Efficacy and safety of a metabolic modulator drug in chronic stable angina: Review of evidence from clinical trials
Efficacy and safety of a metabolic modulator drug in chronic stable angina: Review of evidence from clinical trials
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DOI：
10.1177/107424840400900105
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发表时间：
2004-09-01
影响因子：
2.6
通讯作者：
Chaitman, Bernard R.
中科院分区：
文献类型：
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作者：
Chaitman, Bernard R.
近年来合成了许多新的抗心绞痛药物，包括尼可地尔、曲美他嗪和伊伐布雷定，但雷诺嗪是一种哌嗪衍生物，可部分抑制动物模型中的脂肪酸氧化和晚期INa电流，在机制上特别令人关注。早期的雷诺嗪速释临床试验导致了目前的缓释版本在雷诺嗪稳定型心绞痛单药治疗评估（MARISA）（n = 193）和雷诺嗪稳定型心绞痛联合治疗评估（CARISA）试验（n = 823）中进行了测试，这些试验的患者患有慢性心绞痛和运动能力严重受限（< 5代谢当量）。MARISA是一项安慰剂对照、随机试验，比较雷诺嗪单药治疗（500 mg、1000 mg和1500 mg，每日两次）与安慰剂。CARISA是一项安慰剂对照试验，将背景β受体阻滞剂或钙拮抗剂治疗的患者随机分配至安慰剂或雷诺嗪（750 mg或1000 mg，每日两次）。两项研究均显示总运动时间、至心绞痛发作时间和至ST段压低1 mm时间显著增加。与安慰剂相比，MARISA中检测的3种剂量的运动持续时间的平均增加幅度为峰值29 - 56秒和谷值24 - 46秒，CARISA中使用的2种剂量的运动持续时间比安慰剂长24 - 34秒。在静息或运动心率或血压没有临床重要变化的情况下实现了有益效果。在为期12周的CARISA试验中，每周心绞痛发作频率和硝酸甘油使用量以剂量依赖性方式显著降低。MARISA和CARISA报告的不良反应相似，包括虚弱、恶心、便秘和头晕。在1000 mg每日两次或更高剂量组的8例患者中报告的晕厥可能与α-1受体活性减弱有关。平均QTc间期随剂量增加而增加，雷诺嗪1000 mg每日两次给药时小于10 msec。在MARISA和CARISA开放标签运行研究中，1年和2年的死亡率为2%和小于5%，对于运动能力有限的高风险人群是可接受的。总之，雷诺嗪迄今为止的临床试验证据与其提出的作用机制一致，并证明了有效的抗心绞痛特征，可能使重度慢性心绞痛患者受益。
A number of newer antianginal agents, including nicorandil, trimetazidine, and ivabradine, have been synthesized in recent years, but ranolazine, a piperazine derivative that partially inhibits fatty acid oxidation and the late INa current in animal models, is of particular interest mechanistically. Earlier clinical trials with immediate-release ranolazine led to the current sustained-release version tested in the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) (n = 193) and Combination Assessment of Ranolazine In Stable Angina (CARISA) trials (n = 823) of patients with chronic angina and severe limitation of exercise capacity tie, < 5 metabolic equivalents). MARISA was a placebo-controlled, randomized trial that compared ranolazine monotherapy (500 mg, 1000 mg, and 1500 mg, twice daily) to placebo. CARISA was a placebo-controlled trial that randomized patients on background beta-blocker or calcium antagonist therapy to placebo or ranolazine (750 mg or 1000 mg, twice daily). Both studies showed a significant increase in total exercise duration, time to angina onset, and time to 1 mm ST segment depression. The average magnitude of increase in exercise duration over placebo was 29 to 56 seconds at peak and 24 to 46 seconds at trough with the 3 doses tested in MARISA, and 24 to 34 seconds greater than placebo with the 2 doses used in CARISA. The beneficial effect was achieved without clinically important changes in rest or exercise heart rate or blood pressure. Weekly angina attack frequency and nitroglycerin usage were significantly reduced in a dose-dependent manner in the 12-week CARISA trial. Reported adverse effects were similar in MARISA and CARISA and consisted of asthenia, nausea, constipation, and dizziness. Syncope, reported in 8 patients at doses of 1000 mg twice daily or more may be related to attenuation of alpha-1 receptor activity. The mean QTc interval increased with dose and was less than 10 msec on ranolazine at 1000 mg twice daily. The mortality rates at 1 and 2 years in MARISA and CARISA open-label run-on studies were 2% and less than 5%, acceptable for this high-risk population with limited exercise capacity. In conclusion, clinical trial evidence with ranolazine to date is consistent with its proposed mechanism of action and demonstrates an effective antianginal profile that may benefit patients with severe chronic angina.