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Evaluation of Ranolazine in Patients with Type 2 Diabetes Mellitus and Chronic Stable Angina Results from the TERISA Ran

Evaluation of Ranolazine in Patients with Type 2 Diabetes Mellitus and Chronic Stable Angina Results from the TERISA Randomized Clinical Trial.

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Evaluation of Ranolazine in Patients with Type 2 Diabetes Mellitus and Chronic Stable Angina Results from the TERISA Ran

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  1. Evaluation of Ranolazine inPatients with Type 2 Diabetes Mellitusand Chronic Stable AnginaResults from theTERISA Randomized Clinical Trial Mikhail Kosiborod, Suzanne V. Arnold, John A. 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. Funding • TERISA was sponsored by Gilead Sciences Inc. • Saint Luke’s Mid America 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, an 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) Treatment Phase: Randomized double-blind parallel group phase (8 weeks): ranolazine (target dose 1000 mg bid vs. matching placebo) TERISA: Study Design Treatment Phase 8 weeks Run-in Phase*4 weeks FU safetyphone call Wk 2 visit Wk 8 visit Randomization Ranolazine Screening FU – 2 wks FU safetyphone 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. Data Acquisition • Angina frequency and SL NTG use captured daily using electronic diary • Daily data transfer

  9. TERISA Sites 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) Randomized to Placebo (n=476) Discontinuation of Treatment (n=11) Discontinuation of Treatment (n=11) Analyzed (n=462) Analyzed (n=465)

  11. Baseline Characteristics by Study Group

  12. Baseline Characteristics by Study Group

  13. Baseline Characteristics by Study Group

  14. Primary Endpoint

  15. Weekly Angina Frequency by Study Group Treatment Phase Run In Phase Weekly Angina Frequency 6 Placebo Ranolazine p=0.008 4 Study Week 2 0 -2 0 2 4 6 8

  16. Key Secondary Endpoint

  17. SL NTG Doses Treatment Phase Run In Phase Placebo Ranolazine 4 3 Weekly SL NTG Doses 2 1 p=0.003 0 -2 2 4 6 8 0 Study Week

  18. Subgroup Analyses of the Primary End Point of Weekly Angina Frequency p forinteraction Ranolazine better Placebo better 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

  19. Subgroup Analyses of the Primary End Point of Weekly Angina Frequency p forinteraction Ranolazine better Placebo better Other Russia, Ukraine, Belarus 0.016 2 antianginal medications 1 antianginal medications 0.89 Prespecified stratifications ≥ 3 baseline episodes < 3 baseline episodes 0.85 Age ≥ 65 Age < 65 0.97 Men Women 0.46 Prior PCI No Prior PCI 0.61 Prior CABG No Prior CABG 0.28 0.7 0.8 0.9 1 1.1 1.2 Incidence Density Ratio

  20. Exploratory Analysis – HbA1c p for interaction 0.046 0.047 0.022 0.041 0.038 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 0.7 0.8 0.9 1 1.1 1.2 Incidence Density Ratio

  21. Safety and Tolerability

  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 greater • 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 • Evaluation of Ranolazine in Patients with Type 2 Diabetes Mellitus and Chronic Stable Angina. Results from the TERISA randomized clinical trial • Journal of the American College of Cardiology (2013), doi:10.1016/j.jacc.2013.02.011.

  24. Back-up Slides

  25. Weekly Angina Frequency by Study Group Stratified by Geographic Region Run In Phase Treatment Phase 6 4 Weekly Angina Frequency Placebo Ranolazine 2 Russia, Ukraine,Belarus (n=667) 4.1 vs. 4.3  (ranolazine vs. placebo), p=0.31 0 -2 0 2 4 6 8 Study Week Run In Phase Treatment Phase 6 4 Weekly Angina Frequency Placebo Ranolazine 2 3.1 vs. 4.1 (ranolazine vs. placebo), p=0.002 Other (n=282) 0 -2 0 2 4 6 8 Study Week

  26. Secondary Endpoints

  27. Baseline Characteristics of Patientsby Geographic Region

  28. Baseline Characteristics of Patientsby Geographic Region

  29. Baseline Characteristics of Patientsby Geographic Region

  30. Incidence Density Ratios for Angina Frequency Omitting Individual Countries IDR for overall cohort: 0.894

  31. Incidence Density Ratios for Angina Frequency Omitting Individual Sites (Russian Sites in Red) IDR for overall cohort: 0.894 Incidence Density Ratio, Angina Frequency Site

  32. Enrollment in TERISA by Country

  33. The Cycle of Myocardial Ischemia:Ischemia Begets Ischemia ↓Oxygen Supply: Demand Ischemia Ranolazine  MVO2  O2 Supply Diabetic Heart (↑ Glucose) ↑ Late INa Contracture ( LVEDP) Arrhythmias Hypothesis Na+i & Ca++i Overload Hypothesis : Glucose increases pCaMKII, which increases late INa Modified from Belardinelli L. et al. Eur Heart J. Suppl. 2006

  34. Diabetic Cardiomyopathy:Dual Benefit of Ranolazine Ranolazine Late INa High Glucose Hypothesis * Hypothesis : Glucose increases pCaMKII, which increases late INa * Nishio et al JMCC 52 (2012) 1103–1111 * Luo and Anderson et al JCI, 2013 * Mourouzis et al Unpublished data 2013

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