Second study of combination therapy with new antianginal drug shows fewer anginal attacks, less nitroglycerin use

Cardiology Review® Online, Decmber 2005, Volume 22, Issue 12

Coronary artery disease

Dallas—The antianginal agent ranolazine, in phase 3 clinical studies, reduced the frequency of anginal attacks in patients with coronary artery disease (CAD) who experienced three or more attacks per week despite daily treatment with amlodipine (Norvasc), said Peter Stone, MD, at the American Heart Association’s Scientific Sessions 2005.

Ranolazine is the first of a new class of agents called the pFOX inhibitors. It is thought to work by partial inhibition of partial fatty acid oxidation and reciprocal increases in glucose oxidation during periods of myocardial stress. Consistent with this mechanism, ranolazine does not have clinically significant effects on heart rate or blood pressure. It may be a good choice, therefore, in patients with lower heart rates or blood pressure, who have angina despite therapy with a beta blocking agent or calcium antagonist, and in whom increasing the dosage of the beta blocker or calcium antagonist would have unwanted hemodynamic effects.

In the Evaluation of Ranolazine in Chronic Angina (ERICA), 565 patients with a documented diagnosis of CAD and angina, despite already taking the maximum labeled dose of amlodipine (10 mg/day) for at least 2 weeks, were randomly assigned to ranolazine, 1,000 mg twice daily, or placebo. Patients could be on a stable dose of long-acting nitrates for at least 2 weeks before entering the study. Forty-five percent of the patients enrolled were taking nitrates at baseline.

Compared with placebo, ranolazine significantly decreased the mean number of anginal episodes per week (P = .028), improved the anginal frequency component of the Seattle Angina Questionnaire (P = .008), and reduced mean weekly nitroglycerin consumption (P = .014).

“Ranolazine has a novel pharmacodynamic profile with anti-ischemic properties that do not depend on changes in determinants of myocardial oxygen demand, making it an effective complimentary therapy to existing agents that depend on hemodynamics,” said Dr. Stone, lead investigator of ERICA and codirector of the Samuel A. Levine Cardiac Unit at Brigham and Women’s Hospital in Boston. “It improves the manifestations of ischemia, such as myocardial stiffness and increased wall tension.”

There was a consistent treatment effect of ranolazine across the subgroups analyzed: users versus nonusers of long-acting nitrates, men versus women, and patients aged less than 65 versus those 65 years or older. No clinically significant effect on heart rate or blood pressure was observed in ranolazine recipients.

Study-drug—related adverse events were more common in the ranolazine versus the placebo group (21% versus 6%), but serious adverse events occurred in only 1% of each group, and only 1% of patients in each group withdrew from the study because of adverse events. As a single agent, ranolazine has been shown to be at least as effective as atenolol (Atenolol, Tenormin), 100 mg/day, in reducing the frequency of angina, the time to 1 mm of ST-segment depression, and improving exercise duration, he said.

In a trial known as Combination Assessment of Ranolazine in Stable Angina, ranolazine in combination with routine doses of other antianginal agents (amlodipine, 5 mg; atenolol, 50 mg; and diltiazem [Taztia XT, Tiazac], 180 mg) improved the manifestations of ischemia.