Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture.

BACKGROUND: Clinical guidelines recommend low-molecular-weight heparin for thromboprophylaxis in patients with fractures, but trials of its effectiveness as compared with aspirin are lacking. METHODS: In this pragmatic, multicenter, randomized, noninferiority trial, we enrolled patients 18 years of age or older who had a fracture of an extremity (anywhere from hip to midfoot or shoulder to wrist) that had been treated operatively or who had any pelvic or acetabular fracture. Patients were randomly assigned to receive low-molecular-weight heparin (enoxaparin) at a dose of 30 mg twice daily or aspirin at a dose of 81 mg twice daily while they were in the hospital. After hospital discharge, the patients continued to receive thromboprophylaxis according to the clinical protocols of each hospital. The primary outcome was death from any cause at 90 days. Secondary outcomes were nonfatal pulmonary embolism, deep-vein thrombosis, and bleeding complications. RESULTS: A total of 12,211 patients were randomly assigned to receive aspirin (6101 patients) or low-molecular-weight heparin (6110 patients). Patients had a mean (±SD) age of 44.6±17.8 years, 0.7% had a history of venous thromboembolism, and 2.5% had a history of cancer. Patients received a mean of 8.8±10.6 in-hospital thromboprophylaxis doses and were prescribed a median 21-day supply of thromboprophylaxis at discharge. Death occurred in 47 patients (0.78%) in the aspirin group and in 45 patients (0.73%) in the low-molecular-weight-heparin group (difference, 0.05 percentage points; 96.2% confidence interval, -0.27 to 0.38; P<0.001 for a noninferiority margin of 0.75 percentage points). Deep-vein thrombosis occurred in 2.51% of patients in the aspirin group and 1.71% in the low-molecular-weight-heparin group (difference, 0.80 percentage points; 95% CI, 0.28 to 1.31). The incidence of pulmonary embolism (1.49% in each group), bleeding complications, and other serious adverse events were similar in the two groups. CONCLUSIONS: In patients with extremity fractures that had been treated operatively or with any pelvic or acetabular fracture, thromboprophylaxis with aspirin was noninferior to low-molecular-weight heparin in preventing death and was associated with low incidences of deep-vein thrombosis and pulmonary embolism and low 90-day mortality. (Funded by the Patient-Centered Outcomes Research Institute; PREVENT CLOT ClinicalTrials.gov number, NCT02984384.).

Patients Place More of an Emphasis on Physical Recovery Than Return to Work or Financial Recovery.

