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老年心肌梗死患者的有创治疗
Invasive Treatment Strategy for Older Patients with Myocardial Infarction
背景
对于非ST段抬高型心肌梗死（NSTEMI）老年患者，单纯药物保守治疗与药物联合有创治疗哪个更有益，目前尚未明确。
Whether a conservative strategy of medical therapy alone or a strategy of medical therapy plus invasive treatment is more beneficial in older adults with non–ST-segment elevation myocardial infarction (NSTEMI) remains unclear.
方法
我们开展了一项前瞻性、多中心、随机试验，在英国48个研究中心纳入年龄≥75岁的NSTEMI患者。以1:1比例将患者随机分配接受保守治疗（采用最佳药物治疗）或有创治疗（冠状动脉造影和血运重建联合最佳药物治疗）。患者纳入标准为衰弱或合并症负担较重。主要结局是由心血管原因死亡或非致死性心肌梗死构成的复合结局，在至事件发生时间分析中进行评估。
We conducted a prospective, multicenter, randomized trial involving patients 75 years of age or older with NSTEMI at 48 sites in the United Kingdom. The patients were assigned in a 1:1 ratio to a conservative strategy of the best available medical therapy or an invasive strategy of coronary angiography and revascularization plus the best available medical therapy. Patients who were frail or had a high burden of coexisting conditions were eligible. The primary outcome was a composite of death from cardiovascular causes (cardiovascular death) or nonfatal myocardial infarction assessed in a time-to-event analysis.
结果
共计1518例患者接受随机分组，其中753人被分配到有创治疗组，765人被分配到保守治疗组。患者平均年龄为82岁，45%为女性，32%衰弱。在中位4.1年随访期间，有创治疗组193例患者（25.6%）和保守治疗组201例患者（26.3%）发生了主要结局事件（风险比，0.94；95%置信区间[CI]，0.77~1.14；P=0.53）。有创治疗组15.8%的患者和保守治疗组14.2%的患者发生了心血管原因死亡（风险比，1.11；95% CI，0.86~1.44）。有创治疗组11.7%的患者和保守治疗组15.0%的患者发生了非致死性心肌梗死（风险比，0.75；95% CI，0.57~0.99）。发生手术并发症的患者不到1%。
Result
A total of 1518 patients underwent randomization; 753 patients were assigned to the invasive-strategy group and 765 to the conservative-strategy group. The mean age of the patients was 82 years, 45% were women, and 32% were frail. A primary-outcome event occurred in 193 patients (25.6%) in the invasive-strategy group and 201 patients (26.3%) in the conservative-strategy group (hazard ratio, 0.94; 95% confidence interval [CI], 0.77 to 1.14; P=0.53) over a median follow-up of 4.1 years. Cardiovascular death occurred in 15.8% of the patients in the invasive-strategy group and 14.2% of the patients in the conservative-strategy group (hazard ratio, 1.11; 95% CI, 0.86 to 1.44). Nonfatal myocardial infarction occurred in 11.7% in the invasive-strategy group and 15.0% in the conservative-strategy group (hazard ratio, 0.75; 95% CI, 0.57 to 0.99). Procedural complications occurred in less than 1% of the patients.
结论
对于NSTEMI老年患者，在中位4.1年随访期间，与保守治疗相比，有创治疗并未显著降低心血管原因死亡或非致死性心肌梗死（复合主要结局）风险。（由英国心脏基金会[British Heart Foundation]资助；BHFSENIOR-RITA在ISRCTN注册号为ISRCTN11343602）。
Conclusions
In older adults with NSTEMI, an invasive strategy did not result in a significantly lower risk of cardiovascular death or nonfatal myocardial infarction (the composite primary outcome) than a conservative strategy over a median follow-up of 4.1 years. (Funded by the British Heart Foundation; BHF SENIOR-RITA ISRCTN Registry number, ISRCTN11343602.)
