# Presentation: 760283

## Change in Systolic BP at Week 24 for Patients Receiving Adjuncts After Week 8 (All Randomized Patients)

**Change in SBP (mmHg)**

**HCTZ****(n = 2476)**

**Change in Systolic BP at Week 24 for Patients Receiving Adjuncts After Week 8 (All Randomized Patients)**

**Other Diuretics****(n = 690)**

**Amlodipine****(n = 695)**

**Other CCB****(n = 735)**

**ARB****(n = 274)**

**Beta Blockers****(n = 890)**

**OCTAVE (CV137-120)**

## OCTAVE Group 3: Effectiveness of Omapatrilatin Patients Treated with HCTZ and Amlodipineat Randomization at Week 24

**OCTAVE Group 3: Effectiveness of Omapatrilat****in Patients Treated with HCTZ and Amlodipine****at Randomization at Week 24**

**SBP**

**DBP**

**BP Change (mmHg)**

**OCTAVE (CV137-120)**

## Enalapril Comparison in Severe Hypertension(CV137-049) 

**Enalapril Comparison in Severe Hypertension****(CV137-049) **

**B71**

**Period A**
**Single-Blind Placebo**
**Lead-In**

**Period C**
**Long-Term**
**Open-Label**

**Period B**
**Double-Blind **
**Randomized**

**SeDBP 115-130****mmHg**

**40**

**B1**

**B15**

**A7**

**20**

**20   40**

**20**

**10**

**40   80**

**B8**

**B29**

**Level I**

**Level II**

**Level III**

**Adjunct**

**Omapatrilat**

**Enalapril**

**B1**

**B71**

**C1**

**C1**

**Forced titration****to 40, elective to 80**

**Forced titration to 20, elective to 40**

## Primary Efficacy ResultsMean Changed from Baseline in Trough SeDBP,and SeSBP and SePP at Week 10

**CV137-049**

**Primary Efficacy Results****Mean Changed from Baseline in Trough SeDBP,****and SeSBP and SePP at Week 10**

## Most Common Adverse Events*

**Most Common Adverse Events*******

*** 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**

**Definition of Hospitalization ****for Heart Failure**

**OVERTURE (CV137-068)**

## Study Design (CV137-071)

**4 Wk**
**Period B**

**10 mg**

**40 mg**

**80 mg**

**Omapatrilat**

**3 Wk (max)**
**Period A**

**Placebo**

**ETT**

**ETT**

**ETT**

**ETT**

**R**

** ****wk 2**

** ****wk 4**

**Placebo**

**Single blind**

**Double blind**

**Day 28**

**Day 29**

** ****wk 1**

**BMS data on file**

**+CAD**
**+Exertional angina**

**Study Design (CV137-071)**

**Notes:**
This was the study design.  Prior to study entry, pts were taken off of CCBs and long-acting nitrates.  They could remain on or start beta blockers at a fixed dose. During an initial single-blind placebo period, ETTs were performed to establish each pt’s baseline exercise performance.  Pts were then randomized to pbo or a forced titration of omapatrilat, starting at 10 mg, followed by 40 mg and then 80 mg.  If an uptitration wasn’t tolerated, the dose was dropped to the previous level and continued for the remainder of the trial.  After at least 2 weeks at the maximum tolerated dose, pts underwent a ETT on Day 28 2-3 hrs after the last dose of double-blind medication.  They returned the following day for a final treadmill test at trough.

## Primary Efficacy Results:Change in Peak Exercise Parameters vs Baseline ETT

**BMS data on file**

**Primary Efficacy Results:****Change in Peak Exercise Parameters vs Baseline ETT**

**Time to Onset**
**of Angina**

**Maximal Exercise**
**Duration **

**Time to ST**
**Depression**

** **

**p ********0.001**

**p ********0.001**

**p ********0.001**

**Increased Time (sec)**

**CV137-071**

**Notes:**
Here are the major endpoints of the trial.  At peak plasma concentrations of omapatrilat, there was a highly significant prolongation of max exercise duration (our primary endpoint), time to onset of angina (an anti-anginal effect), and time to ST segment depression (an anti-ischemic effect), by about 50 sec for each compared with placebo.  This signal is comparable to the improvement in exercise duration by mibefradil on top of beta blocker therapy.  As you all are probably aware, no ACEI has consistently shown benefit in exercise protocols and no ACEI has an indication for angina in their label.

