The Role of Direct Oral Anticoagulants in the Treatment of Cancer-Associated Venous Thromboembolism: Review by Middle East and North African Experts

Figures & data

Table 1 Characteristics and Efficacy and Safety Outcomes of Randomized Trials Comparing the Safety and Efficacy of DOACs (Apixaban, Edoxaban or Rivaroxaban) and Dalteparin in the Treatment of CAT

	Caravaggio		ADAM VTE		Hokusai VTE Cancer		SELECT-D		CASTA-DIVA
	A (n=576)	D (n=579)	A (n=150)^a	D (n=150)^b	E (n=522)	D (n=524)	R (n=203)	D (n=203)	R (n=74)	D (n=84)
Age, mean (SD) or median (range) years	67.2 (11.3)	67.2 (10.9)	64.4 (11.3)	64.0 (10.8)	64.3 (11.0)	63.7 (11.7)	67 (22–87)	67 (34–87)	68.6 (62.9–77.8)^c	70.7 (62.7–78.7)^c
Male, n (%)	292 (50.7)	276 (47.7)	72 (48.0)	73 (48.7)	277 (53.1)	263 (50.2)	116 (57.1)	98 (48.3)	37 (50.0)	40 (47.6)
Active cancer, n (%)	559 (97.0)^d	565 (97.6)^d	150 (100)^e	150 (100)^e	513 (98.3)^f	511 (97.5)^f	203 (100.0)^f	203 (100.0)^f	74 (100.0)	84 (100.0)
Metastatic disease, n (%)	389 (67.5)^g	396 (68.4)^g	96 (64.0)	97 (64.7)	274 (52.5)	280 (53.4)	118 (58.1)	118 (58.1)	53/69 (76.8)	62/82 (75.6)
GI cancers, n (%)	188 (32.6)	187 (32.3)	48 (32.0)	57 (38.0)	165 (31.6)	140 (26.7)	91 (45.0)	86 (42.4)	21 (28.4)	25 (29.8)
Colorectal	121 (21.0)	113 (19.5)	18 (12.2)	29 (19.6)	83 (15.9)	79 (15.1)	55 (27.0)	47 (23.0)	13 (17.6)	19 (22.6)
Upper GI	23 (4.0)	31 (5.4)	7 (4.8)	4 (2.7)	33 (6.3)	21 (4.0)	15 (7.0)	26 (12.0)	2 (2.7)	1 (1.2)
Incidental DVT or PE, n (%)	116 (20.1)	114 (19.7)	NR	NR	167 (32.0)	173 (33.0)	108 (53.2)	105 (51.7)	36 (48.6)	32 (38.1)
Recurrent VTE, n (%)	32 (5.6)	46 (7.9)	1 (0.7)	9 (6.3)	41 (7.9)	59 (11.3)	8 (4.0)^h	18 (11.0)^h	4 (6.4)	6 (10.1)
HR (95% CI); DOAC vs dalteparin	0.63 (0.37–1.07)		0.099 (0.013–0.78)		0.71 (0.48–1.06)		0.43 (0.19–0.99)		0.75 (0.21–2.65)^i
Major bleeding, n (%)	22 (3.8)	23 (4.0)	0	2 (1.4)	36 (6.9)	21 (4.0)	11 (6.0)^h	6 (4.0)^h	1 (1.4)	3 (3.7)
HR (95% CI); DOAC vs dalteparin	0.82 (0.40–1.69)		0.0 (0.0–)		1.77 (1.03–3.04)		1.83 (3–11)		0.36 (0.04–3.43)^i
Major GI bleeding, n (%)	11 (1.9)	10 (1.7)	0	0	20 (3.8)	6 (1.1)	8 (3.9)	4 (2.0)	NR	NR
HR (95% CI); DOAC vs dalteparin	1.05 (0.44–2.50)		NE		NR		NR		NR
CRNM bleeding, n (%)	52 (9.0)	35 (6.0)	9 (6.2)	7 (4.2)	76 (14.6)	58 (11.1)	25 (13.0)^h	7 (4.0)^h	8 (10.8)	5 (6.0)
HR (95% CI); DOAC vs dalteparin	1.42 (0.88–2.30)		NR		1.38 (0.98–1.94)		3.76 (1.63–8.69)		NR
Mortality, n (%)	135 (23.4)	153 (26.4)	23 (16.0)	15 (11.0)	206 (39.5)	192 (36.6)	48 (23.6)	56 (27.6)	19 (25.7)	20 (23.8)
HR (95% CI); DOAC vs dalteparin	0.82 (0.62–1.09)		1.40 (0.82–2.43)		1.12 (0.92–1.37)		NR		1.05 (0.56–1.97)^h

