1. Ranexa™ for Chronic Angina An Unmet Need
2. Chronic Angina—An Unmet Need (CM)
4/13/2017 4:00 PM
Ranexa™ for Chronic Angina An Unmet Need
Eugene Braunwald, MD, FACC
Harvard Medical School
Brigham and Women’s Hospital

2. 2. Chronic Angina—An Unmet Need (CM)
4/13/2017 4:00 PM
CM-2
There is a strong disorder in the breast. The seat of it, and sense of strangling and anxiety with which it is attended, may make it not improperly be called angina pectoris.… Those who are afflicted with it, are seized, while they are walking with a painful and most disagreeable sensation in the breast, which seems as if it would take their life away, if it were to increase or to continue.
Heberden. Medical Transaction, Royal College of Physicians
of London. 1772;2:59-67.

3. Epidemiology of Chronic Angina
2. Chronic Angina—An Unmet Need (CM)
4/13/2017 4:00 PM
Epidemiology of Chronic Angina
AHA reports that at least 6.6 million Americans suffer with angina pectoris
Despite therapeutic advances
> 13 million episodes of angina a week in the US
> 1000 episodes of angina every minute
Growing prevalence of chronic angina due to reductions in cardiovascular mortality
Improved treatment of angina is an important goal

4. Comorbid Conditions Complicate Therapy
2. Chronic Angina—An Unmet Need (CM)
4/13/2017 4:00 PM
Comorbid Conditions Complicate Therapy
Studies of VA patients with CAD demonstrate the following comorbidity incidence rates
Diabetes: 26% to 31%
COPD: 13% to 22%
Peripheral vascular disease: 16% to 28%
Congestive heart failure: 20%
Rumsfeld, 1999.

5. Persistent Angina Despite Current Drug Therapy
2. Chronic Angina—An Unmet Need (CM)
4/13/2017 4:00 PM
Persistent Angina Despite Current Drug Therapy
Despite use of traditional anti-anginal agents (-blockers, CCBs, and nitrates), patients still reported an average of 2 anginal attacks/week†
A significant percentage of patients have relative intolerance to full doses of -blockers, CCBs, and nitrates
-blockers and many CCBs have similar depressive effects on BP, HR and/or AV nodal conduction
It would be desirable to develop an anti-anginal drug without these limitations
†Pepine, 1994.

6. Persistent Angina Despite Percutaneous Intervention (PCI)
2. Chronic Angina—An Unmet Need (CM)
4/13/2017 4:00 PM
Persistent Angina Despite Percutaneous Intervention (PCI)
Angina at 1-yr follow-up by events during or after initial PCI
1 yr after PCI for. . .
Symptom relief (N = 1403)
Treatment of acute myocardial infarction (N = 352)
. . . the overall prevalence of angina was 26%
Events, n
Angina at follow-up, %
Events occurring after post-PCI discharge only MI No
1576
25.2
Yes 44
38.6
CABG
1522
26.3 98
15.3
Repeat PCI
1370
24.1
250
34.0
Holubkov R, et al. NHLBI Dynamic Registry. Am Heart J. 2002;144:

7. Persistent Angina Despite Optimal Revascularization
2. Chronic Angina—An Unmet Need (CM)
4/13/2017 4:00 PM
Persistent Angina Despite Optimal Revascularization
1 yr after optimal revascularization by stenting or surgery for relief of ischemia (ie, not to prolong survival) …
TABLE 3. STATUS WITH RESPECT TO ANGINA AND MEDICATION USE AND QUALITY OF LIFE AMONG SURVIVING PATIENTS.*
VARIABLE
12 MO AFTER INTERVENTION
STENTING GROUP
SURGERY GROUP
P value
Free of angina (%)
78.9
89.5
<0.001
Free of antianginal medication (%)
21.1
41.5
Free of angina and antianginal medication (%)
19.1
38.4
~ 60% to 80% are still taking anti-anginal medications
~ 10% to 20% still have angina
Serruys PW, et al. for the ARTS Study Group. N Engl J Med. 2001;344:

8. Self Rating of Health for Angina Patients
2. Chronic Angina—An Unmet Need (CM)
4/13/2017 4:00 PM
Self Rating of Health for Angina Patients
100
Normal US population
Angina patients 90 80
General
health 70
Vitality 60
SF36 scores 50 40 30 20 10
Physical
function
Bodily pain
Chen AY, et al. Med Decis Making. 1996;16:

9. Angina Frequency and Depression
2. Chronic Angina—An Unmet Need (CM)
4/13/2017 4:00 PM
Angina Frequency and Depression
1957 patients completed SAQ 7 mo after ACS
History of depression documented in 526 (26.7%) patients following ACS
Strong correlation of angina frequency with depression 50 45 40 35 30
% depression 25 20 15 10 5
None
Monthly
Weekly
Daily
Angina frequency
ACS = acute coronary syndrome
SAQ = Seattle Angina Questionnaire
Rumsfeld JS, et al. Am Heart J. 2003;145:492.

10. Unmet Need of Chronic Angina
2. Chronic Angina—An Unmet Need (CM)
4/13/2017 4:00 PM
Unmet Need of Chronic Angina
Angina continues in many patients despite medical therapy and mechanical revascularization
The personal burden can deprive many patients of their functional independence, forcing them to downsize their lives
The economic toll of angina places a huge burden on patients, their families, the healthcare system, and society

11. Unmet Need of Chronic Angina
2. Chronic Angina—An Unmet Need (CM)
4/13/2017 4:00 PM
Unmet Need of Chronic Angina
When angina cannot be eliminated by current drugs, it is often their additive effects on BP, HR, AV conduction, and other important side effects (depression, fatigue, sexual/sleep disorders, etc.) that preclude complete relief.

12. Novel Therapies Needed for a Growing Angina Burden
2. Chronic Angina—An Unmet Need (CM)
4/13/2017 4:00 PM
Novel Therapies Needed for a Growing Angina Burden 6 4
Patients,
millions 2
1900
2000

13. Angina—Evolution of Therapy
2. Chronic Angina—An Unmet Need (CM)
4/13/2017 4:00 PM
Angina—Evolution of Therapy
Nitrates
 block
CABG
CCB
PCI
Ranexa™
TREATMENT
O2 demand
O2 supply + + ? +
ATP/O
Likely mechanisms