From the Department of Medicine, University of Toronto, Toronto (F.W.); Orphan Therapeutics, Annandale (S.C.P.), and Mallinckrodt Pharmaceuticals, Bedminster (S.E., K.J.) - both in New Jersey; the Department of Medicine, Beth Israel Deaconess Medical Center, Boston (M.P.C.); the University of Pennsylvania, Philadelphia (K.R.R.); Piedmont Transplant Institute, Piedmont Healthcare, Atlanta (R.A.R.); the Department of Medicine, Vanderbilt University Medical Center, Nashville (M.K.P.); the Department of Medicine, Baylor Scott and White All Saints Medical Center, Fort Worth (S.A.G.), and the Department of Medicine, University of Texas Southwestern Medical Center, Dallas (M.J.M.) - both in Texas; Ohio State University, Columbus (K.M.); the Department of Medicine, University of Minnesota, Minneapolis (N.L.), and the Department of Medicine, Mayo Clinic, Rochester (D.A.S.) - both in Minnesota; the Department of Medicine, University of Michigan Medical Center, Ann Arbor (P.S.); Virginia Commonwealth University, Richmond (A.J.S.); and Hepatology and Liver Transplantation, California Pacific Medical Center, San Francisco (R.T.F.).
N Engl J Med. 2021 Mar 4;384(9):818-828. doi: 10.1056/NEJMoa2008290.
The vasoconstrictor terlipressin is used for type 1 hepatorenal syndrome (HRS-1) in many parts of the world and is part of the clinical practice guidelines in Europe.
We conducted a phase 3 trial to confirm the efficacy and safety of terlipressin plus albumin in adults with HRS-1. The patients were randomly assigned in a 2:1 ratio to receive terlipressin or placebo for up to 14 days; in both groups, concomitant use of albumin was strongly recommended. The primary end point was verified reversal of HRS, defined as two consecutive serum creatinine measurements of 1.5 mg per deciliter or less at least 2 hours apart and survival without renal-replacement therapy for at least 10 days after the completion of treatment. Four prespecified secondary end points were analyzed with the Hochberg procedure to account for multiple comparisons.
A total of 300 patients underwent randomization - 199 were assigned to the terlipressin group and 101 to the placebo group. Verified reversal of HRS was reported in 63 patients (32%) in the terlipressin group and 17 patients (17%) in the placebo group (P = 0.006). With respect to the prespecified secondary end points, HRS reversal, defined as any serum creatinine level of 1.5 mg per deciliter or less during the first 14 days, was reported in 78 patients (39%) in the terlipressin group and 18 (18%) in the placebo group (P<0.001); HRS reversal without renal-replacement therapy by day 30, in 68 (34%) and 17 (17%), respectively (P = 0.001); HRS reversal among patients with systemic inflammatory response syndrome (84 patients in the terlipressin group and 48 patients in the placebo group), in 31 (37%) and 3 (6%), respectively (P<0.001); and verified reversal of HRS without recurrence by day 30, in 52 (26%) and 17 (17%), respectively (P = 0.08). At day 90, liver transplantations had been performed in 46 patients (23%) in the terlipressin group and 29 patients (29%) in the placebo group, and death occurred in 101 (51%) and 45 (45%), respectively. More adverse events, including abdominal pain, nausea, diarrhea, and respiratory failure, occurred with terlipressin than with placebo. Death within 90 days due to respiratory disorders occurred in 22 patients (11%) in the terlipressin group and 2 patients (2%) in the placebo group.
In this trial involving adults with cirrhosis and HRS-1, terlipressin was more effective than placebo in improving renal function but was associated with serious adverse events, including respiratory failure. (Funded by Mallinckrodt Pharmaceuticals; CONFIRM ClinicalTrials.gov number, NCT02770716.).
血管加压素特利加压素在世界许多地区被用于 1 型肝肾综合征（HRS-1），并被纳入欧洲临床实践指南。
我们开展了一项 3 期临床试验，旨在确认特利加压素联合白蛋白治疗 HRS-1 成人患者的疗效和安全性。患者以 2:1 的比例随机分配接受特利加压素或安慰剂治疗，最多 14 天；两组均强烈建议同时使用白蛋白。主要终点是验证 HRS 逆转，定义为至少相隔 2 小时两次连续测量血清肌酐值均为每分升 1.5 毫克或更低，并且在完成治疗后至少 10 天内无需肾脏替代治疗而存活。采用 Hochberg 程序对 4 个预先指定的次要终点进行分析，以考虑多次比较。
共有 300 名患者接受了随机分组，其中 199 名患者被分配至特利加压素组，101 名患者被分配至安慰剂组。特利加压素组有 63 名（32%）患者报告 HRS 逆转，安慰剂组有 17 名（17%）患者报告 HRS 逆转（P=0.006）。对于预先指定的次要终点，特利加压素组有 78 名（39%）患者在第 14 天内报告任何血清肌酐值为每分升 1.5 毫克或更低，安慰剂组有 18 名（18%）患者报告 HRS 逆转（P<0.001）；特利加压素组有 68 名（34%）患者在第 30 天无需肾脏替代治疗即可实现 HRS 逆转，安慰剂组有 17 名（17%）患者报告 HRS 逆转（P=0.001）；特利加压素组有 84 名患者存在全身炎症反应综合征，其中 31 名（37%）患者报告 HRS 逆转，安慰剂组有 48 名患者存在全身炎症反应综合征，其中 3 名（6%）患者报告 HRS 逆转（P<0.001）；特利加压素组有 52 名（26%）患者在第 30 天报告 HRS 无复发且逆转，安慰剂组有 17 名（17%）患者报告 HRS 无复发且逆转（P=0.08）。在第 90 天，特利加压素组有 46 名（23%）患者接受了肝移植，安慰剂组有 29 名（29%）患者接受了肝移植，特利加压素组有 101 名（51%）患者死亡，安慰剂组有 45 名（45%）患者死亡。与安慰剂相比，特利加压素组发生了更多的不良反应，包括腹痛、恶心、腹泻和呼吸衰竭。特利加压素组有 22 名（11%）患者在 90 天内因呼吸障碍而死亡，安慰剂组有 2 名（2%）患者因呼吸障碍而死亡。
在这项涉及肝硬化和 HRS-1 成人患者的试验中，与安慰剂相比，特利加压素在改善肾功能方面更有效，但与严重的不良反应有关，包括呼吸衰竭。（由 Mallinckrodt 制药公司资助；CONFIRM 临床试验。gov 编号，NCT02770716。）
