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Transcript of 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
10
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
11
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
12
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
13
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.
14
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
15
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
17
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
18
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
19
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
20
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
21
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
22
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
23
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
24
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
25
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
26
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
27
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
28
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
29
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
30
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
31
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
33
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
Week 1 Week 3 Week 5 Week 7
Avalide
Irbesartan Monotherapy
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
Week 1 Week 3 Week 5 Week 7
Avalide
Irbesartan Monotherapy
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
Irbesartan Monotherapy
Avalide
37%
21%
42%
36%
16%
30%
5%
14%
††
37
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
Irbesartan Monotherapy
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
Irbesartan Monotherapy
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
IrbesartanIrbesartanMonotherapyMonotherapy
AvalideAvalide
IrbesartanIrbesartanMonotherapyMonotherapy
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.
42
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
AvalideAvaliden = 468n = 468
IrbesartanIrbesartanMonotherapyMonotherapy
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
% of Subjects% of Subjects
AvalideAvaliden = 468n = 468
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
% of Subjects% of Subjects
AvalideAvaliden = 468n = 468
IrbesartanIrbesartanMonotherapyMonotherapy
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
% of Subjects% of Subjects
AvalideAvaliden = 468n = 468
IrbesartanIrbesartanMonotherapMonotherap
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
No syncopeNo syncope
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
AvalideAvaliden = 328n = 328
IrbesartanIrbesartanMonotherapyMonotherapy
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
Week 2 Week 4 Week 8 Week 12
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
Week 2 Week 4 Week 8 Week 12
Avalide Irbesartan Monotherapy HCTZ
*
**
*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
% of Subjects% of Subjects
AvalideAvaliden = 328n = 328
IrbesartanIrbesartanMonotherapyMonotherapy
n = 106n = 106HCTZHCTZ
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
% of Subjects% of Subjects
AvalideAvaliden = 328n = 328
IrbesartanIrbesartanMonotherapyMonotherapy
n = 106n = 106HCTZHCTZ
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
% of Subjects% of Subjects
AvalideAvaliden = 328n = 328
IrbesartanIrbesartanMonotherapMonotherap
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
No syncopeNo syncope
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
IrbesartanIrbesartanMonotherapyMonotherapy
AvalideAvalide
IrbesartanIrbesartanMonotherapyMonotherapy
% 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
% of Subjects% of Subjects
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%
Week 2 Week 4 Week 8 Week 12
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)
AvalideIrbesartan Monotherapy
* 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
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
Baseline SBP (mmHg)Baseline SBP (mmHg) Baseline DBP (mmHg)Baseline DBP (mmHg)
% o
f P
atie
nts
% o
f P
atie
nts
AvalideIrbesartan Monotherapy
0102030405060708090
100
90 100 110
Probability of Achieving BP <130/80Probability of Achieving BP <130/80at Week 8at Week 8
Probability of Achieving BP <130/80Probability of Achieving BP <130/80at Week 8at Week 8
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
Baseline SBP (mmHg)Baseline SBP (mmHg) Baseline DBP (mmHg)Baseline DBP (mmHg)
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
Black Non-Black Black Non-Black
Avalide Irbesartan Monotherapy HCTZ
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
Avalide Irbesartan Monotherapy
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
Avalide Irbesartan Monotherapy HCTZ
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
ARB (Fixed Combination)ARB (Monotherapy)
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
ARB (Fixed Combination)ARB (Monotherapy)
% 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
ARB (Fixed Combination)ARB (Monotherapy)
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
Black Non-Black Black Non-Black
Avalide Irbesartan Monotherapy
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
Avalide Irbesartan Monotherapy
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
Avalide Irbesartan Monotherapy
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