# Presentation: 659448

## Omapatrilat in the Treatmentof HypertensionEfficacy and Safety

- Omapatrilat in the Treatmentof Hypertension**Efficacy and Safety**

**NDA 21-188**

**FDA Cardiovascular and Renal Drugs****Advisory Committee Meeting**
***July 19, 2002***

**Elliott Levy, M.D.**Vice President, Clinical Design and EvaluationPharmaceutical Research Institute

## Efficacy

**Efficacy**

## 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**

## Order of Presentation

**In 4 placebo-controlled trials (2369 patients), dose****related reduction demonstrated in systolic and diastolic blood pressure**
**In 6 active-controlled trials (2742 patients), omapatrilat****80 mg shown to be more effective monotherapy than lisinopril 40 mg, amlodipine 10 mg, losartan 100 mg**
**In OCTAVE (25,302 patients), omapatrilat-based regimen consistently more effective than enalapril-based regimen**
**Greater BP reduction preserved in patients with comorbidity and difficult to control hypertension**

## Dose-Related Mean Reductionfrom Baseline in Trough Blood Pressure

**Dose-Related Mean Reduction****from Baseline in Trough Blood Pressure**

**Weeks 6-9****CV137-006, -022, -024 and -045**

## Changes in Trough Systolic BP versus Active Comparators at Maximal Recommended Dose

**** p ******** 0.001 vs. comparator**

**Changes in Trough Systolic BP versus Active Comparators at Maximal Recommended Dose**

**CV137-030****(n = 492)**

**CV137-037****(n = 437)**

**SBP Change (mmHg)**

**CV137-077****(n = 203)**

**-3.1***

**-5.2****

**-7.2****

**Week 10**

**oma**
**80 mg**

**aml**
**10 mg**

**oma**
**80 mg**

**lis**
**40 mg**

**oma**
**80 mg**

**los**
**100 mg**

## Changes in 24-Hour Average AmbulatorySystolic BP versus Active Comparatorsat Maximal Recommended Doses

**Changes in 24-Hour Average Ambulatory****Systolic BP versus Active Comparators****at Maximal Recommended Doses**

**CV137-032****(n = 379)**

**CV137-031****(n = 317)**

**ASBP Change (mmHg)**

**CV137-066****(n = 673)**

**-5.9****

**-6.8****

**-5.4****

**Week 10**

**-8.9****

**oma**
**80 mg**

**aml**
**10 mg**

**oma**
**80 mg**

**lis**
**40 mg**

**oma**
**80 mg**

**aml**
**10 mg**

**los**
**100mg**

## Effects of Omapatrilat and Amlodipine on Ambulatory Systolic Blood Pressure, by Hour

**Effects of Omapatrilat and Amlodipine on Ambulatory Systolic Blood Pressure, by Hour**

**ASBP (mmHg)**

**Difference in 24-hour****Average ASBP = -5.9****

**CV137-032**

****** **p ******** 0.001 vs. Amlodipine**

**Omapatrilat (n = 192)**
**Amlodipine (n = 187)**

**Omapatrilat 80 mg**
**Amlodipine 10 mg**

_**Baseline                **_

_**Week 10**_

## OCTAVE: Rationale

**In 6 active controlled monotherapy trials, omapatrilat 80 mg reduced blood pressure****to a greater extent than maximal doses of amlodipine, losartan and lisinopril**
**OCTAVE was designed to evaluate whether****omapatrilat would be superior to another agent (enalapril) in clinical use conditions, where therapy is titrated electively and supplemented****by other agents to reach BP target**
**OCTAVE was large enough to characterize efficacy and safety in important subgroups**

