2019年4月4日NEJM论著摘要

在使用药物预防静脉血栓的危重患者中，辅助间歇充气加压能否达到比单独药物预防更低的深静脉血栓形成发生率仍不确定。

本试验纳入按照参与中心当地标准（≥14、≥16或≥18岁）被视为成人的患者，我们在其入住重症监护病房（ICU）后48小时内进行随机分组，一组患者使用未分级或低分子量肝素预防血栓+每日至少18小时间歇充气加压（充气加压组），另一组患者单独使用药物预防血栓（对照组）。主要结局是新发下肢近端深静脉血栓形成，检测方式是随机分组后第三个日历日之后，每周进行2次下肢超声检查，直至患者离开ICU、死亡、实现完全活动或试验第28日（以先发生者为准）。

共有2003例患者被随机分组，其中991例被分配至充气加压组，1012例被分配至对照组。每日使用间歇充气加压的时间中位数时22小时（四分位距，21~23），使用间歇充气加压的天数中位数是7天（四分位距，4~13）。充气加压组957例患者中的37例（3.9%）和对照组985例患者中的41例（4.2%）发生了主要结局（相对危险度，0.93；95%置信区间[CI]，0.60~1.44；P=0.74）。充气加压组991例患者中的103例（10.4%）和对照组1012例患者中的95例（10.4%）发生了静脉血栓栓塞（肺栓塞或下肢深静脉血栓形成）（相对危险度，1.11；95% CI，0.85~1.44），分别有990例患者中的258例（26.1%）和1011例患者中的270例（26.7%）在90日时因任何原因死亡（相对危险度，0.98；95% CI，0.84~1.13）。

在使用药物预防血栓的危重患者中，辅助间歇充气加压未使下肢近端深静脉血栓形成发生率显著低于单独使用药物预防血栓的患者。（由阿卜杜拉阿齐兹国王科技城[King Abdulaziz City for Science and Technology]和阿卜杜拉国王国际医学研究中心[King Abdullah International Medical Research Center]资助；PREVENT在ClinicalTrials.gov注册号为NCT02040103；在Current Controlled Trials注册号为ISRCTN44653506。）

Yaseen M. Arabi, Fahad Al-Hameed, Karen E.A. Burns, et al. Adjunctive Intermittent Pneumatic Compression for Venous Thromboprophylaxis. DOI: 10.1056/NEJMoa1816150

甲状腺过氧化物酶抗体与流产和早产风险增加相关，即使孕妇的甲状腺功能正常。小规模试验表明，使用左甲状腺素可降低这些不良结局的发生率。

我们开展了一项双盲、安慰剂对照试验，目的是在有甲状腺过氧化物酶抗体并且有流产或不育史的甲状腺功能正常的女性中，研究左甲状腺素治疗可否提高活产率。英国49家医院的总共19,585名女性接受了甲状腺过氧化物酶抗体检测和甲状腺功能检查。我们将952名女性随机分组，分别接受每日1次、每次50 μg左甲状腺素治疗（476名女性）或接受安慰剂治疗（476名女性），治疗从受孕前持续至妊娠结束。主要结局是妊娠至少34周后活产。

主要结局的随访率为98.7%（952名女性中的940名）。共有左甲状腺素组470名女性中的266名（56.6%）和安慰剂组470名女性中的274名（58.3%）受孕。左甲状腺素组和安慰剂组的活产率分别为37.4%（470名女性中的176名）和37.9%（470名女性中的178名）（相对危险度，0.97；95%置信区间[CI]，0.83~1.14，P=0.74；绝对差异，-0.4个百分点；95% CI，-6.6~5.8）。其他妊娠结局（包括妊娠丢失或早产）或新生儿结局无显著组间差异。左甲状腺素组5.9%的女性和安慰剂组3.8%的女性发生了严重不良事件（P=0.14）。

与安慰剂相比，有甲状腺过氧化物酶抗体的甲状腺功能正常女性使用左甲状腺素未达到较高的活产率。（由英国国家健康研究所[United Kingdom National Institute for Health Research]资助；TABLET在Current Controlled Trials注册号为ISRCTN15948785。）

Rima K. Dhillon-Smith, Lee J. Middleton, Kirandeep K. Sunner, et al. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. DOI: 10.1056/NEJMoa1812537

Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors

andexanet alfa是人凝血因子Xa的重组改构非活性形式，开发用于逆转因子Xa抑制剂的作用。

我们评价了在给予因子Xa抑制剂后18小时内发生急性大出血的352例患者。患者接受了andexanet推注，随后接受了2小时输入。共同主要结局为andexanet治疗后抗因子Xa活性的变化百分比，以及在输入结束后12小时，止血效果根据预设标准被裁定为优秀或良好的患者百分比。本试验在被证实有大出血并且基线抗因子Xa活性至少为75 ng/mL（对于接受依诺肝素治疗的患者为≥0.25 IU/mL）的患者亚组中评估了疗效。

