1. Adjuvant Ranolazine for Patients With Incomplete Revascularization
Pathways to Reduce Ischemia
Adjuvant Ranolazine for Patients With Incomplete Revascularization
Giora Weisz, MD
Director of Cardiovascular Clinical Research,
Center for Interventional Vascular Therapy
Columbia University Medical Center
Cardiovascular Research Foundation
New York, NY

2. Giora Weisz, MD Tryton Medical, Inc. Consulting: InfraReDx, Inc.
Svelte Therapeutics
Philips Medical Systems, Inc.
Stocks, Stock Options, other ownership interest:
Simbionix
Bloxr
Sync-RX

4. Why Might Complete Revascularization be Beneficial
Why Might Complete Revascularization be Beneficial? Potential advantages:
Symptomatic relief
Less subsequent procedures
Improve / preservation of LV function
Better tolerance of events in other coronary distributions
Reduced mortality
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5. Incomplete Revascularization is Common

6. CTO: Impact on Therapy Recommended
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With Occlusion (n=220)
Without Occlusion (n=357)
Delacretaz et al, 1997

7. Adjuvant Pharmacotherapy

8. CAD: Management options
• PCI/CABG with goal to achieve at least “reasonably” complete revascularization
• If incomplete revasc: Medical management for residual angina/ischemia
Secondary prevention (statins, etc.)
Nitrates
β-blockers
Ca++ channel blockers
Ranolazine
Medical management is often added to treat angina and ischemia.

9. LB overview of RAN MOA & Anti-anginal ischemic effects
9/10/2018 7:59 PM
Ranolazine
Ranolazine is an inhibitor of the late Ina channel resulting in anti-ischemic and anti-anginal effects
Ranolazine does not…
a) slow the heart rate (no bradycardia)
b) decrease contractility (no depression of LV function)
c) affect coronary or peripheral flow: no vasoconstriction or vasodilation (no spasm or hypotension)
d) slow AV nodal conduction (no PR prolongation)
Post-PCI Executive Committee Mtg New York

10. Ischemia Begets Ischemia
 (Oxygen Supply: Demand)
Ischemia
Hypoxia, Ischemic metabolites,
acidosis, and ROS
Ranolazine
 MVO2
 O2 Supply
 Late INa
With myocardial ischemia, we have a vicious cycle of “ischemia begets ischemia”. Ischemia cause activation of late Na channels that cause intracellular Ca overload, that results is increased LVEDP which further reduce regional blood flow and increase O2 demand, resulting in more ischemia. Ranolazine inhibit the late Na channel, thus reducing ischemia.
Contracture ( LVEDP)
(Arrhythmias)
[Na+]i Ca++ Overload
Modified from: Belardinelli L, et al. Eur Heart. 2006;8 (Suppl. A):A10-A13.

11. LB overview of RAN MOA & Anti-anginal ischemic effects
9/10/2018 7:59 PM
Myocardial Perfusion Imaging in Patients with Coronary Artery Disease Treated with Ranolazine
Exploratory study in 20 patients with CAD and angina
Images from representative patient
P = 0.003
N = 14
Before Ranolazine
PDS = 25% of LV
Peak HR = 142 bpm
After Ranolazine
PDS = 11% of LV
Peak HR = 142 bpm
We can see an objective evidence of reduced ischemia with ranolzaine, a 55% decease in the ischemic myocardium, as compared with baseline without ranolazine.
Treadmill exercise time increased by 32 seconds (p=0.017, n=20)
Among the 15 patients with reduced angina, 11 (73%) had an improvement in perfusion.
Modified from Venkataraman etal.. JACC Imaging 2009;2:1301-9
Post-PCI Executive Committee Mtg New York