关于妊娠极早期药物流产的随机试验
Randomized Trial of Very Early Medication Abortion
背景
联用米非司酮和米索前列醇进行的药物流产非常有效并且安全。然而，目前尚无充分证据表明，在超声检查观察到妊娠囊之前，在妊娠极早期进行药物流产的有效性和安全性。
我们开展了一项多中心、非劣效性、随机对照试验，本试验纳入在妊娠42天以内要求进行药物流产的女性，并且超声检查未明确宫内妊娠（观察到空宫腔或者无卵黄囊或胚极的囊状结构）。参与者被随机分成两组，一组立即启动流产（早期启动组），另一组接受延迟至明确宫内妊娠之后的标准治疗（标准组）。主要结局是完全流产。非劣效性界值设定为组间绝对差异3.0个百分点。
Methods
We conducted a multicenter, noninferiority, randomized, controlled trial involving women requesting medication abortion at up to 42 days of gestation with an unconfirmed intrauterine pregnancy on ultrasound examination (visualized as an empty cavity or a sac-like structure without a yolk sac or embryonic pole). Participants were randomly assigned to either immediate start of abortion (early-start group) or standard-care treatment delayed until intrauterine pregnancy was confirmed (standard group). The primary outcome was complete abortion. The noninferiority margin was set at 3.0 percentage points for the absolute between-group difference.
九个国家26个试验中心共纳入1504名女性，她们被随机分配到早期启动组（754人）或标准组（750人）。在意向性治疗分析中，早期启动组710名参与者中的676人（95.2%）和标准组688名参与者中的656人（95.3%）完全流产；组间绝对差异为－0.1个百分点（95%置信区间，－2.4~2.1）。早期启动组741名参与者中的10人（1.3%）和标准组724名参与者中的6人（0.8%）发生了异位妊娠，其中一人在确诊前破裂（早期启动组）。早期启动组737名参与者中的12人（1.6%）和标准组718名参与者中的5人（0.7%）发生了严重不良事件（P=0.10）；其中大多数是因治疗异位妊娠或不完全流产而单纯住院患者。
Result
In total, 1504 women were included at 26 sites in nine countries and were randomly assigned to the early-start group (754 participants) or the standard group (750 participants). In an intention-to-treat analysis, a complete abortion occurred in 676 of 710 participants (95.2%) in the early-start group and in 656 of 688 (95.3%) in the standard group; the absolute between-group difference was −0.1 percentage points (95% confidence interval, −2.4 to 2.1). Ectopic pregnancies occurred in 10 of 741 participants (1.3%) in the early-start group and in 6 of 724 (0.8%) in the standard group, with one rupture before diagnosis (early-start group). Serious adverse events occurred in 12 of 737 participants (1.6%) in the early-start group and in 5 of 718 (0.7%) in the standard group (P=0.10); the majority were uncomplicated hospitalizations for treatment of ectopic pregnancy or incomplete abortion.
结论
在完全流产方面，在明确宫内妊娠之前进行药物流产不劣于标准的延迟治疗。（由瑞典研究理事会[Swedish Research Council]等资助；VEMA在EudraCT编号为2018-003675-35；在ClinicalTrials.gov注册号为NCT03989869）。
新辅助纳武利尤单抗联合伊匹木单抗治疗可切除Ⅲ期黑色素瘤
Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma
背景
在对可切除的肉眼可见Ⅲ期黑色素瘤患者进行的1~2期试验中，新辅助免疫疗法比辅助免疫疗法更有效。
在此项3期试验中，我们将可切除的肉眼可见Ⅲ期黑色素瘤患者随机分组，一组接受两个周期的伊匹木单抗联合纳武利尤单抗新辅助治疗，之后接受手术，另一组接受手术，之后接受12个周期的纳武利尤单抗辅助治疗。在新辅助治疗组中，只有达到部分缓解或未达到缓解的患者接受了辅助治疗。主要终点是无事件生存率。
Methods
In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. Only patients in the neoadjuvant group with a partial response or nonresponse received adjuvant treatment. The primary end point was event-free survival.
