Cardiology

Ranolazine, Ivabradine, and Newer Anti-Anginal Agents

General (including evidence of efficacy)

Effective treatment of coronary artery disease requires a variety of distinct goals: controlling symptomatic angina, decreasing the adverse events associated with ischemia, and providing vascular protection against the atherosclerotic process. While there are a number of treatment options for controlling symptomatic angina, including medical therapy using beta blockers, calcium channel blockers, and nitrates and coronary revascularization, there are a significant number of patients who may benefit from a therapeutic mechanism of action different than those associated with traditional antianginal therapy.

Ranolazine and ivabradine are newer, nontraditional antianginal medication used for the treatment of symptomatic angina in the setting of chronic, stable ischemic heart disease. Ranolazine is approved in the U.S. and Europe for treatment both as first line therapy and as add-on therapy in addition to standard medical therapy. Ivabradine is approved for use in Europe but not in the U.S. at this time.

Ranolazine

Ranolazine is a selective late-sodium current inhibitor. By blocking the late sodium current during ischemia, the drug inhibits the subsequent calcium overload within the myocyte that is normally a hallmark of an ischemic cell. In untreated ischemic cells, calcium overload leads to diastolic activation of contractile proteins and subsequent tonic contraction and increased energy consumption in an already energy-depleted myocyte. Thus, ranolazine decreases diastolic tension.

Ranolazine has been studied in several settings in patients with chronic, stable angina. Ranolazine monotherapy was compared to a placebo in the Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) trial and it increased total exercise duration, increased time to the onset of angina during exercise, and increased the exercise time to the onset of 1.0 mm ST-segment depression compared with a placebo.

In the Combination Assessment of Ranolazine in Stable (CARISA) trial, ranolazine was used as part of a multidrug regimen to control angina and improve exercise capacity in patients with stable disease. Patients were treated with ranolazine or a placebo in addition to atenolol or a calcium channel blocker, and ranolazine was associated with increased exercise time and longer periods of exercise until symptom onset.

These changes were independent of the rate-pressure product, consistent with the drug having a different mechanism of action compared to previous agents. In the Evaluation of Ranolazine in Chronic Angina (ERICA) study, patients were treated with ranolazine or a placebo on a background of amlodipine treatment (with or without long-acting nitrates). Those treated with ranolazine had significantly fewer anginal episodes each week than those treated with a placebo.

Ranolazine has also been studied in the setting of non-ST segment myocardial infarction acute coronary syndrome in the MERLIN-TIMI 36 trial, in which patients were randomized to ranolazine or a placebo for secondary prevention of ischemic events. The primary analysis of the trial showed no significant benefit of ranolazine in the prevention of a composite of cardiovascular death, myocardial infarction, or recurrent ischemia, but ranolazine did exert a significantly beneficial effect in reducing recurrent ischemic events.

Ivabradine

Ivabradine is a novel antianginal medication also for the treatment of patients with stable coronary artery disease. It is an I f ("funny current") inhibitor and acts by reducing heart rate in a mechanism that is distinct from either beta-blockers or calcium channel blockers.

In patients with stable angina, ivabradine has been compared to atenolol as antianginal monotherapy in the International Trial on the Treatment of Angina with Ivabradine Versus Atenolol (INITIATIVE). In this study, ivabradine was found to be noninferior to atenolol with respect to exercise duration, time to limiting angina, and time to angina onset.

In the Efficacy and Safety of Ivabradine on Top of Atenolol in Stable Angina Pectoris (ASSOCIATE) trial, combination therapy with ivabradine or a placebo added to atenolol at a fixed dose of 50 mg daily was associated with significant improvement in exercise time, time to angina, and ischemic threshold compared to atenolol alone. It is unclear if an increase in the atenolol dose would have similarly improved exercise performance as was observed by adding ivabradine to the regimen.

The morbidity-mortality evaluation of the If inhibitor ivabradine in patients with coronary disease and left ventricular dysfunction (BEAUTIFUL) study demonstrated that ivabradine in patients with stable coronary disease, left ventricular dysfunction (EF <40%), and a heart rate greater than 70 bpm, was not associated with a decrease in the primary study endpoint, a composite of cardiovascular death, hospitalization for acute myocardial infarction, or new-onset or worsening heart failure compared to a placebo, but it was associated with decreased myocardial infarction and coronary revascularization events.

Differences between drugs within the class

Traditional antianginal agents are effective by optimizing the balance of myocardial oxygen supply and demand. As myocardial oxygen extraction is maximal at rest, the only mechanism to improve the balance of oxygen supply and demand has been to reduce the determinants of myocardial oxygen demand.