12. LB Late Sodium Current Angina Therapy
Revised
CARISA
Randomization
placebo
placebo b.i.d. (n=269)
Eligible patients maintained on one antianginal drug:
- 50 mg atenolol
- 5 mg amlodipine
- 180 mg diltiazem*
Sublingual nitrates
used as needed
placebo
750 mg ran
750 mg b.i.d. ranolazine** (n=279)
placebo
1000 mg ran
1000 mg b.i.d. ranolazine (n=275)
placebo
Trough ETTs
CARISA: Study Design
Speaker Points
CARISA was a randomized, 3-group parallel, double-blind, placebo-controlled trial.
Randomization was stratified by the 3 background antianginal therapies:
Atenolol (43%), amlodipine (31%), and diltiazem (26%)
Sublingual nitrates were used as needed.
All patients continued to receive one background antianginal therapy throughout the duration of the trial.
Ranolazine is contraindicated in patients on potent and moderately potent CYP3A inhibitors, including diltiazem.
Patients were randomized to receive placebo, 750 mg ranolazine, or 1000 mg ranolazine twice daily. The 750 mg dose of ranolazine is not approved.
Exercise protocol:
Patients had 2 modified Bruce exercise tolerance tests conducted 1 week apart at baseline.
Subsequent exercise tests were performed at trough drug levels (12 hours post-dosing) 2, 6, and 12 weeks after randomization.
At 2 and 12 weeks after randomization, a peak exercise test was performed approximately 4 hours after dosing.
Background
Patients were enrolled to have an equal distribution of subjects on the beta-blocker atenolol and the CCBs amlodipine and diltiazem.
The choice of background therapy was at the discretion of the investigator, and the doses were fixed throughout the study.
References
Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004;291(3):
Ranexa® (ranolazine extended-release tablets) PI. February 2006.
CVT data on file RAN -2 0† 2† 6
12† ‡
Weeks
2 days
Chaitman BR, et al. JAMA

13. CARISA: Ranolazine Increases Exercise Treadmill Test Performance
LB Late Sodium Current Angina Therapy
Revised
CARISA: Ranolazine Increases Exercise Treadmill Test Performance
Trough
Peak
Exercise Duration
Angina Onset
1 mm ST Depression
Time (seconds) 40 80
120
160
Comparison to placebo at week 12
* P≤0.05
114.3
140.3
88.9
126.8
26.0s*
37.9s*
125.1
146.2
59.2
93.8
21.1s
34.6s*
65.4
91.5
26.1s*
Primary endpoint
91.7
115.8
24.1s*
Placebo
Ranolazine 1000 mg BID
In the CARISA trial, 823 patients with chronic angina were randomized to R vs P.
R was associated with improved exercise treadmill test performance, >>>>
CARISA: Ranolazine Increases Exercise Treadmill Test Performance
Comparison to placebo at week 12
Speaker Points
Exercise duration, time to angina, and time to 1 mm ST depression, at peak only, for patients taking ranolazine were significantly increased compared with the placebo group.
The slide depicts improvement from baseline in exercise duration, time to onset of angina, and time to 1 mm ST depression in the placebo and 1000 mg b.i.d. ranolazine treatment groups.
The primary endpoint was treadmill exercise duration at trough ranolazine levels (ie, 12 hours after dosing) compared to placebo.
This effect was sustained through 12 weeks of therapy.
The improvement in exercise treadmill tests in females was about 33% of that in males receiving 1000 mg b.i.d. ranolazine.
Tolerance to ranolazine did not develop after 12 weeks of therapy, and rebound angina, as measured by exercise duration, has not been observed.
Doses >1000 mg b.i.d. should not be used.
Background
There were 275 patients in the ranolazine 1000 mg group and 269 patients in the placebo group.
Exercise duration for patients on both doses of ranolazine was increased compared with placebo (P=0.01). Each dose increased treadmill exercise duration at both trough (P=0.03) and peak (P<0.02).
Exercise treadmill results at baseline were longer at peak than at trough for both ranolazine doses and placebo. Changes from baseline with both ranolazine doses and placebo were generally smaller at peak than at trough. Patients were on background antianginal therapies at baseline and through 12 weeks of therapy.
Differences between both ranolazine 750 mg and 1000 mg doses and placebo were greater at peak than at trough.
Exercise treadmill results showed no increase in effect on exercise at the 1000 mg dose compared to the 750 mg dose.
The 750 mg dose of ranolazine is not approved.
References
Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004;291:
Ranexa® (ranolazine extended-release tablets) PI. February 2006.
CVT data on file RAN
Chaitman BR, et al. JAMA

