Sackler Faculty of Medicine, Tel Aviv University, Ramat-Aviv, Tel Aviv, Israel.
Department of Medicine E, Rabin Medical Center, Beilinson Hospital, Jebotinski 39, Petah Tikva, Israel.
BMC Infect Dis. 2021 Mar 31;21(1):309. doi: 10.1186/s12879-021-05995-y.
Population external validity is the extent to which an experimental study results can be generalized from a specific sample to a defined population. In order to apply the results of a study, we should be able to assess its population external validity. We performed an investigator-initiated randomized controlled trial (RCT) (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria. In order to examine the study's population external validity and to substantiate the use of AIDA study results in clinical practice, we performed a concomitant observational trial.
The study was conducted between October 1st, 2013 and January 31st, 2017 (during the RCTs recruitment period) in Greece, Israel and Italy. Patients included in the observational arm of the study have fulfilled clinical and microbiological inclusion criteria but were excluded from the RCT due to receipt of colistin for > 96 h, refusal to participate, or prior inclusion in the RCT. Non-randomized cases were compared to randomized patients. The primary outcome was clinical failure at 14 days of infection onset.
Analysis included 701 patients. Patients were infected mainly with Acinetobacter baumannii [78.2% (548/701)]. The most common reason for exclusion was refusal to participate [62% (183/295)]. Non-randomized and randomized patients were similar in most of the demographic and background parameters, though randomized patients showed minor differences towards a more severe infection. Combination therapy was less common in non-randomized patients [31.9% (53/166) vs. 51.2% (208/406), p = 0.000]. Randomized patients received longer treatment of colistin [13 days (IQR 10-16) vs. 8.5 days (IQR 0-15), p = 0.000]. Univariate analysis showed that non-randomized patients were more inclined to clinical failure on day 14 from infection onset [82% (242/295) vs. 75.5% (307/406), p = 0.042]. After adjusting for other variables, non-inclusion was not an independent risk factor for clinical failure at day 14.
The similarity between the observational arm and RCT patients has strengthened our confidence in the population external validity of the AIDA trial. Adding an observational arm to intervention studies can help increase the population external validity and improve implementation of study results in clinical practice.
The trial was registered with ClinicalTrials.gov, number NCT01732250 on November 22, 2012.
人群外部有效性是指从特定样本推广到特定人群的实验研究结果的程度。为了应用研究结果，我们应该能够评估其人群外部有效性。我们进行了一项由研究者发起的随机对照试验（RCT）（AIDA 研究），比较了黏菌素-美罗培南联合治疗与黏菌素单药治疗感染碳青霉烯类耐药革兰氏阴性菌的患者。为了检验研究的人群外部有效性，并证实 AIDA 研究结果在临床实践中的应用，我们进行了一项伴随的观察性试验。
该研究于 2013 年 10 月 1 日至 2017 年 1 月 31 日进行（在 RCT 招募期间），在希腊、以色列和意大利进行。纳入观察臂的患者符合临床和微生物学纳入标准，但由于接受黏菌素治疗 >96 小时、拒绝参与或先前纳入 RCT 而被排除在外。非随机病例与随机患者进行比较。主要结局是感染发病后 14 天的临床失败。
分析纳入了 701 例患者。患者主要感染鲍曼不动杆菌[78.2%（548/701）]。最常见的排除原因是拒绝参与[62%（183/295）]。非随机和随机患者在大多数人口统计学和背景参数方面相似，但随机患者的感染程度较轻。非随机患者联合治疗的比例较低[31.9%（53/166）比 51.2%（208/406），p=0.000]。随机患者接受黏菌素治疗的时间更长[13 天（IQR 10-16）比 8.5 天（IQR 0-15），p=0.000]。单因素分析显示，非随机患者在感染发病后第 14 天更倾向于临床失败[82%（242/295）比 75.5%（307/406），p=0.042]。调整其他变量后，未纳入不是第 14 天临床失败的独立危险因素。
观察臂和 RCT 患者之间的相似性增强了我们对 AIDA 试验人群外部有效性的信心。在干预性研究中增加观察臂可以帮助提高人群外部有效性，并改善研究结果在临床实践中的应用。
该试验于 2012 年 11 月 22 日在 ClinicalTrials.gov 注册，编号为 NCT01732250。
