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

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

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

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

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

• 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

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

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

TERISASites 105 Sites from 14 Countries

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)

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 (%)

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 (%)

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)

Primary Endpoint Ranolazine Placebo p-value Least squares mean (95% CI) Angina frequency, baseline (#/wk) Angina frequency, on treatment (#/wk) 6.6 (6.3-7.0) 3.8 (3.6-4.1) 6.8 (6.4-7.2) 4.3 (4.0-4.5) 0.54 0.008

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

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 (3.7-4.6) 1.7 (1.6-1.9) 4.5 (4.1-5.0) 2.1 (1.9-2.3) 0.27 0.003

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

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. 4.3 (ranolazine vs. placebo), p=0.31 0.7 0.8 0.9 1 1.1 1.2 Incidence Density Ratio

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 0.7 0.8 0.9 1 1.1 1.2 Incidence Density Ratio

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

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

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

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:10.1016/j.jacc.2013.02.011.