14. CARISA: Ranolazine Reduces Weekly Angina Frequency vs Placebo
LB Late Sodium Current Angina Therapy
Revised
CARISA: Ranolazine Reduces Weekly Angina Frequency vs Placebo 5
Placebo
Ranolazine 1000 mg BID 4
3.3
36% Reduction in Angina Frequency
Mean number of angina attacks/week 3
2.1
P<0.001 2
>>> 36% reduction in frequency of the angina symptoms, and>>>
CARISA: Ranolazine Reduces Weekly Angina Frequency vs Placebo
Speaker Points
Over a 12-week period, ranolazine significantly reduced the mean weekly angina attacks by 36% compared to placebo (P<0.001).
Mean angina attacks per week were 2.1 for the 1000 mg b.i.d. ranolazine group and 3.3 for the placebo group.
At baseline, patients were symptomatic, experiencing an average of 4.5 angina attacks per week in the ranolazine group and 4.6 angina attacks per week in the placebo group.
The effect on angina rate appeared to be smaller in women than men.
Background
Randomization was stratified by the 3 background antianginal therapies (atenolol, amlodipine, and diltiazem) that patients were taking at the time of enrollment. Sublingual nitrates were used as needed.
There were 275 patients in the 1000 mg b.i.d. ranolazine group and 269 patients in the placebo group.
The 750 mg dose of ranolazine is not approved.
References
Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004;291:
Ranexa® (ranolazine extended-release tablets) PI. February 2006.
CVT data on file RAN
Mean number of angina attacks/wk at baseline 1
Placebo + background therapy
Ranolazine 1000 mg BID + background therapy
4.6
4.5
Double-blind
Chaitman BR, et al. JAMA 2004

15. CARISA: Ranolazine Reduces Weekly Nitroglycerin Use vs Placebo
LB Late Sodium Current Angina Therapy
Revised
CARISA: Ranolazine Reduces Weekly Nitroglycerin Use vs Placebo 5
Placebo
Ranolazine 1000 mg BID 4
43% Reduction in NTG use
3.1
Mean nitroglycerin doses/week 3
P<0.001
1.8 2
>>>> and reduction in Nitroglycerine use.
CARISA: Ranolazine Reduces Weekly Nitroglycerin Use vs Placebo
Speaker Points
Over a 12-week period, ranolazine reduced mean nitroglycerin use per week by 43% compared to placebo (P<0.001).
Mean nitroglycerin use per week was 1.8 tablets for 1000 mg b.i.d. ranolazine group and 3.1 tablets for the placebo group.
At baseline, patients averaged 3.7 nitroglycerin tablets per week in the ranolazine group and 4.0 nitroglycerin tablets per week in the placebo group.
Background
Randomization was stratified by the 3 background antianginal therapies (atenolol, amlodipine, and diltiazem) that patients were taking at the time of enrollment. Sublingual nitrates were used as needed.
There were 275 patients in the 1000 mg ranolazine group and 269 patients in the placebo group.
Patients were permitted to use sublingual nitrates as needed throughout the study.
References
Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004;291:
Ranexa® (ranolazine extended-release tablets) PI. February 2006.
CVT data on file RAN
Mean number of nitroglycerin doses/wk at baseline 1
Placebo + background therapy
1000 mg b.i.d. ranolazine + background therapy
4.0
3.7
Double-blind
Chaitman BR, et al. JAMA 2004

16. LB Late Sodium Current Angina Therapy
MERLIN - TIMI 36 Trial
Revised
N = 5600 pts
442 sites
17 countries
UA/NSTEMI
(Moderate-High Risk)
Standard Therapy
RANDOMIZE (1:1)
Double-blind
Ranolazine IV to PO
Placebo
Matched IV/PO
Holter
Continuous
7-day recording
Objectives
Efficacy: Composite of CV Death, MI or RI.
Safety: Clinically Significant Arrhythmia (Holter)
Long-term Follow-up
(Median 348 Days)
Visits Q4 months
Morrow DA et al. JAMA 2007; 297: 16

17. LB Late Sodium Current Angina Therapy
Revised
MERLIN-TIMI 36 Trial: Cardiovascular Death or MI and Recurrent Ischemia
Cardiovascular Death or MI
Recurrent Ischemia
Ranolazine
Placebo
Ranolazine
Placebo
Hazard Ratio
0.99 (95% CI )
P=0.87
Recurrent Ischemia (%)
Recurrent Ischemia (%)
but R was associated with significantly less recurrent ischemia.
Hazard Ratio
0.87 (95% CI )
P=0.03
Follow-Up (days)
Follow-Up (days)
Morrow DA, et al. JAMA. 2007;297:

