Evaluation of the safety and effectiveness of direct oral anticoagulants and low molecular weight heparin in gastrointestinal cancer-associated venous thromboembolism

Table 1 Clinical trials for low molecular weight heparin primary efficacy and secondary safety compared to vitamin K antagonist

Study (yr)	InterventionLMWH	Reported efficacy (rVTE) (%)	Reported safety (MB) (%)	Control VKA	Reported efficacy (rVTE) (%)	Reported safety (MB) (%)	Mortality Benefit at 12 mo
CLOT (2003)[3]	Dalteparin	9.0	6.0	Warfarin	17.0	4.0	HR 0.50, 95%CI: 0.27-0.95
LITE (2006)[4]	Tinzaparin	7.0	0.0	Warfarin	16.0	2.1	NS
CANTHANOX (2002)[5]	Enoxaparin	10.5	5.0	Warfarin	21.1	12.0	NS
ONCENOX (2006)[6]	Enoxaparin	6.3	6.5	Warfarin	10.0	2.1	NS
CATCH (2015)[7]	Tinzaparin	7.2	2.6	Tinzaparin + Warfarin	10.5	2.4	NS

LMWH: Low molecular weight heparin; VKA: Vitamin K antagonist; rVTE: Recurrent venous thromboembolism; MB: Major bleeding.

Table 2 Clinical trials for direct oral anticoagulants reported recurrent venous thromboembolism and reported mayor bleed outcomes compared to cancer subgroup

Study	Intervention DOAC	Control	Reported efficacy (rVTE) (%)	Cancer subgroup efficacy (%)	Reported safety (MB) (%)	Cancer subgroup safety (%)	Yr
AMPLIFY[17]	Apixaban	Enoxaparin + Warfarin	2.30	3.70	0.6	2.3	2013
AMPLIFY-EXT[18]	Apixaban	Placebo	4.00	NA	0.2	NA	2013
RE-COVER[19]	Dabigatran	Heparin + Warfarin	3.10	3.10	1.60	4.20	2009
RE-COVER II[20]	Dabigatran	Heparin + Warfarin	2.30	2.40	1.20	< 1	2013
RE-MEDY[21]	Dabigatran	Warfarin	1.80	3.30	0.90	NA	2013
RE-SONATE[21]	Dabigatran	Placebo	0.40	NA	0.30	NA	2013
HOKUSAI-VTE[22]	Edoxaban	Warfarin	3.20	3.70	1.40	4.50	2013
EINSTEIN-Choice[25]	Rivaroxaban	Aspirin	1.50	NA	0.5	NA	2017
EINSTEIN-DVT[23]	Rivaroxaban	Enoxaparin+ Warfarin	2.10	3.40	0.8	14.4	2010
EINSTEIN-EXT[26]	Rivaroxaban	Placebo	1.30	2.10	0.7	12.3	2016
EINSTEIN-PE[24]	Rivaroxaban	Enoxaparin+ Warfarin	2.10	2	1.1	12.3	2012

DOAC: Direct oral anticoagulant; LMWH: Low molecular weight heparin; VKA: Vitamin K antagonist; rVTE: Recurrent venous thromboembolism; MB: Major bleeding.

Table 3 Baseline characteristics of the study population

Baseline characteristics	LMWH (%)	DOACs (%)	Apixaban (%)	Rivaroxaban (%)
N (%)	40	66	29 (44)	37 (56)
Age at cancer diagnosis (median years)	66	67	68	65
(range)	37-80	37-83	43-83	37-79
Age at VTE event (median years)	66	68	68	65
(range)	40-80	37-83	43-83	37-79
Weight (median kg)	71.0	73.0	69.5	77.0
(range)	42-130	42-168	42-168	56-130
Gender (Male)	18 (45)	41 (62)	17 (59)	24 (65)
Race (white)	32 (80)	52 (79)	21 (72)	31 (84)
Current smoker	10 (25)	12 (18)	6 (21)	6 (15)
Antiplatelet therapy	5 (12.5)	8 (12)	5 (17)	3 (8)
Prior treated VTE	2 (5)	7 (11)	2 (7)	5 (13)
Cancer diagnosis
Pancreas	15 (37.5)	28 (42)	14 (50)	14 (38)
Colon	8 (20)	18 (27)	8 (25)	10 (27)
Rectal	2 (5)	5 (8)	1 (3.5)	4 (11)
NET	3 (7.5)	4 (6)	1 (3.5)	3 (8)
Gastric	4 (10)	3 (5)	1 (3.5)	2 (5)
Esophageal	0	3 (5)	1 (3.5)	2 (5)
Appendix	1 (2.5)	3 (5)	2 (7)	1 (3)
Biliary	3 (7.5)	1 (1)	1 (3.5)	0
GEJ	1 (2.5)	1 (1)	0	1 (3)
HCC	3 (7.5)	0	0	0
Stage at VTE diagnosis
I	1 (2.5)	1 (1)	1 (3.5)	0
II	7 (17.5)	7 (11)	3 (10.75)	4 (10)
III	3 (7.5)	12 (19)	3 (10.75)	9 (25)
IV	29 (72.5)	46 (69)	22 (75)	24 (65)
Prior chemotherapy	24 (40)	24 (36)	11 (38)	13 (35)
Current chemotherapy	24 (40)	29 (47)	18 (62)	13 (35)
VTE diagnosis
PE/DVT	11 (27.5)	8 (12)	5 (17)	3 (8)
PE	7 (17.5)	8 (12)	2 (7)	6 (16)
DVT	22 (55)	50 (75)	22 (75)	28 (76)
Identifiable risk factor		10 (16)	5 (17)	5 (14)
Recent surgery/Hospitalization	2 (5)	4 (6)	3 (10)	1 (3)
Central venous catheter	2 (5)	6 (9)	2 (7)	4 (11)
Khorana score
Low	11 (27.5)	19 (28)	7 (24)	12 (32)
Intermediate	18 (45)	25 (38)	11 (38)	14 (38)
High	11 (27.5)	22 (34)	11 (38)	11 (30)
Therapy completion	25 (62.5)	43 (65)	20 (69)	23 (62)
Anticoagulation length (median mo)	4	6.5	8	6
(range)	1-33	0.3-40	2-29	0.3-40

VTE: Venous thromboembolism; PE: Pulmonary embolism; DVT: Deep vein thrombosis; NET: Neuroendocrine tumor; GEJ: Gastro-esophageal junction; HCC: Hepatocellular carcinoma; DOAC: Direct oral anticoagulant; LMWH: Low molecular weight heparin.

Table 4 Clinical risk factors of a primary or secondary outcome for all anticoagulation therapies

Clinical risk factor	Odds ratio	95%CI	Significance level
Active treatment	5.1	1.3-19.3	P = 0.0167
Khorana score high	5.5	1.7-17.1	P = 0.0033
Active smoker	6.7	2.1-21.0	P = 0.0012
Pancreatic cancer	6.8	1.9-23.2	P = 0.0023
Stage IV	9.9	1.2-79.1	P = 0.0306
Death after an event	17.4	4.7-63.4	P < 0.0001