This can be achieved by several mechanisms including lowering heart rate, decreasing afterload or blood pressure, decreasing myocardial contractility, or decreasing preload. Beta-blockers decrease heart rate, decrease contractility, and have some efficacy in reducing blood pressure.

Nitrates decrease preload and enhance coronary arterial vasodilation, but have no effect on heart rate or myocardial contractility. Dihydropyridine calcium channel blockers decrease blood pressure and enhance coronary arterial vasodilation, but may increase contractility and heart rate due to activation of sympathetic reflexes. Nondihydropyridine calcium channel blockers decrease heart rate and blood pressure, and enhance coronary arterial vasodilation, and, to a lesser degree, decrease myocardial contractility.

Ranolazine appears to work by improving regional blood flow in areas of myocardial ischemia, a different mechanism of action compared to the traditional antianginals, and it exerts little effect on heart rate and blood pressure.

Ivabradine works by decreasing heart rate through its action on If and has no effect on blood pressure or contractility.

Administration

Ranolazine is available as an extended release oral tablet. The half-life of the tablet is approximately 7 hours. The drug is usually started at a dose of 500 mg twice daily and can be titrated to 1,000 mg twice daily.

Ivabradine is administered orally at 5 or 7.5 mg twice daily, depending on heart rate reduction.

Pharmacologic action

Ranolazine works by a different mechanism than traditional antianginals. Instead of acting on the oxygen supply-demand balance, the mechanism of action of beta-blockers, calcium channel blockers, and nitrates, ranolazine is a selective late-sodium current inhibitor.

By blocking the late sodium current during ischemia, the drug inhibits the calcium overload within the myocyte that is normally a hallmark of an ischemic cell. In untreated ischemic cells, calcium overload leads to diastolic activation of contractile proteins and subsequent tonic contraction and increased energy consumption in an already energy-depleted myocyte. Thus ranolazine decreases diastolic tension during ischemia.

Ivabradine acts on the If (or so-called "funny current"), which is highly expressed in the tissue in the sinoatrial node. If is a mixed Na+-K+ inward current activated by hyperpolarization and modulated by the autonomic nervous system. It regulates the pacemaker activity in the sinoatrial node. Ivabradine inhibits If in a dose-dependent manner, thus causing greater heart rate reductions at higher doses.

Indications and contraindications

Ranolazine was approved by the U.S. Food and Drug Administration in 2006 for the treatment of chronic, stable angina. It is approved for use either as primary therapy or as a combination therapy in addition to traditional agents, such as beta-blockers, calcium channel blockers, and/or nitrates.

Given the lack of a clear mortality benefit in the MERLIN-TIMI 36 study, ranolazine should not be used as routine treatment of patients after non-ST segment myocardial infarction. Since ranolazine has no major effect on heart rate or blood pressure, it can be used safely in clinical scenarios where low heart rate or blood pressure limits the use of other antianginal agents.

Ranolazine is contraindicated in patients with cirrhosis and in patients who are taking strong inhibitors (ketoconazole, clarithromycin, etc.) or inducers (rifampin, phenytoin, etc.) of CYP3A.

Ivabradine is indicated for the treatment of chronic, stable angina for patients in sinus rhythm who cannot take beta-blockers or for patients with chronic, stable angina who have inadequate heart rate control (>60 beats/min) while on beta-blockers. Ivabradine was approved for use in Europe in 2005, but has not been approved in the United States. Ivabradine has also been used effectively for the off-label treatment of inappropriate sinus tachycardia.

Ivabradine is contraindicated in patients with sick sinus syndrome and in patients taking inhibitors of CYP3A4.

Undesirable effects

Ranolazine is generally well-tolerated. The most common adverse effects include dizziness, headache, constipation, and nausea. Ranolazine does cause a very minor dose-related prolongation of the QTc interval. In the largest clinical study of ranolazine, MERLIN-TIMI 36, there was not an increased risk of proarrhythmia or sudden death despite minor QTc prolongation.

Ivabradine is associated with significant bradycardia or heart block slightly more commonly than with beta-blockers. Approximately 15% of patients also experience "luminous phenomena" or "phosphenes" described by patients most often as sensations of enhanced brightness in fully maintained visual fields. These sensations are mediated by blockade of the Ih current in the retina, which is similar to If in the heart. These sensations are often mild and are fully reversible. Only a small proportion of patients require drug discontinuation.

Alternative approaches

There are other antianginal medications that have been used for the treatment of refractory symptoms in patients who are not suitable candidates for revascularization or further titration of medical therapy.