18. MERLIN-TIMI 36 Diabetes Subanalysis for Recurrent Ischemia
LB Late Sodium Current Angina Therapy
Revised
MERLIN-TIMI 36 Diabetes Subanalysis for Recurrent Ischemia
Diabetes Mellitus
(n=1477)
No Diabetes Mellitus
(n=2829)
Ranolazine
Placebo
Ranolazine
Placebo
19.2%
15.1%
14.6%
Recurrent Ischemia (%)
Recurrent Ischemia (%)
The favorite effect of R on reducing recurrent ischemia was significantly higher in patients with DM, with a reduction of 21%
13.3%
Hazard Ratio
0.75 (95% CI )
P=0.008
Hazard Ratio
0.95 (95% CI )
P=0.50
Follow-Up (days)
Follow-Up (days)
Morrow DA, et al. Circulation. 2009;119:

19. MERLIN: Patients with History of Angina
Placebo
N=1776
Ranolazine
N = 1789 HR
P value
Primary endpoint
29.4%
25.2%
0.86
p = 0.017
CV death or MI
12.5%
11.9%
0.97
p = 0.71
Recurrent ischemia
21.1%
16.5%
0.78
p = 0.002
Severe recurrent ischemia
14.4%
0.81
p = 0.026
Prompting revascularization
6.4%
4.5%
0.66
p = 0.006
Worsening angina
8.2%
5.6%
0.77
p = 0.048
Similar benefit with R was observed in patents with prior history of angina. As compared to placebo, R resulted in reduced rates of…
Wilson S et al. J Am Coll Cardiol 2009;53:1510–6

20. MERLIN: Patients with History of Angina Treated with PCI for NSTE-ACS
Placebo
N=443
Ranolazine
N = 473 HR
P value
Primary endpoint
30.2%
21.1%
0.67
p = 0.002
CV mortality
3.4%
1.1%
0.69
p = 0.014
Myocardial Infarction
6.3%
5.3%
0.83
P=0.5
Recurrent ischemia
23%
16.7%
11.6%
p = 0.023
Revascularization
10.2%
0.60
p = 0.022
Re-hospitalization
15.8%
10.8%
0.66
And when looking specifically at the patients that were treated with PCI for the ACS event, adding the treatment with R resulted not only in reduced ischemic symptoms, but also significant reduction in CV morality.
Wilson S et al. J Am Coll Cardiol 2009;53:1510–6

21. Principal Investigator: Giora Weisz, MD Study Chair: Gregg W Stone, MD
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Effects of Ranolazine on Major Adverse Cardiovascular Events in Subjects with a History of Chronic Angina Who Undergo Percutaneous Coronary Intervention with Incomplete Revascularization
Principal Investigator: Giora Weisz, MD Study Chair: Gregg W Stone, MD

22. N=1300 N=1300 History of angina Post PCI
Incomplete revascularization (≥50 %DS in ≥2 mm RVD)
1:1 randomization
stratified by: ACS vs. non-ACS, DM vs. non-DM
Ranolazine
N=1300
Placebo
N=1300
200 sites, 15 countries
Standard medical therapy
Follow-up: event driven, ≥1 yr
10 EP: Time to ischemia-driven revascularization or hospitalization
20 EPs: Mortality, MI, QoL, cost-effectiveness,
Exploratory EPs: Δ in HbA1c, new onset DM

23. Summary (1) Ranolazine, Is a late NA+ channel blocker
Effectively reduce ischemia and angina and improve exercise tolerance
In the MERLIN sub-analysis, ranolazine was associated with reduced mortality and ischemic events in patients with history of chronic angina, admitted with ACS, and getting PCI.

24. Summary (2)
RIVER-PCI,
The first large study to prospectively evaluate patients with incomplete revascularization
2600 patients from 200 centers in 15 countries
Incomplete revascularization post PCI
ACS or high-risk non-ACS
History of angina
Randomization 1:1 – Ranolazine vs. placebo

25. Summary (3) RIVER-PCI, Primary Endpoint
The time from randomization to the first occurrence of:
Ischemia-driven revascularization
Ischemia-driven hospitalization
Enrollment ongoing!

26. Thank You!