## OCTAVE: Study Design

**OCTAVE: Study Design**

** ****10  mg**

**5 mg**

**SBP ******** 140**
**      ****or **
**DBP ******** 90 **

** ****2**

**4**

**6**

**8**

**16**

**24**

**20**

**10**

**40**

**20**

**80**

**40**

**+ Adjunctive Rx**

**+ Adjunctive Rx**

** ****Week:**

**Omapatrilat**

**Enalapril**

**Titration to Target**

**Adjunctive Rx to Target**

**Target BP: ******** 140/90 mmHg**

- *

***Forced Titration**

## OCTAVE: Study Groups

**JNC VI Stage I-III****Untreated**

**JNC VI Stage I****Despite Treatment **

**Replacement**
**(Group 2)**

**Add-on**
**(Group 3)**

**Initial**
**(Group 1)**

**n = 9,292**

**n = 11,224**

**n = 4,751**

**Ena**

**Oma**

**Ena**

**Oma**

**Ena**

**Oma**

**OCTAVE: Study Groups**

**JNC VI Stage II****Despite Treatment **

**Baseline BP****(mmHg)**

**156 / 96**

**150 / 91**

**166 / 97**

## Efficacy (Co-Primary)
Change in systolic blood pressure from baseline to Week 8, by study group
Use of new adjunctive antihypertensive therapy between Weeks 8 and 24,by study group
Safety
Incidence of adverse events
Incidence and severity of angioedema

**Efficacy (Co-Primary)**
**Change in systolic blood pressure from baseline to Week 8, by study group**
**Use of new adjunctive antihypertensive therapy between Weeks 8 and 24,****by study group**
**Safety**
**Incidence of adverse events**
**Incidence and severity of angioedema**

## OCTAVE: Efficacy Results at Week 8

**% of Patients**

**Change in Systolic BP**

**Titration to Top Dose****(Oma 80 mg, Ena 40 mg)**

**Initial****Group 1**

**Replacement****Group 2**

**Add-on****Group 3**

**-3.2****

**-3.8****

**-3.6****

**Initial****Group 1**

**Replacement****Group 2**

**Add-on****Group 3**

**SBP Change (mmHg)**

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

******

******

******

## OCTAVE: Efficacy Results at Week 24

**Change in Systolic BP**

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

**Initial****Group 1**

**Replacement****Group 2**

**Add-on****Group 3**

**-3.1****

**-3.1****

**-2.8****

**Initial****Group 1**

**Replacement****Group 2**

**Add-on****Group 3**

**SBP Change (mmHg)**

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

******

******

******

**% of Patients**

## Demographic Subgroups:Change in Systolic BP at Week 24

**OCTAVE (CV137-120)**

## 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)**

## OCTAVE Conclusion

**OCTAVE Conclusion**

**Greater BP reduction with omapatrilat-based regimen, despite more frequent use of maximal doses and adjunctive therapy with enalapril**
**Highly consistent results regardless of patient subgroup or manner of use of study drug**
**Greater BP reduction observed at week 8****and preserved over 24 weeks, despite use****of adjunctive therapy**

## Role of Omapatrilat in Difficult to Control Hypertension

**Role of Omapatrilat in ****Difficult to Control Hypertension**

**In many patients, hypertension can be readily controlled with existing therapy**
**OCTAVE and other large clinical trials demonstrate that hypertension is difficult to control in many patients **
**In patients not readily controlled with existing therapies, an omapatrilat-based regimen provides lasting efficacy advantage**

