Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina.

OBJECTIVES: The primary objective of the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial was to determine the dose-response relationship of ranolazine, a potentially new anti-anginal compound, on symptom-limited exercise duration. BACKGROUND: Fatty acids rise precipitously in response to stress, including acute myocardial ischemia. Ranolazine is believed to partially inhibit fatty acid oxidation, shift metabolism toward carbohydrate oxidation, and increase the efficiency of oxygen use. METHODS: Patients (n = 191) with angina-limited exercise discontinued anti-anginal medications and were randomized into a double-blind four-period crossover study of sustained-release ranolazine 500, 1,000, or 1,500 mg, or placebo, each administered twice daily for one week. Exercise testing was performed at the end of each treatment during both trough and peak ranolazine plasma concentrations. RESULTS: Exercise duration at trough increased with ranolazine 500, 1,000, and 1,500 mg twice daily by 94, 103, and 116 s, respectively, all greater (p < 0.005) than the 70-s increase on placebo. Dose-related increases in exercise duration at peak and in times to 1 mm ST-segment depression at trough and peak and to angina at trough and peak were also demonstrated (all p < 0.005). Ranolazine had negligible effects on heart rate and blood pressure. One year survival rate combining data from the MARISA trial and its open-label follow-on study was 96.3 +/- 1.7%. CONCLUSIONS: In chronic angina patients, ranolazine monotherapy was well tolerated and increased exercise performance throughout its dosing interval at all doses studied without clinically meaningful hemodynamic effects. One-year survival was not lower than expected in this high-risk patient population. This metabolic approach to treating myocardial ischemia may offer a new therapeutic option for chronic angina patients.

Assessment of the kinematic variability among 12 motion analysis laboratories.

Variability of kinematic measurements among sites participating in a collaborative research investigation is a primary factor in determining number of subjects, level of detectable difference and statistical power of a multi-site research study. In this study, one subject was evaluated by 24 examiners at 12 motion analysis laboratories and the observed variability of nine kinematic parameters are reported. Following implementation of a standardized gait analysis protocol the same subject returned for another evaluation at each of the 12 laboratories. Additionally, system accuracy and variability of the subject within and between test days are included as factors that may affect between site variability. Marker placement among examiners is identified as the largest source of variability. A 20% decrease in variability was noted following implementation of the standardized protocol.