During the 10th ICTHIC, Prof. Marcello di Nisio (University of Chieti, Italy) and Prof. Marc Carrier (Ottawa Hospital Research Institute, Canada) discussed the management of incidental venous thromboembolsim (iVTE). Is iVTE comparable to symptomatic events, or is it like mixing apples and oranges? Should iVTE and symptomatic VTE be treated the same way?
iVTE is defined as deep venous thrombosis or pulmonary embolism (PE) diagnosed on an imaging test performed for reasons other than a clinical suspicion of VTE. It is frequent in patients with cancer because they have an increased risk of VTE and undergo imaging tests frequently to assess cancer staging and treatment .
Thanks to the development of imaging techniques, diagnoses of iVTE increased dramatically in recent years .
iVTE: to treat or not to treat? The YES side.
At the beginning of the debate at the 10th ICTHIC, 96% of the audience agreed that iVTE needs to be treated as symptomatic VTE.
Dr. di Nisio thinks so too. “Incidental VTE represents about half of all thrombosis events in cancer patients, and when it develops it is associated with a high risk of recurrent thrombosis,” said Prof. di Nisio.
A prospective observational study on 340 adult patients with cancer found that 28% of VTEs and nearly half the PEs were incidentally diagnosed and asymptomatic at clinical evaluation. In the iVTE group, most thrombi involved large vessels (central PE, vena cava and iliac veins), while symptomatic VTE occurred mostly in the limbs .
A single-center, retrospective cohort study on 195 patients with established PE and active malignancy found a comparable 1-year recurrence risk for VTE, bleeding complications and mortality between patients with cancer with incidental and symptomatic PE .
A pooled analysis of 926 patients with cancer-associated incidental PE showed a 6-month VTE recurrence risk of 12% (95% CI: 4.7–23%) in patients who were left untreated. In the pre-treatment analysis, the incidence rate of recurrent VTE in patients who did not receive anticoagulant treatment was 30% patient-years (95% CI: 8.2–77), emphasizing the high risk of symptomatic recurrent VTE in cancer patients with incidental PE .
A sub-analysis of the Hokusai-VTE Cancer Study (NCT02073682, a randomized controlled trial comparing edoxaban with dalteparin for cancer-associated VTE) analyzed the composite of first recurrent VTE or major bleeding in patients with incidental or symptomatic VTE during 12 months. 7.9% of patients with incidental VTE developed recurrent VTE (mostly symptomatic PE) during 12 months of follow-up, despite initiating anticoagulant treatment. In addition, the 12-month major bleeding risk was numerically higher in patients with incidental VTE (6.6%) than in those with symptomatic VTE (4.9%; HR: 1.31, 95% CI: 0.76–2.24) .
The study suggests that in cancer patients with iVTE, the risk of recurrent VTE is substantial despite the initiation of anticoagulant treatment. Incidental VTE is a serious condition, which should be treated like symptomatic VTE .
These data were recently pooled with those of other two studies, the Caravaggio and the SELECT-D studies, in a systematic review and meta-analysis comparing the efficacy and safety of direct oral anticoagulants (DOACs) and low-molecular-weight heparins (LMWH) in cancer patients. The incidence of recurrent thrombosis in this study was about 5% in patients presenting with index iVTE and cancer. The use of DOACs reduced the incidence of recurrence by about a half compared to LMWH and without increasing the risk of major bleeding .
The most recent guidelines recommend anticoagulant treatment for patients with cancer and iVTE as for those with symptomatic VTE.
The American Society of Hematology’s guidelines recommends for patients with cancer and incidental PE a short-term anticoagulation treatment rather than observation .
The American Society of Clinical Oncology’s guidelines indicates that incidental PE and deep vein thrombosis (DVT)should be treated the same manner as symptomatic VTE .
The European Society of Cardiology recommends managing incidental PE in the same manner as symptomatic PE if it involves segmental or more proximal branches, multiple subsegmental vessels, or a single subsegmental vessel in association with proven DVT .
For all these reasons, Prof. di Nisio suggests that Incidental VTE is highly prevalent and prognostically relevant, and treatment with LMWH or DOACs should be considered.
Incidental VTE: to treat or not to treat? The NO side.
Prof. Marc Carrier thinks that iVTE is not the same as symptomatic VTE. “Comparing the two events is like comparing oranges and apples,” says Prof. Carrier.
Considering incidental DVT events, in the HIDDen study (a prospective observational study of 346 patients with advanced cancer), 34% (95% CI: 28–40) of patients with evaluable scans had femoral vein thrombosis. No statistical difference in survival between patients with or without DVT was found over time . “The reason to prescribe anticoagulant is to prevent a fatal event, and there is no indication of that in this study,” said Prof. Carrier. “Therefore, studies on the natural history of screening-detected DVT in patients with cancer are needed before we can incorporate them in inclusion criteria or primary outcome measures of randomized trials.”
Incidental PE diagnosis is generally performed through a non-dedicated scan. For this reason, it is of utmost importance to define which filling defects can be defined as PE.