## Efficacy at Week 24 in SubgroupsDefined by Baseline JNC-VI Stage

**Omapatrilat**

**Enalapril**

**SBP Change (mmHg)**

**-2.6****

**-3.0****

**-4.6****

**Stage I****(n = 4160)**
**147**

**Stage II****(n = 3864)**
**160**

**Stage III****(n = 983)**
**178**

**% of Patients**

**Stage I**

**Stage II**

**Stage III**

**Use of New Adjunctive Antihypertensive Therapy****JNC-VI**

**Change in Systolic BP – JNC-VI**

**Baseline SBP (mmHg)**

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

**OCTAVE (CV137-120)****Group 1**

******

******

******

## Control of BP (140/90 mmHg) in Multi-Drug Resistant Patients in Group 3 at Week 24

**Control of BP (********140/90 mmHg) in Multi-Drug Resistant Patients in Group 3 at Week 24**

**% Controlled**

**Omapatrilat**

**Enalapril**

**2 or More Baseline Meds****(n = 2309)**

**OCTAVE (CV137-120)**

**3 or More Baseline Meds****(n = 703)**

## Difficult to Control Hypertension: Patients Uncontrolled with ACE-Inhibitor Regimen

**Maximal ACE-I (alone or as part of regimen)**

**SBP ******** 140 or **
**DBP ******** 90**

**Titration**
**2-4 Weeks**

**Maintenance**
**4 Weeks**

**Enrollment / Lead-In**
**2+ weeks**

**Randomization**
**D/C ACE-I**
**Continue other antihypertensives (if any) at established dose**

**CV137-073**

**Omapatrilat**

**20          40            80**

**Lisinopril**

**20          20            40**

## Changes in Ambulatory Systolic BP in Subjects Uncontrolled with ACE-Inhibitor Regimen

**Hour Post-Dose**

**Changes in Ambulatory Systolic BP in Subjects Uncontrolled with ACE-Inhibitor Regimen**

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

**Average ambulatory difference from Lisinopril = -8.8******Trough difference from Lisinopril = -7.0****

**Omapatrilat 80 mg (n = 124)**

**Lisinopril 40 mg (n = 122)**

**CV137-073**

## 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**

**Omapatrilat 80 mg**

**Lisinopril 40 mg**

**-7.6****

**-11.5****

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

## Efficacy at Week 24: OCTAVE Patients Not at Target with ACE-Inhibitor Regimens at Baseline

**ACE-I Monotherapy**
**(n = 2278)**

**ACE-I + 1****Antihypertensive Med **
**(n = 1368)**

**SBP Change (mmHg)**

**Efficacy at Week 24: OCTAVE Patients Not at Target with ACE-Inhibitor Regimens at Baseline**

**ACE-I + 2 or More Antihypertensive Meds **
**(n = 546) **

**-3.5****

**-3.0****

**-5.9****

**Group 2**
**** p ********0.001 vs. enalapril**

## Efficacy at Week 24: OCTAVE Patients withDiabetes Not at Target with ACE-InhibitorRegimens at Baseline

**ACE-I****Monotherapy**
**(n = 466)**

**ACE-I + 1**** Antihypertensive Med **
**(n = 322)**

**SBP Change (mmHg)**

**ACE-I + 2 or More Antihypertensive****Meds **
**(n = 169)**

**Efficacy at Week 24: OCTAVE Patients with*****Diabetes***** Not at Target with ACE-Inhibitor****Regimens at Baseline**

**-4.8****

**-6.9****

**-8.5***

*** p ******** 0.05**
**** p ********0.001 vs. enalapril**

**Group 2**

## Efficacy Conclusions

**Greater antihypertensive efficacy with regimen based on omapatrilat**
**Greater efficacy apparent across patient subgroups and continued over time**
**Greater efficacy maintained even when physicians encouraged to add adjunct****to achieve BP goal**
**In patients with difficult to control hypertension, omapatrilat provides antihypertensive effect not achieved****with current drugs**

## Safety

**Safety**

## Omapatrilat Safety Database

**Omapatrilat Safety Database**

**Overall:**
**34,780 hypertensive patients**
**18,723 exposed to omapatrilat **
**Patients exposed by omapatrilat dose: **
**10 mg = 15,058 ******
**20 mg = 16,655  **
**Patients exposed to omapatrilat by duration:**
** ********3 months = 12,995**
** ******** ****1 year      =   1,478**
**Heart Failure (OVERTURE)**

**40 mg = 11,317  **
**80 mg =   6,922**

## Safety Summary

**Safety well-characterized through extensive****program**
**Overall incidence of AE, SAE, D/C due to AE comparable for omapatrilat and ACE-I**
**Angioedema 3 times more common with****omapatrilat**

## Angioedema:  Clinical Overview

**FDA Cardiovascular and Renal Drugs****Advisory Committee Meeting**
***July 19, 2002***

**Allen Kaplan, M.D.****Medical University of South Carolina****Charleston, SC**

## Localized edema in a variety of anatomical sites
Superficial (e.g., eyelids, lips, face)
Oropharyngeal (e.g., tongue, pharynx)
Lower airway (e.g., larynx)
Other (e.g., hands)
Most common etiologies are inherited and drug-induced
Bradykinin is the mediator of inherited and ACE-Iinduced angioedema
ACE-I are the most common cause of drug-inducedangioedema
Anaphylaxis and angioedema are differentclinical syndromes

