The rationale, design, and methods of a randomized, controlled trial to evaluate the efficacy and safety of an active strategy for the diagnosis and treatment of acute pulmonary embolism during exacerbations of chronic obstructive pulmonary disease

Introduction Some previous studies have suggested a high prevalence of pulmonary embolism (PE) during exacerbations of chronic obstructive pulmonary disease (ECOPD). The SLICE trial aims to assess the efficacy and safety of an active strategy for the diagnosis and treatment of PE (vs usual care) in patients hospitalized because of ECOPD. Methods SLICE is a phase III, prospective, international, multicenter, randomized, open‐label, and parallel‐group trial. A total of 746 patients hospitalized because of ECOPD will be randomized in a 1:1 fashion to receive either an active strategy for the diagnosis and anticoagulant treatment of PE or usual care (ie, standard care without any diagnostic test for diagnosing PE). The primary outcome is a composite of all‐cause death, non‐fatal (recurrent) venous thromboembolism (VTE), or readmission for ECOPD within 90 days after enrollment. Secondary outcomes are (a) death from any cause within 90 days after enrollment, (b) non‐fatal (recurrent) VTE within 90 days after enrollment, (c) readmission within 90 days after enrollment, and (d) length of hospital stay. Results Enrollment started in September 2014 and is expected to proceed until 2020. Median age of the first 443 patients was 71 years (interquartile range, 64‐78), and 26% were female. Conclusions This multicenter trial will determine the value of detecting PEs in patients with ECOPD. This has implications for COPD patient morbidity and mortality. Trial registration number: NCT02238639.


| BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. 1-3 COPD patients may suffer episodes of exacerbation of symptoms (ECOPD) that contribute to poor health status, and increased healthcare costs. 4 The majority of ECOPD cases develop in response to infections 5,6 and air pollution, 7 but the exact cause is not clear in up to 30% of cases. 8 In addition, other frequent clinical conditions may mimic the symptoms of ECOPD, including congestive heart failure, pneumonia, pneumothorax, pleural effusion, and pulmonary embolism (PE). 8 Previous studies suggest a high prevalence of PE in ECOPD. [9][10][11][12] Tillie-Leblond et al evaluated PE in a series of 197 consecutive patients with ECOPD and found that the frequency of PE was 25%. 13 However, that study was performed in a highly selected subgroup of patients. In fact, a recent meta-analysis found a lower prevalence of PE of 16% in ECOPD compared with previous studies. 14 In patients with clinical suspicion of PE, there are some data suggesting that some PE diagnoses are less severe and these patients might not benefit from anticoagulation therapy. 15 Particularly for patients with ECOPD, some PE might be clinically unimportant, and the risk of submitting a patient with a clinically insignificant PE to anticoagulant treatment might outweigh the benefit. 16 Therefore, we designed the significance of puLmonary embolism in COPD exacerbations (SLICE) trial to assess the efficacy and safety of an active strategy for the diagnosis and treatment of PE compared to usual care (ie, standard care without any diagnostic test for diagnosing PE) in patients hospitalized because of ECOPD.

| METHODS
SLICE complies with the standard protocol items: recommendations for interventional trials statement. 17

| Study hypothesis
This trial is designed to demonstrate the superiority of an active strategy for the diagnosis and treatment of PE compared to usual care in patients hospitalized because of ECOPD.  Table 1; the flow diagram is displayed in Figure 1. The study information for all ineligible and eligible non-recruited participants will be retained in an anonymized form to provide detailed data on these patients in comparison to the study participant population. The study is being conducted in 16 centers in Spain and France.

| Randomization and trial interventions
In a patient with ECOPD who requires hospital admission, randomization should occur in the first 24 hours after admission. The trial uses a A central independent adjudication committee whose members are unaware of management allocation adjudicates all suspected study outcomes during the study period.

