SAN FRANCISCO, CA—Ranolazine was more effective than placebo in reducing angina frequency and sublingual nitroglycerin (SL NTG) use in patients with type 2 diabetes, coronary artery disease, and chronic angina, according to results of a study presented at ACC.13, the American College of Cardiology’s 62nd Annual Scientific Session.
The Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina (TERISA) “is the first randomized, double-blind placebo-controlled trial of ranolazine specifically focused on patients with diabetes mellitus, coronary artery disease, and stable angina requiring treatment with 1–2 anti-anginal agents,” said Mikhail Kosiborod, MD, associate professor of medicine at the University of Missouri, Kansas City, cardiologist at St. Luke’s Mid America Heart Institute, and the study’s lead author.
“Previously, the anti-anginal efficacy of ranolazine in patients with diabetes has not been prospectively tested,” he added.
After a single-blind, 4-week placebo run-in phase, patients were randomly assigned to 8 weeks of ranolazine (target dose 1000mg twice daily) or matching placebo. “The number of anginal episodes was recorded and transmitted daily using a novel electronic diary,” he reported.
Primary study end point was the average weekly number of anginal episodes from weeks 2-8 of treatment. The key secondary end point was average weekly number of SL NTG doses, also from weeks 2–8 of treatment.
Of 1,185 patients screened at 105 sites in 14 countries, 949 were randomized, 473 to ranolazine and 476 to placebo. Mean age was 64 years, 61% were male, 96% had hypertension, 74% had prior MI, and 52% had a prior coronary revascularization; 16% were smokers. Mean duration of diabetes mellitus was 7.5 yrs, and mean HbA1c was 7.3%. Utilization of guideline-recommended therapy was high: 87% of patients were on antiplatelet agents, 82% on statins, 88% on ACE inhibitors or angiotensin receptor blockers, and 90% on beta-blockers.
Compliance with daily diary entry was 98%, and adherence to study drug was 94%, Dr. Kosiborod reported. At baseline, 56% of patients received one anti-anginal medication and 44% received two. Baseline angina frequency was 6.6 in the ranolazine arm and 6.8 in the placebo arm (P=0.54).
Following treatment, angina frequency was 3.8 times per week in the ranolazine arm and 4.3 in the placebo arm (P=0.008), Dr. Kosiborod reported. Use of sublingual nitroglycerin also declined, from 4.1 to 1.7 in the ranolazine arm and from 4.5 to 2.1 in the placebo arm (P=0.003).
In a post hoc exploratory analysis, the researchers also found that ranolazine was significantly more effective in patients with Hba1c >6%, >7%, and >8% compared with ≤6%, ≤7%, and ≤8%, respectively, vs. placebo.
“If the glucose-lowering action of ranolazine is confirmed in future studies, patients with diabetes and angina may derive a dual benefit from this drug,” Dr. Kosiborod said.
A subgroup analysis of patients by geographic region found the “therapeutic effectiveness of ranolazine was more pronounced in patients enrolled outside of Russia, Ukraine, and Belarus and in those with higher baseline HbA1c.” Among patients enrolled in other countries, those treated with ranolazine experienced a significant reduction in angina frequency compared with placebo (3.1 vs. 4.1 episodes per week; P=0.002).
“The reasons for this geographic difference are not clear,” Dr. Kosiborod said. “It wasn’t explained by differences in baseline characteristics but was driven by several sites located in Russia. We’re exploring it.”
He concluded, “Future studies are needed to explore potential dual effects of ranolazine on angina and glucose control in patients with type 2 diabetes.”