Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina
Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina
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DOI：
10.1016/j.jacc.2003.11.045
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发表时间：
2004-04-21
影响因子：
24
通讯作者：
Wolff, AA
中科院分区：
文献类型：
--
作者：
Chaitman, BR;Skettino, SL;Wolff, AA
雷诺嗪在稳定型心绞痛（MARISA）试验中的单药治疗评估的主要目的是确定雷诺嗪（一种潜在的新抗心绞痛化合物）对限制性运动持续时间的剂量-反应关系。雷诺嗪被认为部分抑制脂肪酸氧化，改变代谢向碳水化合物氧化，并增加氧的使用效率。方法心绞痛患者（n = 191）限制运动停止抗心绞痛药物，并随机进入一个双盲四阶段交叉研究的缓释雷诺嗪500，1,000，或1,500毫克，或安慰剂，每天两次给药，持续一周。在每次治疗结束时，在雷诺嗪血浆浓度的谷值和峰值期间进行运动试验。结果雷诺嗪500、1，000和1，500 mg每日两次使谷值运动持续时间分别增加94、103和116 s，均大于安慰剂组70 s的增加（p <0.005）。也证实了峰值运动持续时间、谷值和峰值ST段压低1 mm的时间以及谷值和峰值心绞痛的时间的剂量相关性增加（所有p <0.005）。雷诺嗪对心率和血压的影响可忽略不计。结合MARISA试验及其开放标签随访研究的数据，1年生存率为96.3 +/-1.7%。结论：在慢性心绞痛患者中，雷诺嗪单药治疗耐受性良好，在所有剂量下，在整个给药间隔期间均能增加运动表现，且无临床意义的血流动力学影响。在这一高危患者人群中，1年生存率并不低于预期。这种治疗心肌缺血的代谢途径可能为慢性心绞痛患者提供一种新的治疗选择。(C)2004年美国心脏病学会基金会
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. (C) 2004 by the American College of Cardiology Foundation