Ranolazine for Type 2 Diabetes, Coronary Artery Disease, and Chronic Stable Angina

San Francisco—Patients with type 2 diabetes, coronary artery disease, and chronic stable angina who took ranolazine had fewer angina episodes and fewer sublingual nitroglycerin dosages compared with a group receiving placebo, according to a randomized, double-blind, placebo-controlled study.

The FDA has approved ranolazine to treat chronic angina as a first-line therapy and as an add-on therapy when symptoms are not relieved using other anti-anginal drugs.

Between weeks 2 and 8 of treatment, the mean angina frequency was 3.8 episodes per week in the ranolazine group compared with 4.3 episodes per week in the placebo group (P=.008). During that same time period, the mean number of sublingual nitroglycerin doses per week was 1.7 in the ranolazine group and 2.1 in the placebo group (P=.003).

Mikhail Kosiborod, MD, the study’s lead author, presented the data in a late-breaking clinical trial session at the ACC meeting. Results were simultaneously published online in the Journal of the American College of Cardiology [10.1016/j.jacc.2013.02.011]. Gilead Sciences, Inc., the drug’s manufacturer, funded the study.

Dr. Kosiborod said 8 million people in the United States have angina, which is associated with a negative impact on health status and quality of life as well as repeat hospitalizations and high costs. He also said patients with diabetes are at an increased risk of coronary artery disease and have a greater angina burden.

The TERISA [Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina] study recruited patients at 105 sites in 14 countries and was the first to test the anti-anginal effect of ranolazine in patients with diabetes. All patients had experienced symptoms despite receiving 1 or 2 anti-anginal medications.

The authors collected data on angina frequency and sublingual nitroglycerin use on a daily basis using an electronic diary tool. During the study, 98% of patients added the data in their diary daily.

The trial began with a 4-week, single-blind, run-in phase during which all patients received placebo to establish the baseline angina frequency and to ensure patients were compliant with the study medication and with an electronic symptom diary, according to Dr. Kosiborod. The 949 patients were then randomized to receive 1000 mg of ranolazine (n=473) or placebo (n=476) twice daily for 8 weeks.

The groups were well balanced at baseline. The mean age was approximately 64 years, 61% were male, and 99% were white. The mean duration of diabetes was approximately 7.5 years, the mean hemoglobin A1c level was 7.3%, and 93% of patients were taking glucose-lowering medications. More than 80% of patients were taking concomitant statins or antiplatelet agents.

A subgroup analysis found that among patients recruited from Russia, Ukraine, and Belarus, there was no significant difference in mean angina frequency: 4.1 episodes per week in the ranolazine group and 4.3 episodes per week in the placebo group (P=.31). However, there was a significant difference among patients recruited from the other 11 countries, with patients taking ranolazine having a mean angina frequency of 3.1 episodes per week compared with 4.1 episodes per week in the placebo group (P=.002).

In addition, according to an exploratory, post hoc analysis, the benefit in angina frequency favoring ranolazine was significant in patients regardless of their HbA1c level, although the drug’s effect was more profound in patients with a higher HbA1c level at baseline. Further, there was no significant difference in serious adverse events, which occurred in 3.4% of patients in the ranolazine group and 4.2% of patients in the placebo group (P=.51). Dr. Kosiborod added non-serious adverse events such as dizziness, nausea, and constipation were more frequent in the ranolazine group, but they were “overall infrequent.”