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JACC CardioOncol
JACC CardioOncol
JACC: CardioOncology
2666-0873
Elsevier

S2666-0873(24)00213-8
10.1016/j.jaccao.2024.03.014
Letters
To the Editor
Assessing the Certainty of Evidence on Efficacy and Safety of Anticoagulants for Cancer-Associated Thrombosis
Khan Faizan PhD faizan.khan1@ucalgary.ca
∗
Carrier Marc MD
Rochwerg Bram MD
∗ Department of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary AB T2N 4N1, Canada faizan.khan1@ucalgary.ca
02 7 2024
8 2024
02 7 2024
6 4 622623
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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pmcIn their comprehensive systematic review and network meta-analysis, Fujisaki et al1 compared the efficacy and safety of direct oral anticoagulants (DOACs) for managing venous thromboembolism (VTE) in patients with cancer. We appreciate the authors’ efforts in synthesizing the evidence to guide clinicians on the selection of DOACs in this patient population. However, we noted that assessments of the certainty of evidence were not provided. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines recommend presenting assessments of certainty in the body of evidence for all outcomes analyzed.2 This information is crucial for readers to understand the reliability of treatment effect estimates, aiding clinicians in accurately interpreting and applying the findings in clinical practice.

In the authors’ analysis, apixaban was identified as the best anticoagulant for both recurrent VTE and major bleeding outcomes. However, relying solely on treatment rankings can lead to potentially spurious conclusions for several reasons.3 First, differences in rankings may be caused by chance. Second, even if differences are real, they may not be clinically significant. Lastly, and perhaps most importantly, treatment rankings do not account for the certainty of evidence; although apixaban is ranked highest, the evidence supporting this may be of low or very low certainty. Patients and clinicians may prefer a lower-ranked treatment with more certain evidence over a higher-ranked treatment with uncertain evidence. Therefore, it is essential to consider the certainty of evidence when determining treatment rankings to ensure that patients and clinicians make informed decisions on the implementation of findings from a network meta-analysis.

We used the Grading of Recommendations, Assessment, Development, and Evaluations3 approach to assess the certainty of evidence from the authors’ network meta-analysis for comparisons involving apixaban and outcomes of recurrent VTE and major bleeding. With respect to recurrent VTE, we found high certainty evidence for parenteral anticoagulation; moderate certainty for vitamin K antagonists; and very low certainty for rivaroxaban, edoxaban, and dabigatran compared to apixaban (Table 1). For major bleeding, we found very low certainty evidence for all anticoagulants compared to apixaban (Table 1). Therefore, the authors’ conclusion that DOACs seem to have similar efficacy, whereas apixaban may offer a more favorable safety profile is only supported by very low certainty evidence; this level of uncertainty, as per Grading of Recommendations, Assessment, Development, and Evaluations interpretation, indicates “an uncertain effect.” Clinicians should take this certainty of evidence into consideration when assessing the risk-benefit ratios of different DOACs for managing VTE in cancer patients.Table 1 GRADE Assessments of Certainty of Evidence From Fujisaki et al’s Network Meta-Analysis1

Comparison	Direct Estimate HR (95% CI)	GRADE Certaintya	Indirect Estimate HR (95% CI)	GRADE Certaintya	NMA Estimate HR (95% CI)	GRADE Certainty	Narrative Summary	
Recurrent VTE	
 VKA vs apixaban	1.80 (0.42-7.69)	High	2.85 (1.66-4.89)	Moderateb	2.69 (1.62-4.47)	Moderatec	VKA probably increases the risk of recurrent VTE compared to apixaban.	
 Rivaroxaban vs apixaban	Not applicable	Not applicable	1.27 (0.66-2.46)	High	1.27 (0.66-2.46)	Very lowd	There is an uncertain effect of rivaroxaban compared to apixaban on recurrent VTE.	
 Parenteral vs apixaban	1.75 (1.10-2.77)	High	1.11 (0.25-4.85)	Moderateb	1.68 (1.08-2.61)	High	Parenteral anticoagulants increase the risk of recurrent VTE compared to apixaban.	
 Edoxaban vs apixaban	Not applicable	Not applicable	1.22 (0.68-2.18)	High	1.22 (0.68-2.18)	Very lowd	There is an uncertain effect of edoxaban compared to apixaban on VTE.	
 Dabigatran vs apixaban	Not applicable	Not applicable	1.70 (0.48-5.99)	Moderateb	1.70 (0.48-5.99)	Very lowd	There is an uncertain effect of dabigatran compared to apixaban on recurrent VTE.	
Major bleeding	
 VKA vs apixaban	2.25 (0.39-13.09)	High	1.68 (0.73-3.85)	High	1.77 (0.84-3.75)	Very lowd	There is an uncertain effect of VKA compared to apixaban on major bleeding.	
 Rivaroxaban vs apixaban	Not applicable	Not applicable	1.22 (0.47-3.19)	High	1.22 (0.47-3.19)	Very lowd	There is an uncertain effect of rivaroxaban compared to apixaban on major bleeding.	
 Parenteral vs apixaban	1.44 (0.70-2.96)	High	1.93 (0.32-11.73)	High	1.50 (0.77-2.92)	Very lowd	There is an uncertain effect of parenteral anticoagulants compared to apixaban on major bleeding.	
 Edoxaban vs apixaban	Not applicable	Not applicable	2.66 (1.07-6.58)	High	2.66 (1.07-6.58)	Very lowd	There is an uncertain effect of edoxaban compared to apixaban on major bleeding.	
 Dabigatran vs apixaban	Not applicable	Not applicable	0.76 (0.12-4.99)	High	0.76 (0.12-4.99)	Very lowd	There is an uncertain effect of dabigatran compared to apixaban on major bleeding.	
GRADE = Grading of Recommendations, Assessment, Development, and Evaluations; NMA = network meta-analysis; VKA = vitamin K antagonist; VTE = venous thromboembolism.

a Does not incorporate imprecision (only assessed at the network meta-analysis level).

b Certainty downrated for inconsistency in comparisons making up the most informative first-order loop.

c The vast majority of evidence coming from an indirect estimate, which is of moderate certainty.

d Certainty downrated multiple levels because of extremely serious imprecision with very wide CIs that do not exclude the possibility of important benefit or harm.

Dr Khan has received financial support through the Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research. Dr Carrier has received grants from BMS, Leo Pharma, and Pfizer; and has received personal fees from BMS, Leo Pharma, Bayer, Pfizer, Servier, and Sanofi. Dr Rochwerg has reported that he has no relationships relevant to the contents of this paper to disclose.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
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References

1 Fujisaki T. Sueta D. Yamamoto E. Comparing anticoagulation strategies for venous thromboembolism associated with active cancer: a systematic review and meta-analysis J Am Coll Cardiol CardioOnc 6 1 2024 99 113
2 Page M.J. McKenzie J.E. Bossuyt P.M. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews BMJ 372 2021 n71
3 Puhan M.A. Schünemann H.J. Murad M.H. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis BMJ 349 2014 g5630