Notes: This table collates data from the cited published papers,^32–36 also over viewed in two previously published studies^55,56 and new data available since then. ^aPrimary analysis population (n=145). ^bPrimary analysis population (n=142). ^cInterquartile range. ^dCancer diagnosed within the past 6 months; receiving anticancer treatment at the time of enrollment or within the past 6 months; or recurrent locally advanced or metastatic cancer. ^eAny evidence of cancer on cross-section or PET imaging; metastatic disease; and/or cancer-related surgery, chemotherapy, or radiation therapy within the past 6 months. ^fCancer diagnosed within the past 6 months; recurrent, regionally advanced or metastatic cancer; cancer for which treatment had been administered within the past 6 months; hematologic cancer not in complete remission. ^gRecurrent locally advanced or metastatic disease. ^hCumulative percentages. ⁱSubdistribution hazard ratio.

Abbreviations: A, apixaban; CAT, cancer-associated thrombosis; CI, confidence interval; CRNM, clinically relevant nonmajor; D, dalteparin; DOAC, direct oral anticoagulant; DVT, deep-vein thrombosis; E, edoxaban; GI, gastrointestinal; HR, hazard ratio; NE, not evaluated; NR, not reported; PE, pulmonary embolism; PET, positron emission tomography; R, rivaroxaban; SD, standard deviation; VTE, venous thromboembolism.

Table 2 Efficacy and Safety Outcomes of Meta-Analyses of the Hokusai VTE Cancer, SELECT-D, ADAM VTE and Caravaggio Trials of DOACs versus LMWH for the Treatment of CAT

Meta-Analysis	Number of Patients Analyzed	VTE Recurrence^a	Major Bleeding^a	CRNMB^a
Mulder et al^Citation64 b	2607	RR, 0.68; 95% CI, 0.39–1.17	RR, 1.36; 95% CI, 0.55–3.35	RR, 1.63; 95% CI, 0.73–3.64
Giustozzi et al^Citation62	2894	RR, 0.62; 95% CI, 0.43–0.91	RR, 1.31; 95% CI, 0.83–2.08	RR, 1.65; 95% CI, 1.19–2.28
Moik et al^Citation20	2894	RR, 0.62; 95% CI, 0.43–0.91	RR, 1.31; 95% CI, 0.83–2.08	RR, 1.65; 95% CI, 1.19–2.28
Tao et al^Citation66	2894	HR, 0.62; 95% CI, 0.43–0.91	HR, 1.31; 95% CI, 0.83–2.08	HR, 1.65; 95% CI, 1.19–2.28
Haykal et al^Citation63	2907	RR, 0.62; 95% CI, 0.44–0.87	RR, 1.33; 95% CI, 0.45–4.22	RR, 1.58; 95% CI, 1.11–2.24
Saleem et al^Citation65	2907	HR, 0.54; 95% CI, 0.23–1.28	HR, 1.38; 95% CI, 0.45–4.22	HR, 1.77; 95% CI, 0.49–6.40

Notes: This table collates data from the cited published papers,^62–66 also over viewed in two previously published studies.^{55,56 a}DOACs versus LMWH. ^bADAM VTE not included.

Abbreviations: CAT, cancer-associated thrombosis; CI, confidence interval; CRNMB, clinically relevant nonmajor bleeding; DOAC, direct oral anticoagulant; HR, hazard ratio; LMWH, low-molecular-weight heparin; RR, risk ratio; VTE, venous thromboembolism.

