A consensus viewpoint on the role of direct factor Xa inhibitors in the management of cancer-associated venous thromboembolism in the UK

Figures & data

Table 1. Trials evaluating direct factor Xa inhibitors versus LMWH in cancer-associated VTE populations.

Trial	Intervention/ Comparator	Population	Cancer types	Primary outcome(s)	VTE recurrence	MB	CRNMB	Summary of outcomes
					HR (95% CI)	HR (95% CI)	HR (95% CI)
Apixaban
Caravaggio NCT03045406^12	Apixaban vs. dalteparin	Cancer pts with symptomatic or incidental acute proximal DVT/PE	Cancers exc. BCC or SCC of the skin, primary brain tumor, intracerebral metastases or acute leukemia	Recurrent VTE (<6 months)	0.63 (0.37, 1.07); p <.001*	0.82 (0.40, 1.69). p = .60	1.16 (0.77, 1.75)	Apixaban (oral) was noninferior to dalteparin (SC) for the treatment of cancer associated VTE without an increased risk of MB.
ADAM VTE NCT02585713^10	Apixaban vs. dalteparin	Cancer pts with acute DVT/PE/splanchnic or CVT	Solid and hematologic malignancies	Major bleeding (<6 months)	0.099 (0.013, 0.780); p = .0281	Not estimable†	NR	Apixaban (oral) was associated with low MB and VTE recurrence rates for the treatment of VTE in cancer patients.
Rivaroxaban
SELECT-D NCT02583191^15	Rivaroxaban vs. dalteparin	Cancer pts with symptomatic or incidental PE/symptomatic lower extremity proximal DVT	Solid and hematologic malignancies exc. BCC or SCC of the skin	Recurrent VTE (<6 months)	0.43 (0.19, 0.99)	1.83 (0.68, 4.96)	3.76 (1.63, 8.69)	Rivaroxaban was associated with significantly lower VTE recurrence but higher MB and significantly higher CRNMB compared with dalteparin.
CASTA DIVA NCT02746185^17	Rivaroxaban vs. dalteparin	Cancer pts with symptomatic or incidental proximal lower limb DVT/iliac or inferior vena cava thrombosis and/or PE	Solid active cancer, high grade lymphoma or myeloma	Recurrent VTE (<3 months)	SHR: 0.75 (0.21, 2.66); p = .13	SHR: 0.36 (0.04, 3.43)	1.48 (1.18, 1.85)	The number of patients was insufficient to reach the predefined criteria for noninferiority, but efficacy and safety results were consistent with those previously reported with DOACs
Edoxaban
Hokusai VTE Cancer NCT02073682^13^,^14	Edoxaban vs. dalteparin	Cancer pts with acute symptomatic or incidental proximal DVT and/or PE	GI, lung, urogenital, breast, hematological, gynecological	Recurrent VTE or major bleeding over 12 months	0.97 (0.70, 1.36) p = .006*	1.77 (1.03, 3.04) p = .04	1.38 (0.98, 1.94)	Edoxaban was noninferior to dalteparin for the composite outcome of recurrent VTE or major bleeding. The rate of recurrence was lower but the rate of major bleeding was higher with edoxaban. Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups.

*p-value for non-inferiority; †0 bleeding events in apixaban group.

BCC, basal cell carcinoma; CRNMB, clinically relevant non-major bleeding; CVT, cerebral vein thrombosis DVT, deep vein thrombosis; GI, gastrointestinal; HR, hazard ratio; MB, major bleeding; NR, not reported; PE, pulmonary embolism SCC, squamous cell carcinoma; SHR, subdistribution hazard ratio; VTE, venous thromboembolism.

Table 2. Summary of cancer-associated VTE clinical guidelines.

