1. Evaluation of Ranolazine in Patients with Type 2 Diabetes Mellitus
and Chronic StableAngina
Results from the
TERISA Randomized Clinical Trial
Mikhail Kosiborod, Suzanne V.Arnold, JohnA. Spertus, Darren K. McGuire,
Yan Li, Patrick Yue, Ori Ben-Yehuda,Amos Katz, Phillip G. Jones,
Ann Olmsted, Luiz Belardinelli, Bernard R. Chaitman
On behalf of the TERISA Investigators

2. Disclosures • TERISAwas sponsored by Gilead Sciences Inc.
– Saint Luke’s MidAmerica Heart Institute received
funding for independent data analysis from Gilead
Sciences, Inc.

3. Background • Despite advances in therapy, chronic angina
remains a common problem
– Affects 8 million patients in the US
– Negative impact on health status and QoL
– Major driver of repeat hospitalizations and costs
• Patients with diabetes have more extensive
CAD, and greater angina burden than those
without diabetes

4. Background • Ranolazine, a selective inhibitor of the late
sodium current (late INa), is effective in
treating chronic angina
• Ranolazine may also lower fasting glucose
and HbA1c
• The anti-anginal efficacy of ranolazine in
patients with diabetes has not been
prospectively tested

5. TERISA: Primary Objective
• Evaluate efficacy of ranolazine versus placebo on
angina frequency in patients with type 2 diabetes,
CAD, and chronic stable angina who remain
symptomatic despite treatment with 1 or 2 anti-
anginal medications

6. • Run-in Phase: Single-blind placebo (4 weeks)
TERISA: Study Design
• Run-in Phase: Single-blind placebo (4 weeks)
• Treatment Phase: Randomized double-blind parallel
group phase (8 weeks): ranolazine (target dose 1000 mg
bid vs. matching placebo)
Run-in Phase*
4 weeks
Treatment Phase
8 weeks
FU safety
Wk 2 visit
Wk 8 visit
phone call
Randomization
Ranolazine
Screening
FU – 2 wks
FU safety
phone call
Wk 2 visit
Wk 8 visit
Placebo
Antianginal Background Therapy
*Subjects taking >2 antianginal medications or disallowed antianginal agents
were allowed additional 2 week washout period prior to the run-in phase

7. Study Endpoints • Primary:Average weekly number of angina
episodes from weeks 2-8 of treatment
• Key Secondary:Average weekly number of SL
NTG doses from weeks 2-8 of treatment

8. DataAcquisition • Angina frequency and SL NTG use captured daily
using electronic diary
• Daily data transfer

9. TERISASites
105 Sites from 14 Countries

10. Enrollment and Randomization
Assessed for Eligibility (n=1185)
Excluded (n=236)
• Not meeting inclusion criteria (n=43)
• Failed run-in (n=193)
Randomized (n=949)
Randomized to Ranolazine (n=473)
Discontinuation of Treatment (n=11)
Analyzed (n=462)
Randomized to Placebo (n=476)
Discontinuation of Treatment (n=11)
Analyzed (n=465)

11. Baseline Characteristics by Study Group
Ranolazine
n=462
63.2
61.3
98.7
95.0
79.4
15.4
75.4
42.7
18.2
Placebo
n=465
64.2
61.5
99.4
95.9
80.3
16.6
72.7
38.8
18.9
Age (yr)
Men (%)
White (%)
Hypertension (%)
Dyslipidemia (%)
Current smoking (%)
Prior myocardial infarction (%)
Prior angioplasty (%)
Prior bypass graft surgery (%)

12. Baseline Characteristics by Study Group
Ranolazine
n=462
7.2±6.7
7.3±1.5
93.3
17.5
Placebo
n=465
7.7±7.0
7.3±1.5
92.7
20.6
Duration of diabetes (yr)
HbA1c (%)
Glucose Lowering Medication (%)
Insulin (%)

13. Baseline Characteristics by Study Group
Ranolazine
n=462
56.1
43.9
90.5
26.8
34.8
82.5
89.8
88.1
98 (95-98)
Placebo
n=465
55.7
44.3
89.9
30.8
32.5
82.4
86.5
87.5
98 (95-98)
Antianginal medications
on 1 (%)
on 2 (%)
Beta blockers (%)
Calcium channel blockers (%)
Long acting nitrates (%)
Statins (%)
Antiplatelet agents (%)
ACE-I/ARBs (%)
Diary compliance - median % (IQR)