患者平均年龄为77岁，大多数患严重的心血管疾病。出血主要为颅内出血（227例患者[64%]）或胃肠出血（90例患者[26%]）。在接受阿哌沙班治疗的患者中，中位抗因子Xa活性从基线时的149.7 ng/mL降低至andexanet推注后的11.1 ng/mL（降低92%；95%置信区间[CI]，91~93）；在接受利伐沙班治疗的患者中，中位值从211.8 ng/mL降低至14.2 ng/mL（降低92%；95% CI，88~94）。在可评价的249例患者中，204例（82%）达到了优秀或良好止血。在30日内，49例患者（14%）死亡，34例（10%）发生了血栓性事件。抗因子Xa活性降低在总体患者中不能预测止血效果，但在颅内出血患者中能一定程度预测止血效果。

在发生因子Xa抑制剂相关急性大出血的患者中，andexanet治疗显著降低了抗因子Xa活性，并且根据预设标准，82%的患者在12小时达到优秀或良好的止血效果。（由Portola Pharmaceuticals资助；ANNEXA-4在ClinicalTrials.gov注册号为NCT02329327。）

Stuart J. Connolly, Mark Crowther, John W. Eikelboom, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. DOI: 10.1056/NEJMoa1814051

嗜酸细胞增多综合征是根据血液或组织嗜酸性粒细胞显著增多及嗜酸性粒细胞相关临床表现定义的一组疾病。benralizumab是人嗜酸性粒细胞表达的白细胞介素5受体α的单克隆抗体。

这项随机、双盲、安慰剂对照、2期试验纳入患PDGFRA阴性嗜酸细胞增多综合征并且嗜酸性粒细胞绝对计数至少为1000细胞/mm3的20例有症状患者，我们给患者每月3次皮下注射benralizumab（剂量为30 mg）或安慰剂；所有患者均正在接受针对该病的稳定治疗（药物或改变饮食）。采用这一治疗方案的治疗期结束后有一个开放标签阶段（此阶段可根据耐受情况逐渐降低患者背景治疗的剂量）和一个扩展阶段。随机试验阶段的主要终点是第12周时嗜酸性粒细胞绝对计数减少至少50%。

在随机试验阶段，benralizumab组发生主要终点的患者数量比安慰剂组多（10例患者中的9例[90%] vs. 10例患者中的3例[30%]，P=0.02）。在开放标签阶段，我们观察到19例患者中的17例（89%）有临床和血液学缓解，19例患者中有14例（74%）的缓解持续48周；在缓解持续48周的14例患者中，9例（64%）的背景治疗可以逐渐降低剂量。benralizumab还可抑制骨髓和组织嗜酸性粒细胞增多。在首剂benralizumab给药后，32%的患者发生了最常见的药物相关不良事件（头痛和乳酸脱氢酶水平升高），并且所有患者的这些事件均在48小时内消退。两组中其他不良事件的发生率相似。本试验分析了预测患者疾病缓解的许多潜在因素，其中只有临床疾病亚型似乎与初始缓解或复发相关。

在这项小规模2期试验中，与接受安慰剂治疗的PDGFRA阴性嗜酸细胞增多综合征患者相比，接受12周benralizumab治疗患者的嗜酸性粒细胞绝对计数较低。在开放标签阶段，74%患者的临床和血液学缓解持续48周。不良事件并未限制患者的治疗。（由美国国立过敏和传染病研究所[National Institute of Allergy and Infectious Diseases]资助；在ClinicalTrials.gov注册号为NCT00001406和NCT02130882。）

Fei Li Kuang, Fanny Legrand, Michelle Makiya, et al. Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome. DOI: 10.1056/NEJMoa1812185

Whether adjunctive intermittent pneumatic compression in critically ill patients receiving pharmacologic thromboprophylaxis would result in a lower incidence of deep-vein thrombosis than pharmacologic thromboprophylaxis alone is uncertain.

We randomly assigned patients who were considered adults according to the local standards at the participating sites (≥14, ≥16, or ≥18 years of age) within 48 hours after admission to an intensive care unit (ICU) to receive either intermittent pneumatic compression for at least 18 hours each day in addition to pharmacologic thromboprophylaxis with unfractionated or low-molecular-weight heparin (pneumatic compression group) or pharmacologic thromboprophylaxis alone (control group). The primary outcome was incident (i.e., new) proximal lower-limb deep-vein thrombosis, as detected on twice-weekly lower-limb ultrasonography after the third calendar day since randomization until ICU discharge, death, attainment of full mobility, or trial day 28, whichever occurred first.