BACKGROUND: Value-based healthcare models aim to incentivize healthcare providers to offer interventions that address determinants of health. Understanding patient priorities for physical and socioeconomic recovery after injury can help determine which services and resources are most useful to patients. QUESTIONS/PURPOSES: (1) Do trauma patients consistently identify a specific aspect/domain of recovery as being most important at 6 weeks, 6 months, and 12 months after an injury? (2) Does the relative importance of those domains change within the first year after injury? (3) Are differences in priorities greater between patients than for a given patient over time? (4) Are different recovery priorities associated with identifiable biopsychosocial factors? METHODS: Between June 2018 and December 2018, 504 adult patients with fractures of the extremities or pelvis were surgically treated at the study site. For this prospective longitudinal study, we purposefully sampled patients from 6 of the 12 orthopaedic attendings' postoperative clinics. The participating surgeons surgically treated 243 adult patients with fractures of the extremities or pelvis. Five percent (11 of 243) of patients met inclusion criteria but missed their appointments during the 6-week recruitment window and could not be consented. We excluded 4% (9 of 243) of patients with a traumatic brain injury, 1% (2) of patients with a spinal cord injury, and 5% (12) of non-English-speaking patients (4% Spanish speaking [10]; 1% other languages [2]). Eighty-six percent of eligible patients (209 of 243) were approached for consent, and 5% (11 of 209) of those patients refused to participate. All remaining 198 patients consented and completed the baseline survey; 83% (164 of 198 patients) completed at least 6 months of follow-up, and 68% (134 of 198 patients) completed the 12-month assessment. The study participants' mean age was 44 ± 17 years, and 63% (125 of 198) were men. The primary outcome was the patient's recovery priorities, assessed at 6 weeks, 6 months, and 12 months after fracture using a discrete choice experiment. Discrete choice experiments are a well-established method for eliciting decisional preferences. In this technique, respondents are presented with a series of hypothetical scenarios, described by a set of plausible attributes or outcomes, and asked to select their preferred scenario. We used hierarchical Bayesian modeling to calculate individual-level estimates of the relative importance of physical recovery, work-related recovery, and disability benefits, based on the discrete choice experiment responses. The hierarchical Bayesian model improves upon more commonly used regression techniques by accounting for the observed response patterns of individual patients and the sequence of scenarios presented in the discrete choice experiment when calculating the model estimates. We computed the coefficient of variation for the three recovery domains and compared the between-patient versus within-patient differences using asymptotic tests. Separate prognostic models were fit for each of the study's three recovery domains to assess marginal changes in the importance of the recovery domain based on patient characteristics and factors that remained constant over the study (such as sex or preinjury work status) and patient characteristics and factors that varied over the study (including current work status or patient-reported health status). We previously published the 6-week results. This paper expands upon the prior publication to evaluate longitudinal changes in patient recovery priorities. RESULTS: Physical recovery was the respondents' main priority at all three timepoints, representing 60% ± 9% of their overall concern. Work-related recovery and access to disability benefits were of secondary importance and were associated with 27% ± 6% and 13% ± 7% of the patients' concern, respectively. The patients' concern for physical recovery was 6% (95% CrI 4% to 7%) higher at 12 months after fracture that at 6 weeks postfracture. The mean concern for work-related recovery increased by 7% (95% CrI 6% to 8%) from 6 weeks to 6 months after injury. The mean importance of disability benefits increased by 2% (95% CrI 1% to 4%) from 6 weeks to 6 months and remained 2% higher (95% CrI 0% to 3%) at 12 months after the injury. Differences in priorities were greater within a given patient over time than between patients as measured using the coefficient of variation (physical recovery [245% versus 7%; p < 0.001], work-related recovery [678% versus 12%; p < 0.001], and disability benefits [620% versus 33%; p < 0.001]. There was limited evidence that biopsychosocial factors were associated with variation in recovery priorities. Patients' concern for physical recovery was 2% higher for every 10-point increase in their Patient-reported Outcome Measure Information System (PROMIS) physical health status score (95% CrI 1% to 3%). A 10-point increase in the patient's PROMIS mental health status score was associated with a 1% increase in concern for work-related recovery (95% CrI 0% to 2%). CONCLUSION: Work-related recovery and accessing disability benefits were a secondary concern compared with physical recovery in the 12 months after injury for patients with fractures. However, the importance of work-related recovery was elevated after the subacute phase. Priorities were highly variable within a given patient in the year after injury compared with between-patient differences. Given this variation, orthopaedic surgeons should consider assessing and reassessing the socioeconomic well-being of their patients throughout their continuum of care. LEVEL OF EVIDENCE: Level II, therapeutic study.

Does Topical Vancomycin Powder Use in Fracture Surgery Change Bacteriology and Antibiotic Susceptibilities? An Analysis of the VANCO Trial.