**Superficial (e.g., eyelids, lips, face)**
**Oropharyngeal (e.g., tongue, pharynx)**
**Lower airway (e.g., larynx)**
**Other (e.g., hands)**
**Most common etiologies are inherited and drug-induced**
**Bradykinin is the mediator of inherited and ACE-I****induced angioedema**
**ACE-I are the most common cause of drug-induced****angioedema**
**Anaphylaxis and angioedema are different****clinical syndromes**

**Angioedema: Background Information**

## Angioedema: Clinical Information

**Generally develops over several hours but may progress over 1-2 hours in severe cases**
**Patients are aware of the swelling of angioedema**
**In contrast to antihistamines, treatment****with epinephrine can halt further****progression of episode**
**Laryngeal edema without other symptoms ****is very rare**

## Anaphylaxis Compared with Angioedema

**Anaphylaxis Compared with Angioedema**

**Time Course**
**Symptoms**
**Mediators****Treatment**

**Rapid evolution; typically occurs****over several minutes after****antigen exposure**
**Mucocutaneous - swelling, erythema, urticaria**
**Cardiovascular - hypotension, shock**
**Respiratory - laryngeal edema, bronchial constriction**
**Multiple inflammatory mediators including histamine**
**Epinephrine, steroids,****anti-histamine**

**Evolves over hours**
**Mucocutaneous - localized edema of face, oropharynx**
**Cardiovascular - none**
**Respiratory - laryngeal edema**
**Bradykinin****Epinephrine; observation**

**Drug-Induced or Inherited Angioedema**

**Anaphylaxis**

## Safety of Omapatrilat

**Safety of Omapatrilat**

## Angioedema reported as adverse event
Precise incidence of angioedema difficultto determine
ICD-9 based coding system assignedpotential angioedema events to severalterms (angioedema, head/neck edema)
AE reports generally did not providesufficient detail to further assess cases

**Precise incidence of angioedema difficult****to determine**
**ICD-9 based coding system assigned****potential angioedema events to several****terms (angioedema, head/neck edema)**
**AE reports generally did not provide****sufficient detail to further assess cases**

**Angioedema with Omapatrilat:****Findings Prior to OCTAVE**

## Frequency of Angioedema andHead and Neck Edema with Omapatrilat(Prior to OCTAVE*)

**Adverse Event**

**Frequency of Angioedema and****Head and Neck Edema with Omapatrilat**(Prior to OCTAVE*)

**Head and Neck Edema,****n (%)**

**Airway Compromise,****n (%)**

**Angioedema,****n (%)****	**

****** ****20 mg**
**(N = 1544)**

****** ****20 mg**
**(N = 2740)**

**11 (0.71)**

**29 (1.06)**

**0      (0)**

**  ****4 (0.15)**

**7 (0.45)**

**37 (1.35)**

**Total**
**(N = 4284)**

**40 (0.93)**

**  ****4 (0.09)**

**44 (1.03)**

***Randomized controlled HTN studies**

## Description of Airway Compromise Cases (Prior to OCTAVE)

**Description of Airway Compromise Cases **(Prior to OCTAVE)

** ****4 patients required airway protection in previous NDA submission**

**Race**

**White**

**Black**

**Black**

**Clinical****Presentation**

**Initial dose (20 mg)****2 hours post dose****experienced flushing, swelling of face, tongue and lips. Presented to ER and following many interventions, developed stridor and desatrurated.**

**11 days since****randomization****(20 mg)  2-3 hours****post dose****experienced facial****and glosso-****pharyngeal edema****and difficulty****breathing**

**Within 1 hour of****first dose (20 mg) experienced****swelling of lips, throat, and dyspnea. Evaluated in ER, treated and released. Presented to ER 3 hr later with difficulty breathing.**

**Treatment**

**Epi, steroids,****diphenhydramine,****lidocaine,****tracheostomy**

**Epi, steroids,****diphenhydramine,****diltiazem, intubation**

**Epi, steroids,****diphenhydramine,****albuterol nebulizer**** tx, intubated**

**Current**
**Smoker**

**Yes**

**No**

**Yes**

**Patient 4**

**(CV137-042;094-009)**

**White**

**6 days since****randomization****(20 mg) hospitalized****for LOC with head ****injury. While under****observation developed ****subsequent glottis and ****laryngeal edema,****tongue swelling and****difficulty speaking.**

