Combination Assessment of Ranolazine in Stable Angina - CARISA

Description:

Combination Assessment of Ranolazine in Stable Angina (CARISA) was a randomized controlled trial designed to study the effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina.

Hypothesis:

Ranolazine sustained release (SR) 750 and 1000 mg twice daily will prolong symptom-limited treadmill exercise at trough plasma levels (12 hours after dosing) in chronic angina patients who remain symptomatic on atenolol, diltiazem CD, or amlodipine.

Study Design

Study Design:

Patients Enrolled: 823
Mean Follow Up: 12 weeks
Female: 22

Patient Populations:

Men and women with chronic angina in the previous three months and documented coronary artery disease; all patients receiving one of the three concomitant medications; other antianginal drugs (e.g., long-acting nitrates) withdrawn >5 days prior to first qualifying treadmill test and for the remainder of the trial; reproducible exercise-induced angina, ischemic ST depression, and limited exercise capacity defined as inability to exercise into standard Bruce Stage II (3-9 minutes), using a modified protocol with 2-3 minute warm-up stages (reproducibility of exercise time prerandomization was defined as within 20% of the longer of the two tests, and within one minute of each other)

Exclusions:

Resting ST depression >1 mm in any lead; other ECG abnormalities that precluded satisfactory interpretation of the exercise ECG; digitalis therapy; New York Heart Association class III or IV heart failure; or acute coronary syndrome or revascularization procedure within the previous two months

Primary Endpoints:

Symptom-limited treadmill exercise duration at trough (two-stage, step-down procedure)

Secondary Endpoints:

Exercise duration at peak, time to angina, time to ischemic ST depression at peak and trough, angina diary, vital signs, safety, and tolerability

Drug/Procedures Used:

Ranolazine versus placebo as add-on therapy to prolong exercise duration in chronic angina patients, without affecting blood pressure or heart rate

Concomitant Medications:

Atenolol, 50 mg once a day (qd); diltiazem CD, 180 mg qd; and amlodipine, 5 mg qd

Principal Findings:

Symptom-limited exercise duration was significantly prolonged on ranolazine as compared to placebo at trough (p=0.01). This significant benefit was apparent even though exercise duration was increased 92 seconds on placebo alone.

Furthermore, exercise duration at trough was significantly prolonged for both the 750 mg and 1000 mg doses (both p=0.03). Absence of an apparent dose-response relationship is in contrast to the clear dose response seen in an earlier trial (MARISA), where a larger range of doses was tested.

Ranolazine’s effect on improved exercise duration was maintained over the 12 weeks of therapy at both dose levels tested. Multivariate analysis did not identify the type of background therapy as a significant predictor of treatment effect (p=0.63).

Exercise time to angina onset was significantly prolonged at trough (p≤0.05) and at peak (p≤0.005) versus placebo for both dose levels. Exercise time to 1 mm ischemic ST depression was significantly prolonged at peak (p≤0.001, 750 mg; p≤0.005, 1000 mg). The difference did not reach statistical significance at trough levels.

The average number of angina attacks per week at baseline was ~4.5 in the three groups. Angina frequency was significantly decreased from baseline by about one attack/week, with each dose tested as compared to placebo. This change after 12 weeks of therapy was significant (p<0.01, 750 mg; p<0.001, 1000 mg).

Minimal differences in systolic blood pressure and heart rate were observed, with an average reduction in blood pressure of ~3 mm (p≤0.05) and 2 beats/min heart rate with the 1000 mg dose. Serious adverse events were seen in 6-7% of patients in each of the three groups, although the study was not powered to assess cardiovascular clinical endpoints such as death or infarction. The number of events was small, within 1-6% of each other in the three groups.

Ranolazine was associated with a dose-related increase in QTc interval prolongation (p<0.001 vs. placebo). The magnitude of increase was small, ranging from a mean of 3-12 ms at trough and peak. No patients were observed with torsade de pointes.

The investigators concluded that ranolazine, a pFOX inhibitor, represents a new class of antianginal drug therapy for patients with chronic angina. It exerts its effect with minimal changes on systolic blood pressure and heart rate, which is consistent with its proposed mechanism of action.