OBJECTIVE: To determine whether intrawound vancomycin changes the bacteriology of surgical site infection pathogens and investigate the emergence of antibiotic-resistant pathogens. DESIGN: Secondary analysis of phase III, prospective, randomized clinical trial. SETTING: Thirty-six US trauma centers. PATIENT SELECTION CRITERIA: Patients who became infected after fixation of tibial plateau or pilon fracture. OUTCOME MEASURES AND COMPARISONS: Pathogen types and bacterial susceptibilities as determined from routine clinical culture in the operating room. RESULTS: Seventy-four patients were studied who were 67.5% male with a mean age of 48.6 years. A lower proportion of gram-positive cocci was observed in the vancomycin powder compared with the standard-of-care group (3.7% vs. 8.0%, P = 0.01). Methicillin-resistant Staphylococcus aureus infection incidence was comparable in both the vancomycin powder and the standard-of-care groups, but rates of methicillin-susceptible S. aureus infections were lower in the treatment group (1.4% vs. 4.8%, P = 0.01). The incidence of coagulase-negative Staphylococci and gram-negative rod infections were similar in both groups. There was no significant difference in susceptibilities between groups in rates of vancomycin-resistant enterococcus. CONCLUSIONS: Topical vancomycin powder decreases the likelihood of gram-positive infections consistent with the biologic activity of vancomycin. Fewer methicillin-susceptible S. aureus and coagulase-negative Staphylococci infections were observed in the group treated with vancomycin powder. An effect of vancomycin powder on methicillin-resistant S. aureus infection risk was not detected given the low incidence in both the intrawound vancomycin and the standard-of-care groups. There was no emergence of gram-negative rod infections or increased resistance patterns observed. Use of topical vancomycin powder does not seem to produce infections in these patients with greater antibiotic resistance than would have occurred without its use. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Poor Agreement Between Next-Generation DNA Sequencing and Bacterial Cultures in Orthopaedic Trauma Procedures.

BACKGROUND: Next-generation DNA sequencing (NGS) detects bacteria-specific DNA corresponding to the 16S ribosomal RNA gene and can identify bacterial presence with greater accuracy than traditional culture methods. The clinical relevance of these findings is unknown. The purpose of the present study was to compare the results from bacterial culture and NGS in order to characterize the potential use of NGS in orthopaedic trauma patients. METHODS: A prospective cohort study was performed at a single academic, level-I trauma center. Three patient groups were enrolled: (1) patients undergoing surgical treatment of acute closed fractures (presumed to have no bacteria), (2) patients undergoing implant removal at the site of a healed fracture without infection, and (3) patients undergoing a first procedure for the treatment of a fracture nonunion who might or might not have subclinical infection. Surgical site tissue was sent for culture and NGS. The proportions of culture and NGS positivity were compared among the groups. The agreement between culture and NGS results was assessed with use of the Cohen kappa statistic. RESULTS: Bacterial cultures were positive in 9 of 111 surgical sites (110 patients), whereas NGS was positive in 27 of 111 surgical sites (110 patients). Significantly more cases were positive on NGS as compared with culture (24% vs. 8.1%; p = 0.001), primarily in the acute closed fracture group. No difference was found in terms of the percent positivity of NGS when comparing the acute closed fracture, implant removal, and nonunion groups. With respect to bacterial identification, culture and NGS agreed in 73% of cases (κ = 0.051; 95% confidence interval, -0.12 to 0.22) indicating only slight agreement compared with expected chance agreement of 50%. CONCLUSIONS: NGS identified bacterial presence more frequently than culture, but with only slight agreement between culture and NGS. It is possible that the increased frequency of bacterial detection with molecular methods is reflective of biofilm presence on metal or colonization with nonpathogenic bacteria, as culture methods have selection pressure posed by restrictive, artificial growth conditions and there are low metabolic activity and replication rates of bacteria in biofilms. Our data suggest that NGS should not currently substitute for or complement conventional culture in orthopaedic trauma cases with low suspicion of infection. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.

The impact of COVID-19 restrictions on participant enrollment in the PREPARE trial.