**Steroids, Amoxicillin****cricothyrotomy with****subsequent****tracheostomy **

**No**

## OCTAVE: Assessment of Angioedema

**OCTAVE: Assessment of Angioedema**

**Compare incidence of angioedema with****omapatrilat (10-80 mg) and enalapril (5-40 mg)**
**Incidence of angioedema with a starting dose****of 10 mg vs. 20 mg omapatrilat was not tested**
**Special process created for evaluation****of angioedema**
**Active collection of all potential events**
**Detailed follow-up information collected****on structured questionnaire**
**Potential angioedema cases adjudicated****by expert committee without knowledge****of treatment assignment**

## OCTAVE: Incidence of Angioedema

**Omapatrilat**

** ****(N = 12,609)**

**Enalapril**

** ****(N = 12,557)**

**Patients with**

**Angioedema, n (%)**

**274 (2.17%)**

**86 (0.68%)**

**Risk Ratio (95% CI)**

**3.17 (2.52, 4.12)**

## OCTAVE: Pre-specified Severity Scale

**OCTAVE: Pre-specified Severity Scale**

**Severity**

**I**

**No treatment administered or antihistamines****only**

**Treated with catecholamines or steroids**

**Hospitalized but no mechanical airway****protection**

**IIIa****  No airway compromise**

**IIIb****  With airway compromise**

**IV**

**Mechanical airway protection or death from****airway compromise***

**III**

**II**

## OCTAVE: Pre-specified Severity Scale

**OCTAVE: Pre-specified Severity Scale**

**Number (%) of Patients**

**Severity**

**Omapatrilat**

**(N = 12,609)**

**Enalapril**

**(N = 12,557)**

**I**

**No treatment administered or antihistamines****only**

**Treated with catecholamines or steroids**

**Hospitalized but no mechanical airway****protection**

**IIIa****  No airway compromise**

**IIIb****  With airway compromise**

**IV**

**Mechanical airway protection or death from****airway compromise***

**161 (1.28%)**

**  ****94 (0.75%)**

**  ****18 (0.14%)**

**  ****17**

**    ****1**

**    ****1 (0.01%)**

**65 (0.52%)**

**19 (0.15%)**

**  ****2 (0.02%)**

**  ****2**

**  ****0**

**  ****0 (0.00%)**

**274 (2.17%)**

*** No deaths occurred from angioedema**

**Total**

**86 (0.68%) **

**III**

**II**

## Risk of Angioedema withAirway Compromise

**N**

**Number **
**of****events **
**(%)**

**Rate of Angioedema**
**Events with Airway**
**Compromise per**
** ****10,000 treated**
** ****(95% CI)**

**Treatment**

**12,557**

**OCTAVE**

**0**

**  ****0 (0.0, 2.9)**

**Enalapril**

**12,609**

**OCTAVE**

**2**

**1.6 (0.2, 5.7)**

**Omapatrilat**

**Duration**
**(weeks)**

**24**

**24**

**18,723**

**Combined OCTAVE/****Pre-OCTAVE Studies**

**6**

**3.2 (1.2, 7.0)**

**Omapatrilat**

**8 - 24**

## OCTAVE: Angioedema with Airway Compromise

**OCTAVE: Angioedema with Airway Compromise**

**Did Not Require Airway Protection (n = 1)**

**Race**

**Clinical****Presentation**

**Treatment**

**White**

**Black**

**Required**** Airway Protection (n = 1)**

**Current Smoker**

**Yes**

**No**

**Edema of the **
**Eyelid(s)**
**Lip(s)**
**Neck**
**Difficulty speaking**
**Difficulty swallowing**
**Dyspnea**
**Hoarseness**
**Hypotensive**
**Cyanotic**

**Epinephrine**

**Edema of the **
**Eyelid(s)**
**Face**
**Lip(s)**
**Mucous Membranes**
**Neck**
**Pharynx**
**Tongue**
**Difficulty speaking**
**Difficulty swallowing**

