1. The Management of Patients With Incomplete Revascularization
Giora Weisz, MD
Director of Cardiovascular Clinical Research,
Center for Interventional Vascular Therapy
Columbia University Medical Center
New York, NY

2. Giora Weisz, MD
Ownership Interest (stock, stock options, or other ownership interests):
Medicasting

3. Complete Revascularization
Successful dilatation of all significant stenoses in vessels that are of sufficient size supplying viable myocardium
Anatomical vs. functional
Functional= viable myocardium or ischemia
Significant stenosis = 50 or 70%
Sufficient size = ≥ 1.5, 2, or 2.5 mm
Proximal vs. distal
Variation in the definitions of Incomplete Revascularization

4. Incomplete Revascularization
NY State database, DES era
Defined as major epicardial arteries, major diagonal and marginals
Is Common:
7795/11294 = 69%
Range per hospital: 45-89%
Hannan et al, J Am Coll Cardiol Intv 2009;2:17–25

5. Incomplete Revascularization
NY State database CR
ICR
Significant baseline differences between CR & IC
Age
Gender
Race EF
Prior MI
CV disease
PAD DM
Renal failure
No. of diseased vessels
BMS vs. DES
Models based upon multivariate analyses adjust for differences in baseline variables but cannot eliminate confounders
Hannan et al, J Am Coll Cardiol Intv 2009;2:17–25

6. Relationship between ICR and 1-yr MACE
ACUITY Angiographic Sub-study
%DS
Threshold
ICR CR
HR [95% CI]
P-value
≥30%
20.4%
15.3%
1.36 [1.11, 1.68]
0.003
≥40%
21.6%
16.1%
1.38 [1.16, 1.64]
0.0002
≥50%
23.4%
16.6%
1.47 [1.24, 1.74]
<0.0001
≥60%
25.2%
17.1%
1.55 [1.30, 1.85]
≥70%
26.4%
17.6%
1.59 [1.30, 1.93]
Irrespective of the threshold %DS used to define ICR, the presence of ICR after PCI was strongly associated with 1-year MACE.
Increased threshold of % DS is associated with higher rates of events (click), increasing from 20.4% to 26.4% MACE at 1 year).
Rosner G. Submitted for publication 2012

7. Outcomes @ 1y (ICR @ 50% DS) Sub-analysis from ACUITY
HR [95% CI]
P-value
MACE
23.4%
16.6%
1.47 [1.24, 1.74]
<0.0001
Death
3.1%
2.2%
1.43 [0.90, 2.27]
0.13 MI
12.0%
8.2%
1.50 [1.18, 1.89]
0.0007
Revasc
15.7%
10.2%
1.58 [1.28, 1.96]
PCI
12.7%
8.8%
1.45 [1.15, 1.84]
0.002
CABG
3.9%
1.8%
2.32[1.46, 3.69]
0.0003
TVR
10.1%
7.3%
1.39 [1.08, 1.80]
0.01
Non-TVR
10.9%
6.4%
1.76 [1.36, 2.29]
Using the threshold of 50% DS to define ICR, the presence of ICR after PCI was strongly associated with 1-year MACE, driven by increased rates of MI and unplanned repeat revascularization.
Rosner G. Submitted for publication 2012

8. PROSPECT: Untreated Disease Outcomes @ 1 y – Non-culprit lesions
Any NCL ≥ 50%
All NCL < 50%
Hazard Ratio
P-value
MACE
12.6%
4.0%
3.30 [1.71,6.35]
0.001
Cardiac death, arrest, MI
0.0%
0.6%
0.24
Rehospitalization
3.4%
3.89 [1.94,7.79]
0.0001
Revascularization
10.8%
2.82 [1.44,5.51]
0.002
Data from PROSPECT also showed that patients who had non-culprit lesion of at least 50% left untreated, had higher rates of rehospitalization and revascularization.

9. Angina Status and Cost > $ 4000, p <0.001
8 mo follow up – 2 fold inrease in cost from none to daily
Similar across geographic regions
Medication costs not significant, but less statin and more anginal meds in daily.
Arnold Circ CQO 2009;2:

10. CAD - Management options
Complete revascularization
CABG limitations:
Cannot vascularize every branch
SVG early and degenerative failure
PCI challenges:
CTO’s
Branches <2.5mm
Ideally we would like to have CR, but this often not possible.

11. CAD - Management options
Medical Management of Angina / Ischemia
Secondary prevention
β-Blockers
Ca++ Channel inhibitors
Nitrates
Ranolazine
Medical management is often added to treat angina and ischemia.

12. LB overview of RAN MOA & Anti-anginal ischemic effects
9/10/ :54 PM
Ranolazine
Ranolazine has anti-ischemic and antianginal effects.
Ranolazine does not
a) slow heart rate (No bradycardia)
b) decrease contractility (No depression of LV function)
c) increase coronary or peripheral flow: not a vasodilator (No hypotension)
d) slow AV nodal conduction (No PR prolongation)
Ranolazine: an inhibitor of Late INa
Post-PCI Executive Committee Mtg New York

13. 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.

