During the ICTHIC webinar, “Updates in cancer-associated thrombosis,” Dr. Luis Jara-Palomares gave a lecture on the management of incidental venous thromboembolism (VTE) in cancer patients. Here, we summarize the key messages of his speech. You can also watch Jara-Palomares’s lecture in the video below and the full webinar recording here.
The annual death rate of cancer-associated thrombosis (CAT) is 448 per 100,000 people. People with cancer have a 47-fold increase in VTE compared with the general population, and infections and VTE are the second highest cause of death in the cancer population [1].
Guidelines
All the guidelines about the management of VTE in cancer patients agree that incidental VTE and symptomatic VTE should be addressed and treated in the same manner [2-5]. Of note, the American College of Chest Physicians (ACCP) 2021 guidelines label the suggestion of the same initial and long-term anticoagulation treatment for patients with incidental and symptomatic VTE as a weak recommendation with moderate certainty evidence [4].
Overview of relevant data
The TESEO registry study found that half of the patients with VTE are unsuspected [6].
However, this percentage might vary in different cohorts or based on the location of the VTE analyzed.
For example, another study including patients with VTE in different locations (e.g., pulmonary embolism, subclavian and jugular, femoropopliteal, inferior vena cava, cerebral veins, and more) found that 28% of patients with VTE have incidental VTE [7].
Unfortunately, the studies available in the field are very heterogenous in outcomes and follow-up, which can influence the results. In addition, most published studies focus on pulmonary embolism (PE) only, comparing patients with symptomatic PE versus asymptomatic PE.
A systematic review and meta-analysis comparing patients with incidental VTE versus symptomatic VTE analyzed more than 3,000 papers obtaining three randomized control trials (with low risk of bias) and 20 observational studies worth being included [8].
The quality of the 20 observational studies was heterogenous: 45% did not adjust outcomes by different variables (which implies a lack of comparability), 30% did not report an assessment of outcome, and 40% did not report adequate follow-up. Clinically relevant non-major bleeding events were rarely reported in observational studies [8].
Results show that the range of incidental VTE is very wide, from 3.8% to more than 80%, depending on the study’s design. In addition, as stated before, 89% of the observational studies only compared incidental versus symptomatic PE [8].
In most observational studies, survival was better in patients with incidental VTE [8].
Considering only the randomized control trial, the study shows that at 6 months, patients with incidental VTE have less recurrent VTE compared to patients with symptomatic VTE, with a rate ratio of 0.62 and a risk difference of incidental VTE less than 3.2% [8].
Moreover, there was a numerical difference, but not a statistical difference, in major bleeding: it seems that patients with incidental VTE experience more major bleeding at six months. The study did not highlight any differences regarding overall mortality between patients with incidental versus symptomatic VTE [8].
Focus on subgroup analyses
Subgroup analyses are generally performed to assess potential heterogenous treatment effects in specific subgroups of patients. However, inappropriate conduct and interpretation of subgroup analyses can result in misleading subgroup effects.
An editorial analyzed the quality and reliability of subgroup analysis from clinical trials, showing that only 16% of these studies claiming a subgroup effect have high credibility [9].
Also, 33% of statements in publications of 246 RCTs about pre-specification of subgroup analyses were not supported by documentation in the protocol [9].
These results need to be taken into consideration because, theoretically, multiple subgroup analyses can be performed until the finding of interest is achieved, and, to perform a valid sub-analysis the pre-specification of the subgroup analysis should be included in the original trial protocol.
As an example, if investigators select only five subgroup variables to assess the heterogeneity of treatment effects for the primary efficacy and the primary safety outcome (i.e., a test of 10 hypotheses), the chance of at least one false-positive finding at a significance level of 0.05 is 40%.
In addition, subgroup analysis effects should be considered as hypothesis-generating more than confirmatory.
These data push toward a more careful approach to interpreting subgroup analyses.
Conclusion
In conclusion, incidental VTE should be treated as symptomatic VTE, and patients with incidental VTE have less recurrent VTE and might be at risk of more major bleeding.
Finally, more randomized control trials with a clear pre-specification of subgroup analyses in the protocol are needed to ensure results reliability.
References
- Khorana AA. Venous thromboembolism and prognosis in cancer. Thromb Res. 2010;125(6):490-493. doi:10.1016/j.thromres.2009.12.023
- Key NS, Khorana AA, Kuderer NM, et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2020;38(5):496-520. doi:10.1200/JCO.19.01461
- Lyman GH, Carrier M, Ay C, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv. 2021;5(4):927-974. doi:10.1182/bloodadvances.2020003442
- Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest. 2021;160(6):e545-e608. doi:10.1016/j.chest.2021.07.055
- Farge D, Frere C, Connors JM, et al. 2022 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, including patients with COVID-19. Lancet Oncol. 2022;23(7):e334-e347. doi:10.1016/S1470-2045(22)00160-7
- Carmona-Bayonas A, Gómez D, Martínez de Castro E, et al. A snapshot of cancer-associated thromboembolic disease in 2018-2019: First data from the TESEO prospective registry. Eur J Intern Med. 2020;78:41-49. doi:10.1016/j.ejim.2020.05.031
- Font C, Farrús B, Vidal L, et al. Incidental versus symptomatic venous thrombosis in cancer: a prospective observational study of 340 consecutive patients. Ann Oncol. 2011;22(9):2101-2106. doi:10.1093/annonc/mdq720
- Caiano L, Carrier M, Marshall A, et al. Outcomes among patients with cancer and incidental or symptomatic venous thromboembolism: A systematic review and meta-analysis. J Thromb Haemost. 2021;19(10):2468-2479. doi:10.1111/jth.15435
- Tritschler T, Sadeghipour P, Bikdeli B. Subgroup analysis in randomized controlled trials: Useful or misleading?. Thromb Res. 2022;S0049-3848(22)00426-1. doi:10.1016/j.thromres.2022.10.009