An observational study including 9571 autopsies of patients with cancer highlighted that of the 1191 patients iwth pulmonary artery obstruction identified, 16% were not PE but rather tumor thrombosis, septic embolism, fat tissue embolism, and bone marrow embolism. On these, anticoagulant therapy would be of little benefit .
“When identifying a filling defect through a non-dedicated scan, it is important to consider that it might not be incidental PE and that anticoagulant therapy might not be useful,” said Prof. Carrier.
But also, when diagnosing incidental PE over time, it is essential to define if they are associated with the same risk of recurrence as a symptomatic event.
Going back to the post-hoc analysis of the Hokusai-VTE Cancer study mentioned by Prof. di Nisio, we can highlight a bias in result interpretation. A 3% difference (non-statistically significant) exists between the absolute rate of recurrent VTE in patients with iVTE compared to symptomatic VTE. “When interpreting the results from the same study about DOACs and LMWH in decreasing the risk of recurrent VTE, a 3.4% difference between the two types of drugs is enough to let us think that DOACs are better than LMWH. But when we look at the 3% difference in the risk of recurrent VTE between incidental and symptomatic VTE, the conclusions are different. Suddenly there is no difference at all,” says Dr. Carrier.
In a systematic review and meta-analysis comparing the risk of recurrence for incidental and symptomatic treated patients, the incidental VTE has a statistically significant lower risk of recurrence than the symptomatic one, with a trend in increased major bleeding events .
In an international prospective observational cohort study in patients with cancer and incidental PE mostly treated with LMWH, the risk of recurrent VTE over 12 months was about 6% .
“The rate reported in randomized controlled trials at 12 months was 9% for the Select-D and CLOT studies, 11.3% for the Hokusai-VTE Cancer study, and 7.9% for the Caravaggio study. This means that the risk of recurrence in iVTE in the real-world data is almost half of what has been described in the LMWH randomized control data,” said Prof. Carrier.
In conclusion, it is important to bear in mind that screening-detected DVT may or may not be as clinically important as symptomatic DVT in patients with cancer. The same goes for incidental PE; it may or not be thromboembolism and may not be associated with the same risk of recurrent VTE despite anticoagulation.
Dr. Carrier’s take-home message is, “Treat for now, but more data are needed to confirm that we are doing the right thing by exposing patients with incidental VTE to long-term anticoagulants.”
More research is needed to understand the best treatment for incidental VTE. At the end of the debate, Dr. Carrier was able to drag to his side 23% of the audience, who changed their mind and voted not to treat iVTE in a new poll at the end of the debate.
What about you? Did you change your mind?
1- Meyer G, Planquette B. Incidental venous thromboembolism, detected by chance, but still venous thromboembolism. Eur Respir J. 2020;55(2):2000028. doi:10.1183/13993003.00028-2020
2- 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
3- den Exter PL, Hooijer J, Dekkers OM, Huisman MV. Risk of recurrent venous thromboembolism and mortality in patients with cancer incidentally diagnosed with pulmonary embolism: a comparison with symptomatic patients. J Clin Oncol. 2011;29(17):2405-2409. doi:10.1200/JCO.2010.34.0984
4- van der Hulle T, den Exter PL, Planquette B, et al. Risk of recurrent venous thromboembolism and major hemorrhage in cancer-associated incidental pulmonary embolism among treated and untreated patients: a pooled analysis of 926 patients. J Thromb Haemost. 2016;14(1):105-113. doi:10.1111/jth.13172
5- Mulder FI, Di Nisio M, Ay C, et al. Clinical implications of incidental venous thromboembolism in cancer patients. Eur Respir J. 2020;55(2):1901697. doi:10.1183/13993003.01697-2019
6- Mulder FI, Bosch FTM, Young AM, et al. Direct oral anticoagulants for cancer-associated venous thromboembolism: a systematic review and meta-analysis. Blood. 2020;136(12):1433-1441. doi:10.1182/blood.2020005819
7- 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
8- 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
9- Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543-603. doi:10.1093/eurheartj/ehz405
10- White C, Noble SIR, Watson M, et al. Prevalence, symptom burden, and natural history of deep vein thrombosis in people with advanced cancer in specialist palliative care units (HIDDen): a prospective longitudinal observational study. Lancet Haematol. 2019;6(2):e79-e88. doi:10.1016/S2352-3026(18)30215-1
11- Gimbel IA, Mulder FI, Bosch FTM, et al. Pulmonary embolism at autopsy in cancer patients. J Thromb Haemost. 2021;19(5):1228-1235. doi:10.1111/jth.15250
12- 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;10.1111/jth.15435. doi:10.1111/jth.15435
13- Kraaijpoel N, Bleker SM, Meyer G, et al. Treatment and Long-Term Clinical Outcomes of Incidental Pulmonary Embolism in Patients With Cancer: An International Prospective Cohort Study. J Clin Oncol. 2019;37(20):1713-1720. doi:10.1200/JCO.18.01977