Department of Cardiovascular Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia.
University of Newcastle, Newcastle, New South Wales, Australia.
JAMA Cardiol. 2021 Jul 1;6(7):762-768. doi: 10.1001/jamacardio.2021.0676.
After anterior ST-segment elevation myocardial infarction (STEMI), left ventricular (LV) remodeling results in heart failure and death. Calcium/calmodulin-dependent protein kinase II delta (CaMKIId) is a key molecular mediator of adverse LV remodeling.
To determine whether NP202, an orally active inhibitor of CaMKIId, prevents LV remodeling in patients after anterior STEMI with early residual LV dysfunction.
DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled multicenter clinical trial of NP202 vs placebo in patients after primary percutaneous coronary intervention (PCI) for anterior STEMI was performed from November 19, 2015, to August 1, 2018. The study was performed at 32 sites across the US, Australia, and New Zealand. Patients presenting with anterior STEMI who underwent PCI within 12 hours of symptom onset and left ventricular ejection fraction (LVEF) less than 45% on screening echocardiogram 48 hours after primary PCI were included in the study. Baseline cardiovascular magnetic resonance (CMR) imaging was performed within 5 days of the STEMI and before administration of the study drug. Follow-up CMR was performed after 3 months. Data were analyzed from November 19, 2015, to August 1, 2018.
Patients were randomly assigned to NP202, 1000 mg, daily for 3 months vs corresponding placebo.
The primary end point was change in LV end-systolic volume index (LVESVi) on CMR. Secondary end points were change in LV end-diastolic volume index, change in LVEF, change in infarct size, and change in diastolic function. Safety and tolerability were also assessed.
A total of 147 patients (mean [SD] age, 58 [11] years; 129 men [88%]; 130 White patients [88%]) who experienced anterior STEMI treated with primary PCI were randomized to receive NP202 (73 [49.7%]) or placebo (74 [50.3%]). Baseline LVEF was similar between groups. At baseline, patients randomized to NP202 had greater LVESVi (48.2 mL/m2) than that in the placebo group (41.3 mL/m2; P = .03). However, the groups were otherwise well matched. For the primary end point of change in LVESVi from baseline to 3 months, there was no significant difference between the placebo (median [interquartile range] change, -0.60 [-9.28 to 5.99] mL/m2) and NP202 groups (-3.53 [-9.24 to 4.81] mL/m2) (P = .78). There was also no difference in the secondary efficacy end points assessed by CMR. NP202 was well tolerated and demonstrated an acceptable safety profile. Major adverse cardiac and cerebrovascular event rates were similar between groups. Two deaths occurred in each group during the follow-up period.
Three months of treatment with NP202 after primary PCI for anterior STEMI with residual LV dysfunction did not improve LV remodeling. The drug was safe and well tolerated.
ClinicalTrials.gov Identifier: NCT02557217.
急性前壁 ST 段抬高型心肌梗死（STEMI）后，左心室（LV）重构会导致心力衰竭和死亡。钙/钙调蛋白依赖性蛋白激酶 II 德尔塔（CaMKIId）是不良 LV 重构的关键分子介质。
确定 NP202，一种口服活性 CaMKIId 抑制剂，是否可预防经皮冠状动脉介入治疗（PCI）后早期 LV 功能障碍的前壁 STEMI 患者的 LV 重构。
设计、地点和参与者：这是一项在美国、澳大利亚和新西兰的 32 个地点进行的随机、双盲、安慰剂对照的 NP202 与安慰剂治疗经皮冠状动脉介入治疗（PCI）后前壁 STEMI 患者的多中心临床试验。该研究于 2015 年 11 月 19 日至 2018 年 8 月 1 日进行。研究纳入的患者为：症状发作后 12 小时内行 PCI 治疗的前壁 STEMI，且初次 PCI 后 48 小时心脏超声心动图显示左心室射血分数（LVEF）小于 45%。基线心脏磁共振（CMR）成像于 STEMI 后 5 天内和研究药物给药前进行。3 个月后进行随访 CMR。数据分析于 2015 年 11 月 19 日至 2018 年 8 月 1 日进行。
患者随机分为 NP202 组（每天 1000mg，持续 3 个月）和相应的安慰剂组。
CMR 上 LV 收缩末期容积指数（LVESVi）的变化。次要终点：LV 舒张末期容积指数的变化、LVEF 的变化、梗死面积的变化和舒张功能的变化。还评估了安全性和耐受性。
共纳入 147 例接受经皮冠状动脉介入治疗的前壁 STEMI 患者（平均[SD]年龄 58[11]岁；129 例男性[88%]；130 例白人患者[88%]），随机接受 NP202（73[49.7%]）或安慰剂（74[50.3%]）治疗。两组基线 LVEF 相似。NP202 组患者基线时的 LVESVi（48.2mL/m2）大于安慰剂组（41.3mL/m2；P=0.03）。然而，两组之间的其他方面匹配良好。对于从基线到 3 个月时 LVESVi 的主要终点变化，安慰剂组（中位数[四分位距]变化，-0.60[-9.28 至 5.99]mL/m2）和 NP202 组（-3.53[-9.24 至 4.81]mL/m2）之间没有显著差异（P=0.78）。CMR 评估的次要疗效终点也没有差异。NP202 耐受良好，安全性特征可接受。两组之间的主要不良心脏和脑血管事件发生率相似。两组在随访期间各有 2 例死亡。
前壁 STEMI 经皮冠状动脉介入治疗后，残留 LV 功能障碍患者使用 NP202 治疗 3 个月，LV 重构并未改善。该药物安全且耐受良好。
ClinicalTrials.gov 标识符：NCT02557217。
