Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina - TERISA

Mar 10, 2013
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Gilead Sciences
Date Presented:
01/01/2013
Date Published:
01/01/2013
Date Updated:
03/10/2013
Original Posted Date:
03/10/2013
References

Description:

The current trial sought to study the safety and efficacy of ranolazine in improving symptoms of angina in patients with diabetes and stable angina.

Hypothesis:

Ranolazine would be superior to placebo in reducing angina frequency in patients with diabetes and stable angina.

Study Design

  • Placebo Controlled
  • Blinded
  • Randomized
  • Parallel

Patient Populations:

  • Chronic stable angina for at least 3 months
  • Stable dose of 1-2 antianginal medications for at least 2 weeks
  • Diabetes mellitus type 2

    Number of screened applicants: 1,185
    Number of enrollees: 949
    Duration of follow-up: 8 weeks
    Mean patient age: 64 years
    Percentage female: 39%

Exclusions:

  • New York Heart Association class III/IV symptoms
  • Acute coronary syndrome within past 2 months
  • Planned coronary revascularization during the study period
  • Stroke or transient ischemic attack within 6 months prior to screening
  • Uncontrolled hypertension
  • Clinically significant hepatic impairment
  • Prior treatment with ranolazine
  • Dialysis

Primary Endpoints:

  • Average weekly number of angina episodes from weeks 2-8 of treatment

Secondary Endpoints:

  • Average weekly number of sublingual NTG doses from weeks 2-8 of treatment
  • Number of angina-free days
  • Proportion of subjects with ≥50% reduction in average weekly angina frequency
  • Health-related quality of life, as assessed by the Medical Outcomes Short Form-36 (SF-36) and the Patient’s Global Impression of Change (PGIC) scale score

Drug/Procedures Used:

After a run-in phase of 4 weeks to assess adherence, patients were randomized in a 1:1 fashion to receive either ranolazine or matching placebo for 8 weeks. Ranolazine was initiated at 500 mg BID for 1 week and, if tolerated, increased to 1000 mg bid (subjects taking verapamil or diltiazem were maintained on 500 mg bid of ranolazine or matching placebo).

Concomitant Medications:

Insulin (19%), statins (82%), antiplatelet agents (88%), and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (88%)

Principal Findings:

A total of 949 patients were randomized at 105 sites in 14 countries, 473 to ranolazine and 476 to placebo. Baseline characteristics were fairly similar between the two arms. Approximately 74% had suffered a prior myocardial infarction (MI), 40% had undergone prior angioplasty, and 19% prior coronary artery bypass grafting. The mean glycated hemoglobin (HbA1c) was 7.3%. Approximately 56% of the patients were on one antianginal medication only; the rest were on two antianginal medications. These included beta-blockers in 90%, calcium channel blockers in 28%, and long-acting nitrates in 34%. Compliance was very high, approximately 98%.

Baseline angina frequency (6.6 vs. 6.8 episodes/week) and sublingual (SL) nitroglycerin (NTG) use (4.1 vs. 4.5 times/week) were similar between the ranolazine and placebo arms. There was a significant reduction over the duration of follow-up in the ranolazine arm (3.8 vs. 4.3 episodes/week, p = 0.0008). Similarly, SL NTG use also decreased in the ranolazine arm (1.7 vs. 2.1 times/week, p = 0.003). There appeared to be benefit irrespective of whether patients were on one or two antianginal medications at baseline. The incidence of serious side effects was similar between the two arms. Health-related quality of life was similar between the two arms as well.

Interpretation:

The results of the TERISA trial indicate that ranolazine is effective for angina relief in diabetic patients with refractory angina over an intermediate period of follow-up (approximately 2 months). Although the majority of patients were on one antianginal medication only, the effect appeared to be robust on subgroup analysis. These results are somewhat similar to those noted in CARISA and MARISA trials (which assessed angina-free exercise duration), but focus exclusively on diabetic patients. Interestingly, in these two trials, formal testing for interaction with diabetes status was negative.

Only 40% of these patients had undergone prior percutaneous coronary intervention (PCI) (timing unclear). Current guidelines recommend PCI for treatment of refractory stable angina. Thus, it is unclear if this benefit would be noted in patients with refractory angina post-PCI as well. Recent trials such as FAME-2 have demonstrated that ischemia-driven revascularization is effective in ameliorating symptoms of stable angina. Further studies will need to focus on the cost-effectiveness of ranolazine (with or without PCI) as well as outcomes with long-term ranolazine use.

References:

Kosiborod M, Arnold SV, Spertus JA, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial. J Am Coll Cardiol 2013;Mar 10:[Epub ahead of print].

Presented by Dr. Mikhail Kosirobod at ACC.13, San Francisco, March 10, 2013.

Keywords: Diltiazem, Myocardial Infarction, Follow-Up Studies, Angina, Stable, Enzyme Inhibitors, Piperazines, Angioplasty, Calcium Channel Blockers, Percutaneous Coronary Intervention, Glycated Hemoglobin A, Quality of Life, Nitrates, Verapamil, Coronary Artery Bypass, Diabetes Mellitus, Nitroglycerin


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