共计423例患者接受了随机分组。中位9.9个月随访时，新辅助治疗组的估计12个月无事件生存率为83.7%（99.9%置信区间[CI]，73.8~94.8），辅助治疗组为57.2%（99.9% CI，45.1~72.7）。限制性平均生存时间的差异为8.00个月（99.9% CI，4.94~11.05；P<0.001；进展、复发或死亡的风险比，0.32；99.9% CI，0.15~0.66）。在新辅助治疗组中，59.0%的患者达到了主要病理学缓解，8.0%达到了部分缓解，26.4%未达到缓解（残留存活肿瘤>50%），2.4%的患者疾病进展；4.2%的患者尚未进行手术或豁免手术。在新辅助治疗组中，以下人群的估计12个月无复发生存率如下：达到主要病理学缓解的患者为95.1%，达到部分缓解的患者为76.1%，未达到缓解的患者为57.0%。在新辅助治疗组和辅助治疗组中，分别有29.7%和14.7%的患者出现了与全身性治疗相关的3级或更高级别的不良事件。
Result
A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% in patients in the neoadjuvant group who had a major pathological response, 76.1% among those with a partial response, and 57.0% among those with a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of patients in the neoadjuvant group and in 14.7% in the adjuvant group.
结论
在可切除的肉眼可见Ⅲ期黑色素瘤患者中，与手术后跟纳武利尤单抗辅助治疗相比，伊匹木单抗联合纳武利尤单抗新辅助治疗后跟手术和应答情况驱动的辅助治疗延长了无事件生存期。（由百时美施贵宝公司等资助；NADINA在ClinicalTrials.gov注册号为NCT04949113）。
达拉非尼联合曲美替尼辅助治疗Ⅲ期黑色素瘤的最终结果
Total Hip Replacement or Resistance Training for Severe Hip Osteoarthritis
背景
本试验的5年结果表明，在BRAF V600突变的Ⅲ期黑色素瘤患者中，与安慰剂相比，达拉非尼联合曲美替尼辅助治疗延长了无复发生存期和无远处转移生存期。我们需要更长期数据，包括总生存期数据。
我们将870例切除术后BRAF V600突变的Ⅲ期黑色素瘤患者随机分组，一组接受为期12个月的达拉菲尼（150 mg，每天两次）联合曲美替尼（2 mg，每天一次）治疗，另一组接受两种匹配的安慰剂治疗。本文报告此项试验的最终结果，包括总生存期、黑色素瘤特异性生存期、无复发生存期和无远处转移生存期结果。
Methods
We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis–free survival.
达拉非尼联合曲美替尼组的中位随访时间为8.33年，安慰剂组为6.87年。达拉非尼联合曲美替尼组的总生存期Kaplan–Meier估计值优于安慰剂组，但获益并不显著（死亡风险比，0.80；95%置信区间[CI]，0.62~1.01；分层时序检验P=0.06）。在几个预设亚组中观察到一致生存获益，包括792例BRAF V600E突变的黑色素瘤患者（死亡风险比，0.75；95% CI，0.58~0.96）。达拉非尼联合曲美替尼组的无复发生存期优于安慰剂组（复发或死亡的风险比，0.52；95% CI，0.43~0.63），前者的无远处转移生存期也优于后者（远处转移或死亡的风险比，0.56；95% CI，0.44~0.71）。没有报告新的安全信号，这一结果与之前的试验报告一致。
Result
The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan–Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P=0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis–free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports.
结论
经过近10年随访，在切除术后Ⅲ期黑色素瘤患者中，达拉非尼联合曲美替尼辅助治疗的无复发生存期和无远处转移生存期均优于安慰剂治疗。总生存期的分析结果表明，联合疗法的死亡风险比安慰剂低20%，但获益并不显著。结果提示，在BRAF V600E突变的黑色素瘤患者中，联合疗法的死亡风险降低了25%。（由葛兰素史克公司和诺华公司资助；COMBI-AD在ClinicalTrials.gov注册号为NCT01682083；E在udraCT编号为2012-001266-15）。
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