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Change in Systolic BP at Week 24 for Patients Receiving
Adjuncts After Week 8 (All Randomized Patients)
Other Other Beta
HCTZ Diuretics Amlodipine CCB ARB Blockers
(n = 2476) (n = 690) (n = 695) (n = 735) (n = 274) (n = 890)
0
-2
Change in SBP (mmHg)
-4
-6
-8
-10
-12
-12.3
-14 -12.9
-13.8
-16 -14.6
-15.7 -15.9 -15.8
-18 -16.8 -16.8
-17.4 -17.8
-18.4 Omapatrilat Enalapril
-20
OCTAVE (CV137-120)
OCTAVE Group 3: Effectiveness of Omapatrilat
in Patients Treated with HCTZ and Amlodipine
at Randomization at Week 24
SBP DBP
0
-5
BP Change (mmHg)
-10
-9.5
-15 -13.2
-20
-19.3
-21.9
-25 Omapatrilat (n = 65)
Enalapril (n = 70)
-30
OCTAVE (CV137-120)
Enalapril Comparison in Severe Hypertension
(CV137-049)
B1 B8 B15 B29 B71
20 40 40 80
Forced titration
Omapatrilat to 40, elective to 80
C1
Level I Level II Level III Adjunct
SeDBP 115-130
mmHg Forced titration to
Enalapril 20, elective to 40
10 20 20 40
A7 B1 B71 C1
Period A Period B Period C
Single-Blind Placebo Double-Blind Long-Term
Lead-In Randomized Open-Label
Primary Efficacy Results
Mean Changed from Baseline in Trough SeDBP,
and SeSBP and SePP at Week 10
Omapatrilat Enalapril
Regimen Regimen
Efficacy Variable (n = 128) (n = 57)
Trough SeDBP, mmHg
Baseline Mean (sd) 118.3 (3.3) 118.3 (2.6)
Adjusted Mean Change from - 28.6 (0.8) - 26.4 (1.1)
baseline (se)
Difference from Enalapril (95% CI) -2.2 (-4.9, 0.5)
Trough SeSBP, mmHg
Baseline Mean (sd) 176.2 (17.3) 173.3 (15.4)
Adjusted Mean Change from -37.4 (1.3) -36.4 (1.9)
baseline (se)
Difference from Enalapril (95% CI) -1.0 (-5.5, 3.6)
Trough Pulse Pressure, mmHg
Baseline Mean (sd) 57.9 (16.5) 55.0 (15.3)
Adjusted Mean Change from -8.9 (1.0) -10.0 (1.5)
baseline (se)
Difference from Enalapril (95% CI) -1.1 (-2.5, 4.7)
CV137-049
Most Common Adverse Events*
(%) of Subjects
Omapatrilat Enalapril
Primary Term (N = 12,609) (N = 12,557)
Cough 8.7% 8.8%
Headache 7.4% 8.9%
Dizziness 6.8% 5.4%
Upper Respiratory Infection 6.8% 6.9%
Musculoskeletal Pain 5.2% 5.5%
Sinus Abnormality 3.2% 3.3%
Nausea / Vomiting 3.1% 3.0%
Fatigue 3.0% 3.0%
Tracheobronchitis 2.9% 2.8%
Flushing 2.3% 1.3%
* Excluding Angioedema
OCTAVE (CV137-120)
Definition of Hospitalization
for Heart Failure
OVERTURE Trial
– Included all hospitalizations attributable to
heart failure as adjudicated by Endpoint
Committee which required IV treatment
and had a duration > 24 hours
SOLVD Treatment Trial
– Included all hospitalizations attributable to
heart failure by the investigator regardless
of treatment or duration
OVERTURE (CV137-068)
Study Design (CV137-071)
Single blind Double blind
Placebo Omapatrilat
10 mg 40 mg 80 mg
+CAD
+Exertional angina
wk 1
wk 2
wk 4
R
ETT ETT
Placebo
ETT ETT
3 Wk (max) 4 Wk Day 28 Day 29
Period A Period B
BMS data on file
Primary Efficacy Results:
Change in Peak Exercise Parameters vs Baseline ETT
100
p < 0.001
p < 0.001
p < 0.001
Increased Time (sec)
80
60
40
20
0
Maximal Exercise Time to Onset Time to ST
Duration of Angina Depression
BMS data on file Omapatrilat Placebo
CV137-071
Diabetic Patients (CV137-046)
