Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Shinshu University Hospital, Matsumoto, Nagano, Japan.
JAMA Cardiol. 2019 May 1;4(5):466-472. doi: 10.1001/jamacardio.2019.0849.
Patients with cardiac amyloidosis demonstrate reduced myocardial strain with associated sparing of the cardiac apex. In the APOLLO randomized clinical trial, patisiran, an RNA interference therapeutic that inhibits transthyretin synthesis, improved left ventricular (LV) global longitudinal strain (LV GLS) compared with placebo in patients with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy and evidence of cardiac involvement.
To evaluate the treatment association of patisiran with regional LV myocardial strain in cardiac manifestation in hATTR amyloidosis.
DESIGN, SETTING, AND PARTICIPANTS: This exploratory analysis of APOLLO, a randomized, double-blind, placebo-controlled, phase 3, multicenter international clinical trial that was conducted from December 2013 to January 2016, included patients with hATTR amyloidosis with polyneuropathy who were randomized 2:1 to receive patisiran or placebo. The prespecified cardiac subpopulation (126 of 225 [56%]) comprised patients with a baseline LV wall thickness of 13 mm or more and no history of hypertension or aortic valve disease. This post hoc data analysis was performed between September 2018 and January 2019.
Placebo or patisiran, 0.3 mg/kg, via intravenous infusion once every 3 weeks for 18 months.
The association of patisiran with LV regional longitudinal strain at 18 months.
Of the 126 patients included in the prespecified cardiac subpopulation, 36 patients (28.6%) received placebo (median [interquartile range] age, 62 [57-72] years) and 90 patients (71.4%) received patisiran (median [interquartile range] age, 60 [54-66] years); 98 (77.8%) were men, 28 (22.2%) were from North America, and 43 (34.1%) were from Western Europe. At baseline, LV GLS was impaired and regional longitudinal strains were lowest in the basal segments with apical sparing. There were no differences in regional longitudinal strains between the treatment groups at baseline. Patisiran improved the absolute GLS (least-squares mean [SE] difference, 1.4% [0.6%]; 95% CI, 0.3%-2.5%; P = .02) compared with placebo at 18 months, with the greatest differential increase observed in the basal region (overall least-squares mean [SE] difference, 2.1% [0.8%]; 95% CI, 0.6%-3.6%; P = .006) and no significant differences in the mid and apical regions among groups.
Patisiran prevented the deterioration of LV GLS over 18 months, driven primarily by attenuating disease progression in the basal region, suggesting that basal longitudinal strain may be a more sensitive marker of treatment associations with the cardiac manifestation in hATTR amyloidosis and that basal region may be influenced by disease-modifying therapies more than other ventricular regions.
ClinicalTrials.gov identifier: NCT01960348.
患有心脏淀粉样变性的患者表现出心肌应变减少，伴有心尖的节段性保留。在 APOLLO 随机临床试验中，一种抑制转甲状腺素蛋白合成的 RNA 干扰疗法 patisiran，与安慰剂相比，改善了遗传性转甲状腺素介导（hATTR）淀粉样变性伴有多发性神经病和心脏受累证据患者的左心室（LV）整体纵向应变（LV GLS）。
评估 patisiran 在 hATTR 淀粉样变性心脏表现中的区域性 LV 心肌应变的治疗相关性。
设计、地点和参与者：这项对 APOLLO 的探索性分析是一项随机、双盲、安慰剂对照、多中心的 3 期国际临床试验，于 2013 年 12 月至 2016 年 1 月进行，包括患有 hATTR 淀粉样变性伴有多发性神经病的患者，他们以 2:1 的比例随机接受 patisiran 或安慰剂。预设的心脏亚组（225 例中的 126 例[56%]）包括基线 LV 壁厚度为 13mm 或以上且无高血压或主动脉瓣疾病史的患者。该事后数据分析于 2018 年 9 月至 2019 年 1 月进行。
安慰剂或 patisiran，0.3mg/kg，每 3 周静脉输注一次，共 18 个月。
18 个月时 patisiran 与 LV 节段性纵向应变的关联。
在预设的心脏亚组中，126 例患者中有 36 例（28.6%）接受安慰剂（中位数[四分位间距]年龄，62[57-72]岁），90 例（71.4%）接受 patisiran（中位数[四分位间距]年龄，60[54-66]岁）；98 例（77.8%）为男性，28 例（22.2%）来自北美，43 例（34.1%）来自西欧。基线时，LV GLS 受损，心尖段节段性纵向应变最低，心尖段保留。治疗组之间在基线时的节段性纵向应变无差异。与安慰剂相比，patisiran 在 18 个月时改善了绝对 GLS（最小二乘均值[SE]差异，1.4%[0.6%]；95%CI，0.3%-2.5%；P=0.02），在基底区域观察到最大的差异增加（总体最小二乘均值[SE]差异，2.1%[0.8%]；95%CI，0.6%-3.6%；P=0.006），各组之间中、心尖区域之间无显著差异。
patisiran 防止了 18 个月期间 LV GLS 的恶化，主要是通过减轻基底区域的疾病进展，这表明基底纵向应变可能是 hATTR 淀粉样变性心脏表现的治疗相关性的更敏感标志物，并且基底区域可能比其他心室区域更容易受到疾病修饰治疗的影响。
ClinicalTrials.gov 标识符：NCT01960348。