Guideline	Initial treatment	<6 Months	>6 Months
NCCN^34 (2022), USA	First 5–10 days LMWH, UFH, fondaparinux, rivaroxaban or apixaban are recommended for the first 5–10 days.	LMWH is preferred in pts with proximal DVT or PE and for prevention of recurrent VTE in pts with advanced metastatic cancer. For patients who refuse/contraindicated to LMWH, direct factor Xa inhibitors should be considered	Warfarin, edoxaban, or dabigatran
	Patients with gastric or gastroesophageal tumors treated with direct factor Xa inhibitors are at greater risk of hemorrhage. Apixaban may be safer than edoxaban/rivaroxaban for patients with gastric or gastric esophageal lesions (category 2B)
CHEST^20 (2021), USA	First 5–21 days Apixaban, edoxaban, rivaroxaban preferred over LMWH for 3 months	<3 Months Apixaban, edoxaban, rivaroxaban preferred over LMWH for 3 months	>3 Months Direct factor Xa inhibitors recommended, with reduced-dose apixaban or rivaroxaban preferred VKAs are recommended in those who cannot receive direct factor Xa inhibitors. Aspirin is recommended over no therapy at all.
	Edoxaban and rivaroxaban appear to be associated with a higher risk of GI major bleeding than LMWH in patients with CAT and a luminal GI malignancy, while apixaban does not. Apixaban or LMWH may be the preferred option in patients with luminal GI malignancies.
ASH^19 (2021), USA	Week 1 Apixaban, rivaroxaban or LMWH. LMWH preferred over UFH and fondaparinux.	For patients with active cancer, apixaban, edoxaban, or rivaroxaban preferred over LMWH, with both preferred over VKAs.	Recommended to continue indefinitely on direct factor Xa inhibitors or LMWH for patients with active cancer and VTE
	Note: DOACs should be used carefully in patients with GI cancers, considering specific clinical setting to minimise risk, after careful consideration of potential DDIs, bleeding risk, patient preference and availability of treatment options including cost considerations
NICE^22 (2020), UK	Offer anticoagulation for 3–6 months. DOAC recommended. If not suitable, consider one of: LMWH LMWH and a VKA for at least 5 days or until INR ≥2.0 on 2 consecutive readings, then a VKA alone		Consider stopping after provoked DVT/PE if uncomplicated and the provoking factor is not present. Consider continuing after an unprovoked DVT/PE if well tolerated. In this who decline to continue, consider aspirin
	Take into account tumor site, drug interactions including cancer drugs, and bleeding risk (HAS-BLED score)
ASCO^35 (2020), USA	First 5–10 days LMWH recommended (if CrCl ≥30 mL/min) LMWH, UFH, fondaparinux or rivaroxaban	LMWH, edoxaban, or rivaroxaban preferred for at least 6 months VKAs should be considered only if LMWH or direct factor Xa inhibitors are inaccessible	Selective continuation beyond 6 months (e.g. unprovoked DVT/PE; metastatic disease; receiving SACT) Reassess intermittently to ensure an appropriate risk-benefit profile
ITAC^36 (2019), international	First 5–10 days LMWH recommended (if CrCl ≥30 mL/min) Rivaroxaban (0–10 days) or edoxaban (>5 days after parenteral anticoagulation) are alternatives UFH/fondaparinux may be used if LMWH/direct factor Xa inhibitors are contraindicated	Minimum treatment period of 6 months LMWH and direct factor Xa inhibitors (edoxaban/rivaroxaban) preferred over VKAs	Any continuation should be evaluated based on appropriate risk-benefit profile
ISTH^37 (2018), international	Low-risk of bleeding: Edoxaban and rivaroxaban preferred based on available evidence LMWH is also an acceptable option Individualized decision making including patient consultation High risk of bleeding (e.g. GI/genitourinary malignancy or mucosal abnormalities): LMWH are recommended Edoxaban and rivaroxaban are acceptable alternatives, if no DDI with current therapy

Abbreviations. ASCO, American Society of Clinical Oncology; ASH, American Society of Hematology; CHEST, the American College of Chest Physicians; CrCl, creatinine clearance; DOAC, direct oral anticoagulants; DVT, deep vein thrombosis; FDA, Food & Drug Administration; ISTH, International Society on Thrombosis and Haemostasis; ITAC, International Initiative on Thrombosis and Cancer; LMWH, low molecular weight heparin; NCCN, National Comprehensive Cancer Network; NICE, National Institute for Health and Care Excellence; PE, pulmonary embolism; UFH, unfractionated heparin; VKA, vitamin-K antagonists; VTE, venous thromboembolism.

Figure 1. Synopsis.

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Data availability  statement

None