Risk assessment of thromboembolic events in hospitalized cancer patients: the INDICATE study

Background

Thromboprophylaxis (TP) with low-molecular-weight heparins (LMWHs) and direct oral anticoagulants (DOACs) was demonstrated to approximately halve venous thromboembolic event (TE) risk in ambulatory cancer patients.^1,2

However, given the related risk of bleeding, several TE risk assessment models (RAMs) have been developed in order to limit TP in patients at high TE risk, while sparing low-risk patients from developing unnecessary TP-related complications. The most widely used risk stratification tool is represented by the Khorana Score (KS), which groups patients into risk categories based on tumor type, blood count and body mass index (BMI).^3,4.

All RAMs were designed and validated in the outpatient setting, as 75% of TE cases occur in this population but were not validated in hospitalized cancer patients.^5,6

In this setting international guidelines recommend TP in cancer patients in the presence of acute medical illness or reduced mobility; in all other cases, the decision to provide TP is left to the clinicians’ judgment.⁶ This uncertainty frequently leads to a gray area of heterogeneous and sometimes inappropriate prescriptions, with potential drug interactions, preventable side effects and increased healthcare costs.

Hospitalization is an independent risk factor for thrombosis,⁵ and hospitalization-related thrombotic complications frequently result in increased morbidity and mortality in cancer patients. At the same time, these patients are also at increased risk for bleeding, so that the prevention of one adverse event may result in an unjustified higher risk of the other.⁷

For these reasons, it is of primary importance to define the best strategy to prevent TEs without causing bleeding as a side effect. In this view, the definition and validation of a RAM for TEs in hospitalized cancer patients is an unmet need. Initial results from two retrospective series investigating the role of the KS to assess TE risk in the hospitalized cancer population^8,9 showed a low rate of TEs among patients with low-risk KS (1.4–2.5%), paralleled by a significant higher TE risk in patients with KS ≥2 (odds ratio 1.8 and 2.3, respectively). However, their results were derived from retrospective, non-European cohorts and without considering the post-discharge window.

The study

A recent prospective observational study (INDICATE¹⁰) investigated RAMs for hospitalization-related TEs in an Italian cohort of cancer patients. The primary objective of the INDICATE study was to evaluate the negative predictive value (NPV) of low-grade KS (0), evaluated at the time of patients’ in-hospital admission, as a tool to predict the risk of TEs in cancer patients during and after (next 45 days) hospitalization. As secondary objectives, the study also assessed the KS-positive predictive value (PPV), the impact of hospitalization-related TEs on patients’ overall survival (OS), and aimed at developing a new RAM tailored for the hospitalized cancer patient population.

Khorana score NPV and PPV in the study population

According to the statistical plan, the study enrolled 535 patients, of whom 153 had KS = 0. INDICATE met its primary endpoint, demonstrating an NPV of the KS >95%. However, though the study cohort was not powered for this evaluation, the PPV of the KS was found to be very low (~6%). This result was likely due to the low prevalence of TEs, which, in line with previous reports, was 5.4%. Notably, nearly 60% of these events occurred after discharge, highlighting the need to consider the post-hospitalization window as a high-risk period. As expected, the authors confirmed that hospitalization-related TEs are associated with significantly poorer OS.

Development of a new RAM

Given the low performance of the KS, the investigators developed a new RAM: this model is based on three parameters, namely albumin, LDH levels, as measured at in-hospital admission, and presence of tumor-related vascular compression. The new RAM was internally validated, and a corresponding nomogram was designed. Furthermore, a web calculator was created to estimate hospitalization-related TEs risk in a quick and user-friendly mode for clinicians (https://federico-nichetti.shinyapps.io/indicate_webcalc/).

Conclusion

In summary, the study confirmed that hospitalization-related TEs is a negative prognostic factor in cancer patients and that its optimal prediction and prevention is still an unmet need. The INDICATE study has some limitations, including the heterogeneous population enrolled and the monocentric nature of the investigation. Indeed, external validation of the new risk model was hampered by the pandemic, which delayed research efforts and collaborations and is thus desirable in the near future to make this new model more robust and adopted in clinical practice.

References

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2. Carrier, M. et al. Apixaban to prevent venous thromboembolism in patients with cancer. N. Engl. J. Med. 380, 711–719. https://doi. org/ 10. 1056/ NEJMo a1814 468 (2019).
3. Khorana, A. A., Kuderer, N. M., Culakova, E., Lyman, G. H. & Francis, C. W. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 111, 4902–4907. https:// doi. org/ 10. 1182/ blood- 2007- 10- 116327 (2008).
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7. Di Nisio, M. et al. Bleeding and venous thromboembolic events in patients with active cancer hospitalized for an acute medical illness. Thromb. Res. 169, 44–49. https:// doi. org/ 10. 1016/j. throm res. 2018. 07. 010 (2018).
8. Patell, R., Rybicki, L., McCrae, K. R. & Khorana, A. A. Predicting risk of venous thromboembolism in hospitalized cancer patients: Utility of a risk assessment tool. Am. J. Hematol. 92, 501–507. https:// doi. org/ 10. 1002/ ajh. 24700 (2017).
9. Parker, A. et al. Risk stratification for the development of venous thromboembolism in hospitalized patients with cancer. J. Thromb. Haemost. 16, 1321–1326. https:// doi. org/ 10. 1111/ jth. 14139 (2018).
10. Nichetti, F et al. Risk assessment of thromboembolic events in hospitalized cancer patients. Scientfic Reports, 11:18200. https://doi.org/10.1038/s41598-021-97659-9 (2021)