Background: At the initiation of the COVID-19 pandemic, restrictions forced researchers to decide whether to continue their ongoing clinical trials. The PREPARE (Pragmatic Randomized Trial Evaluating Pre-Operative Alcohol Skin Solutions in Fractured Extremities) trial is a pragmatic cluster-randomized crossover trial in patients with open and closed fractures. PREPARE was enrolling over 200 participants per month at the initiation of the pandemic. We aim to describe how the COVID-19 research restrictions affected participant enrollment. Methods: The PREPARE protocol permitted telephone consent, however, sites were obtaining consent in-person. To continue enrollment after the initiation of the restrictions participating sites obtained ethics approval for telephone consent scripts and the waiver of a signature on the consent form. We recorded the number of sites that switched to telephone consent, paused enrollment, and the length of the pause. We used t-tests to compare the differences in monthly enrollment between July 2019 and November 2020. Results: All 19 sites quickly implement telephone consent. Fourteen out of nineteen (73.6%) sites paused enrollment due to COVID-19 restrictions. The median length of enrollment pause was 46.5 days (range, 7-121 days; interquartile range, 61 days). The months immediately following the implementation of restrictions had significantly lower enrollment. Conclusion: A pragmatic design allowed sites to quickly adapt their procedures for obtaining informed consent via telephone and allowed for minimal interruptions to enrollment during the pandemic.

Systemic Absorption and Nephrotoxicity Associated With Topical Vancomycin Powder for Fracture Surgery.

OBJECTIVES: To determine whether using topical vancomycin powder in fracture surgery may result in low levels of vancomycin in the serum and not result in nephrotoxicity. DESIGN: Prospective observational at a single site as a substudy of the VANCO trial. SETTING: Single, large urban level I trauma center. PATIENTS/PARTICIPANTS: Fifty-eight patients with tibial plateau and pilon fractures randomized to the treatment arm at the principal investigator's site. INTERVENTION: Topical vancomycin powder (1000 mg) applied directly in the wound over all metal implants at the time of wound closure. MAIN OUTCOME MEASUREMENTS: Serum vancomycin levels at 1 hour and 6-8 hours after surgery. Secondary outcomes included serum creatinine before surgery, a day after surgery, and at 2 weeks postoperatively and complete blood count at 2 weeks postoperatively. RESULTS: Except in 2 patients who also received intravenous vancomycin, none of the study patients had detectable (>5 µg/mL) serum vancomycin levels at 1 hour and 6-8 hours after surgery. One patient with a history of elevation of serum creatinine had a minor increase of serum creatinine but had undetectable vancomycin levels. None of the other patients had a clinically significant increase in creatinine levels. CONCLUSIONS: Despite its relatively widespread usage, little data exist regarding the systemic levels and nephrotoxicity associated with the topical use of vancomycin powder in orthopaedic fracture surgery. These prospective data indicate that there seems to be little clinical concern regarding toxicity associated with systemic absorption of vancomycin powder in this specific clinical application. LEVEL OF EVIDENCE: Therapeutic Level IV. See instructions for authors for a complete description of levels of evidence.

Implementing stakeholder engagement to explore alternative models of consent: An example from the PREP-IT trials.

INTRODUCTION: Cluster randomized crossover trials are often faced with a dilemma when selecting an optimal model of consent, as the traditional model of obtaining informed consent from participant's before initiating any trial related activities may not be suitable. We describe our experience of engaging patient advisors to identify an optimal model of consent for the PREP-IT trials. This paper also examines surrogate measures of success for the selected model of consent. METHODS: The PREP-IT program consists of two multi-center cluster randomized crossover trials that engaged patient advisors to determine an optimal model of consent. Patient advisors and stakeholders met regularly and reached consensus on decisions related to the trial design including the model for consent. Patient advisors provided valuable insight on how key decisions on trial design and conduct would be received by participants and the impact these decisions will have. RESULTS: Patient advisors, together with stakeholders, reviewed the pros and cons and the requirements for the traditional model of consent, deferred consent, and waiver of consent. Collectively, they agreed upon a deferred consent model, in which patients may be approached for consent after their fracture surgery and prior to data collection. The consent rate in PREP-IT is 80.7%, and 0.67% of participants have withdrawn consent for participation. DISCUSSION: Involvement of patient advisors in the development of an optimal model of consent has been successful. Engagement of patient advisors is recommended for other large trials where the traditional model of consent may not be optimal.

