Many patients with chronic angina experience anginal episodes despite
revascularization and antianginal medications. In a previous trial, antianginal
monotherapy with ranolazine, a drug believed to partially inhibit fatty acid
oxidation, increased treadmill exercise performance; however, its long-term
efficacy and safety have not been studied in combination with β-blockers
or calcium antagonists in a large patient population with severe chronic angina.
To determine whether, at trough levels, ranolazine improves the total
exercise time of patients who have symptoms of chronic angina and who experience
angina and ischemia at low workloads despite taking standard doses of atenolol,
amlodipine, or diltiazem and to determine times to angina onset and to electrocardiographic
evidence of myocardial ischemia, effect on angina attacks and nitroglycerin
use, and effect on long-term survival in an open-label observational study
Design, Setting, and Patients
A randomized, 3-group parallel, double-blind, placebo-controlled trial
of 823 eligible adults with symptomatic chronic angina who were randomly assigned
to receive placebo or 1 of 2 doses of ranolazine. Patients treated at the
118 participating ambulatory outpatient settings in several countries were
enrolled in the Combination Assessment of Ranolazine In Stable Angina (CARISA)
trial from July 1999 to August 2001 and followed up through October 31, 2002.
Patients received twice-daily placebo or 750 mg or 1000 mg of ranolazine.
Treadmill exercise 12 hours (trough) and 4 hours (peak) after dosing was assessed
after 2, 6 (trough only), and 12 weeks of treatment.
Main Outcome Measures
Change in exercise duration, time to onset of angina, time to onset
of ischemia, nitroglycerin use, and number of angina attacks.
Trough exercise duration increased by 115.6 seconds from baseline in
both ranolazine groups (pooled) vs 91.7 seconds in the placebo group (P = .01). The times to angina and to electrocardiographic
ischemia also increased in the ranolazine groups, at peak more than at trough.
The increases did not depend on changes in blood pressure, heart rate, or
background antianginal therapy and persisted throughout 12 weeks. Ranolazine
reduced angina attacks and nitroglycerin use by about 1 per week vs placebo
(P<.02). Survival of 750 patients taking ranolazine
during the CARISA trial or its associated long-term open-label study was 98.4%
in the first year and 95.9% in the second year.
Twice-daily doses of ranolazine increased exercise capacity and provided
additional antianginal relief to symptomatic patients with severe chronic
angina taking standard doses of atenolol, amlodipine, or diltiazem, without
evident adverse, long-term survival consequences over 1 to 2 years of therapy.