活化型重组人组织型纤溶酶原激活物治疗严重脓毒症的有效性和安全性：一项荟萃分析和元回归研究。

Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression.

机构信息

Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5400, USA.

出版信息

Lancet Infect Dis. 2012 Sep;12(9):678-86. doi: 10.1016/S1473-3099(12)70157-3. Epub 2012 Jul 17.

DOI:10.1016/S1473-3099(12)70157-3

PMID:22809883

Abstract

BACKGROUND

Drotrecogin alfa (activated) was approved for use in severe sepsis in 2001 on the basis of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, but controversies about its effectiveness remain. We aimed to assess effectiveness and safety of use of this drug in the past 10 years and compare them with the original PROWESS results.

METHODS

We searched PubMed, Embase, Ovid, Cochrane Library, Evidence-Based Medicine, and the American College of Physicians Journal Club databases for experimental and analytical studies of drotrecogin alfa (activated) in adults with severe sepsis until Jan 31, 2012. We calculated adjusted risk ratios for effectiveness and safety outcomes with random-effects models. We did a metaregression to assess the effect of severity of illness on the risk of death and the risk of bleeding associated with drotrecogin alfa (activated).

FINDINGS

We included nine controlled trials (41,401 patients) and 16 single-group studies (5822 patients) in effectiveness analyses and 20 studies (8245 patients) in safety analyses. Hospital mortality was reduced by 18% with drotrecogin alfa (activated) compared with controls (relative risk 0·822, 95% CI 0·779-0·867; p<0·0001; I(2)=40%). This mortality reduction was much the same as was noted in PROWESS (0·851, 0·740-0·979), but smaller than that of patients in PROWESS with high disease severity (0·708, 0·590-0·849). Propensity-adjusted studies also showed a significant mortality reduction with lower heterogeneity (0·844, 0·800-0·891; p<0·0001, I(2)=18%). These findings were not changed by the addition of PROWESS-SHOCK results. Metaregression showed greater benefits of drotrecogin alfa (activated) with increasing control mortality (p=0·01) and more severe disease (p=0·04). Hospital mortality for single-group studies of drotrecogin alfa (activated) was 41% (95% CI 35-48), and was higher than that noted in PROWESS at 31% (27-36; p<0·0001). The serious bleeding rate with drotrecogin alfa (activated) was 5·6% (4·5-6·9), which was higher than the 3·5% (2·5-5·0) noted in PROWESS (p=0·003), but similar to that reported in PROWESS high disease severity (p=0·073).

INTERPRETATION

Real-life use of drotrecrogin alfa (activated) was associated with significant reduction in hospital mortality and increased rates of bleeding in patients with severe sepsis. Our effectiveness findings were in line with the PROWESS trial but not with the PROWESS-SHOCK trial.

FUNDING

None.

摘要

背景

基于重组人活化蛋白 C 对严重脓毒症的全球评估（PROWESS）试验，drotrecogin alfa（激活）于 2001 年被批准用于严重脓毒症，但其疗效仍存在争议。我们旨在评估过去 10 年中该药物的有效性和安全性，并将其与原始 PROWESS 结果进行比较。

方法

我们在 PubMed、Embase、Ovid、Cochrane 图书馆、循证医学和美国医师学会杂志俱乐部数据库中搜索了成人严重脓毒症中 drotrecogin alfa（激活）的实验和分析性研究，直到 2012 年 1 月 31 日。我们使用随机效应模型计算了有效性和安全性结局的调整风险比。我们进行了荟萃回归分析，以评估疾病严重程度对 drotrecogin alfa（激活）相关死亡率和出血风险的影响。

结果

我们在有效性分析中纳入了 9 项对照试验（41401 例患者）和 16 项单组研究（5822 例患者），在安全性分析中纳入了 20 项研究（8245 例患者）。与对照组相比，drotrecogin alfa（激活）治疗可使住院死亡率降低 18%（相对风险 0.822，95%CI 0.779-0.867；p<0.0001；I²=40%）。这种死亡率降低与 PROWESS 中观察到的死亡率降低（0.851，0.740-0.979）非常相似，但小于 PROWESS 中疾病严重程度高的患者（0.708，0.590-0.849）。倾向调整研究也显示出显著的死亡率降低，异质性更低（0.844，0.800-0.891；p<0.0001，I²=18%）。加入 PROWESS-SHOCK 结果后，这些发现并未改变。荟萃回归显示，随着对照组死亡率的增加（p=0.01）和疾病严重程度的增加（p=0.04），drotrecogin alfa（激活）的获益更大。单组研究中 drotrecogin alfa（激活）的住院死亡率为 41%（95%CI 35-48），高于 PROWESS 中的 31%（27-36；p<0.0001）。drotrecogin alfa（激活）的严重出血率为 5.6%（4.5-6.9），高于 PROWESS 中的 3.5%（2.5-5.0）（p=0.003），但与 PROWESS 中严重疾病的报告相似（p=0.073）。