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FEBRUARY 2002:    Contents

Clin. Cardiol. 25, 81 (2002)

Progress in Clinical Trials

CARISA (Combination Assessment of Ranolazine in Stable Angina)

Presenter: Bernard Chaitman, M.D., at the American Heart Association 2001 Scientific Sessions, Anaheim, California.

Background: During myocardial ischemia, serum fatty acid levels rise precipitously. Glucose oxidation, however, is more oxygen-efficient than fatty acid oxidation. With ranolazine administration, lactic acid accumulation is reduced, thereby reducing myocardial ischemic response. In the earlier Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) trial with immediate-release ranolazine as monotherapy, exercise times increased after one dose with no effect on blood pressure or heart rate.

Objective: CARISA was undertaken to evaluate the hypothesis that ranolazine SR (750 and 1,000 mg b.i.d.) would prolong symptom-limited treadmill exercise duration at trough plasma levels (12 h after dosing) in patients with chronic angina who remained symptomatic on background therapy of atenolol 50 mg q.d., diltiazem-CD 180 mg q.d., or amlodipine 5 mg q.d.

Patient population: Included patients (823 in 15 countries) had chronic (>=3 months) history of angina and coronary artery disease. Despite administration of the anti-anginal drugs named above, they had reproducibly poor angina-limited exercise tolerance within 3–9 min on a modified Bruce protocol (<5 METS), and >=1 mm ST-segment depression in >=1 electrocardiographic (ECG) lead. Patients with >=1 mm ST depression at rest in any ECG lead, those with New York Heart Association class III or IV congestive heart failure, or unstable angina, myocardial infarction (MI), coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty, and so forth, within 2 months were excluded. Mean patient age was 64 years (78% male), with 58% having prior MI and 18% prior CABG.

Study design: Patients were randomized to placebo or either of the two ranolazine doses (all b.i.d.) for 12 weeks. The primary endpoint was symptom-limited treadmill exercise duration at trough. Secondary endpoints included exercise duration at peak, time to exercise-induced angina at trough and peak, and time to ischemic ST-segment depression at peak (750 mg b.i.d. + 1,000 mg b.i.d.) versus placebo.

Results: Among 791 completers, the primary endpoint increases for symptom-limited exercise duration compared with both placebo and with baseline were significant, with p values of 0.01 for the two ranolazine doses combined, and 0.03 for each of them taken separately. Increases were also reported for the secondary endpoints. Effects persisted over 12 weeks. Angina frequency decreased significantly, by about one attack per week, with each ranolazine dose compared with placebo.

Changes in blood pressure and heart rate were minimal at both ranolazine doses, and QTc interval was prolonged to a minor degree.

Conclusion: Ranolazine, as monotherapy or as combination therapy for patients remaining symptomatic on calcium-blocker or beta-blocker therapy, is a potentially effective antianginal drug for the treatment of chronic angina.


ALIVE (Azimilide Post Infarct Survival Evaluation Trial)

Presenter: A. John Camm, M.D., at the American Heart Association 2001 Scientific Sessions, Anaheim, California.

Background: Azimilide prolongs the duration of the action potential and is therefore a Vaughan Williams Class III antiarrhythmic agent. It requires no dose adjustments for renal or hepatic impairment, or for use with warfarin or digoxin.

Purpose: The purpose of ALIVE was to determine the effect of 100 mg of orally administered azimilide versus placebo on survival in recent post-myocardial infarction patients at risk of sudden death.

Patient population: ALIVE enrolled 3,381 patients with recent (5–21 days) myocardial infarction (MI) and low left ventricular ejection fraction (15–35%). A subgroup with heart rate variability (HRV) ¾20 units (n = 1,264) identified via 24-h Holter monitoring was prespecified for evaluation. Data from earlier trials have shown highly significant increases in death among patients with HRV index ¾20 units. Mean age was 60.5 years (78% male).

Trial design: ALIVE was conducted by 483 investigators in 26 countries. Patients were randomized to 100 mg of azimilide (n = 1,690) or placebo (n = 1,691). The primary endpoint was all-cause mortality. Patient survival and safety were monitored for up to one year.

Results: Among high-risk patients receiving placebo there were 96 deaths, compared with 88 deaths among those receiving 100 mg azimilide. The difference was not significant (p = 0.739). Among the total at-risk population, there were 196 deaths in the placebo group and 197 in the azimilide group (p = NS). At one year, survival was significantly lower (p = 0.0005) in the high-risk than in the low-risk group (15 versus 9.5% mortality). There was a low incidence of transient torsade de pointes and severe neutropenia associated with azimilide.

Among patients in sinus rhythm at baseline, atrial fibrillation/flutter (AF/FL) developed in 19 of 1,648 patients taking placebo and in 8 of 1,630 patients taking azimilide (HR [hazard ratio] = 0.43, p = 0.04). Among those in atrial fibrillation at baseline, 4 of 37 patients in the placebo and 15 of 56 patients in the azimilide group converted (HR = 2.63, p = 0.076).

Conclusion: Low HRV identified a post-MI population at high risk of mortality. Azimilide showed no beneficial or adverse effect on all-cause mortality. Fewer patients in normal sinus rhythm at baseline developed AF/FL while taking azimilide than placebo. ALIVE results provide further support for the development of azimilide as a treatment for AF/FL.

Comment (Douglas Zipes, M.D.): An antiarrhythmic that does not confer harm is certainly a blessing.