| Surveillance and follow-up
The study requires the following scheduled visits: enrollment, 1 week,

| Statistical analysis
All analyses will be performed on the intention-to-treat population, defined as all patients randomized, regardless of the management actually received. A per-protocol analysis, excluding protocol violations, will be performed as a sensitivity analysis. The distribution of continuous variables will be assessed by the Kolmogorov-Smirnov test. Categorical variables are expressed as frequencies or percentages and compared by χ 2 statistics or Fisher's exact test. Continuous variables will be summarized as the means ± SD or median and compared using Student's t test (for normal data) and Mann-Whitney U test (for non-normally distributed variables). Survival curves with time-to-event data will be generated by the Kaplan-Meier method and compared using the log-rank test. Comparisons between the two groups will be performed using the Cox proportional hazard model. A P-value <0.05 will be considered statistically significant. All analyses will be performed with the use of the statistical programme SPSS V.24.0. Subgroup analyses will include: age (<75 vs ≥75 years), sex (female vs male), COPD severity (FEV1 > 80%, 50% < FEV1 < 80%, 30% < FEV1 < 50%, and FEV1 < 30%), hospital volume (<300 beds vs ≥300 beds), and season of the year (autumn, winter, spring, and summer).
Two sensitivity analyses are planned for the primary outcome.
The first is an analysis of primary-outcome events after excluding those patients in the intervention group with a diagnosis of isolated sub-segmental PE. The second is an analysis of outcomes after excluding patients with a history of cancer.

| Study organization
The SLICE is an independent, investigator-initiated trial with an aca-

| Study Committees
The structure of the SLICE study includes a Steering Committee, a central independent adjudication committee, and a DSMB.
The Steering Committee members have the final responsibility for the conduction of the study as well as the verification and analyses of all the study data. All the members of the Steering Committee have access to the study data, vouch for their accuracy, and completeness; they will contribute to the interpretation of the results, approve the final version of the manuscript verifying the fidelity of the article to the study protocol, and make the decision to submit the manuscript for publication.

| Adjudication committee
A central independent adjudication committee, whose members are unaware of management allocation, adjudicates all suspected outcome events (see Outcomes).

| Data and safety monitoring board
An independent DSMB periodically reviews the study outcomes with all information available concerning management allocation. The DSMB is composed of three expert clinicians with experience in the conduction and monitoring of clinical trials.

| Ethics and dissemination
The study is performed in accordance with the provisions of the Dec- The SLICE trial is currently enrolling patients to assess the efficacy and safety of an active strategy for the diagnosis and treatment of PE in patients with ECOPD. The trial has the potential to improve the management of exacerbations in patients with COPD. It is anticipated that the findings of this study will enhance our understanding of the exacerbations of COPD. This rigorously designed trial will address the role of PE in the decompensation of patients with COPD, potentially leading to better care.
Previous studies and meta-analyses have assessed the prevalence of PE in ECOPD. 9 To the best of our knowledge, this is the first randomized controlled trial that will determine the value of detecting PEs in patients with ECOPD. 25 Our trial has some limitations. This is an open-label trial, and ascertainment bias is inherent to the trial design. To mitigate potential bias, all events are adjudicated by a committee whose members are unaware of the intervention assignments. The decision to use a composite outcome that includes readmissions for ECOPD might prove challenging for the interpretation of results. There are some reasons for including readmission as an outcome in the study protocol. First, exacerbations of COPD are associated with accelerated loss of lung function and death. 26 Second, management of these outcomes may reduce the risk of reaching other endpoints (mainly death). Finally, some of readmissions for ECOPD might be caused by thromboembolic events. Thus, the Steering Committee felt justified in using a composite outcome that includes (recurrent) VTE and readmission for ECOPD. In addition, the components of the composite variable will be also analyzed separately.
In conclusion, the SLICE trial will provide high-quality evidence regarding the risks as well as the benefits of using CTPA in the evaluation of ECOPD.

ACKNOWLEDGMENTS
The study is supported by public funding, specifically by a grant from the Spanish Government (Ministry of Health; PI14/00400). In addition, the Sponsor has obtained grants from the Chest Foundation Research Grant in Venous Thromboembolism, Sociedad Española de Neumología y Cirugía Torácica (SEPAR) and from Daiichi-Sankyo.
According to the study protocol, neither the Spanish Government, Chest, SEPAR nor any part of the industry is involved at any stage of design, conduct of the trial, data management and data analysis or may exert any influence on decisions to discontinue the trial due to futility or safety concerns.

CONFLICTS OF INTEREST
The authors declare no potential conflict of interests.