Division of Nephrology, Department of Medicine, New York University Grossman School of Medicine, New York, New York.
Department of Biostatistics, Epidemiology and Informatics, and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Kidney360. 2020 Oct 15;1(12):1380-1389. doi: 10.34067/KID.0004342020. eCollection 2020 Dec 31.
Combination therapy with isosorbide dinitrate (ISD) and hydralazine (HY) reduces heart failure mortality. The safety and tolerability in individuals requiring maintenance hemodialysis (HD) is unknown.
Single-center, randomized, placebo-controlled, double-blind pilot trial to explore safety and tolerability of ISD/HY in maintenance HD. Participants were randomized to placebo or combination ISD/HY. Dose was escalated over 3 weeks from ISD 10 mg/HY 10 mg to ISD 40 mg/HY 75 mg three times per day with the maximum tolerated dose maintained for the subsequent 21 weeks. Primary endpoints included adverse events, adverse events precluding further treatment with study medication, serious hypotension (., requiring hospitalization or emergency room visit), and recurrent intra-dialytic hypotension. Efficacy signals included change in mitral annular E' velocity by tissue Doppler echocardiography and change in left ventricular coronary flow reserve on positron emission tomography.
A total of 17 individuals were randomized to ISD/HY (=7) or placebo (=10). All participants assigned to ISD/HY completed dose escalation to 40/75 mg, but dose reductions were required in two participants. No participants discontinued therapy. There were no serious hypotension events. Recurrent intradialytic hypotension was less frequent with ISD/HY (0.47 events/patient-year) than placebo (1.83 events/patient-year, =0.04). In contrast, nausea (ISD/HY, 1.90 events/patient-year; placebo, 0.50 events/patient-year, =0.03) was significantly more frequent, and headache and diarrhea were numerically but not significantly more frequent with ISD/HY. Adverse events were more frequent with ISD/HY (11.4 events/patient-year) than placebo (6.31 events/patient-year). We did not detect between-group differences in the change in E' (=0.34); ISD/HY showed a mean increase of 0.6 cm/s (SD 1.1), and placebo showed a mean decrease of 0.04 cm/s (SD 0.9). Changes in coronary flow reserve were minimal, -0.3 (0.2) with ISD/HY and -0.03 (0.5) in the placebo group, =0.19.
ISD/HY appears to be well tolerated in patients being treated with maintenance HD, but headache and gastrointestinal side effects occur more frequently with ISD/HY compared with placebo.
硝酸盐异山梨酯（ISD）和肼屈嗪（HY）联合治疗可降低心力衰竭死亡率。 但对于需要维持性血液透析（HD）的患者，其安全性和耐受性尚不清楚。
这是一项单中心、随机、安慰剂对照、双盲的初步试验，旨在探讨 ISD/HY 在维持性 HD 患者中的安全性和耐受性。 将参与者随机分配至安慰剂或 ISD/HY 联合治疗组。 在 3 周的时间内，剂量从 ISD 10 mg/HY 10 mg 逐渐增加到 ISD 40 mg/HY 75 mg，每日三次，最大耐受剂量维持 21 周。 主要终点包括不良事件、因药物治疗导致的不良事件、严重低血压（如需要住院或急诊就诊）和复发性透析中低血压。 疗效信号包括组织多普勒超声心动图测量的二尖瓣环 E'速度变化和正电子发射断层扫描测量的左心室冠状动脉血流储备变化。
共有 17 名参与者被随机分配至 ISD/HY 组（n=7）或安慰剂组（n=10）。 所有被分配至 ISD/HY 组的参与者均完成了 40/75 mg 的剂量递增，但有 2 名参与者需要减少剂量。 没有参与者停止治疗。 没有严重低血压事件发生。 与安慰剂组（1.83 次/患者/年）相比，ISD/HY 组的复发性透析中低血压（0.47 次/患者/年）频率更低（=0.04）。 相比之下，ISD/HY 组恶心（1.90 次/患者/年）的发生率明显更高，头痛和腹泻的发生率虽有增加但无统计学意义。 ISD/HY 组不良事件（11.4 次/患者/年）的发生频率高于安慰剂组（6.31 次/患者/年）。 我们未发现两组间 E'变化（=0.34）的差异； ISD/HY 组平均增加 0.6 cm/s（SD 1.1），安慰剂组平均降低 0.04 cm/s（SD 0.9）。 冠状动脉血流储备的变化较小，ISD/HY 组为-0.3（0.2），安慰剂组为-0.03（0.5）（=0.19）。
ISD/HY 似乎在接受维持性 HD 治疗的患者中耐受良好，但与安慰剂相比，ISD/HY 组头痛和胃肠道副作用的发生频率更高。
