DOACs in patients with brain cancers - promising but still a long way to go

Sep 24, 2026

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Response to editor comments regarding a recent meta-analysis of direct oral anticoagulants (DOACs) versus low-molecular-weight heparin (LMWH) for patients with primary or metastatic brain cancers and VTE. The letter addresses limitations of prior evidence, including retrospective design, small samples, and selection bias, and argues updated analyses are consistent with a lower intracranial bleeding (ICH) risk for DOACs. It reports updated pooled risk ratios favoring DOACs, discusses clinical similarity across studies, and calls for future research using prospective or randomized designs.

LanguageEnglish

CategoryHealthcare

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Pages2

Reading Time5 min

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Response to the editor

Meta-analysis limitations and author agreement

Updated results and pooled risk estimates

Need for future trials and study designs

RESPONSE TO THE EDITOR: DOACs in patients with brain cancers: promising but still a long way to go Michela Giustozzi, 1 Cecilia Becattini, 1 Fausto Roila,2 Giancarlo Agnelli, 1 and Mario Mandal`a2 1 Internal, Vascular and Emergency Medicine–Stroke Unit, University of Perugia, Perugia, Italy; and 2 Unit of Medical Oncology, University of Perugia, Perugia, Italy We wish to thank Buka and Sutton for their comments on our recently published article.1 Among the results of our meta-analysis of patients with primary or metastatic brain cancer and VTE, the authors focused their attention on the lower risk of intracranial bleeding (ICH) in patients treated with direct oral anticoagulants (DOACs) than that in those receiving low-molecular weight heparin (LMWH) and advice caution for implementing this ﬁnding in the clinical practice. The authors state that these conclusions are driven mainly by Carney’s study, which has several limitations including (1) the retrospective design, (2) the patient population, and (3) the potential selection bias.2 Buka and Sutton concluded that differences in outcomes between DOACs and LMWH are likely to be small in patients with primary brain cancer or brain metastases and therapy should be determined on a case-by-case basis. We indeed agree with the authors that in patients with primary or metastatic brain cancer and VTE, comparison between DOACs and LMWH requires caution and we are aware that all the 5 included studies have a retrospective design, a limited sample size, and some potential bias, not addressable by speciﬁc statistical analyses such as propensity score matching method. Nevertheless, our results seem to support DOACs as a valid option for the treatment of VTE in these patients for the following reasons: (1) the heterogeneity of our meta-analysis was 0%, which means that the variation in study results between studies is low. Moreover, after excluding the ﬁndings by Carney et al,2 the risk of ICH remains lower in patients treated with DOACs than that in those treated with LMWH, although not statistically signiﬁcant because of the small number of patients included (Relative risk [RR], 0.71; 95% conﬁdence interval [CI], 0.30-1.68); heterogeneity remains 0% . Furthermore, as shown in Table 1, the clinical features of the patients treated with DOACs or with LMWH are similar in all the included studies. Notably, in the study by Carney et al,2 patients with primary brain cancer or brain metastases treated with DOACs were more likely to have additional risk factors for bleeding than patients treated with LMWH, including concomitant use of aspirin, diagnosis of hypertension or chronic kidney disease. This is somehow reassuring in terms of the safety of DOACs in these patients. Finally, to better investigate this speciﬁc topic, we have updated our meta-analysis (since November 2022) on the risk of ICH inpatients with primary brain cancer and brain metastases treated with DOACs or LMWH by including 2 newly published studies.3,4 Both these studies are retrospective, one included both patients with primary brain cancer and brain metastases (a total of 125 patients) and the other only included patients with glioblastoma (a total of 121 patients) . Overall, 7 studies on a total of 256 patients treated with DOACs and 423 patients treated with LMWH have now been considered. The risk ratio for ICH in the updated meta-analysis is 0.41 (95% CI, 0.25-0.68) in favor of DOACs, and heterogeneity is 0%(Figure 1) . After excluding the ﬁndings by Carney et al, the RR is 0 . 51 (95% CI, 0 .26-1. 00; I2, 0%) . These results support the safety of DOACs compared with that of LMWH, with regard to reduction of ICH in patients with primary brain cancer and brain metastases treated for VTE. We recognize that, in the future, a randomized controlled trial comparing LMWH and DOACs in these patients is advocated to investigate the efﬁcacy and safety of these agents. However, because of the fragility of this popul

FAQs

What comparison does the response focus on for patients with brain cancer and VTE?

It compares direct oral anticoagulants (DOACs) with low-molecular-weight heparin (LMWH) regarding the risk of intracranial bleeding (ICH).

Why do the authors caution against applying the findings directly to clinical practice?

They highlight that included studies are retrospective, have limited sample sizes, and may involve selection bias that is not fully resolved by specific statistical methods such as propensity score matching.

What change does the updated meta-analysis include, and what overall conclusion is reached?

It incorporates two newly published retrospective studies after November 2022, increasing the total number of analyzed patients. The updated pooled results favor DOACs for reducing ICH risk compared with LMWH, despite ongoing calls for more definitive study designs.

Sep 24, 2026

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