Table 3 Guideline Recommendations for the Treatment of Cancer-Associated VTE

Guideline	Recommendations
	Initial Treatment	Treatment Duration
ACCP^a	Apixaban, edoxaban or rivaroxaban (strong recommendation) Apixaban or LMWH may be preferred in luminal GI malignancies.	Extended-phase DOAC therapy (>3 months) Reassess periodically.
	DOAC (apixaban or rivaroxaban) or LMWH (conditional recommendation) Caution with DOACs in GI cancers.	Treat for 3–6 months with a DOAC (apixaban, edoxaban or rivaroxaban) over LMWH or VKA (conditional recommendations). Treat for >6 months rather than short term (3–6 months) in patients with active cancer (conditional recommendation). Suggest continuing indefinitely rather than stopping after completion of a definitive period of anticoagulation (conditional recommendation). Use a DOAC or LMWH (conditional recommendation).
NCCN^a	Apixaban (category 1), edoxaban after ≥5 days of parenteral anticoagulation (category 1) or rivaroxaban (category 2A) preferred for patients without gastric or gastroesophageal lesions Caution in GU tract lesions LMWH preferred for patients with gastric or gastroesophageal lesions (category 1). Dabigatran if above regimens are not appropriate or unavailable.	≥3 months or as long as active cancer or cancer therapy.
ASCO^b	LMWH, UFH, fondaparinux, rivaroxaban, or apixaban For long-term anti-coagulation, LMWH, edoxaban, rivaroxaban, or apixaban for at least 6 months are preferred over VKAs. Caution with direct factor Xa inhibitors in patients with GI and GU cancers or other high-risk settings.	Offer LMWH, DOACs or VKAs beyond the initial 6 months to select patients with active cancer, such as those with metastatic disease or those receiving chemotherapy. LMWH, edoxaban or rivaroxaban preferred. LMWH preferred in settings with increased bleeding risk. Assess intermittently to ensure a continued favorable risk-benefit profile. Patients needing extended pharmacologic antithrombotic prophylaxis post cancer surgery Prophylactic doses of LMWH
ESC^b	PE and cancer: LMWH for the first 3–6 months (IIa. A) Edoxaban (IIa. B) or rivaroxaban (IIa. C) may be used except in GI cancer patients.	Extend indefinitely or until the cancer is cured (IIa. B). Consider LMWH, DOAC or VKA.
ITAC^b	LMWH when CrCl ≥30 mL/min (grade 1A). Apixaban or rivaroxaban (first 10 days) or edoxaban (started after initial LMWH/UFH for 5 days) can be used for initial treatment if CrCl ≥30 mL/min and patient is not at high risk of GI or GU bleeding (grade 1 A).	LMWH or DOACs for ≥6 months (grade 1 A) DOACs when CrCl ≥30 mL/min if no impairment in GI absorption or strong DDIs (grade 1 A), but caution advised in GI malignancies, especially upper GI tract. After 6 months, termination or continuation of anticoagulation based on benefit–risk ratio, tolerability, drug availability, patient preference and cancer activity (guidance).
ISTH^b	Patients with low bleeding risk and no DDIs: edoxaban or rivaroxaban; LMWHs are acceptable alternatives. Patients with high bleeding risk^c: LMWH; edoxaban or rivaroxaban as an alternative if no potential DDI.	No specific recommendation.
NICE^b	Consider DOAC if active cancer and confirmed proximal DVT or PE. If DOAC unsuitable, consider LMWH alone or VKA (following initial LMWH). Choice of anticoagulant should consider tumor site, DDIs and bleeding risk.	Review treatment at 3 to 6 months according to clinical need.
ESMO	During the acute phase (first 5–10 days after diagnosis) Consider LMWH, UFH, fondaparinux, apixaban or rivaroxaban (I, A) LMWH is preferable to UFH and fondaparinux (V, A)	For long-term anticoagulation for at least 6 months LMWH, apixaban, edoxaban or rivaroxaban are preferred to VKAs (I, A) In patients with luminal GI cancer, urothelial cancer (II, B), patients at high risk of GI bleeding, receiving powerful inducers and/or inhibitors of CYP3A4 or P-gp, (IV, B) LMWH is preferred. Beyond initial 6 months, LMWH, apixaban, edoxaban, rivaroxaban or VKAs based on benefit–risk assessment (III, B) Regularly assess risk–benefit profile of anticoagulation therapy for favorable balance (IV, C)

