Ranolazine (Ranexa), the first antiangina drug approved by the FDA in over 2 decades, is now available to the 6.4-8.2 million Americans with chronic angina who continue to experience pain despite therapy with beta-blockers, calcium channel blockers (CCBs), or nitrates. This new treatment is indicated for patients who are resistant to or have not responded to current therapies.

Ranolazine is a novel molecular entity whose mechanism of action is still not completely understood, and its antiangina and antiischemic effects do not depend on reductions in heart rate or blood pressure (BP). Ranolazine should be used in combination with the CCB amlodipine (Amvaz, Norvasc), beta-blockers, or nitrates.

Several clinical trials have evaluated ranolazine in patients with chronic stable angina. In a randomized, placebo-controlled trial of 191 patients with angina symptom-limited exercise duration, treatment with ranolazine, 500, 1000, or 1500 mg twice daily resulted in 94-, 103-, and 116-second increases, respectively, in trough exercise duration compared with a 70-second increase with placebo (J Am Coll Cardiol. 2004;43:1375-1382). No reductions in expected 1-year survival were seen in the treatment group, and BP and heart rate did not change.

In another trial, 823 adults with symptomatic chronic angina were randomized to either 750 or 1000 mg of ranolazine twice daily, or to placebo (JAMA. 2004;291: 309-316). All patients continued the antianginal medication they were taking at enrollment, which included atenolol (Tenormin) 50 mg, diltiazem (Cardizem) 180 mg, and amlodipine 5 mg. They were not allowed to take atenolol plus the calcium antagonist. Benefits with ranolazine therapy persisted throughout the 12-week treatment period (Table).

The use of ranolazine reduced the numbers of angina attacks and use of nitroglycerin each week compared with placebo. At up to 2 years of follow-up, no increased mortality events were seen compared with placebo.

The Evaluation of Ranolazine in Chronic Angina (ERICA) trial included 565 patients who had coronary artery disease and 3 or more angina attacks weekly despite maximum amlodipine dose (10 mg/d). Patients were randomized to ranolazine 500 mg twice daily (titrated up to 1000 mg bid) or placebo. Some 44% of patients also took long-acting nitrates. Ranolazine significantly reduced the number of angina attacks and reduced the need for nitroglycerin compared with placebo, regardless of use of long-acting nitrates.

Prescribing Ranolazine

The starting dose of ranolazine is 500 mg twice daily and can be titrated up to 1000 mg twice daily.

Ranolazine is primarily metabolized by the cytochrome (CY) P450-3A system and therefore should not be combined with other drugs metabolized via CYP 450-3A, including ketoconazole (Nizoral) or other azole derivatives, macrolide antibiotics, HIV protease inhibitors, diltiazem, or verapamil (eg, Calan, Covera-HS).

Ranolazine is contraindicated in patients with a long QT interval or who are taking drugs known to prolong the QT interval, or in those with moderate or severe hepatic impairment. The most common side effects reported with ranolazine are constipation, nausea, dizziness, headache, and, rarely, syncope.

Obtain an electrocardiogram (ECG) before starting therapy with this drug, to rule out long QT interval and/or to document the baseline QT interval. The ECG should be repeated within 1 or 2 months to determine if ranolazine therapy has resulted in significant prolongation of the QT interval.