Frishman W H, Bittar N, Glasser S, Habib G, Smith W, Pordy R
Department of Medicine, New York Medical College/Westchester Medical Center, Valhalla, New York 10595, USA.
Clin Cardiol. 1998 Jul;21(7):483-90. doi: 10.1002/clc.4960210707.
Mibefradil, a newly approved antihypertensive and antianginal drug, is the first member of a new class of calcium antagonists (CAs), the tetralol derivatives, that selectively blocks T-type Ca2+ channels in contrast to classical CAs which, at therapeutic concentrations, block only L-type Ca2+ channels. Since patients with chronic stable angina pectoris typically may be treated with the combination of a long-acting nitrate and a CA, the additive efficacy and safety of mibefradil in combination with nitrate therapy needs to be determined.
This study was designed to assess the efficacy, tolerability, and safety of mibefradil when added to long-acting nitrate therapy in patients with chronic stable angina pectoris.
Following a 1-week placebo run-in period, patients were randomized to receive either mibefradil 50 mg (n = 96) or placebo (n = 93) once daily in addition to their nitrate therapy. After 2 weeks of active treatment, patients receiving the mibefradil were force titrated to 150 mg once daily for an additional 2 weeks. Exercise tolerance tests (ETTs) were performed at the end of Weeks 2 and 4; patients also maintained an anginal diary during the 4-week treatment period.
After 2 weeks of treatment with 50 mg mibefradil (within the current recommended dose range), a statistically significant but modest increase in total exercise duration was observed (treatment effect 16.4 s, p = 0.04). Similarly, there was a significant increase in time to onset of ischemia (treatment effect 26 s, p = 0.008). The adverse event profile of the 50 mg dose was indistinguishable from placebo, indicating that this dose was extremely well tolerated. At Week 4, the mibefradil-treated patients were taking 150 mg, which is above the current recommended dose range. The increase in total exercise duration was larger for the mibefradil 150 mg group than for the placebo group. For the intent-to-treat population, this difference did not reach statistical significance, whereas in the standard population it did (treatment effect 21 s, p = 0.05). The other two ETT variables, time to onset of angina and time to onset of 1 mm ST-segment depression, demonstrated significantly greater effect with mibefradil 150 mg (treatment effects 40 s, p = 0.002, and 55 s, p < 0.001, respectively, for the intent-to-treat population). Mibefradil 150 mg was associated with more adverse events than placebo, specifically, dizziness, leg edema, and postural hypotension.
This study demonstrates that mibefradil 50 mg once daily in the setting of the background long-acting nitrate therapy produces additive antianginal and anti-ischemic effects and is extremely well tolerated.
米贝拉地尔是一种新批准的抗高血压和抗心绞痛药物，是新型钙拮抗剂（CAs）即四氢萘酚衍生物类的首个成员，与传统的钙拮抗剂不同，后者在治疗浓度下仅阻断L型钙通道，而米贝拉地尔可选择性阻断T型钙通道。由于慢性稳定型心绞痛患者通常可用长效硝酸盐和钙拮抗剂联合治疗，因此需要确定米贝拉地尔与硝酸盐疗法联合应用时的附加疗效和安全性。
本研究旨在评估在慢性稳定型心绞痛患者中，米贝拉地尔添加到长效硝酸盐治疗中的疗效、耐受性和安全性。
经过1周的安慰剂导入期后，患者被随机分组，除硝酸盐治疗外，分别每日一次接受50mg米贝拉地尔（n = 96）或安慰剂（n = 93）治疗。经过2周的积极治疗后，接受米贝拉地尔治疗的患者被强制滴定至每日150mg，再治疗2周。在第2周和第4周结束时进行运动耐量测试（ETT）；患者在4周治疗期内还需记录心绞痛日记。
用50mg米贝拉地尔治疗2周后（在当前推荐剂量范围内），观察到总运动持续时间有统计学意义但适度的增加（治疗效果为16.4秒，p = 0.04）。同样，缺血发作时间也有显著增加（治疗效果为26秒，p = 0.008）。50mg剂量的不良事件谱与安慰剂无差异，表明该剂量耐受性极佳。在第4周时，接受米贝拉地尔治疗的患者服用剂量为150mg，高于当前推荐剂量范围。米贝拉地尔150mg组的总运动持续时间增加幅度大于安慰剂组。对于意向性分析人群，这种差异未达到统计学意义，而在符合方案人群中则达到了统计学意义（治疗效果为21秒，p = 0.05）。另外两个ETT变量，心绞痛发作时间和ST段压低1mm的发作时间，在米贝拉地尔150mg组显示出显著更大的效果（意向性分析人群的治疗效果分别为40秒，p = 0.002，和55秒，p < 0.001）。米贝拉地尔150mg组比安慰剂组有更多不良事件，具体为头晕、腿部水肿和体位性低血压。
本研究表明，在背景长效硝酸盐治疗基础上，每日一次服用50mg米贝拉地尔可产生附加的抗心绞痛和抗缺血作用，且耐受性极佳。