A total of 2003 patients underwent randomization — 991 were assigned to the pneumatic compression group and 1012 to the control group. Intermittent pneumatic compression was applied for a median of 22 hours (interquartile range, 21 to 23) daily for a median of 7 days (interquartile range, 4 to 13). The primary outcome occurred in 37 of 957 patients (3.9%) in the pneumatic compression group and in 41 of 985 patients (4.2%) in the control group (relative risk, 0.93; 95% confidence interval [CI], 0.60 to 1.44; P=0.74). Venous thromboembolism (pulmonary embolism or any lower-limb deep-vein thrombosis) occurred in 103 of 991 patients (10.4%) in the pneumatic compression group and in 95 of 1012 patients (9.4%) in the control group (relative risk, 1.11; 95% CI, 0.85 to 1.44), and death from any cause at 90 days occurred in 258 of 990 patients (26.1%) and 270 of 1011 patients (26.7%), respectively (relative risk, 0.98; 95% CI, 0.84 to 1.13).

Among critically ill patients who were receiving pharmacologic thromboprophylaxis, adjunctive intermittent pneumatic compression did not result in a significantly lower incidence of proximal lower-limb deep-vein thrombosis than pharmacologic thromboprophylaxis alone. (Funded by King Abdulaziz City for Science and Technology and King Abdullah International Medical Research Center; PREVENT ClinicalTrials.gov number, NCT02040103; Current Controlled Trials number, ISRCTN44653506.)

Yaseen M. Arabi, Fahad Al-Hameed, Karen E.A. Burns, et al. Adjunctive Intermittent Pneumatic Compression for Venous Thromboprophylaxis. DOI: 10.1056/NEJMoa1816150

Thyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes.

We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 μg once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation.

The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P=0.74; absolute difference, −0.4 percentage points; 95% CI, −6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P=0.14).

The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. (Funded by the United Kingdom National Institute for Health Research; TABLET Current Controlled Trials number, ISRCTN15948785.)

Rima K. Dhillon-Smith, Lee J. Middleton, Kirandeep K. Sunner, et al. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. DOI: 10.1056/NEJMoa1812537

Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors

Background Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors.

We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti–factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti–factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin).

Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti–factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti–factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage.

In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti–factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.)

Stuart J. Connolly, Mark Crowther, John W. Eikelboom, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. DOI: 10.1056/NEJMoa1814051

Hypereosinophilic syndrome is a group of diseases defined by marked eosinophilia in blood or tissue and eosinophil-related clinical manifestations. Benralizumab is a monoclonal antibody against interleukin-5 receptor α, which is expressed on human eosinophils.

In this randomized, double-blind, placebo-controlled, phase 2 trial, we administered a series of three monthly subcutaneous injections of either benralizumab (at a dose of 30 mg) or placebo in 20 symptomatic patients who had PDGFRA-negative hypereosinophilic syndrome and an absolute eosinophil count of at least 1000 cells per cubic millimeter; all the patients were receiving stable therapy (drugs or dietary changes) for this disease. This regimen was followed by an open-label phase, during which the patient’s background therapy could be tapered as tolerated, and an extension phase. The primary end point of the randomized phase was a reduction of at least 50% in the absolute eosinophil count at week 12.

During the randomized phase, the primary end point occurred in more patients in the benralizumab group than in the placebo group (9 of 10 patients [90%] vs. 3 of 10 patients [30%], P=0.02). During the open-label phase, clinical and hematologic responses were observed in 17 of 19 patients (89%) and were sustained for 48 weeks in 14 of 19 patients (74%); in the latter group, in 9 of 14 patients (64%), background therapies could be tapered. Bone marrow and tissue eosinophilia were also suppressed with benralizumab therapy. The most common drug-related adverse events, headache and an elevated lactate dehydrogenase level, occurred in 32% of the patients after the first dose of benralizumab and resolved within 48 hours in all patients. Other adverse events occurred with similar frequency in the two groups. Of the many potential predictors of response that were examined, only clinical disease subtype appeared to be associated with the initial response or relapse.

In this small phase 2 trial, patients with PDGFRA-negative hypereosinophilic syndrome who received benralizumab for 12 weeks had lower absolute eosinophil counts than those who received placebo. During the open-label phase, clinical and hematologic responses were sustained for 48 weeks in 74% of the patients. Adverse events did not limit treatment. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov numbers, NCT00001406 and NCT02130882.)

Fei Li Kuang, Fanny Legrand, Michelle Makiya, et al. Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome. DOI: 10.1056/NEJMoa1812185

点击“阅读原文” 第一时间获得NEJM最新论著摘要