Center for Hemostasis and Thrombosis Research, Tufts Medical Center, Tufts University School of Medicine, Boston, MA (A.K., S.E.T., E.K.F., D.H.C., L.C.).
Inova Center for Thrombosis Research and Translational Medicine, Inova Fairfax Hospital, Falls Church, VA and Sinai Hospital of Baltimore, MD (P.A.G., K.P.B.).
Arterioscler Thromb Vasc Biol. 2020 Dec;40(12):2990-3003. doi: 10.1161/ATVBAHA.120.315168. Epub 2020 Oct 8.
Arterial thrombosis leading to ischemic injury worsens the prognosis of many patients with cardiovascular disease. PZ-128 is a first-in-class pepducin that reversibly inhibits PAR1 (protease-activated receptor 1) on platelets and other vascular cells by targeting the intracellular surface of the receptor. The TRIP-PCI (Thrombin Receptor Inhibitory Pepducin in Percutaneous Coronary Intervention) trial was conducted to assess the safety and efficacy of PZ-128 in patients undergoing cardiac catheterization with intent to perform percutaneous coronary intervention. Approach and Results: In this randomized, double-blind, placebo-controlled, phase 2 trial, 100 patients were randomly assigned (2:1) to receive PZ-128 (0.3 or 0.5 mg/kg), or placebo in a 2-hour infusion initiated just before the start of cardiac catheterization, on top of standard oral antiplatelet therapy. Rates of the primary end point of bleeding were not different between the combined PZ-128 doses (1.6%, 1/62) and placebo group (0%, 0/35). The secondary end points of major adverse coronary events at 30 and 90 days did not significantly differ but were numerically lower in the PZ-128 groups (0% and 2% in the PZ-128 groups, 6% and 6% with placebo, p=0.13, p=0.29, respectively). In the subgroup of patients with elevated baseline cardiac troponin I, the exploratory end point of 30-day major adverse coronary events + myocardial injury showed 83% events in the placebo group versus 31% events in the combined PZ-128 drug groups, an adjusted relative risk of 0.14 (95% CI, 0.02-0.75); =0.02.
In this first-in-patient experience, PZ-128 added to standard antiplatelet therapy appeared to be safe, well tolerated, and potentially reduced periprocedural myonecrosis, thus providing the basis for further clinical trials. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02561000.
导致缺血损伤的动脉血栓形成使许多心血管疾病患者的预后恶化。PZ-128 是一种首创的 Pepducin，通过靶向受体的细胞内表面，可逆地抑制血小板和其他血管细胞上的 PAR1（蛋白酶激活受体 1）。TRIP-PCI（经皮冠状动脉介入治疗中的凝血酶受体抑制 Pepducin）试验旨在评估 PZ-128 在意图进行经皮冠状动脉介入治疗的接受心导管检查的患者中的安全性和疗效。方法和结果：在这项随机、双盲、安慰剂对照、2 期试验中，100 名患者被随机分配（2:1）接受 PZ-128（0.3 或 0.5mg/kg）或安慰剂，在开始心导管检查前 2 小时内开始输注，加用标准口服抗血小板治疗。联合 PZ-128 剂量组（1.6%，62 例中有 1 例）和安慰剂组（0%，35 例中 0 例）的主要出血终点发生率无差异。30 天和 90 天的次要终点主要不良冠状动脉事件也无显著差异，但 PZ-128 组的发生率略低（PZ-128 组分别为 0%和 2%，安慰剂组分别为 6%和 6%，p=0.13，p=0.29）。在基线心脏肌钙蛋白 I 升高的患者亚组中，30 天主要不良冠状动脉事件+心肌损伤的探索性终点显示安慰剂组有 83%的事件，而联合 PZ-128 药物组有 31%的事件，调整后的相对风险为 0.14（95%CI，0.02-0.75）；=0.02。结论：在这项首例患者经验中，PZ-128 加用标准抗血小板治疗似乎是安全的，耐受良好，并且可能减少围手术期心肌坏死，从而为进一步的临床试验提供了依据。注册：网址：https://www.clinicaltrials.gov。唯一标识符：NCT02561000。
