A, Entire study population; B, focuses on the most common changes from baseline to 8 weeks (86% of the study population). Cumulative response curves plotted change in SAQ angina frequency from baseline to 8 weeks on the x-axis and the percentage of patients who achieved at least that amount of change on the y-axis.
Arnold SV, Kosiborod M, McGuire DK, Li Y, Yue P, Ben-Yehuda O, Spertus JA. Effects of Ranolazine on Quality of Life Among Patients With Diabetes Mellitus and Stable Angina. JAMA Intern Med. 2014;174(8):1403-1405. doi:10.1001/jamainternmed.2014.2120
In the Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina (TERISA) trial, ranolazine reduced the frequency of angina episodes and use of sublingual nitroglycerin in patients with type 2 diabetes mellitus (T2DM) and stable angina, as assessed by a daily diary.1 Using data from the same trial, we evaluated the effect of ranolazine on a broader range of patients’ health status and quality of life.
TERISA was approved by the national regulatory authority in each participating country and the institutional review board or local ethics committee for each site, and all participating patients provided written informed consent. TERISA was a randomized, double-blind, placebo-controlled trial in 104 sites in 14 countries in which patients with chronic stable angina receiving 1 to 2 antianginal medications and T2DM were randomized to placebo or ranolazine (Gilead Sciences; dosage goal, 1000 mg twice daily) for 8 weeks.1 Health status was assessed at baseline and at 8 weeks with the Seattle Angina Questionnaire (SAQ),2 Rose Dyspnea Scale,3 and the Medical Outcomes Short Form-36 (SF-36) component scores.4 A 10-point increase in SAQ angina frequency represents a clinically important intraindividual change.2 Linguistically valid, country-specific instruments were used.
Scores were compared using analysis of covariance, adjusted for baseline health status and prespecified stratification covariates.1 We tested interactions between treatment and baseline angina; number of antianginals; geography (Russia, Ukraine, and Belarus vs other [as prespecified in the TERISA analytic plan]), age, and sex.
Overall, 917 patients were randomized: mean age of 64 years, 61% men, 99% white, and mean hemoglobin A1c level of 7.3%. Both treatment groups had high symptom burden at baseline and experienced improvements in all health status measures at follow-up (Table). Compared with placebo, ranolazine significantly improved SAQ angina frequency, treatment satisfaction, and SF-36 physical component summary scale scores. These effects did not differ for all measures across each of the prespecified subgroups (geography, baseline angina episodes, number of antianginals, sex, and age [P > .05 for all interactions]), except the SF-36 mental component, which improved more with ranolazine in other countries (mean effect, 1.8; 95% CI, 0.01 to 3.5) than in Russia, Ukraine, and Belarus (mean effect, −0.9; 95% CI, −2.0 to 0.2 [P value for interaction, .009]).
A greater percentage of patients treated with ranolazine vs placebo had at least a 10-point improvement in SAQ angina frequency scores (67% vs 58% [P = .004]; Figure), suggesting that 11 patients need to be treated with ranolazine for 1 to experience a clinically significant improvement in angina. The number needed to treat was lower among patients taking more antianginals (17 vs 8 for 1 vs 2 medications) and among patients with more angina at baseline (7 vs 49 for SAQ angina frequency <50 vs ≥50).
In a multinational trial of patients with T2DM and stable angina, ranolazine modestly improved key measures of disease-specific and generic health status, with benefits generally consistent across each prespecified subgroup. Furthermore, a greater proportion of patients experienced clinically meaningful improvements in angina with ranolazine vs placebo, particularly among those with more baseline angina and taking more antianginal medications. These data complement our prior reports of reduced angina frequency using an electronic diary by revealing that, from patients’ perspectives, multiple health status domains improved more with ranolazine than with placebo.
TERISA was limited by a racially narrow patient population. Furthermore, our interaction analyses may have been underpowered, leading to potential type II error. Specifically, the interaction of geography by treatment was significant in the main TERISA study using an angina diary, but not from patients’ perspectives using the SAQ.
In conclusion, ranolazine reduced angina, particularly among those with more severe angina, improved treatment satisfaction and physical functioning in patients with T2DM and chronic stable angina.
Corresponding Author: Suzanne V. Arnold, MD, MHA, St Luke’s Mid America Heart Institute, 4401 Wornall Rd, Kansas City, MO 64111 (email@example.com).
Published Online: June 2, 2014. doi:10.1001/jamainternmed.2014.2120.
Author Contributions: Dr Arnold had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Arnold, Kosiborod, Yue, Ben-Yehuda, Spertus.
Acquisition, analysis, or interpretation of data: Arnold, Kosiborod, Li, Yue, Ben-Yehuda, Spertus.
Drafting of the manuscript: Arnold, Ben-Yehuda.
Critical revision of the manuscript for important intellectual content: Arnold, Kosiborod, Li, Yue, Ben-Yehuda, Spertus.
Statistical analysis: Arnold, Li.
Obtained funding: Kosiborod, Yue, Ben-Yehuda.
Administrative, technical, or material support: Yue.
Study supervision: Kosiborod, Ben-Yehuda, Spertus.
Conflict of Interest Disclosures: Dr Arnold received research support from Gilead Sciences, Genentech, and sanofi-aventis. Dr Kosiborod received research support from Gilead Sciences, American Heart Association, Medtronic Minimed, Genentech, sanofi-aventis, Glumetrics, and Maquet; is a consultant for Gilead Sciences, Genentech, F Hoffmann-La Roche, Medtronic Minimed, AstraZeneca, Abbvie, and Regeneron; and served on the advisory board for Gilead Sciences. Dr McGuire is a consultant for Janssen Pharmaceuticals, Daiichi Sankyo, Pfizer, Boehringer-Ingelheim, Regeneron, Genentech, F Hoffmann–La Roche, Merck, Bristol-Myers Squibb, Tethys Biosciences, AstraZeneca, Orexigen, Eli Lilly, and Takeda. Dr Yue is an employee of and owns stock and stock options in Gilead Sciences. Dr Ben-Yehuda is a former employee of Gilead Sciences. Dr Spertus has received research support from Gilead Sciences, National Heart, Lung, and Blood Institute, American College of Cardiology, American Heart Association, Patient-Centered Outcomes Research Institute, Amorcyte, Genentech, and Eli Lilly; is a consultant for Gilead Sciences, Genentech, Amgen, and United Healthcare (Scientific Advisory Group); is a board member for Health Outcomes Sciences; and holds the copyrights for the Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire, and Peripheral Artery Questionnaire. No other disclosures are reported.
Funding/Support: The TERISA trial was sponsored by Gilead Sciences. Saint Luke’s Mid America Heart Institute received funding for the independent statistical analysis of the TERISA trial from Gilead Sciences.
Role of the Sponsor: As the present study was a planned secondary analysis of the TERISA trial, Gilead Sciences had a role in the design and conduct of the study. The data were collected by Gilead Sciences, who had a role in interpretation of the data and in the preparation and review of the manuscript. An independent statistical analysis of the data was conducted by the study authors. The sponsor had no role in approval of the manuscript and decision to submit the manuscript for publication.
Previous Presentation: This study was presented at the American Heart Association Scientific Sessions; November 19, 2013; Dallas, Texas.
Trial Registration: clinicaltrials.gov Identifier: NCT01425359