14. Primary Endpoint Ranolazine Placebo p-value
Least squares mean (95% CI)
Angina frequency,
baseline (#/wk)
Angina frequency, on
treatment (#/wk)
6.6 ( )
3.8 ( )
6.8 ( )
4.3 ( )
0.54
0.008

15. WeeklyAngina Frequency by Study Group
Run In Phase
Treatment Phase 6 4
WeeklyAngina Frequency 2
Placebo
Ranolazine
p=0.008 -2 2 4 6 8
Study Week

16. Key Secondary Endpoint
Ranolazine
n=462
Placebo
n=465
p-value
Least squares mean (95% CI)
SL NTG doses,
baseline – (#/wk)
SL NTG doses, on
treatment (#/wk)
4.1 ( )
1.7 ( )
4.5 ( )
2.1 ( )
0.27
0.003

17. SL NTG Doses Run In Phase Study Week Treatment Phase p=0.003 4 3 2 1
Run In Phase
Placebo
Ranolazine
Weekly SL NTG Doses -2 2 4 6 8
Study Week

18. SubgroupAnalyses of the Primary End
Point of Weekly Angina Frequency
Ranolazine better
Placebo better
p for
interaction
Other
Russia, Ukraine, Belarus
0.016
Pre-specified
stratifications
Other:
3.1 vs. 4.1 (ranolazine vs. placebo), p=0.002
Russia, Ukraine, Belarus:
4.1 vs (ranolazine vs. placebo), p=0.31 1
Incidence Density Ratio

19. SubgroupAnalyses of the Primary End
Point of Weekly Angina Frequency
Ranolazine better
Placebo better
p for
interaction
Other
Russia, Ukraine, Belarus
2 antianginal medications
1 antianginal medications
Prespecified ≥ 3 baseline episodes
stratifications < 3 baseline episodes
Age ≥ 65
Age < 65
Men
Women
Prior PCI
No Prior PCI
Prior CABG
No Prior CABG
0.016
0.89
0.85
0.97
0.46
0.61
0.28 1
Incidence Density Ratio

20. ExploratoryAnalysis – HbA1c
p for
interaction
Ranolazine better
Placebo better
HbA1c >6
HbA1c ≤ 6
HbA1c >6.5
HbA1c ≤ 6.5
HbA1c >7
HbA1c ≤ 7
HbA1c >7.5
HbA1c ≤ 7.5
HbA1c >8
HbA1c ≤ 8
0.046
0.047
0.022
0.041
0.038
0.7
0.8
0.9 1
1.1
1.2
Incidence Density Ratio

21. Safety Placebo p-value Serious Adverse Events number (%)
Ranolazine
n=470
Placebo
n=474
p-value
Serious Adverse Events
number (%)
Serious adverse event
Death
Nonfatal myocardial infarction
Stroke/transient ischemic attack
Unstable angina or coronary
revascularization
16 (3.4)
3 (0.6)
1 (0.2)
6 (1.3)
20 (4.2)
2 (0.4)
3 (0.6)
4 (0.8)
7 (1.5)
0.51
0.69
0.62
0.37
0.79
Notable non-serious adverse events
Dizziness
Nausea
Headache
Constipation
Hypoglycemia
AnyAdverse Event
17 (3.6)
7 (1.5)
8 (1.7)
3 (0.6)
126 (26.8)
6 (1.3)
2 (0.4)
9 (1.9)
0 (0.0)
105 (22.2)
0.019
<0.001
0.63
0.063
0.12
0.096

22. Conclusions • Ranolazine was more effective than placebo in reducing
angina frequency and SL NTG use in patients with type
2 diabetes, CAD and chronic angina
• The therapeutic effectiveness of ranolazine was more
pronounced
– In patients enrolled outside of Russia, Ukraine and Belarus
– In those with higher baseline HbA1c
• Future studies are needed to explore potential dual
effects of ranolazine on angina and glucose control in
patients with type 2 diabetes

23. JACC Online • Journal of the American College of Cardiology (2013),
• Evaluation of Ranolazine in Patients
with Type 2 Diabetes Mellitus and
Chronic StableAngina. Results
from the TERISArandomized
clinical trial
• Journal of the American
College of Cardiology (2013),
doi: /j.jacc