Which orthopaedic trauma patients are likely to refuse to participate in a clinical trial? A latent class analysis.

OBJECTIVE: The study aimed to assess systematic differences in the characteristics of patients that consented for the trial compared with the broader pool of eligible patients in a large, pragmatic orthopaedic trauma trial. DESIGN: A retrospective observational study performed from April 2017 to March 2018. SETTING: Academic trauma centre in Baltimore, USA. PARTICIPANTS: There were 642 eligible adult trial participants with an operative fracture to the appendicular skeleton and were indicated for blood clot prophylaxis. The median age of the sample was 50 years (IQR: 31-63), and 60% were male. PRIMARY OUTCOME MEASURE: The primary outcome was the refusal to enrol in the trial. Demographic and injury covariates were included in iterations of latent class models. The final model was selected based on a minimum Bayesian information criterion. RESULTS: The final model identified three clusters with five covariates predictive of cluster membership (age, neighbourhood-based socioeconomic status, alcohol use, multiple fractures, multiple surgeries). The three clusters were associated with 22% (Cluster 1), 38% (Cluster 2) and 62% (Cluster 3) refusal rates, respectively. Members of Cluster 3 (n=84) were most commonly between 66 and 80 years of age (49% vs 6% (Cluster 1) and 21% (Cluster 2)), of high neighbourhood-based socioeconomic status (85% vs 63% (Cluster 1) and 8% (Cluster 2)), with isolated fractures (100% vs 80% (Cluster 1) and 92% (Cluster 2)), and were less likely to have multiple surgeries compared with the other clusters (28% vs 47% (Cluster 1) and 35% (Cluster 2)). CONCLUSION: In this study, the likelihood of refusing to participate in the trial ranged from 22% to 62% in the three identified clusters. Elderly age, high socioeconomic status, and less severe injuries defined the cluster that was most likely to refuse trial participation. TRIAL REGISTRATION NUMBER: NCT02984384.

Patient preferences for nutritional supplementation to improve fracture healing: a discrete choice experiment.

OBJECTIVE: Vitamin D is often prescribed as an adjuvant therapy to aid fracture healing due to its biological role in bone health. However, the optimal frequency, dosage and duration of vitamin D supplementation for non-osteoporotic fracture healing has not been established. The objective of this study was to determine patient preferences for fracture healing relative to hypothetical vitamin D supplementation dosing options. DESIGN: Discrete choice experiment. SETTING: Level 1 trauma centre in Baltimore, Maryland, USA. PARTICIPANTS: 199 adult (18-60 years) patients with a fracture. PRIMARY OUTCOME MEASURES: Parameter estimates of utility for fracture healing relative to dosing regimens were analysed using hierarchical Bayesian modelling. RESULTS: A reduced risk of reoperation (34.3%) and reduced healing time (24.4%) were the attributes of greatest relative importance. The highest mean utility estimates were for a one-time supplementation dose (ß=0.71, 95% CI 0.41 to 1.00) followed by a reduced risk of reoperation (ß=0.41 per absolute % reduction, 95% CI 0.0.36 to 0.46). Supplementation for 24 weeks in duration (ß=-0.83, 95% CI -1.00 to -0.67) and a daily supplement (ß=-0.29, 95% CI -0.47 to -0.11) had the lowest mean utilities. The 'no supplement' option had a large negative value suggesting supplementation was generally desirable in this sample population. Among other possible clinical scenarios, patients expected a 2% reduction in the absolute risk of reoperation or a 3.1-week reduction in healing time from the baseline to accept a treatment regimen requiring two separate doses of supplementation, two blood tests and a cost of $20 within 3 months of injury. CONCLUSIONS: Patients with orthopaedic trauma demonstrated strong willingness to take a vitamin D supplement that would decrease risk of reoperation and reduce healing time. Furthermore, these findings specify the required decrease in reoperation risk and reduction in healing time patients would expect to adhere to possible vitamin D dosing regimens.

