Lead Investigator: Luca Valerio, University Medical Center Mainz
Title of Proposal Research: Performance status and long-term clinical outcomes in pulmonary embolism patients with cancer. An analysis of Hokusai VTE Cancer study
Vivli Data Request: 6633
Funding Source: Commercial Funding – Funded by Daiichi Sankyo Deutschland GmbH in the setting of proposal DSE-DE-CV-20001, research plan “Filling the gaps of knowledge on healthcare outcomes during long-term anticoagulant treatment of pulmonary embolism”, Approved April 2020, Agreement May 2020; contact persons Mathias Lampartner, Wolfgang Zierhut (Regional) and Sheila Vignali, Martin Meier (Local).
Potential Conflicts of Interest: This project is supported by a grant by the data contributor (Daiichi Sankyo).
The Lead Investigator declares no personal, professional or financial relationship with Daiichi Sankyo that could influence or give the appearance of potentially influencing his work in this project, including personal grants, personal fees, patents/copyrights or non-financial support, either in relation to the present project or outside of it, either currently or in the past.
The grant that supports this project was not bequeathed to the Lead Investigator or any of the investigators of the research team, but only to their institution (University Medical Center of the Johannes Gutenberg-University Mainz).
None of the research projects connected to the grant in question, including the project described here, include any evaluation of products in which the sponsor may have a vested commercial interest, but only represent secondary, observational and purely descriptive post-hoc analyses of clinical and post-clinical course of patients selected based on purely clinical criteria, with no relationship whatsoever to the efficacy/safety of a product or any direct or indirect implication for the quality of a product. In these analyses, no specific direction of any found association would be of higher interest than other directions to either the researchers or the sponsor.
Summary of the Proposed Research:
Pulmonary embolism is an acute cardiovascular disease that results from the entrapment of a blood clot, usually originating from deep veins in the lower extremities, in the arterial pulmonary circulation. This condition is estimated to affect 29 to 78 per 100,000 population every year, for a total of about 430,000 annual cases in Europe and up to 600,000 cases in the United States (Heit 2016, Raskob 2014, Rahimtoola 2005). Patients at particularly high risk of pulmonary embolism include patients with cancer, those who experience periods of prolonged immobility (such as patients recovering from surgery, especially after orthopaedic interventions), or pregnant women (Heit 2016). While pulmonary embolism can be fatal and still contributes to approximately 40,000 deaths per year both in the United States and in the World Health Organization European Region, its mortality rate has been reported to be decreasing over the last few years (Barco 2019, Barco 2020). This epidemiologicla shift is progressively increasing the need of high-quality evidence to guide clinical management of survivors of pulmonary embolism. These patients often complain of long-lasting and potentially severe symptoms or disability that may jeopardize their functional status, working ability, and health-related quality of life. Accordingly, they receive long-term clinical monitoring and may require additional testing for comorbidities or rare long-term complications, physical rehabilitation to prevent cardiopulmonary deconditioning, and frequent adjustment of medical (typically anticoagulant) treatment.
The precise nature, temporal course and clinical significance of these long-term sequelae have not been fully characterized, especially in selected populations that pose complex management issues, such as patients with cancer-associated pulmonary embolism. In particular, there is scarce information on the clinical value of performance and quality of life assessment both at baseline and over follow-up. Knowing the prognostic implications of baseline performance status and quality of life scores at baseline would help clinicians to identify at an early stage patients at a high risk of clinical complications and over-average healthcare resource utilization, whereas knowing the typical patterns of performance status over time for specific patient categories of clinical interest would make it possible to identify those patients that are deviating from the expected path and take timely measures to adjust management and prevent clinical and overall deterioration.
Statistical Analysis Plan:
Patients with acute symptomatic and incidental pulmonary embolism from the database of Hokusai VTE Cancer study.
Post-hoc analysis of prospectively collected trial data.
– Distribution of clinical features at baseline by ECOG status (0-1 vs. 2) expressed as frequency (%) for categorical variables, mean (standard deviation) and median (first and third quartile) for continuous variables.
Primary analysis, inferential – association between performance status at baseline and clinical follow-up
– Association between ECOG status at baseline and the 12-month temporal course of clinical and biochemical parameters that may influence the type and dose of anticoagulant therapy expressed as absolute risk difference (12 months minus baseline) with 95% confidence interval for categorical variables, with absolute mean difference (12 months minus baseline) with 95% confidence interval for continuous variables.
– Time to composite outcome VTE recurrence and major bleeding, its components, and all-cause death modelled by the Kaplan-meier estimator.
– Association between ECOG status at baseline (2 vs 0-1) and the time to composite outcome and its components (VTE recurrence, bleeding events) and death expressed as hazard ratios with 95% confidence intervals obtained by Cox proportional hazards model.
– Association between ECOG status at baseline (2 vs 0-1) and re-hospitalization, event-free survival, and ECOG worsening at 12 months expressed as relative risk with 95% confidence intervals.
Secondary analysis, inferential – course of the performance status over the study period
– Evolution of the ECOG status in the whole sample at baseline, 6 months, and 12 months depicted by a Sankey plot (alluvial diagram).
– ECOG status at 12 months by cancer type depicted by a radar plot.
– Univariate and multivariable logistic regression of the association between pre-defined clinically relevant variables at baseline and ECOG-SPS worsening during the study period.
Handling of missing data
– Patients with missing data will be excluded from analysis, and a sensitivity analysis will be conducted to identify the differences in baseline demographic and clinical features between patients with and without missing follow-up data.
A Phase 3b, Prospective, Randomized, Open-label, Blind Evaluator (PROBE) Study Evaluating the Efficacy and Safety of (LMW) Heparin/Edoxaban Versus Dalteparin in Venous Thromboembolism Associated With Cancer
Data Contributor: Daiichi Sankyo, Inc.
Study ID: NCT02073682
Sponsor ID: DU176b-D-U311
Farmakis IT, Barco S, Mavromanoli AC, Konstantinides SV, Valerio L. Performance Status and Long-Term Outcomes in Cancer-Associated Pulmonary Embolism: Insights From the Hokusai-VTE Cancer Study. JACC CardioOncol. 2022 Nov 15;4(4):507-518. doi: 10.1016/j.jaccao.2022.07.008