14. 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

15. 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%
Severe recurrent ischemia
11.6%
p = 0.023
Prompting revascularization
10.2%
0.60
p = 0.022
Leading to 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.

16. Adjunctive Pharmacotherapy

17. Principal Investigator: Giora Weisz, 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

18. Primary Objective
To evaluate the efficacy of ranolazine as compared with placebo when used as part of standard medical therapy in chronic angina subjects with incomplete revascularization post-PCI

19. Study Design Phase III Up to 2600 patients, 200 centers, 14 countries
Randomized, Double-Blind, Placebo-Controlled
1:1 placebo vs. ranolazine (1000mg BID)
Stratified by:
ACS vs. non-ACS
DM vs. non-DM
Follow-up: event driven, at least 1 yr

20. Major Inclusion Criteria (1)
History of chronic angina (at least 2 episodes on separate days between 30 days to 1 year prior to PCI)
Indication for PCI
ACS - hospitalization for anginal pain/discomfort within the previous 24h with elevated myocardial enzymes and/or ECG ST-changes
Non-ACS - at least one of the following:
Previous CABG surgery
Previous PCI
Multivessel CAD ( 50% stenosis in 2 or more epicardial coronary arteries)
Diabetes mellitus

21. Major Inclusion Criteria (2)
Post-PCI evidence of incomplete revascularization:
≥ 50% stenosis in one or more coronary arteries with reference vessel diameter of at least 2.0 mm

22. Study Endpoints Primary Efficacy Endpoint:
Composite of ischemia-driven revascularization or hospitalization
Secondary Endpoints:
Sudden cardiac death
CV death MI
Evaluation of QoL study and health related costs

23. Summary (1)
Incomplete revascularization is common and associated with increased rates of revascularization and hospital re-admissions
Ranolazine, a late Na+ channel blocker, effectively reduce ischemia and angina and improve exercise tolerance
Ranolazine is associated with reduced mortality and ischemic events in patients with history of chronic angina, admitted with ACS, and treated by PCI.

24. Summary (2)
RIVER-PCI,
The first study to prospectively evaluate patients with incomplete revascularization
2600 patients from 200 centers in 14 countries
Randomization 1:1 – Ranolazine vs. placebo
10 endpoint: ischemia-driven revascularization or hospitalization
Integrated QoL and health-related cost

25. The Management of Patients With Incomplete Revascularization
Giora Weisz, MD
Director of Cardiovascular Clinical Research,
Center for Interventional Vascular Therapy
Columbia University Medical Center
New York, NY

26. Optimal %DS to Define ICR
ACUITY Angiographic Sub-study
Defining ICR with a greater %DS threshold decreased the sensitivity but increased the specificity for 1-year MACE, and was associated with greater rates of MACE in patients with ICR.
The overlap point of the two curves represents the “optimal” threshold which balances sensitivity and specificity to predict subsequent MACE in patients with ICR. This occurs at a DS of ~44%
Optimal percentage diameter stenosis threshold of incomplete revascularization to predict 1-year major adverse cardiac events. This graph plots sensitivity and specificity versus percentage diameter stenosis (DS) in 1% absolute increments. Sensitivity to detect 1-year major adverse cardiac events (MACE) is increased with lower percent DS cutoff values for incomplete coronary revascularization (ICR), whereas specificity is increased with higher percent DS cutoff values for ICR. The overlap point of the two curves represents the “optimal” threshold which balances sensitivity and specificity to predict subsequent MACE in non-ST-segment elevation acute coronary syndromes. determined by quantitative coronary angiography after percutaneous coronary intervention in a coronary artery with reference vessel diameter ≥2.0 mm. This is roughly equivalent to a visually estimated DS of 55-60%.
Rosner G. Submitted for publication 2012

27. Inspiring Case 70 yr old (2008) 1981, 1998 MI’s 1985 4v CABG 1985-2007
(LIMA-LAD, SVG-OM & Diag, SVG-RCA)
al least 20 angiograms, 16 PCIs:

28. Long Saga…

29. Incomplete Revascularization Management of Incomplete
Ranolazine
Ranolazine for
Myocardial Ischemia
When you integrate our insights about the impact of ICR, the need to manage it better, and our current knowledge about R and its favorable effects, we can understand the rationales behind the RIVER-PCI study.

30. 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 favorable effect of R on reducing recurrent ischemia was significantly higher in patients with DM, with 21% reduction in recurrent ischemia
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:

31. Angina Status and Outcomes
P< 0.001
P< 0.001
Persistent and frequent angina
Dose response on death, MI, revasc, hospitalization
Dose-response on HRQOL and Physical function
Spertus Circ 2002;106:43-49

32. Extent of Revascularization
90-day Outcome, PROTECT-II
Δ IZ 0-2
N=119
Δ IZ 3-5
N=133
Δ IZ 6-11
N=145
p-value
MAE
55.1
40.6
41.4
0.036
Death/MI/Stroke/Revasc
40.7
25.6
26.2
0.014
MACCE
33.9
24.1
20.0
0.033
MACCE = Death, Stroke, Large MI*, Revasc.)
Popma J. TCT 2011