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Infliximab, Azathioprine, or Combination Therapy f

(2010-04-15 15:35:37)
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杂谈

Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease

ABSTRACT

 背景  在克罗恩病患者中,英夫利西单抗和硫唑嘌呤单药治疗或联合治疗的相对疗效和安全性尚未被了解。 

Background The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for Crohn's disease are unknown.

方法  在这项随机、双盲临床试验中,我们在508例有中至重度克罗恩病,以前没有接受过免疫抑制治疗或生物治疗的患者中,评估英夫利西单抗单药治疗、硫唑嘌呤单药治疗以及两种药物联合治疗的疗效。病人被随机分组,第1组在0、2和6周时接受静脉滴注英夫利西单抗5 mg/kg体重,以后每8周静脉滴注1次,外加每天口服安慰剂胶囊;第2组每天口服硫唑嘌呤2.5 mg/kg,外加按照标准方案滴注安慰剂;第3组接受两药联合治疗。病人接受研究药物治疗30周,并可继续留在盲法扩展研究中直至50周。

Methods In this randomized, double-blind trial, we evaluated the efficacy of infliximab monotherapy, azathioprine monotherapy, and the two drugs combined in 508 adults with moderate-to-severe Crohn's disease who had not undergone previous immunosuppressive or biologic therapy. Patients were randomly assigned to receive an intravenous infusion of 5 mg of infliximab per kilogram of body weight at weeks 0, 2, and 6 and then every 8 weeks plus daily oral placebo capsules; 2.5 mg of oral azathioprine per kilogram daily plus a placebo infusion on the standard schedule; or combination therapy with the two drugs. Patients received study medication through week 30 and could continue in a blinded study extension through week 50.

结果  在接受联合治疗的169例病人中,96例(56.8%)在26周时处于无需使用皮质类固醇的临床缓解状态(主要终点),相比之下,在接受英夫利西单抗单药治疗的169例病人中有75例(44.4%)达到主要终点(P=0.02),在接受硫唑嘌呤单药治疗的170例病人中有51例(30.0%)达到主要终点(与联合治疗相比,P<0.001,与英夫利西单抗治疗相比,P=0.006)。50周时的数值有相似的趋势。26周时,出现黏膜愈合的病例数在接受联合治疗的107例病人中有47例(43.9%),相比之下,在接受英夫利西单抗的93例病人中有28例(30.1%,P=0.06),在接受硫唑嘌呤的109例病人中有18例(16.5%,与联合治疗组相比,P<0.001,与英夫利西单抗组相比,P=0.02)。严重感染的发生率在联合治疗组中为3.9%,在英夫利西单抗组中为4.9%以及在硫唑嘌呤组中为5.6%。

Results Of the 169 patients receiving combination therapy, 96 (56.8%) were in corticosteroid-free clinical remission at week 26 (the primary end point), as compared with 75 of 169 patients (44.4%) receiving infliximab alone (P=0.02) and 51 of 170 patients (30.0%) receiving azathioprine alone (P<0.001 for the comparison with combination therapy and P=0.006 for the comparison with infliximab). Similar numerical trends were found at week 50. At week 26, mucosal healing had occurred in 47 of 107 patients (43.9%) receiving combination therapy, as compared with 28 of 93 patients (30.1%) receiving infliximab (P=0.06) and 18 of 109 patients (16.5%) receiving azathioprine (P<0.001 for the comparison with combination therapy and P=0.02 for the comparison with infliximab). Serious infections developed in 3.9% of patients in the combination-therapy group, 4.9% of those in the infliximab group, and 5.6% of those in the azathioprine group.

结论  有中至重度克罗恩病并接受了英夫利西单抗加硫唑嘌呤或英夫利西单抗单药治疗的病人,比接受硫唑嘌呤单药治疗的病人更可能达到无需使用皮质类固醇的临床缓解状态。

Conclusions Patients with moderate-to-severe Crohn's disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy.

