Editor's Note: Commentary Based on: 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 (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). J Am Coll Cardiol 2013;61:2038-45.

Summary

Despite recent advances in the field of cardiovascular medicine, stable ischemic heart disease is often undertreated and is associated with frequent hospitalizations and poor quality of life. Patients with diabetes mellitus have more diffuse atherosclerotic disease and are prone to a higher anginal burden compared to their non-diabetic counterparts. This multi-institutional randomized, double blind, placebo-controlled trial assessed the efficacy of ranolazine in Type 2 diabetics with chronic stable angina. The primary outcome assessed was the average number of weekly anginal episodes during weeks two thru eight after randomization.

Methods

The study was designed as a randomized, double blind, placebo-controlled trial. Patients with Type 2 diabetes with chronic stable angina (of minimum 3 months duration) on treatment with one to two conventional anti-anginal drugs (beta-blockers, long-acting nitrates, or calcium-channel blockers) for at least two weeks were included. Patients with New York Heart Association functional class III-IV heart failure, recent stroke or transient ischemic attack in the last six months, acute coronary syndromes in the preceding two months, uncontrolled hypertension, planned coronary revascularization during the study period, prior exposure to ranolazine, or dialysis were excluded from the study population.

After a four-week single blind, placebo run-in period in 1,142 trial-eligible patients, 949 patients were finally randomized (based on a ≥85% electronic diary entry of anginal episodes and sublingual nitroglycerin use and a ≥80% adherence to placebo during the run-in period) to either twice-daily placebo or ranolazine for eight weeks. Twenty-two patients (11 in each arm) were either never administered drug or discontinued the drug within the first two weeks of randomization and were excluded from the final analysis.

Results

Data on 927 patients (462 in the ranolazine arm and 465 in the placebo arm) were analyzed. The ranolazine target dose of 1000 mg twice a day (500 mg twice a day in those taking verapamil or diltiazem) was achieved in >95% of patients. The patient population was 99% Caucasian, 61% men, with a mean age of 64+8.5 years. Seventy-four percent of the patients had prior myocardial infarction, and 51% of the study population had undergone prior revascularization (coronary artery bypass grafting or percutaneous coronary intervention). Hypertension (96%), dyslipidemia (80%), use of statins (82.4%), antiplatelet agents (88%), angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers (88%), glucose lowering medications (93%) and beta-blockers (90%) were present in the study population. The average duration of diabetes was 7.5 years, and the mean hemoglobin A1c was 7.3%.

There was a significant decrease in weekly anginal episodes in the ranolazine group during weeks two thru eight after randomization (3.8 episodes on ranolazine versus 4.1 episodes in the placebo group, p =0.008). The weekly sublingual nitrate use was also lower in the treatment group (1.7 doses versus 2.1 doses in the placebo group, p = 0.003). In subgroup and exploratory analysis, the beneficial effects of ranolazine were consistent among all subgroups (baseline weekly anginal episodes, number of concomitant anti-anginal agents, age, sex, and those with a history of revascularization). The anti-anginal effects were more marked in patients with a higher hemoglobin A1c (p interaction = 0.027). Ranolazine was well tolerated. Nine patients in the ranolazine group and 11 patients in the placebo group stopped the study due to adverse events. The most common adverse events in the ranolazine group were nausea, dizziness and constipation.

Conclusion

TERISA (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina), a prospective evaluation of ranolazine in Type 2 diabetics on one to two anti-anginal drugs for chronic stable angina, demonstrated the efficacy of ranolazine over placebo in reducing weekly anginal episodes and sublingual nitroglycerin use with no increase in adverse side effects. These beneficial effects of ranolazine were increased in those with higher baseline hemoglobin A1c values.

Perspective

Ranolazine (Ranexa, Gilead Sciences, Forester City, CA), a sustained release hemodynamically neutral anti-anginal drug, was approved by the United States Food and Drug Administration in 2006. The mechanism of action, according to recent evidence, is the inhibition of the late sodium current (INa) in the ischemic cardiac myocyte. Normally, the late INa makes up only 1% of the total Na⁺ influx, but its augmentation during ischemic states leads to increased intracellular Na⁺, which induces calcium (Ca²⁺) overload by the Na⁺- Ca²⁺ counter exchanger. Increased intracellular calcium leads to myocardial electrical disharmony and increased diastolic tension.¹ Elevated diastolic tension can further compromise the coronary blood flow. By inhibiting the augmented late Na⁺ influx in ischemic myocytes, ranolazine exerts its anti-anginal effects. Its unique mechanism of action places it in a cyto-protective class of anti-anginal drugs.² Ranolazine is commercially available in 500 mg sustained release tablets. It has an elimination half-life of seven hours and is administered as a twice-daily dosing.³ Drug metabolism is mainly by the cytochrome P450 3A4 pathway and is contraindicated in patients on strong CYP3A inhibitors such as ketoconazole, protease inhibitors, and macrolide antibiotics. Patients on verapamil or diltiazem (moderate CYP 3A inhibitors) should not be prescribed a dose > 500 mg twice a day. Ranolazine can lead to QTc prolongation (usually <10 ms at 1000 mg twice a day dosing).

