A new treatment option is now available to the 6.4 million to 8.2 million Americans with chronic angina who continue to experience pain despite therapy with beta-blockers, calcium channel blockers (CCBs), or nitrates. Ranolazine (Ranexa; CV Therapeutics) is the first drug approved by the FDA in over 2 decades for this indication.

"The disease that causes chronic angina, atherosclerosis, is a chronic disease process. Patients can have blocked coronary arteries for many, many years—even decades," said Bernard R. Chaitman, MD, professor of medicine and director, cardiovascular research, Saint Louis University Core ECG Laboratory, Missouri.

Bernard R. Chaitman, MD

"You can have an angioplasty procedure, you can have a bypass procedure. But if the angina comes back, and you are not a candidate to have the artery repaired...or if you would not expose the patient to the risk of doing a balloon angioplasty or a bypass operation, because the artery involved is just not large enough to warrant an intervention, yet the pain is enough to give the patient a lot of aggravation, then drug therapy becomes important," Dr Chaitman explained.

Ranolazine is indicated for patients who are resistant or have not responded to current therapies. It should be used in combination with the CCB amlodipine (Amvaz; Norvasc), beta-blockers, or nitrates. "The typical patient would be on a beta-blocker and would continue to be having angina, or might be on a maximum-approved dose of amlodipine and still be having 2 to 3 episodes of angina per week," says Dr Chaitman.

New Mechanism of Action
Ranolazine is a novel molecular entity whose mechanism of action is still not completely understood. "We think that it may be working by inhibiting the inward late sodium current," says Dr Chaitman. He added that "When the concentration becomes elevated, it activates the sodium calcium exchanger, which extrudes the sodium ions out of the cell but brings calcium in." Because there is too much calcium in the cell, the ischemic part of the myocardium be­comes stiff and dysfunctional.

Before the approval of ranolazine, only 3 drug classes were available for the treatment of chronic angina. "There are patients who continue to be symptomatic, regardless of the existing therapies," Dr Chaitman says. One of the major advantages of ranolazine is "that it does not exert its action through hemodynamic mechanisms like calcium channel blockers, beta-blockers, and nitrates. It is relatively hemodynamically neutral," he explains. Because there are only minimal changes in heart rate and blood pressure (BP), "patients who have marginal blood pressures or heart rates can have some therapeutic benefit in terms of reducing the number of angina attacks without effectuating any change in heart rate or blood pressure," he notes.

Clinical Trials Results
Several clinical trials have evaluated ranolazine in patients with chronic stable angina. The Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) trial included 191 patients with angina symptom–limited exercise duration (J Am Coll Cardiol. 2004;43: 1375-1382). All patients discontinued their antianginal medications and were randomized to ranolazine, 500, 1000, or 1500 mg twice daily, or to placebo. The 3 treatment groups had 94-, 103-, and 116-second increases, respectively, in trough exercise duration compared with a 70-second increase with placebo (P <.005). No detrimental effects were seen in expected 1-year survival or changes in heart rate and BP.

Dr Chaitman was the lead investigator of the Combination Assessment of Ranolazine in Stable Angina (CARISA) trial, in which 823 adults with symptomatic chronic angina were randomized to 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 both atenolol and the calcium antagonist.

The Table lists some of the benefits seen with ranolazine compared with placebo. In addition, ranolazine-treated patients had about a 1/week reduction in the number of angina attacks and nitroglycerin use compared with placebo (P <.02). Long-term follow-up (up to 2 years) showed no adverse consequences on survival.

Results of the Evaluation of Ranolazine in Chronic Angina (ERICA) trial, released at the most recent American Heart Association Scientific Sessions, were equally persuasive. ERICA included 565 patients who had coronary artery disease and Ž3/week angina attacks despite the maximum dose of amlodipine (10 mg/d). The patients were randomized to ran­olazine 500 mg twice daily (titrated up to 1000 mg twice daily) or placebo. Patients were allowed to take long-acting nitrates if needed (44% did). During the 6-week assessment period, ranolazine significantly reduced the mean number of weekly angina attacks, decreased angina frequency, and reduced the need for nitroglycerin compared with placebo, regardless of whether or not the patient took long-acting nitrates.

Prescribing Ranolazine in Primary Care
The starting dose of ranolazine is 500 mg twice daily, which can be increased to up to 1000 mg twice daily, as needed.

Dr Chaitman cautions that since "ranolazine causes a slight prolongation of the QT interval, patients who have a long QT interval or who are on drugs that are known to make the QT interval get longer would not be good candidates." Nor would ranolazine be appropriate for patients taking drugs that interfere with the metabolism of ranolazine, such as ketoconazole (Nizoral) or other azole derivatives, macrolide antibiotics, diltiazem, or verapamil (eg, Calan, Covera-HS), since these agents could increase the plasma concentration of ranolazine.

Avoid this new agent in patients with hepatic impairment.

The most common side effects seen with ranolazine are constipation, nausea, dizziness, headache, and, rarely, syncope. "In CARISA, the 5 syncopal episodes occurred in people over the age of 65 who were on the maximum dose of the drug—1000 mg twice a day," Dr Chaitman says, noting that the parallel study design precluded starting at 500 mg twice daily. He attributed the syncopal episodes, which occurred fairly early after starting therapy, to the older age of these patients, and that they had been given a large dose of ranolazine and were also taking an angiotensin-converting-enzyme inhibitor; 4 were also taking diltiazem.

"But in the ERICA trial, which was the follow-on study in over 500 patients, doses were titrated from 500 mg to 1000 mg as tolerated, and there were no episodes of syncope, even though the patients were on a higher dose of amlodipine—10 mg instead of the 5 mg that we used in CARISA. Many were also on long-acting nitrates," Dr Chaitman says.

Primary care physicians will be prescribing ranolazine. "But they would need to be aware of the caveats. One would be that they should do an electrocardiogram (ECG) before starting therapy. Then after the patient has been on the therapy for a couple of weeks or a month or two, they should repeat the ECG to look at the QT interval and make sure that there's no significant prolongation of the QT ­interval. They should also be aware that the drug is metabolized ­primarily through the CYP 450 system," Dr Chaitman cautions.