**Epinephrine, Steroids, Tracheostomy**

## Angioedema Hospitalizations withoutAirway Compromise

**          **

**          **

**Omapatrilat**** (n = 17)**

**Enalapril**** (n = 2)**

**          **

**          **

**          **

**          **

**          **

**          **

**          **

**          **

**          **

**          **

**          **

**          **

**          **

**          **

**          **

**          **

**          **

**          **

**Airway compromise**

**None**

**None**

**Signs/Symptoms**

**8 tongue swelling**

**9 lip swelling**

**1 tongue swelling**

**2 lip swelling**

**Other Indications****for observation**

**7 late hour**

**3 social factors**

**2 comorbid conditions**

**1 comorbid conditions**

**Progression in****Hospital**

**None**

**None**

**Treatment**

**Epi (5) / steroids (16)**

**Epi (1) / steroids (2)**

**Time to Discharge**

**14 next day**

**3 after 2 days**

**1 next day**

**1 after 6 days**

**Angioedema Hospitalizations without****Airway Compromise**

## Patient Response to Symptomsof Angioedema

**Patient Response to Symptoms****of Angioedema**

**Most (80.5%) angioedema events occurred outside the physician’s office**
**Most (63.7%) patients with angioedema occurring outside of physician’s office****presented to medical facilities more than one hour after onset of symptoms**
**Many (28.6%) patients presented to medical facilities more than 6 hours after onset of symptoms**

**OCTAVE:  Class II-IV Patients**

## Patient’s Abilityto Recognize Angioedema

**Patient’s Ability****to Recognize Angioedema**

**Patients with airway compromise were ****highly symptomatic with a constellation ****of symptoms**
**Patients without airway compromise also****had clinically overt presentation with visible swelling +/- functional complaints**
**No patients with angioedema had non-specific lower airway complaints (stridor, dyspnea, hoarseness) alone**

## OCTAVE: Incidence of Angioedema by Time Period

**OCTAVE (CV137-120)**

## OCTAVE: Summary of Angioedema Riskwith Omapatrilat in Subgroups*

_**Relative Risk**_

**Black race**
**Current smoker****
**Renal disease**
**Seasonal allergies**
**Female gender**
**Former smoker****
**Age ******** 65 years**
**ACE-I use**
**Diabetes**
**Atherosclerotic disease**

**Decreased Risk**

**Increased Risk**

**	***** Multivariate logistic regression model with angioedema as the dependent variable and all other ****	****	****  listed variables as independent variables. **
**	****** vs those who never smoked.**

**  ****72 (5.5%)**
**  ****89 (3.9%)**
**  ****11 (3.6%)**
**  ****55 (3.3%)**
**153 (2.5%)**
**  ****78 (2.1%)**
**  ****70 (2.0%)**
**  ****90 (2.0%)**
**  ****23 (1.3%)**
**  ****14 (1.2%)**

_**Incidence**_

**(vs. those without characteristics)**

_**Subgroup**_

## Angioedema Safety Summary

**Incremental risk of angioedema relative to ACE-I treatment**
**Angioedema has wide spectrum of severity**
**Current smokers and black patients have a higher incidence of angioedema**
**Life-threatening in 1.6/10,000 (95% CI 0.2-5.7)**
**Symptomatic event with characteristic presentation**
**Onset rapid but not fulminant**
**Effective treatment exists for angioedema**

## Risk Management

**Angioedema has clinical features which facilitate****its management through patient education:**
**Symptomatic, recognizable clinical presentation**
**Rapid but not fulminant progression**
**Effective therapy exists which can prevent****poor outcomes**

## Risk Management

**Risk Management**

**Labeling and packaging**
**Indication, warning, risk factors, etc.**
**Unit of use packaging**
**Comprehensive educational program**
**Includes mandatory patient counseling**
**Multiple points of contact (physicians,****patients, pharmacists)**
**Post-marketing surveillance**
**Includes prospective observational cohort study**
**Ongoing assessment of program effectiveness**
**Expert panel**

## Projected Reduction in CV Events Per annum per 10,000 Treated

**CV Risk Category**

**Projected Reduction**
**in CV Events**

**BP****Reduction****3/2 mmHg**

**BP****Reduction****5/3 mmHg**

**Projected**
**CV Events**

**Observed incidence of angioedema with airway compromise ****over 24 weeks in OCTAVE: 1.6 (95% CI 0.2 -- 5.7) per 10,000**