## Diabetic Patients (CV137-046)

**Diabetic Patients (CV137-046)**

## Summary of Primary Efficacy Results

**Study Week**

**Summary of Primary Efficacy Results**

**CV137-046**

**Adjusted Geometric Mean % Change from Baseline ****for Albumin Excretion Rate**

## Losartan Comparison in LVH (CV137-038) 

**omapatrilat**

**Wk 52****(Echo)**

**Baseline Echo****LVH**

**Hypertension****DBP 95-115 mmHg****and / or****SBP 160-200 mmHg**

**Force Titration**

**Open-label adjuncts added to Level III**

**Wk 8**

**Wk 16**

**Wk 24****(Echo)**

**20 mg**

**40 mg**

**80 mg**

** **

**+ HCTZ**

**80 mg   +**

**HCTZ/AML**

**Losartan Comparison in LVH (CV137-038) **

**50 mg**

**100 mg**

**100 mg**

**+ HCTZ**

**100 mg   +**

**HCTZ/AML**

**losartan**

## Summary of Primary Efficacy Results 

**Summary of Primary Efficacy Results **

**CV137-038**

**Mean Changes from Baseline in****Echocardiographic Measures at Week 24**** **

## BP Changes From Baseline Per Study Week

**BP Changes From Baseline Per Study 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**

**0**

**24**

**30**

**36**

**44**

**52**

**Week**

**DBP**

**SBP**

**Change in BP (mmHg)**

**CV137-038**

**0**
**-5**
**-10**
**-15**
**-20**
**-25**
**-30**
**-35**

**Omapatrilat**

**Losartan**

## CHOIRS Background(Conduit Hemodynamics ofOmapatrilat International Research Study)

**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

**CHOIRS: Study Design**

**Randomize: Force-titration****Wks 0, 2, 4**

**Omapatrilat 10 / 40 / 80 mg daily**
**(n = 104)**

**Enalapril 10 / 20 / 40 mg daily**
**(n = 109)**

**8 Wks at maximal dose**

**Trough (24 Hr)****Hemodynamic Study**
**(n = 80)**

**Trough (24 Hr)****Hemodynamic Study**
**(n = 87)**

**Withdrawn **
**(n = 22)**

**Withdrawn **
**(n = 24)**

**Baseline hemodynamic study (n = 213)****SBP ******** 160 mmHg**

## Central and Peripheral Pulse Pressure

**Central and Peripheral Pulse Pressure**

*** = ********0.005**
**† ****= ******** 0.05**
**Mitchell, et al., Circulation 2002; 105:2955**

**Notes:**
Key Message
Omapatrilat produced significantly greater reductions than enalapril in all trough brachial  blood pressure parameters.

## Omapatrilat Target Population

**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**

***Based on WHO-ISH guidelines**

**Use with special caution in black patients****and current smokers**

## Subgroups at Increased CV Risk:Change in Systolic BP at Week 24

**Adjusted SBP Change****at Week 24 (mmHg)**
**Omapatrilat    Enalapril**

**Difference****(oma / ena)**

**-18.7**
**-36.6**

**Severe Hypertension (n = 7197)****     Group 1 (n = 983)****	**

**-2.7****-4.6**

**-17.6**

**Diabetes Mellitus (n = 3275)****	**

**-4.2**

**-20.7**

**Atherosclerotic Disease* (n = 2283)****	**

**-2.7**

** ****-22.2 **

**ISH (n = 1332)**

**-4.5**

**-17.0**

**Renal Disease (n = 582)**

**-3.6**

**-20.9**

**Heart Failure (n = 233)****	**

**-4.5**

**-15.9 ****-32.0**

**-13.4**

**-18.0**

**-17.7**

**-13.4**

**-16.4**

**  *****Includes chronic stable angina, unstable angina, myocardial infarction, and stroke / TIA**
**   ****OCTAVE (CV137-120)**

