Department of Anesthesiology and Critical Care, HUPNVS, Hôpital Beaujon, APHP, 92110, Clichy, France.
Paris Diderot University, Paris, France.
Crit Care. 2017 Jun 27;21(1):162. doi: 10.1186/s13054-017-1755-5.
Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) are often selected for randomized clinical trials (RCTs) aiming at new drug approval. Guidelines for the design of such RCTs have been repeatedly updated by regulatory agencies. We hypothesized that large variability in the enrolled populations, the endpoints assessed and the HAP/VAP definition criteria may impact the results of these studies, and addressed this through a systematic review of HAP/VAP RCTs.
A search (Pubmed-Embase-ICAAC-ECCMID) of all RCTs published between 1994 and 2016 comparing antimicrobial treatment for HAP/VAP in the intensive care unit was conducted. The populations enrolled, inclusion/exclusion criteria, statistical design and endpoints assessed were recorded. All unpublished RCTs recorded on the ClinicalTrials.gov registry were also screened.
From the 93 abstracts reviewed, 39 potentially relevant studies were inspected, leading to 27 studies being included. As expected, illness severity or the proportion with VAP (27-100%) differed greatly among the enrolled populations. The HAP/VAP definition used various clinical and biological criteria, and only 55% of studies required a microbiological sample. The mandatory duration of prior hospital stay was variable; the mechanical ventilation duration was an inclusion criterion in only 41% of VAP studies. Nine studies had non-inferiority design, but nine studies (33%) did not have a pre-specified statistical hypothesis. Clinical cure was the primary endpoint in 24 studies, but was recorded in several populations or as the co-primary endpoint in 13 studies. The definition of clinical cure and the timing of its assessment greatly differed. This variability slightly improved over time but remained significant in the 13 registered but currently unpublished RCTs that we screened.
Our study provides a description of populations and endpoints of RCTs evaluating antimicrobials for treatment of HAP/VAP in the ICU. There was significant heterogeneity in enrollment criteria, endpoints and statistical design, which may influence the ability of studies to demonstrate differences between studied drugs.
医院获得性肺炎（HAP）和呼吸机相关性肺炎（VAP）通常被选择用于旨在获得新药批准的随机临床试验（RCT）。监管机构已多次更新此类 RCT 的设计指南。我们假设，纳入人群、评估终点和 HAP/VAP 定义标准的较大差异可能会影响这些研究的结果，并通过对 HAP/VAP RCT 的系统评价来解决这一问题。
对 1994 年至 2016 年期间在 Pubmed-Embase-ICAAC-ECCMID 上发表的所有比较 ICU 中 HAP/VAP 抗菌治疗的 RCT 进行了检索。记录纳入人群、纳入/排除标准、统计设计和评估的终点。还筛选了 ClinicalTrials.gov 注册中心记录的所有未发表的 RCT。
从审查的 93 篇摘要中，检查了 39 项潜在相关研究，最终纳入了 27 项研究。正如预期的那样，纳入人群的疾病严重程度或 VAP 比例（27%-100%）差异很大。所使用的 HAP/VAP 定义采用了各种临床和生物学标准，只有 55%的研究需要微生物样本。先前住院时间的强制性持续时间是可变的；只有 41%的 VAP 研究将机械通气时间作为纳入标准。9 项研究采用非劣效性设计，但 9 项研究（33%）没有预先指定的统计假设。临床治愈率是 24 项研究的主要终点，但在 13 项研究中，它在多个人群中被记录或作为共同主要终点。临床治愈率的定义及其评估时间有很大差异。这种变异性随时间略有改善，但在我们筛选的 13 项已注册但目前未发表的 RCT 中仍然显著。
本研究提供了 ICU 中评估抗菌药物治疗 HAP/VAP 的 RCT 纳入人群和终点的描述。纳入标准、终点和统计设计存在显著异质性，这可能会影响研究证明研究药物之间差异的能力。