Risk Factors for Knee Stiffness Surgery After Tibial Plateau Fracture Fixation.

OBJECTIVE: To determine the risk factors for knee stiffness surgery after tibial plateau fixation. DESIGN: Retrospective observational cohort study. SETTING: Academic Level I trauma center. PATIENTS/PARTICIPANTS: A study group of 110 patients who underwent knee stiffness surgery (manipulation while under anesthesia, arthroscopic lysis of adhesion, or quadricepsplasty) at a time remote from open reduction and internal fixation of tibial plateau fractures and a control group of 319 patients with tibial plateau fractures treated with open reduction and internal fixation who did not undergo knee stiffness surgery and who had either a minimum of 1 year of follow-up or clearly documented range of motion ≥110 degrees with a minimum of 90 days of follow-up. INTERVENTION: Each case was assessed from the time of index admission through study event, end of minimum follow-up, or achievement of ≥110 degrees range of motion. MAIN OUTCOME MEASUREMENTS: Knee stiffness surgery. RESULTS: Total number of weeks in an external fixator (odds ratio, 1.5 per week; 95% confidence interval, 1.3-1.7; P < 0.001) and the presence of bilateral tibial plateau fractures (odds ratio, 3.3; 95% confidence interval, 1.2-9.1; P = 0.02) were significant predictors of knee stiffness intervention. CONCLUSION: Clinicians should be aware that the time spent in external fixation and the presence of bilateral tibial plateau injuries are strong risk factors for requiring subsequent surgery to treat knee stiffness. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Post-discharge adherence with venous thromboembolism prophylaxis after orthopedic trauma: Results from a randomized controlled trial of aspirin versus low molecular weight heparin.

BACKGROUND: Orthopedic trauma patients are often treated with venous thromboembolism (VTE) chemoprophylaxis with aspirin or low molecular weight heparin (LMWH) after discharge from their index admission, but adherence patterns are not known. We hypothesized that overall adherence would be moderate and greater with aspirin compared to LMWH. METHODS: We conducted a randomized controlled trial of adult trauma patients with an operative extremity fracture or any pelvic/acetabular fracture requiring VTE prophylaxis. Patients were randomized to receive either LMWH 30 mg BID or aspirin 81 mg BID. Patients prescribed outpatient prophylaxis were contacted between 10 and 21 days after discharge to assess adherence measured by the validated Morisky Medication Adherence Scale (MMAS-8). Adherence scores were compared between the two treatment arms with similar results for intention-to-treat and as-treated analyses. As-treated multivariable logistic regression was performed to determine factors associated with low-medium adherence scores. RESULTS: One hundred fifty patients (64 on LMWH, 86 on aspirin) on chemoprophylaxis at time of follow-up completed the questionnaire. As-treated analysis showed that adherence was high overall (mean MMAS 7.2 out of 8, SD 1.5) and similar for the two regimens (LMWH: 7.4 vs. aspirin: 7.0, p = 0.13). However, patients on LMWH were more likely to feel hassled by their regimen (23% vs. 9%, p = 0.02). In a multivariable model, low-medium adherence was associated with taking LMWH as the prophylaxis medication (aOR 2.34, CI 1.06-5.18, p = 0.04), having to self-administer the prophylaxis (aOR 4.44, CI 1.45-13.61, p < 0.01), being of male sex (aOR 2.46, CI 1.10-5.49, p = 0.03), and of younger age (aOR 0.72 per additional 10 years of age, CI 0.57-0.91, p < 0.01). CONCLUSIONS: Overall post-discharge adherence with VTE prophylaxis was high. Several factors, including prophylaxis by LMWH, were associated with decreased adherence. These factors should be considered when managing patients and designing efficacy trials. LEVEL OF EVIDENCE: Therapeutic, level II.