用维生素C和维生素E预防妊娠性高血压的并发症
Vitamins C and E to Prevent Complications of Pregnancy-Associated Hypertension

背景 胎盘灌注差是先兆子痫的特征,有人提出氧化应激是将胎盘灌注差与该病的临床表现相联系的一种机制。我们评估了在妊娠早期就开始补充抗氧化剂维生素C和维生素E,对与妊娠性高血压相关的母亲、胎儿和新生儿严重不良转归危险的影响。 

Background Oxidative stress has been proposed as a mechanism linking the poor placental perfusion characteristic of preeclampsia with the clinical manifestations of the disorder. We assessed the effects of antioxidant supplementation with vitamins C and E, initiated early in pregnancy, on the risk of serious adverse maternal, fetal, and neonatal outcomes related to pregnancy-associated hypertension.

 

方法 我们进行了一项多中心、随机、双盲试验,纳入先兆子痫危险低的未经产妇女。这些妇女被随机分为两组,一组在妊娠9~16周时开始每日补充1000 mg维生素C和400 IU维生素E,另一组服用匹配的安慰剂。主要转归是单纯的严重妊娠性高血压,或者有严重或轻度高血压伴肝酶水平升高、血小板减少、血清肌酐水平升高、子痫发作、有医学指征的早产、胎儿生长受限或围生期死亡。 

Methods We conducted a multicenter, randomized, double-blind trial involving nulliparous women who were at low risk for preeclampsia. Women were randomly assigned to begin daily supplementation with 1000 mg of vitamin C and 400 IU of vitamin E or matching placebo between the 9th and 16th weeks of pregnancy. The primary outcome was severe pregnancy-associated hypertension alone or severe or mild hypertension with elevated liver-enzyme levels, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, medically indicated preterm birth, fetal-growth restriction, or perinatal death.

 

 

  结果 共10154名妇女接受了随机分组。两组之间在基线特征和对研究药物的依从性方面相似。9969名妇女有转归资料。维生素组与安慰剂组之间在主要转归的发生率[分别为6.1%和5.7%,维生素组的相对危险为1.07,95%可信区间(CI)为0.91~1.25],或先兆子痫的发生率(分别为7.2%和6.7%,相对危险为1.07,95%CI为0.93~1.24)方面没有显著差异。两组之间的围生期不良转归发生率无显著差异。

Results A total of 10,154 women underwent randomization. The two groups were similar with respect to baseline characteristics and adherence to the study drug. Outcome data were available for 9969 women. There was no significant difference between the vitamin and placebo groups in the rates of the primary outcome (6.1% and 5.7%, respectively; relative risk in the vitamin group, 1.07; 95% confidence interval [CI], 0.91 to 1.25) or in the rates of preeclampsia (7.2% and 6.7%, respectively; relative risk, 1.07; 95% CI, 0.93 to 1.24). Rates of adverse perinatal outcomes did not differ significantly between the groups.

结论 在1个未经选择的低危、未经产妇女队列中,在妊娠9~16周时开始补充维生素C和维生素E,没有降低与妊娠性高血压相关的母亲或围生期不良转归的发生率。 

 

Conclusions Vitamin C and E supplementation initiated in the 9th to 16th week of pregnancy in an unselected cohort of low-risk, nulliparous women did not reduce the rate of adverse maternal or perinatal outcomes related to pregnancy-associated hypertension

在房颤病人中温和与严格心率控制的比较
Lenient versus Strict Rate Control in Patients with Atrial Fibrillation

  背景 心率控制经常是房颤的首选疗法。指南建议严格控制(患者的)心率,但这不是以临床证据为基础的。我们假设,在有永久性房颤的病人中,在预防心血管并发症和死亡方面,温和的心率控制不劣于严格的心率控制。

Background Rate control is often the therapy of choice for atrial fibrillation. Guidelines recommend strict rate control, but this is not based on clinical evidence. We hypothesized that lenient rate control is not inferior to strict rate control for preventing cardiovascular morbidity and mortality in patients with permanent atrial fibrillation.

 方法 我们将614例有永久性房颤的病人随机分为两组:一组采用温和的心率控制策略(静息时心率<110次/分),另一组采用严格的心率控制策略(静息时心率<80次/分,以及进行中等强度运动时心率<110次/分)。主要复合转归是心血管原因所致死亡,因心力衰竭住院,以及卒中、全身性栓塞、出血和危及生命的心律失常事件。随访持续时间至少2年,最长为3年。

Methods We randomly assigned 614 patients with permanent atrial fibrillation to undergo a lenient rate-control strategy (resting heart rate <110 beats per minute) or a strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years.

