TERISA: A unique benefit of ranolazine in diabetic angina?

March 10, 2013

San Francisco, CA - The first prospective international randomized controlled study focusing specifically on angina in patients with diabetes has shown that ranolazine (Ranexa, Gilead Sciences) is an effective treatment in this patient population[1].

Results of the Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina (TERISA) study were reported by Dr Mikhail Kosiborod (Saint Luke's Mid America Heart Institute, Kansas City, MO) at the American College of Cardiology 2013 Scientific Sessions here today; they were simultaneously published online in the Journal of the American College of Cardiology.

Dr Mikhail Kosiborod

Ranolazine reduced episodes of stable angina in diabetes patients already receiving one or two antianginal drugs and led to less use of sublingual nitroglycerin, and the benefits appeared more prominent in patients with higher rather than lower HbA1c levels, Kosiborod reported. Ranolazine is already approved in the US for first-line use in angina or as an add-on therapy to other antianginal agents, but he noted that it was important to demonstrate a benefit in the particularly "challenging" diabetes population.

In an accompanying commentary[2], Drs Wilbur YW Lew and Anthony N DeMaria (VA San Diego Healthcare System and University of California, San Diego) say: "The strengths of this study are the clear evidence that ranolazine can decrease the frequency of episodes of angina and nitroglycerin use. Although this confirms prior post hoc analyses of subgroups from the CARISA and MERLIN-TIMI 36 [studies], this provides stronger evidence in a prospective trial."

However, they add that "this was a short-term (eight-week) study," and the "major study limitation" is that the absolute effects, although statistically significant, were small—use of ranolazine resulted in only 0.5 fewer episodes of angina and 0.4 fewer sublingual nitroglycerin tablets used per week. "The clinical relevance of such slight absolute differences may be questioned," they write.

But Kosiborod said in an interview: "If you just look at the numbers, you don't see the whole story. The results were modest but clinically meaningful. The efficacy of ranolazine was demonstrated on top of a profound placebo effect." Several studies have indicated that ranolazine, as well as having antianginal effects, may have the additional effect of improving glycemic control, so it may be of "unique benefit" in diabetic patients, he said, although he acknowledged the glucose-lowering effect of ranolazine "is not proven yet" and that several trials are ongoing to examine this issue.

"TERISA is the first in a line of trials that will establish ranolazine's role in diabetic patients with chronic angina; this study shows that ranolazine clearly does what it's supposed to do as an antianginal agent in patients with diabetes," he stressed.

Asked to comment on the findings, Dr Magnus Ohman (Duke University, Durham, NC), who was on the panel that discussed the TERISA results following their presentation, said: "Ranolazine is a drug that is recommended by the guidelines and is in use, but it's not used a lot, and it seems that either physicians forget it or it's not even on their radar screen. It's not generic, so it comes on top of a lot of generic availability.

"This trial result in the diabetic population is very consistent with the other trials that led to its approval. It adds to the growing evidence of the value of this therapy; I don't think cardiologists will get really excited if HbA1c changes a lot—diabetologists might—but we won't change our practice based on that."

Novel electronic diary for symptoms provided 98% compliance

Kosiborod said that patients with diabetes have more extensive coronary disease than those without and "a greater burden of angina, and this is not well-known."

In TERISA, a total of 949 type 2 diabetes patients with an average duration of disease of 7.5 years were randomly assigned across 104 centers in 14 countries to a target dose of ranolazine 1000 mg twice a day or placebo, for eight weeks. These patients also had stable coronary artery disease (CAD) and had a high burden of angina, with around six to seven episodes per week.

"They were highly symptomatic and importantly were already receiving treatment with at least one or two antianginals," Kosiborod explained. Approximately 55% of the study population was taking one antianginal and the remainder at least two.

A "novel feature" of the study was that angina symptoms were self-reported by patients on a daily basis using an electronic diary, he said, and as a result the investigators had "very high" compliance rates of 98%.

The primary end point of the study was average weekly angina frequency between weeks 2 and 8. There was a significant improvement in this outcome in patients treated with ranolazine, who had fewer episodes of angina, 3.8, vs 4.3 per week in those treated with placebo (p=0.008). Weekly use of "rescue" sublingual nitroglycerin was also lower among the ranolazine-treated patients, 1.7 vs 2.1 doses per week (p=0.003).

Exclude Russia, "the outlier," and results are even better

He also noted that several subgroup analyses were conducted, including a geographic one. In the countries of Russia, Ukraine, and Belarus, there was no significant difference between the patients who took ranolazine and those who received placebo, he noted.

When Russia, Ukraine, and Belarus were excluded from the overall analysis, the number of episodes of angina per week was 3.1 in the ranolazine group vs 4.1 in the placebo group, he said, adding, "Of these three countries, Russia is an outlier; it accounted for most of the difference."

Another subgroup analysis focused on HbA1c levels, showing that "patients with higher HbA1c experienced greater therapeutic benefit from ranolazine," Kosiborod said. However, he stressed again that this is "hypothesis-generating and needs to be confirmed in the other ongoing trials."

"It is important to dissect out if ranolazine has preferential benefits in diabetes mellitus that are related to this drug class by inhibiting [the late sodium current] INa and/or related to improving glycemic control," say Lew and DeMaria in their editorial.

But they add that the "results in this stable CAD population provide proof of concept that this antianginal medication with a unique mechanism of action is beneficial, can be added to other well-established antianginal drugs, and is particularly effective with higher HbA1c levels. This is especially relevant for CAD patients with diabetes mellitus, who may have more limited benefits from revascularization and rely to a greater extent on medical management."

Saint Luke's Mid America Heart Institute received funding for the independent statistical analysis of the TERISA trial from Gilead Sciences as well as research funding from Gilead Sciences unrelated to the TERISA trial. Kosiborod reports th at he received research support from Gilead Sciences unrelated to the TERISA trial as well as research support from the American Heart Association, Medtronic Minimed, Genentech, Sanofi, and Glumetrics and is a consultant for Gilead Sciences, Genentech, F H offman-La Roche, Boehringer-Ingelheim, Medtronic Minimed, and CardioMEMS. Disclosures for the coauthors are listed in the article. Lew has disclosed no relevant financial relationships. DeMaria has received grant support and consultant fees from Gilead.


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