (SD) 51.7 (8.6) 52.3 (8.8) 51.3 (9.4)

Gender (% Male) 49.5 51.9 44.2

History of diabetes (%) 21.6 30.9 14.8

History of congestive heart failure (%) 2.8 6.2 2.6

History of cardiovascular disease (%) 1.1 2.7 1.0

Concomitant use of HCTZ (%) 5.65 8.83 —

Concomitant use of other antihypertensives (%)

54.9 62.2 58.2

31 - 79

118

Improved Adherence with Combination Improved Adherence with Combination Therapy: Amlodipine/AtorvastatinTherapy: Amlodipine/Atorvastatin

Retrospective analysis of claims in elderly insured population, n=2,098Adherence defined as % days covered ≥ 80%

Patel et al. Circ 2006: Suppl A

% A

dh

ere

nt

0

10

20

30

40

50

60

70

80

Combo Separate components

P<0.0001

63 - 53

119

Improved Adherence with Combination Improved Adherence with Combination Therapy: Metformin/GlyburideTherapy: Metformin/Glyburide

Retrospective analysis of claims in managed care population, n=6,502Adherence defined as % days covered ≥ 80%

Melikian et al. Clin Ther 2002 Mar;24(3):460-7.

0

5

10

15

20

25

30

35

Switch to combo Add 2nd pill

P<0.001

% A

dh

ere

nt

63 - 54

120

0

10

20

30

40

50

60

70

80

Lisin/HCTZ Enal/HCTZ

Combo Pill

SeparateComponents

Improved Persistence with Combination Improved Persistence with Combination Therapy: ACE/DiureticTherapy: ACE/Diuretic

Dezii CM. Manag Care 2000 Sep;9(9 Suppl):2-6.

Retrospective analysis of claims in managed care population, n=3,942Persistent defined as refilling medication within 3x # days prescribed

% P

ers

iste

nt

*P<0.05

* *

63 - 55

121

PurposePurpose

Research designed to determine the utility of 2-D Research designed to determine the utility of 2-D figures compared to 3-D figures to:figures compared to 3-D figures to:

Interpret the relationship between baseline blood Interpret the relationship between baseline blood pressure and the proportion of patients reaching pressure and the proportion of patients reaching BP goalBP goal

What is the best way to show the magnitude of What is the best way to show the magnitude of the BP reduction datathe BP reduction data

47 - 2

Label Research

122

MethodsMethods Online survey: Online survey:

– 985 US physicians 985 US physicians – >20 hypertensive patients per week >20 hypertensive patients per week

Exposure to:Exposure to:– product descriptionproduct description– one of four displays one of four displays

(two 2-D graphs; two 3-D graphs)(two 2-D graphs; two 3-D graphs)

Asked to:Asked to:– identify % patients attaining goal based on SBP identify % patients attaining goal based on SBP

and/or DBP baseline levelsand/or DBP baseline levels– assess understandability and helpfulness assess understandability and helpfulness

47 - 3

Label Research

123

Graph 1Graph 1

* Using subjects with baseline DBP between 110 and 130 mmHg and SBP < 220 mmHg

Example:The probability of a patient with a baseline BP of 180/115 mmHg achieving a goal BP of <140/90 mmHg would be 14% with monotherapy, and 23% with combination therapy.

47 - 4

Label Research

124

% o

f P

atie

nts

Ach

ievi

ng

BP

<14

0/90

mm

Hg

Baseline SBP (mmHg)

Probability of Achieving BP <140/90 mmHg at Week 5by Treatment Group

ARB (Fixed Combination)ARB (Monotherapy)

% o

f P

atie

nts

Ach

ievi

ng

BP

<14

0/90

mm

Hg

Baseline DBP (mmHg)

Probability of Achieving BP <140/90 mmHg at Week 5by Treatment Group


0102030405060708090

100

150 160 170 180 190 200

0102030405060708090

100

110 115 120

Graph 2Graph 2

Example:The probability of a patient with a baseline SBP of 180 mm Hg achieving a goal BP of <140/90 mmHg would be 13% with monotherapy, and 26% with combination therapy.

Example:The probability of a patient with a baseline DBP of 115 mm Hg achieving a goal BP of <140/90 mmHg would be 14% with monotherapy, and 29% with combination therapy.

