A Portfolio of Secondary Analyses from the PREP-IT Trial

Research reported in this publication was partially supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number 2K24AR076445. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Welcome to the collaboration involving the Aqueous-PREP and PREPARE trials1,2. This combined effort represents one of the largest prospectively collected datasets to measure many aspects of practice variability within modern fracture management. Independently published, the Aqueous-PREP and PREPARE trials answered the fundamental question of whether an iodine or chlorhexidine aseptic skin solution reduces surgical site infections (SSIs) and/or unplanned reoperations in patients with a fracture. This supplement combines the 2 trial datasets and asks a number of other questions regarding the modern management of fractures in patients. The supplement is organized to take the reader through many of the daily clinical decision points with which providers are faced, including the following questions: Do hospital-based infection prevention strategies, such as nasal decolonization, impact infection? What impact does the type and duration of prophylactic antibiotics have on infection rates? Does the use of temporizing external fixators impact infection? Does the preparation solution have an impact on nonunion rates? And, should the patient become infected, what organisms would we see, how soon would they develop, and what is the current practice of medical treatment for these infections? We also explore other topics such as the impact of socioeconomic factors, race, gender, and food deserts on infection development. In addition, we compare a simplified modification of the Orthopaedic Trauma Association Open Fracture Classification (OTA-OFC3) with the prior OTA-OFC and Gustilo-Anderson classification systems for predicting surgical site infection and unplanned reoperation. It is our hope that these studies will aid in daily clinical decision-making, spark interest in further lines of research, and, above all, improve fracture care for patients everywhere. The Aqueous-PREP and PREPARE trials were a part of the PREP-IT (A Program of Randomized Trials to Evaluate Preoperative Antiseptic Skin Solutions in Orthopaedic Trauma) program and shared key aspects of study design3. Please see below for a detailed summary of each trial and their specific findings. Aqueous-PREP Study Overview The Aqueous-PREP (A Pragmatic Randomized Trial Evaluating Preoperative Aqueous Antiseptic Skin Solutions in Open Fractures) trial compared the effect of aqueous 10% povidone-iodine versus aqueous 4% chlorhexidine gluconate as preoperative antisepsis on the risk of SSI in 1,638 patients who were ≥18 years of age and required surgery for an open fracture1. Patients were enrolled from 14 hospitals in the United States, Canada, and Spain. Participating sites were randomly assigned, in a 1:1 ratio, to use either aqueous 10% povidone-iodine or aqueous 4% chlorhexidine gluconate immediately before surgical incision; sites then alternated between the study interventions every 2 months. The primary outcome was SSI, guided by the 2017 U.S. Centers for Disease Control and Prevention National Healthcare Safety Network reporting criteria, which included superficial incisional infection within 30 days or deep incisional or organ space infection within 90 days after the surgery4. The secondary outcome was unplanned fracture-related reoperation within 12 months after the injury. Unplanned reoperation events included treatments for infection, wound-healing complications, and fracture-healing complications such as a delayed union or nonunion. Participants were assessed clinically at 6 weeks and 3, 6, 9, and 12 months after the fracture. Among 1,571 participants in whom the primary outcome was known, SSI rates did not differ between the treatment groups, with 59 (7%) of 787 participants in the povidone-iodine group and 58 (7%) of 784 participants in the chlorhexidine gluconate group experiencing an SSI (odds ratio [OR], 1.11; 95% confidence interval [CI], 0.74 to 1.65; p = 0.61). The rate of an unplanned reoperation within 1 year after the injury also did not differ between the treatment groups, with 118 (16%) of 734 participants in the povidone-iodine group and 115 (16%) of 738 participants in the chlorhexidine gluconate group undergoing a reoperation (OR, 1.08; 95% CI, 0.81 to 1.46; p = 0.59). PREPARE Study Overview The PREPARE (A Pragmatic Randomized Trial Evaluating Preoperative Alcohol Skin Solutions in Fractured Extremities) trial compared the effect of 0.7% iodine povacrylex in 74% isopropyl alcohol (the iodine group) versus 2% chlorhexidine gluconate in 70% isopropyl alcohol (the chlorhexidine group) as preoperative antisepsis on the risk of SSI2. The study cohort consisted of 6,785 patients ≥18 years of age who were undergoing surgery to treat a closed lower-extremity or pelvic fracture and 1,700 patients ≥18 years of age who were undergoing surgery to treat an open fracture. Patients were enrolled from 25 hospitals in the United States and Canada. Participating sites were randomly assigned, in a 1:1 ratio, to use either a solution of 0.7% iodine povacrylex in 74% isopropyl alcohol or a solution of 2% chlorhexidine gluconate in 70% isopropyl alcohol immediately before surgical incision; sites then alternated between the study interventions every 2 months. The PREPARE trial used the same primary outcome (SSI) and secondary outcome (unplanned reoperation) as the Aqueous-PREP trial. Participants were also assessed clinically at 6 weeks and 3, 6, 9, and 12 months after the fracture. The primary outcome was known in 6,477 participants in the closed-fracture population and in 1,651 participants in the open-fracture population. This trial found that patients with a closed fracture in the iodine group (77 [2.4%] of 3,205 patients) experienced fewer postoperative SSIs (OR, 0.74; 95% CI, 0.55 to 1.00; p = 0.049) than those in the chlorhexidine group (108 [3.3%] of 3,272 patients). In the open-fracture population, SSI rates did not differ between the treatment groups, with an SSI occurring in 54 (6.5%) of 825 participants in the iodine group and in 60 (7.3%) of 826 participants in the chlorhexidine group (OR, 0.86; 95% CI, 0.58 to 1.27; p = 0.45). The rate of an unplanned reoperation within 1 year after the injury also did not differ between the treatment groups in both the open and closed-fracture populations.

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