Interpretation:

Under normal conditions, the heart can use either glucose or fatty acids to generate adenosine triphosphate (ATP); however, fatty acids are used preferentially because they contain more calories per gram than glucose. This is problematic in patients where the heart is not receiving enough oxygen due to atherosclerosis. In these patients, the metabolism of glucose would be better, because glucose uses oxygen more efficiently than metabolism of fatty acids. However, during acute myocardial ischemia, fatty acids rise, precipitously inhibiting pyruvate dehydrogenase and consequently, depressing glucose oxidation.

Ranolazine partially inhibits fatty acid oxidation, allowing the heart to use glucose as a fuel by relieving the inhibition on pyruvate dehydrogenase. The net result is reduced lactic acid accumulation, less intracellular acidosis, and a reduction in severity of the myocardial ischemic response.

Placebo-controlled trials using the immediate release form of ranolazine show improved exercise performance of a magnitude approximately equivalent to atenolol 100 mg daily. However, because the duration of effect was under eight hours, the SR formulation was developed. Ranolazine SR was tested as monotherapy for chronic angina in the MARISA trial, which showed a statistically significant increase in all three standard measures of treadmill exercise performance at each dose level and with at least a 12-hour duration of effect. CARISA is the first study of ranolazine SR as add-on therapy for patients with chronic angina who are already taking other antianginal drugs.

During the presentation of this trial at the American Heart Association Annual Scientific Session in 2001, discussant Dr. Bill Weintraub noted that the CARISA trial was well designed, conducted, and analyzed with well defined patients, while adding that there are additional questions that can be answered in future trials: Who are the most appropriate patients for ranolazine therapy? What is the long-term safety and efficacy profile? Will wider use bring more adverse events? What is ranolazine’s relationship to other agents and therapies, especially revascularization? And what are potential areas for study, such as heart failure?

References:

1) Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 2004;291:309-16.
2) Jain D, Dasgupta P, Hughes LO, Lahiri A, Raftery EB. Ranolazine (RS-43285): a preliminary study of a new anti-anginal agent with selective effect on ischaemic myocardium. Eur J Clin Pharmacol 1990;38:111-4.
3) Cocco G, Rousseau MF, Bouvy T, et al. Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with beta-blocker or diltiazem. J Cardiovasc Pharmacol. 1992;20:131-8.
4) Thadani U, Ezekowitz M, Fenney L, Chiang YK. Double-blind efficacy and safety study of a novel anti-ischemic agent, ranolazine, versus placebo in patients with chronic stable angina pectoris. Ranolazine Study Group. Circulation 1994;90:726-34.
5) Hayashida W, van Eyll C, Rousseau MF, Pouleur H. Effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease. Cardiovasc Drugs Ther 1994;8:741-7.
6) Rousseau MF, Chapelle F, Van Eyll C, et al. Medium-term effects of beta-blockade on left ventricular mechanics: a double-blind, placebo-controlled comparison of nebivolol and atenolol in patients with ischemic left ventricular dysfunction. J Card Fail 1996;2:15-23.
7) McCormack JG, Stanley WC, Wolff AA, et al. Ranolazine: a novel metabolic modulator for the treatment of angina. Gen Pharmacol 1998;30:639-45. Review.
8) Wang JX, Maruyama K, Murakami M, et al. Antianginal effects of ranolazine in various experimental models of angina. Arzneimittelforschung 1999;49:193-9.
9) Pepine CJ, Wolff AA. A controlled trial with a novel anti-ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agents. Ranolazine Study Group. Am J Cardiol 1999;84:46-50.
10) Zacharowski K, Blackburn B, Thiemermann C. Ranolazine, a partial fatty acid oxidation inhibitor, reduces myocardial infarct size and cardiac troponin T release in the rat. Eur J Pharmacol 2001; 418:105-10.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), SCD/Ventricular Arrhythmias, Lipid Metabolism, Acute Heart Failure, Chronic Angina

Keywords: Exercise Tolerance, Diltiazem, Coronary Artery Disease, Infarction, Atherosclerosis, Angina, Stable, Fatty Acids, Blood Pressure, Piperazines, Heart Rate, Torsades de Pointes, Glucose, Oxidoreductases, Nitrates, Heart Failure, Lactic Acid, Amlodipine, Exercise Test


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