Type II diabetics
with microalbuminuria
(30-300 mg/gram omapatrilat
creatinine) or overt
nephropathy 20 mg 40 mg 80 mg
(> 300 mg/gram
creatinine)
amlodipine
DBP 85-110 mmHg or 2.5 mg 5 mg 10 mg
SeSBP 130-180 mmHg
wk 4 wk 8
Elective titration
Randomization
12 week
2 week placebo lead-in
Double-blind
Summary of Primary Efficacy Results
Adjusted Geometric Mean % Change from Baseline
for Albumin Excretion Rate
Adjusted GM% Change from Baseline
0
-5
-10
-15
-20
-25
-30
0 4 8 12
Study Week
Omapatrilat Amlodipine
CV137-046
Losartan Comparison in LVH (CV137-038)
omapatrilat
20 mg 40 mg 80 mg + HCTZ 80 mg + HCTZ/AML
Baseline Echo
LVH
Hypertension losartan
DBP 95-115 mmHg
and / or 50 mg 100 mg 100 mg + HCTZ 100 mg + HCTZ/AML
SBP 160-200 mmHg
Wk 8 Wk 16 Wk 24 Wk 52
(Echo) (Echo)
Force Titration
Open-label adjuncts added to Level III
Summary of Primary Efficacy Results
Mean Changes from Baseline in
Echocardiographic Measures at Week 24
Omapatrilat Losartan
20/40/80 mg 50/100/100 mg
Efficacy Variable (n = 158) (n = 160)
LVMI, g/m²
Baseline Mean (sd) 142.7 (29.7) 141.4 (28.5)
Adjusted Mean Change (se) -7.2 (1.7) -3.4 (1.7)
p-value < 0.001 0.039
Difference from Losartan -3.8 --
95% CI (-8.4, 0.9) --
p-value 0.109 --
CV137-038
BP Changes From Baseline Per Study Week
0
Change in BP (mmHg)
Omapatrilat Losartan
-5
-10
-15
DBP
-20
-25
-30 SBP
-35
0 24 30 36 44 52
Week
Adjunctive therapy %
Omapatrilat 6.3 22.2 32.7 32.5 34.4
Losartan 16.5 50.0 54.8 59.3 60.0
CV137-038
CHOIRS Background
(Conduit Hemodynamics of
Omapatrilat International Research Study)
Elevated pulse pressure, an indirect measure
of increased vascular stiffness, associated with:
– Myocardial infarction, stroke
– Development and progression of heart failure
– Increased mortality
Current epidemic of uncontrolled systolic
hypertension due to a lack of treatments that
reduce arterial stiffness
Natriuretic peptides have a favorable effect on large
arteries in basic studies although their effects in
humans have not been elevated
CHOIRS: Study Design
Baseline hemodynamic study (n = 213)
SBP 160 mmHg
Randomize: Force-titration
Wks 0, 2, 4
Enalapril 10 / 20 / 40 mg daily Omapatrilat 10 / 40 / 80 mg daily
(n = 109) (n = 104)
Withdrawn Withdrawn
8 Wks at maximal dose
(n = 22) (n = 24)
Trough (24 Hr) Trough (24 Hr)
Hemodynamic Study Hemodynamic Study
(n = 87) (n = 80)
Central and Peripheral Pulse Pressure
Central Pulse Brachial Pulse
Pressure Pressure
(80 20 mmHg) (78.6 16.6 mmHg)
0 0
-5 -5
-10 -10 †
*†
-15 -15
-20 -20
Omapatrilat Enalapril
* = < 0.005
† = < 0.05
Mitchell, et al., Circulation 2002; 105:2955
Omapatrilat Target Population
Patients with:
A high risk of major cardiovascular events*
– Cardiovascular disease (e.g., MI, CHF)
– Target organ damage (e.g., LVH, proteinuria)
– 3 or more cardiovascular risk factors
– Diabetes or renal disease
and
Hypertension that is difficult to control
with existing medications
Use with special caution in black patients
and current smokers
*Based on WHO-ISH guidelines
Subgroups at Increased CV Risk:
Change in Systolic BP at Week 24
Adjusted SBP Change