Three landmark trials — Monotherapy Assessment of Ranolazine In Stable Angina (MARISA),⁴ Combination Assessment of Ranolazine In Stable Angina (CARISA),⁵ and Efficacy of Ranolazine In Chronic Angina (ERICA)⁶ established the role of ranolazine in the management of chronic stable angina. MARISA was a 4-group, double blind, crossover, placebo-controlled study of three ranolazine dose regimens (500 mg, 1000 mg and 1500 mg twice daily) in 191 patients. The primary endpoint was the exercise duration on treadmill at trough concentrations. There was an incremental increase in exercise duration with increase in dosage of ranolazine (94, 103, 116 seconds compared to 70 seconds increase with placebo, p<0.005).

CARISA enrolled 823 patients in a randomized, double- blind, three-group, placebo-controlled fashion with chronic stable angina on once daily atenolol 50 mg, once daily diltiazem 180 mg, or once daily amlodipine 5 mg. Trough exercise duration increased by 115.6 seconds from baseline in both ranolazine groups (pooled; 750 mg and 1000 mg twice daily) versus 91.7 seconds in the placebo group (p=0.01). The increase in exercise duration persisted throughout the 12 weeks of the study period.

ERICA studied the effects of ranolazine versus placebo in patients on 10 mg daily of amlodipine. The primary endpoint in this study was weekly anginal attack frequency. Ranolazine reduced the weekly frequency of anginal episodes (2.88 +/- 0.19 on ranolazine versus 3.31 +/- 0.22 on placebo, p = 0.028).

A post-hoc analysis of the CARISA trial compared the anti-anginal effects of ranolazine in diabetics versus non-diabetics.⁷ Anti-anginal efficacy and safety were similar in both groups, but ranolazine reduced hemoglobin A1c levels in diabetics compared to placebo (0.48+0.18%, p = 0.008 in those on 750 mg twice daily and 0.70+0.18%, p = 0.0002 in those on 1000 mg twice daily).

Kosiborod et al.⁸ designed the TERISA trial to specifically assess the efficacy of ranolazine in Type 2 diabetics with symptomatic chronic stable angina despite being on up to two anti-anginal drugs. In this first prospective evaluation of ranolazine in a diabetic population, ranolazine was better than placebo in reducing average weekly anginal episodes across all sub-groups (age, sex, number of concomitant anginal medications, and baseline average weekly anginal episodes). Apart from validating its efficacy and safety in this patient population, the authors also observed a higher therapeutic benefit in patients enrolled outside Russia, Ukraine, and Belarus and in patients with a higher hemoglobin A1c. These hypothesis-generating findings need further investigation.

Utilization of the novel electronic diary entry instead of the conventional paper log in the TERISA trial minimized hoarding and low-compliance. The study also used a single-blind placebo run in period to ensure compliance and self-reporting in both groups. Ninety-nine percent of patients in the study population were Caucasians, thus limiting its generalizability to African-Americans, Hispanics and Asians. Since the study duration was eight weeks, the long-term effects of ranolazine in this patient population are unknown. The authors have noted these limitations. This trial is a first prospective evaluation of use of ranolazine in diabetics with chronic stable angina and increases our knowledge in the use of ranolazine in this patient population.

Beta blockers should be prescribed as initial drug therapy for relief of anginal symptoms in patients with stable ischemic heart disease (SIHD) (Class I B indication).⁹ Calcium channel blockers of long-acting nitrates should be prescribed for relief of anginal symptoms when beta blockers are contraindicated or cause unacceptable side effects (Class I B indication).⁹ Calcium channel blockers or long-acting nitrates in combination with beta blockers should be prescribed for relief of anginal symptoms when initial treatment with beta blockers is unsuccessful in patients with SIHD (Class I B indication).⁹ Sublingual nitroglycerin or nitroglycerin spray should be used for immediate relief of angina in patients with SIHD (Class I B indication).⁹

Treatment with verapamil or diltiazem instead of a beta blocker as initial therapy for relief of anginal symptoms is reasonable in patients with SIHD (Class IIa B indication).⁹ Ranolazine can be useful as a substitute for beta blockers for relief of anginal symptoms in patients with SIHD if initial therapy with beta blockers causes unacceptable side effects or is ineffective or if initial therapy with beta blockers is contraindicated (Class IIa B indication).⁹ Ranolazine in combination with beta blockers can be useful when used for relief of anginal symptoms when initial treatment with beta blockers is not successful in patients with SIHD (Class IIb A).⁹ We concur with these recommendations.

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References

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2. Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart 2006;92:iv6–iv14.
3. Nash DT, Nash SD. Ranolazine for chronic stable angina. Lancet 2008;372:1335–1341.
4. Chaitman BR, Skettino SL, Parker JO, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 2004;43:1375–1382.
5. Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 2004;291:309–316.
6. Stone PH, Gratsiansky NA, Blokhin A, Huang I-Z, Meng L, ERICA Investigators. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol 2006;48:566–575.
7. Timmis AD, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J 2006;27:42–48.
8. 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 (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). J Am Coll Cardiol 2013; 61:2038-45
9. Fihn SD, Gardin JM, Abrams J. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: Executive Summary. J Am Coll Cardiol 2012;60:2564-2603.

Keywords: Acetanilides, Angina Pectoris, Angina, Stable, Coronary Artery Disease, Diabetes Mellitus, Diabetes Mellitus, Type 2, Heart Diseases

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