Trimetazidine, a fatty acid oxidation inhibitor, increases cardiac metabolic efficiency by shifting cardiac metabolism toward increased use of glucose, which is more oxygen efficient. Trimetazidine has been studied in the TRIMPOL II study, which evaluated trimetazidine compared to placebo in 426 patients with stable angina on background metoprolol therapy.

At 12 weeks, the trimetazidine treatment resulted in improvements in total workload, the number of anginal episodes per week, and time to ST-segment depression during exercise. Trimetazidine has not been studied in large Phase III clinical trials. The drug is available in Europe for refractory angina persisting after first line therapies. It is not available in the United States.

Nicorandil is a potassium channel activator available in Europe that is an arterial and venous dilator that has been shown to improve coronary blood flow. It is also thought to mimic ischemic preconditioning. Nicorandil has been evaluated in the IONA trial of 5,126 patients with chronic angina.

In addition to background therapy of beta-blockers, calcium channel blockers, and ACE inhibitors, the addition of nicorandil was shown to significantly reduce the composite endpoint of coronary death, nonfatal myocardial infarction, or unplanned hospitalization by 17% compared to placebo. There is little known in terms of nicorandil's utility in treating symptoms of chronic stable angina. Nicorandil is not available in the United States.

Fasudil is a rho-kinase inhibitor and vasodilator that has been used clinically in settings other than for the treatment of angina (cerebral vasospasm, cognitive decline, and pulmonary hypertension). It has been studied in a small, placebo-controlled trial with less than 100 patients and was shown to improve time to ST-segment depression compared to placebo. However, it had little effect on time to angina or frequency of angina. Fasudil is not available for widespread clinical use.

What's the Evidence/References

Chaitman, BR, Skettino, SL, Parker, JO. "Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina". J Am Coll Cardiol. vol. 43. 2004. pp. 1375-1382.

Chaitman, BR, Pepine, CJ, Parker, JO. "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. vol. 291. 2004. pp. 309-316.

Stone, PH, Gratsianksy, NA, Blokhin, A. "Antianginal efficacy of ranolazine when added to treatment with amlodipine: The ERICA (Efficacy of Ranolazine in Chronic Angina) trial". J Am Coll Cardiol. vol. 48. 2006. pp. 566-575.

(The MARISA, CARISA, and ERICA studies provide the clinical basis for the use of ranolazine as an antianginal therapy in patients with chronic, stable angina.)

Morrow, DA, Scirica, BM, Karwatowska-Prokopczuk, E. "Effects of ranolazine on recurrent cardiovascular events in patients with non-ST elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial". JAMA. vol. 297. 2007. pp. 1775-1783.

(The MERLIN-TIMI 36 is the largest randomized trial to evaluate ranolazine. It studied patients after non-ST segment myocardial infarction and found no benefit overall on its primary endpoint.)

Tardif, JC, Ford, I, Tendera, M. "Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina". Eur Heart J. vol. 26. 2005. pp. 2529-2536.

Tardif, JC, Ponikowski, P, Kahan, T. "Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month randomized, placebo-controlled trial". Eur Heart J. vol. 30. 2009. pp. 540-548.

(The INITIATIVE and ASSOCIATE trials are the two randomized studies that form the clinical basis for the use of ivabradine in chronic, stable angina.)

Fox, K, Ford, I, Steg, PG. "Ivabradine for patients with stable coronary artery disease and left ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial". Lancet. vol. 372. 2008. pp. 807-816.

(The BEAUTIFUL study evaluated ivabradine for its potential antiischemic properties and failed to show a benefit in preventing a composite of cardiovascular death, hospitalization for acute myocardial infarction, or new-onset or worsening heart failure.)

Szwed, H, Sadowski, Z, Elikowski, W. "Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II)". Eur Heart J. vol. 22. 2001. pp. 2267-2274.

(The Trimpol II study is the best clinical data supporting the use of trimetazidine in stable angina.)

"Effect of nicorandil on coronary events in patients with stable angina: the Impact of Nicorandil in Angina (IONA) randomised trial". Lancet. vol. 359. 2002. pp. 1269-1275.

(The IONA was a large randomized study and provides the best evidence supporting nicorandil for the treatment of stable angina.)

Vicari, RM, Chaitman, B, Keefe, D. "Efficacy and safety of fasudil in patients with stable angina: a double-blind, placebo-controlled phase 2 trial". J Am Coll Cardiol. vol. 46. 2005. pp. 1803-1811.

(This phase 2 clinical trial provides the best clinical evidence supporting the use of fasudil in treating stable angina.)
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