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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 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
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.
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, 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
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) 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
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
Data Acquisition • Angina frequency and SL NTG use captured daily using electronic diary • Daily data transfer
TERISA Sites 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) Randomized to Placebo (n=476) Discontinuation of Treatment (n=11) Discontinuation of Treatment (n=11) Analyzed (n=462) Analyzed (n=465)
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
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
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
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
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
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
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.
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
Incidence Density Ratios for Angina Frequency Omitting Individual Countries IDR for overall cohort: 0.894
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
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
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