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This year marked the 10th anniversary of the annual International Conference on Thrombosis and Hemostasis Issues in Cancer (ICTHIC), with the meeting running from the 22 to 26 April. Although the conference was fully virtual, the organizers generated a remarkable digital representation of the monumental complex of Sant’Agostino in Bergamo, Italy, where the meeting takes place each year.
Digital representation of the Aula Magna of Sant’Agostino in Bergamo, Italy
Throughout the conference, participants were introduced to new data from clinical studies showing that cancer-associated thrombosis (CAT) is still a dynamic area of research, and new real-world evidence (RWE) demonstrating how outcomes are improving in practice. The remarkable developments that have taken place in clinical guidelines since their first publication in 2005 were also noted. The original American Society of Clinical Oncology (ASCO) guidelines took 1 year to develop, answered five clinical questions and are eight pages long. In contrast, the recently published American Society of Hematology (ASH) guidelines took 6 years to develop, addressed 34 questions and are 47 pages long (with 243 supplementary pages). The focus now is turning towards effective guideline implementation.
The presentation of CASTA-DIVA data commenced on a sombre note with a dedication to the principal investigator, Guy Meyer, who sadly passed away at the end of last year.
CASTA-DIVA was a prospective, multicentre, open-label, non-inferiority trial of rivaroxaban compared with dalteparin that was designed in response to the requirement for more evidence to support the use of rivaroxaban for the treatment of venous thromboembolism (VTE) in cancer. Patients were recruited based on their presumed higher risk of recurrence despite anticoagulation treatment, and the primary endpoint was VTE recurrence at 3 months. There was a trend towards reduced VTE in the ‘Xarelto’ group (6.4% vs 10.1%, HR=0.75, 0.21;2.65) and numerically fewer bleeding events (1.4% vs 3.7%, HR=0.36, 0.04;3.43). However, due to slower than expected recruitment, the study size was smaller than planned. Together with lower than anticipated VTE incidence rates, this resulted in a lack of statistical power and hence the study did not meet its primary endpoint of non-inferiority versus dalteparin. There were also numerically fewer major bleeding events in the rivaroxaban group (1 [1.4%] patient receiving rivaroxaban, 3 [3.7%] patients receiving dalteparin; HR=0.36; 95% CI 0.04–3.43). These results are consistent with other studies in the field, and the authors were able to update a previous meta-analysis with these findings, which will be published alongside the trial results.
CASTA-DIVA is part of the CALLISTO program of studies, a unique program, which studies rivaroxaban in a wide range of cancer types, patient profiles, assessing multiple outcomes, including patient preference, treatment satisfaction and QoL. CASTA DIVA results are confirming and building on the results of SELECT-D (but in patients at higher risk for VTE recurrence), another study of the CALLISTO program, which demonstrated a reduction of VTE recurrence in patients on rivaroxaban with comparable major bleeding events.
Professor Girard (Institut Mutualiste Montsouris) presents the results from the CASTA-DIVA study
The 12-month extension period of the SELECT-D trial1 aimed to investigate the clinical course of VTE in patients who completed 6 months of the SELECT-D trial and who had residual deep vein thrombosis or index pulmonary embolism. Low levels of recruitment meant that none of the results reached a level of statistical significance. However, there was a numerical reduction in the cumulative recurrence rates of VTE in patients treated with rivaroxaban (4%) compared with those treated with placebo (14%) at 12 months. Both major bleeding and clinically relevant non-major bleeding events were numerically higher in the rivaroxaban group (5% and 4%, respectively) compared with placebo (0% for both). There were no venous thromboembolic events in the group of patients who were not randomized into the extension study, suggesting that this may represent a group who are at low risk of recurrence.
Results and conclusions from the SELECT-D 12-month extension poster
Closing out the congress, Bayer sponsored a symposium to discuss controversial topics in the field of CAT. The symposium adopted a conversational format with the Chair, Professor the Lord Ajay Kakkar (University College London), putting queries to the faculty at multiple points throughout their presentations to explore topics of interest further.
Professor Alok Khorana (Cleveland Clinic Lerner College of Medicine) discussed controversies in risk assessment and how these impact acute treatment. During the presentation, Lord Kakkar noted that, according to European Society for Medical Oncology (ESMO), most oncologists underestimate the prevalence and negative impact of VTE and queried why this is. Professor Khorana felt this is potentially related to the fact that CAT is a common complication and therefore, oncologists are becoming used to it. He also highlighted this as an important issue, because there is a higher incidence of VTE in patients with cancer than those without, and VTE is the second leading cause of death in cancer outpatients after cancer progression itself.
Professor Khorana demonstrated why oncologists should be aware of the risk of thrombosis in their patients
Professor Jeffrey Weitz (McMaster University) explored controversies that exist in both the selection and the duration of treatment. The debate in this section centred around which patients should continue to receive anticoagulation for an extended period (beyond 6 months), with the conclusion that patients with persistent risk factors, including active cancer, should continue to receive treatment. As a result of data from clinical studies, ‘Xarelto’ alongside other non-vitamin K antagonist oral anticoagulants (NOACs) are now considered as acceptable alternatives to, or are even preferred over low molecular weight heparin (LMWH) for the treatment of CAT by guidelines. Furthermore, results from the COSIMO trial, the only clinical trial dedicated to treatment satisfaction, patient preference and quality of life in patients with cancer, indicate higher levels of patient treatment satisfaction with rivaroxaban compared with the standard of care.
ESC guidelines on the classification of patients with pulmonary embolism according to risk factors, as presented by Professor Jeffery Weitz
Lastly, Dr Mari Thomas (University College London) presented the case of a patient with metastatic breast cancer and incidental pulmonary embolism who later developed metastatic brain lesions. Throughout the case, the audience were asked to vote on how they would manage the patient, with the participants indicating a roughly equal split between NOACs and LMWH. Dr Thomas also explained the rationale behind her choices, including treatment of the patient with rivaroxaban.
Dr Mari Thomas discussed treatment choices for the patient case
To conclude the session, there was the opportunity for the panel to respond to audience questions, which included queries on how to determine the presence of brain metastases and how these should be treated, and the approach to anticoagulation in low risk cancers. For any questions that were not addressed during the course of the symposium, or those raised by people viewing the symposium on demand, Lord Kakkar will be providing a response in a video to be released in the weeks following ICTHIC. Recordings from the symposium will soon be uploaded to the Thrombosis Management digital platform.
The ICTHIC 2021 digital information desk
Analysis of the Danish Cancer Registry showed that VTE occurred more frequently in a cancer cohort than a matched control. Systemic cancer treatment also emerged as a risk factor.
Treatment with LMWH or NOACs was associated with similar incidences of intracranial haemorrhage in patients with brain metastasis over 12 months in a retrospective cohort study. This study is now being expanded into a large, multinational study.
Results from the GARFIELD-VTE registry demonstrated that patients with cancer who develop thrombosis have a high burden of mortality. These findings have been used to develop the GARFIELD-VTE mortality risk tool, which has been validated using the Danish National Registry and will be presented at International Society on Thrombosis and Haemostasis (ISTH) 2021 (17–21 July, Philadelphia, USA).
Slide showing countries participating in the GARFIELD-VTE registry]
Kakkar AJ et al. ICTHIC Virtual Congress, 22–26 April 2021. Oral Presentation PL-23.
[Presentation Plenary Session 6]
Bayer is committed to continue addressing evidence gaps for CAT patients.