结果 3年时估计的主要转归累计发生率,在温和(心率)控制组为12.9%,以及在严格控制组为14.9%,就温和控制组而言的绝对差为-2.0个百分点(90%可信区间为-7.6 3.5,对于事先规定的非劣效性界限,P<0.001)。两组中主要转归成分的发生率相似。温和控制组中达到心率目标值的病人较多[304例(97.7%)对严格控制组中的203例(67.0%),P<0.001],而且总的就诊次数较少[75次(中位数为0次)对684次(中位数为2次),P<0.001]。两组中的症状和不良事件发生频次相似。

Results The estimated cumulative incidence of the primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group, with an absolute difference with respect to the lenient-control group of –2.0 percentage points (90% confidence interval, –7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets (304 [97.7%], vs. 203 [67.0%] in the strict-control group; P<0.001) with fewer total visits (75 [median, 0], vs. 684 [median, 2]; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups.

结论 在有永久性房颤的病人中,温和的心率控制与严格的心率控制一样有效,而且更容易实现。

Conclusions In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve.

 

置入药物洗脱支架后双重抗血小板疗法的持续时间
Duration of Dual Antiplatelet Therapy after Implantation of Drug-Eluting Stents

 

背景  在接受药物洗脱支架的病人中,使用双重抗血小板疗法超过12个月的潜在益处和危险还未得到确定。 

ABSTRACT

Background The potential benefits and risks of the use of dual antiplatelet therapy beyond a 12-month period in patients receiving drug-eluting stents have not been clearly established.

 

方法  在两项试验中,我们将总共2701例患者随机分为两组:一组接受氯吡格雷加阿司匹林治疗,另一组单纯接受阿司匹林治疗。这些患者曾接受过药物洗脱支架治疗,并且已至少12个月无严重的不良心脏事件或脑血管事件以及严重出血。主要复合终点是心肌梗死或心脏原因所致死亡。两项试验的数据被合并用于分析。 

Methods In two trials, we randomly assigned a total of 2701 patients who had received drug-eluting stents and had been free of major adverse cardiac or cerebrovascular events and major bleeding for a period of at least 12 months to receive clopidogrel plus aspirin or aspirin alone. The primary end point was a composite of myocardial infarction or death from cardiac causes. Data from the two trials were merged for analysis.

 

结果   随访时间的中位数是19.2个月。2年时主要转归的累计危险在使用双重抗血小板疗法组中为1.8%,相比之下,在采用阿司匹林单药治疗组中为1.2%[风险比为1.65,95%可信区间(CI)为0.80 3.36,P 0.17]。心肌梗死、卒中、支架置入后血栓形成、需要再次血运重建、严重出血和任何原因所致死亡的单个危险,在两组之间没有显著差异。然而,与单纯阿司匹林组相比,双重治疗组中心肌梗死、卒中或任何原因所致死亡的复合危险(风险比为1.73,95%CI为0.99 3.00,P 0.051),以及心肌梗死、卒中或心脏原因所致死亡的复合危险(风险比为1.84,95%CI为0.99 3.45,P 0.06)均有所增加,但没有(统计学)显著性。 

Results The median duration of follow-up was 19.2 months. The cumulative risk of the primary outcome at 2 years was 1.8% with dual antiplatelet therapy, as compared with 1.2% with aspirin monotherapy (hazard ratio, 1.65; 95% confidence interval [CI], 0.80 to 3.36; P=0.17). The individual risks of myocardial infarction, stroke, stent thrombosis, need for repeat revascularization, major bleeding, and death from any cause did not differ significantly between the two groups. However, in the dual-therapy group as compared with the aspirin-alone group, there was a nonsignificant increase in the composite risk of myocardial infarction, stroke, or death from any cause (hazard ratio, 1.73; 95% CI, 0.99 to 3.00; P=0.051) and in the composite risk of myocardial infarction, stroke, or death from cardiac causes (hazard ratio, 1.84; 95% CI, 0.99 to 3.45; P=0.06).

 

  结论 在曾接受药物洗脱支架的病人中,使用双重抗血小板治疗的时间长于12个月,在降低心肌梗死发生率或心脏原因所致死亡率方面,不比阿司匹林单药疗法显著更有效。这些结果应通过有长期随访的、更大型的随机试验来加以证实或反驳。 

Conclusions The use of dual antiplatelet therapy for a period longer than 12 months in patients who had received drug-eluting stents was not significantly more effective than aspirin monotherapy in reducing the rate of myocardial infarction or death from cardiac causes. These findings should be confirmed or refuted through larger, randomized clinical trials with longer-term follow-up.

