Calcium channel blockers, beta blockers, and nitrates are commonly used to relieve chronic angina, a condition that affects at least 6.6 million persons in the United States. Patients often receive incomplete relief of symptoms with these drugs. Ranolazine may have anti-ischemic effects that could provide complementary or additive benefit to existing treatment regimens. The Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial demonstrated that ranolazine, taken twice a day, increases exercise tolerance and affords longer exercise duration before the appearance of anginal symptoms and ST-segment depression. Chaitman and colleagues report on the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial, which assessed anginal symptoms in patients with chronic angina and severe coronary disease whose angina was inadequately controlled with atenolol, diltiazem, or amlodipine.
In this randomized, double-blind trial, three groups of subjects were assigned to receive twice-daily placebo, or one of two dosages of sustained-release ranolazine for 12 weeks. The study’s primary end point was to compare the effects of ranolazine with placebo on treadmill exercise duration at trough ranolazine levels (i.e., 12 hours after dosing). End points also included exercise duration at peak drug levels (four hours after dosing), times to angina and to 1-mm ST-segment depression at peak and trough levels, and reported angina attacks and sublingual nitroglycerin uses.
At enrollment, 354 (43 percent) of the 823 randomized patients were taking atenolol, 256 (31.1 percent) were taking amlodipine, and 213 (25.9 percent) were taking diltiazem. Patients were randomized to receive placebo, or 750 or 1,000 mg of ranolazine.
Exercise duration in those taking ranolazine was increased compared with those taking placebo. Each ranolazine dose increased treadmill exercise duration at both trough and peak levels; this effect was sustained throughout the duration of the trial at both dosage levels. Similar effects were observed for times to angina and ischemia, as noted on electrocardiograph tracings. These effects, which were generally greater at peak ranolazine levels, did not differ substantially by background antianginal medication group. Ranolazine reduced the mean number of weekly angina attacks from 3.3 in the placebo group to 2.5 and 2.1 in the 750 and 1,000 mg ranolazine groups, respectively.
Even with revascularization procedures to relieve angina, about one fourth of participants still had attacks. The addition of ranolazine to standard antianginal medication appears to reduce angina frequency and nitroglycerin consumption. Exercise duration increased by 115.6 seconds in patients taking ranolazine compared with 91.7 seconds in those taking placebo. Adverse side effects included constipation, nausea, asthenia, and dizziness in 6.2 percent more patients than those taking placebo.
The authors conclude that ranolazine increases exercise capacity and provides additional antianginal relief in symptomatic patients with severe chronic angina and is well tolerated.