at Week 24 (mmHg) Difference
Omapatrilat Enalapril (oma / ena)
Severe Hypertension (n = 7197) -18.7 -15.9 -2.7
Group 1 (n = 983) -36.6 -32.0 -4.6
Diabetes Mellitus (n = 3275) -17.6 -13.4 -4.2
Atherosclerotic Disease* (n = 2283) -20.7 -18.0 -2.7
ISH (n = 1332) -22.2 -17.7 -4.5
Renal Disease (n = 582) -17.0 -13.4 -3.6
Heart Failure (n = 233) -20.9 -16.4 -4.5
*Includes chronic stable angina, unstable angina, myocardial infarction, and stroke / TIA
OCTAVE (CV137-120)
Target Population – Baseline Demographics
(Diabetes, Renal Disease, Athero Disease, HF)
Omapatrilat Enalapril
(n = 2849) (n = 2840)
Age (Mean) 62 62
Age, n (%)
< 65 years 1654 (58%) 1652 (59%)
65 - 74 years 793 (28%) 802 (28%)
75 years 402 (14%) 385 (14%)
Gender, n (%)
Male 1602 (56%) 1566 (55%)
Female 1247 (44%) 1273 (45%)
Race, n (%)
White 2490 (87%) 2488 (88%)
Black 314 (11%) 309 (11%)
OCTAVE (CV137-120)
OCTAVE: Efficacy in Target Population at Week 24
(Diabetes, Renal Disease, Athero Disease, HF)
Use of New
Change in Systolic BP Adjunctive Therapy
0 50
45
SBP Change (mmHg)
-5
40
% of Patients
35
-10
30
-15.0 30
-15 25 **
-18.7 24
20
-20
15
-3.6** 10
-25
5
-30 0
Omapatrilat Enalapril
** p < 0.001 vs enalapril
Target Population – Severity of
Angioedema Events, Week 24
(Diabetes, Renal Disease, Athero Disease, HF)
Number (%) of Patients
Omapatrilat Enalapril
Severity (n = 2842) (n = 2807)
I. No Treatment Administered or Antihistamines Only 28 (0.99%) 14 (0.50%)
II. Treated with Catecholamines or Steroids 15 (0.53%) 2 (0.07%)
III. Hospitalized but no Mechanical Airway Protection 2 (0.07%) 1 (0.04%)
IIIa. No Airway Compromise 2 1
IIIb. With Airway Compromise 0 0
IV. Mechanical Airway Protection or Death from 0 (0%) 0 (0%)
Airway Compromise
Total 45 (1.58%) 17 (0.61%)
OCTAVE (CV137-120)
Change in 24-Hour Average Ambulatory
Systolic BP in Patients Uncontrolled
with ACE-Inhibitor Regimens at Baseline
ACE-I ACE-I
Monotherapy Combination
(n = 171) (n = 75)
2
0.6
ASBP Change (mmHg)
0
-2 -3.1
-4
-6
-8
-10 -10.7 -10.9
-7.6** -11.5**
-12
Week 4 Maintenance
Omapatrilat 80 mg Lisinopril 40 mg
* *p < 0.001 vs. lisinopril
CV137-073
Difficult to Control Patients
Difficult to Control Patients
Patients Patients
Untreated patients uncontrolled with uncontrolled with
with severe a regimen not a regimen including
hypertension including an ACE-I an ACE-I
Omapatrilat provides consistent benefit in BP
reduction over enalapril in each of these difficult
to control populations.
BP Control in Uncontrolled Patients at Sites with
Highest Adjunct Use (64.0% - 100%) at Week 24
Change
in SBP BP Control
(mmHg) Difference n / N (%)
Omapatrilat (n = 967) -19.1 544 / 907 (60.0%)
-3.4
Enalapril (n = 966) -15.7 466 / 903 (51.6%)
OCTAVE (CV137-120)
Omapatrilat Educational Program
MD Education Counseling Pharmacist
Education
Initial MD-Patient Consultation
Mandatory
Patient Brochure
Counseling Service
Rx Given
Retail Pharmacist
Follow-up MD Education
Patient Consultation
Rx Given
Retail Pharmacist Validation
of Counseling and Delivery
Medication Dispensed in of Patient Education
Unit-of-Use Packaging
Message with PPI