Telaprevir治疗既往经治的慢性HCV感染
Telaprevir for Previously Treated Chronic HCV Infection

  背景  有基因1型丙型肝炎病毒(HCV)感染,但对聚乙二醇干扰素α和利巴韦林疗法没有持续应答的病人,复治成功的可能性低。 

Background Patients with genotype 1 hepatitis C virus (HCV) who do not have a sustained response to therapy with peginterferon alfa and ribavirin have a low likelihood of success with retreatment.

 

方法 我们将有基因1型HCV(感染),接受聚乙二醇干扰素α-利巴韦林治疗后未曾产生持续病毒学应答的病人,随机分配到下述四个治疗组之一:T12PR24组115例病人,接受telaprevir(负荷剂量为1125 mg,然后每8小时750 mg)治疗12周,以及聚乙二醇干扰素α-2a(每周180 μg)和利巴韦林(根据体重使用1000 mg/d或1200 mg/d)治疗24周;T24PR48组113例病人,接受telaprevir治疗 24周以及聚乙二醇干扰素α-2a和利巴韦林治疗48周(剂量同T12PR24组);T24P24组111例病人,接受telaprevir和聚乙二醇干扰素α-2a治疗24周(剂量同T12PR24组); PR48(或对照)组114例病人,接受聚乙二醇干扰素α-2a和利巴韦林治疗48周(剂量同T12PR24组)。主要终点是持续病毒学应答(在使用最后一剂研究药物后24周,检测不到HCV RNA水平)。 

Methods We randomly assigned patients with HCV genotype 1 who had not had a sustained virologic response after peginterferon alfa–ribavirin therapy to one of four treatment groups: 115 patients to the T12PR24 group, receiving telaprevir (1125-mg loading dose, then 750 mg every 8 hours) for 12 weeks and peginterferon alfa-2a (180 µg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 24 weeks; 113 patients to the T24PR48 group, receiving telaprevir for 24 weeks and peginterferon alfa-2a and ribavirin for 48 weeks (at the same doses as in the T12PR24 group); 111 patients to the T24P24 group, receiving telaprevir and peginterferon alfa-2a for 24 weeks (at the same doses as in the T12PR24 group); and 114 patients to the PR48 (or control) group, receiving peginterferon alfa-2a and ribavirin for 48 weeks (at the same doses as in the T12PR24 group). The primary end point was sustained virologic response (undetectable HCV RNA levels 24 weeks after the last dose of study drugs).

 

结果 3个telaprevir组的持续病毒学应答率—— T12PR24组51%,T24PR48组53%,以及T24P24组24%——均显著高于对照组的该比率(14%,分别为P<0.001、P<0.001和P=0.02)。既往曾经复发病人中的应答率,高于无应答者中的应答率。Telaprevir组中最常见的不良事件之一是皮疹(总体上看,发生于51%的病人,其中5%为严重皮疹)。因不良事件而停用研究药物的病例,在telaprevir组比在对照组更常见(15%对4%)。 

Results The rates of sustained virologic response in the three telaprevir groups — 51% in the T12PR24 group, 53% in the T24PR48 group, and 24% in the T24P24 group — were significantly higher than the rate in the control group (14%; P<0.001, P<0.001, and P=0.02, respectively). Response rates were higher among patients who had previously had relapses than among nonresponders. One of the most common adverse events in the telaprevir groups was rash (overall, occurring in 51% of patients, with severe rash in 5%). Discontinuation of study drugs because of adverse events was more frequent in the telaprevir groups than in the control group (15% vs. 4%).

 

  结论 在最初聚乙二醇干扰素α和利巴韦林治疗失败的HCV感染病人中,用telaprevir联合聚乙二醇干扰素α-2a和利巴韦林进行复治,比单用聚乙二醇干扰素α-2a和利巴韦林进行复治更有效。

Conclusions In HCV-infected patients in whom initial peginterferon alfa and ribavirin treatment failed, retreatment with telaprevir in combination with peginterferon alfa-2a and ribavirin was more effective than retreatment with peginterferon alfa-2a and ribavirin alone.

 

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