## Target Population – Baseline Demographics (Diabetes, Renal Disease, Athero Disease, HF)

**OCTAVE (CV137-120)**

## OCTAVE: Efficacy in Target Population at Week 24 (Diabetes, Renal Disease, Athero Disease, HF)

**Change in Systolic BP**

**Use of New****Adjunctive Therapy**

**-3.6****

**SBP Change (mmHg)**

**** p***** *********0.001 vs enalapril**

******

**% of Patients**

## Target Population – Severity of Angioedema Events, Week 24 (Diabetes, Renal Disease, Athero Disease, HF)

**Target Population – Severity of ****Angioedema Events, Week 24**** **(Diabetes, Renal Disease, Athero Disease, HF)

**OCTAVE (CV137-120)**

**Number (%) of Patients**

**Omapatrilat**
**(n = 2842)**

**Enalapril**
**(n = 2807)**

**Severity**

**I. No Treatment Administered or Antihistamines Only**

**II. Treated with Catecholamines or Steroids**

**III. Hospitalized but no Mechanical Airway Protection**

**   **

**IIIa. No Airway Compromise**

**   **

**IIIb. With Airway Compromise**

**IV. Mechanical Airway Protection or Death from **
**	****Airway Compromise**

**Total**

**	****   ****28 (0.99%)**

**	****14 (0.50%)**

**	****   ****15 (0.53%)**

**	****2 (0.07%)**

**	****   ****2 (0.07%)**

**	****1 (0.04%)**

**	****   ****2**

**	****1**

**	****   ****0**

**	****0**

**	****   ****0  (0%)**

**	**** ****0  (0%)**

**	****   ****45 (1.58%)**

**	****17 (0.61%)**

## Change in 24-Hour Average AmbulatorySystolic BP in Patients Uncontrolledwith ACE-Inhibitor Regimens at Baseline

**ASBP Change (mmHg)**

**ACE-I Monotherapy****(n = 171)**

**ACE-I****Combination****(n = 75)**

**Change in 24-Hour Average Ambulatory****Systolic BP in Patients Uncontrolled****with ACE-Inhibitor Regimens at Baseline**

**-7.6****

**-11.5****

**Week 4 Maintenance**
*** *p ******** 0.001 vs. lisinopril**

## Omapatrilat provides consistent benefit in BP reduction over enalapril in each of these difficultto control populations.

**Patients uncontrolled with****a regimen not including an ACE-I**

**Omapatrilat provides consistent benefit in BP reduction over enalapril in each of these difficult****to control populations.**

**Difficult to Control Patients**

**Untreated patients with severe hypertension**

**Patients uncontrolled with****a regimen including an ACE-I**

***Difficult to Control Patients***

## BP Control in Uncontrolled Patients at Sites with Highest Adjunct Use (64.0% - 100%) at Week 24

**BP Control in Uncontrolled Patients at Sites with Highest Adjunct Use (64.0% - 100%) at Week 24**

**OCTAVE (CV137-120)**

**Change in SBP**
**(mmHg)**

**BP Control**
**n / N (%)**

**Omapatrilat (n = 967)**
**Enalapril (n = 966)**

**544 / 907 (60.0%)**
**466 / 903 (51.6%)**

**Difference**

**-19.1 **
**-15.7**

**-3.4**

## Omapatrilat Educational Program

**Omapatrilat Educational Program**

**MD Education**

**Initial MD-Patient Consultation****Patient Brochure****Rx Given**

**Mandatory ****Counseling Service**

**Retail Pharmacist****Education**

**Follow-up MD Patient Consultation****Rx Given**

**Counseling Pharmacist****Education**