Notes: This table collates data from the cited published papers,^{31,37–42,69,72} also over viewed in two previously published studies^55,56 and new data available since then. ^aRecommendations based on ADAM VTE, Caravaggio, Hokusai VTE Cancer and SELECT-D trial results. ^bRecommendations based on Hokusai VTE Cancer and SELECT-D trial results. ^cHigh bleeding risk includes patients with luminal gastrointestinal cancers with an intact primary; cancers at risk of bleeding from the genitourinary tract, bladder, or nephrostomy tubes; or active GI mucosal abnormalities (eg, duodenal ulcers, gastritis, esophagitis, or colitis).

Abbreviations: ACCP, American College of Chest Physicians; ASCO, American Society of Clinical Oncology; CrCl, creatinine clearance; CYP3A4, cytochrome P450 3A4; DDI, drug–drug interaction; DOAC, direct oral anticoagulant; ESC, European Society of Cardiology; ESMO, European Society for Medical Oncology; GI, gastrointestinal; GU, genitourinary; ISTH, International Society on Thrombosis and Haemostasis; ITAC, International Initiative on Thrombosis and Cancer; LMWH, low-molecular-weight heparin; NICE, National Institute for Health and Care Excellence; NCCN, National Comprehensive Cancer Network; P-gp, P-glycoprotein; PE, pulmonary embolism; UFH, unfractionated heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Table 4 Guidance for the Use of DOACs to Treat Cancer-Associated VTE in Challenging Patient Subgroups

Patient Subgroup	Treatment Suggestions
GI cancer	LMWH preferred in patients with intact primary lower GI tumors and patients with upper GI tumors. Apixaban suggested for patients with resected primary lower GI tumors and patients who refuse LMWH or prefer oral therapy. LMWH preferred after proximal GI surgery for tumor resection.
GU cancer	LMWH preferred. DOAC (apixaban, edoxaban or rivaroxaban) suggested for patients who refuse LMWH or prefer oral therapy.
Intracranial tumors	Standard anticoagulation with a DOAC (apixaban, edoxaban or rivaroxaban) or LMWH.
Concomitant anticancer treatment	Check for potential DDIs before DOACs are used in patients receiving chemotherapy or targeted cancer therapies. Consider LMWH if DDIs are a concern with DOACs.
Concomitant antiplatelet agents	DOAC (apixaban preferred) combined with one antiplatelet agent (P2Y12 inhibitor) in the event of cancer-associated VTE and a new coronary stent. Start DOAC (apixaban preferred) and stop one antiplatelet agent in patients receiving dual antiplatelet therapy for CAD.
Low body weight (≤60 kg)	Full-dose apixaban or rivaroxaban. Half-dose edoxaban.
Renal impairment	CrCl ≥30 mL/minute: apixaban, edoxaban (half-dose for CrCl 30–50 mL/min) or rivaroxaban. CrCl <30 mL/minute: dose-adjusted LMWH (with anti-Xa level monitoring) or consider apixaban (unless CrCl <25 mL/min).
Hepatic impairment	Avoid DOACs in patients with Child-Turcotte-Pugh class B or C cirrhosis. Apixaban and edoxaban: avoid if total bilirubin (not due to Gilbert’s syndrome) >1.5 × ULN or transaminases >2 × ULN). Dabigatran or rivaroxaban: avoid if transaminases >3 × ULN.
Thrombocytopenia	Platelet count >50 × 10^9/L: full-dose DOAC. Platelet count <25 × 10^9/L: hold anticoagulation. Platelet count 25–50 × 10^9/L: dose-adjusted LMWH (preferred) or half-dose DOAC (apixaban, edoxaban or rivaroxaban).
Incidental VTE	Treat in the same manner as symptomatic VTE (DOAC or LMWH according to bleeding risk and patient preference).

Abbreviations: CAD, coronary artery disease; CrCl, creatinine clearance; DDI, drug–drug interaction; DOAC, direct oral anticoagulant; GI, gastrointestinal; GU, genitourinary; LMWH, low-molecular-weight heparin; ULN, upper limit of normal; VTE, venous thromboembolism.

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