47 - 5

Label Research

125

Graph 3Graph 3

Example:The probability of a patient with a baseline SPB of 180 mm Hg achieving a goal SBP of <140 mmHg would be 16% with monotherapy, and 34% with combination therapy.

Example:The probability of a patient with a baseline DPB of 115 mm Hg achieving a goal DBP of <90 mmHg would be 28% with monotherapy, and 42% with combination therapy.

% o

f P

atie

nts

Ach

ievi

ng

SB

P <

140

mm

Hg

Baseline SBP (mmHg)

Probability of Achieving SBP <140 mmHg at Week 5by Treatment Group


% o

f P

atie

nts

Ach

ievi

ng

DB

P <

90 m

mH

g

Baseline DBP (mmHg)

Probability of Achieving DBP <90 mmHg at Week 5by Treatment Group


0102030405060708090

100

150 160 170 180 190 200

0102030405060708090

100

110 115 120

47 - 6

Label Research

126

Graph 4Graph 4

Example:The probability of a patient with a baseline BP of 180/115 mmHg achieving a goal BP of <140/90 mmHg would be 14% with monotherapy, and 23% with combination therapy.

47 - 7

Label Research

127

ResultsResults

3-D3-D 2-D2-D

Graph 1Graph 1

(n = 245)(n = 245)

Graph 4Graph 4

(n = 243)(n = 243)

Graph 2Graph 2

(n = 253)(n = 253)

Graph 3Graph 3

(n = 244)(n = 244)

Unable to Respond*Unable to Respond* 22%22% 29%29% 11%11%†† 11%11%††

Comprehension**Comprehension** 2% - 13%2% - 13% 3% - 13%3% - 13% 1% - 7%1% - 7% 2% - 8%2% - 8%

Easy to UnderstandEasy to Understand 6%6% 5%5% 45%45%†† 45%45%††

Helpful***Helpful*** 38%38% 29%29% 63%63%†† 69%69%††

*% of physicians responding “Don’t know/Can’t tell”

**Represents the range of the mean percent difference from correct answer of those responding to each of the four baseline sample BPs given

*** When choosing fixed combination vs monotherapy as initial therapy

†Statistically significant difference from Graphs 1 and 4 47 - 8

Label Research

128

Mean BP Change at Week 5 Mean BP Change at Week 5 by Race by Race Study 176

-26.8

-31.5

-22.0-24.3

-13.7

-22.2

-12.9

-20.3

-40

-30

-20

-10

0



Ch

ang

e in

Blo

od

Pre

ssu

re (

mm

Hg

)

Systolic Diastolic

n = 59 29 364 177 59 29 364 177

25 - 54

129

Current Avalide Labeling – Race Current Avalide Labeling – Race

Irbesartan monotherapy was effective in reducing Irbesartan monotherapy was effective in reducing blood pressure regardless of raceblood pressure regardless of race– the effect was somewhat less in blacks the effect was somewhat less in blacks

(usually a low-renin population)(usually a low-renin population)

Black patients show an improved response with Black patients show an improved response with the addition of a low dose diuretic (e.g., 12.5 mg the addition of a low dose diuretic (e.g., 12.5 mg hydrochlorothiazide) as in Avalidehydrochlorothiazide) as in Avalide

41 - 31

130

176: Magnitude of Response at Week 5176: Magnitude of Response at Week 5

-60

-50

-40

-30

-20

-10

0


Baseline SBP (mmHg)

Post-hoc analysisPost-hoc analysis

n = 33 16 63 33 112 53 92 46 74 34 23 12 26 12

<150 150-159 160-169 170-179 180-189 190-199 ≥200

SB

P C

han

ge

fro

m B

asel

ine

(mm

Hg

)S

BP

Ch

ang

e fr

om

Bas

elin

e (m

mH

g)

51 - 30

131

176: Magnitude of Response at Week 5176: Magnitude of Response at Week 5

Post-hoc analysisPost-hoc analysis

-50

-40

-30

-20

-10

0


SB

P C

han

ge

fro

m B

asel

ine

(mm

Hg

)S

BP

Ch

ang

e fr

om

Bas

elin

e (m

mH

g)

Baseline SBP (mmHg)

<180 ≥180n = 300 148 123 58

51 - 31

1 Avalide ® (irbesartan/hydrochlorothiazide) NDA 20-758 S-037 For Initial Treatment of Severe...

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