Table 4.

Studies assessing the clinical benefit of anticoagulants for the prevention of venous thromboembolism in ambulatory pancreatic cancer (PC) patients.

Reference Study Design	Number of Patients Analyzed	Follow-Up	Population	Intervention	VTE Incidence	Safety	Survival
PROTECHT Agnelli et al. 2009 [91] Randomized, placebo-controlled, double-blind, multicenter study	Overall population Arm A: 769 patients Arm B: 381 patients PC subgroup Arm A: 36 patients Arm B: 17 patients	120 days	Ambulatory patients >18 years on chemotherapy with metastatic or locally advanced lung, gastrointestinal, breast, ovarian, or head and neck cancer	Arm A: nadroparin 3800 IU/day Arm B: placebo For duration of chemotherapy (up to 4 months maximum)	Overall population Arm A: 11/769 (1.4%) Arm B: 11/381 (2.9%) p = 0.02 PC subgroup Arm A: 3/36 (8.3%) Arm B: 1/17 (5.9%) p = 0.755	Overall population Major bleeding Arm A: 5/769 (0.7%) Arm B: 0/381 p = 0.18 Minor bleeding Arm A: 57/769 (7.4%) Arm B: 30/381 (7.9%) p = ns PC subgroup NS	Overall population Arm A: 33/769 (4∙3%) Arm B: 16/381 (4.2%) p = ns PC subgroup NS
SAVE ONCO Agnelli et al. 2012 [92] Randomized, placebo-controlled, double-blind, multicenter study	Overall Population Arm A: 1608 patients Arm B: 1604 patients PC subgroup Arm A: 126 patients Arm B: 128 patients	3 months	Patients with metastatic or locally advancedlung, pancreatic, gastric, colorectal, bladder, and ovarian cancer beginning to receive a course of chemotherapy	Arm A: Semuloparin, 20 mg/day Arm B: placebo For duration of chemotherapy (median: 3.5 months)	Overall population Arm A: 20/1608 (1.2%) Arm B: 55/1064 (1.2%) HR 0.36 (95%CI 0.21–0.60) p < 0.001 PC subgroup Arm A: 3/126 (2.4%) Arm B: 14/128 (10.9% HR 0.22 (95%CI 0.06–0.76) p = 0.015	Overall population Major bleeding Arm A: 19/1589 (1.2%) Arm B: 18/1583 (1.1%) OR 1.05 (95% CI 0.55–2.04) CRNMB Arm A: 26/1589 (2.8%) Arm B: 14/1583 (0.9%) OR 1.86 (95% CI 0.98–3.68) PC subgroup NS	NS
FRAGEM Marayevas et al. 2012 [93] Randomized, controlled Phase 2b study	Arm A: 59 patients Arm B: 62 patients	3 months	Patients aged 18 years or older Histologically/cytologically confirmed advanced ormetastatic pancreatic cancer Karnofsky performance status (KPS): 60–100	Arm A: Gemcitabine + Dalteparin 200 IU/kg sc, od, for 4 weeks, followed by a step‑down regimen to 150 IU/kg for a further 8 weeks) Arm B: Gemcitabine alone For up to 12 weeks	At 3 months Arm A: 2/59(3%) Arm B: 14/62 (23%) RR 0.145 (95% CI 0.035–0.612) p = 0.002 Entire study Arm A: 7/59 (12%) Arm B: 17/62 (28%) RR 0.419 (95%CI 0.187–0.935) p = 0.039	ISTH severe Arm A: 2/59 (3%) Arm B: 2/62 (3%) ISTH non severe Arm A: 5/59 (9%) Arm B: 2/62 (3%)	Arm A: 8.7 months Arm B: 9.7 months
CONKO-0004 Pelzer et al. 2015 [94] Prospective, open label, randomized, multicenter and group-sequential 2b trial	Arm A: 160 patients Arm B: 152 patients	3 months	Patients with histologically proven advanced pancreatic cancer were randomly assigned to ambulant first-line chemotherapy	Arm A: Enoxaparin 1 mg/kg/day Arm B: no enoxaparin	At 3 months Arm A: 2/160 (1.25%) Arm B: 15/152 (9.8%) HR 0.12 (95%CI 0.03–0.52) p = 0.001 Cumulative incidence rates Arm A: 6.4% Arm B: 15.1% HR 0.40 (95% CI 0.19–0.83) p = 0.01	Cumulative incidence rates Of major bleeding Arm A: 8.3% Arm B: 6.9% HR 1.23 (95% CI 0.54–2.79) p = 0.63	Arm A: 8.2 months Arm B: 8.51 months HR 1.01 (95% CI 0.87–1.38) p = 0.44
CASSINI Khorana et al. 2019 [96] Double-blind, randomized, placebo-controlled, parallel-group, multicenter study	Overall population Arm A: 420 patients Arm B: 404 patients PC patients Arm A: 135 patients Arm B: 138 patients	6 months	Adult ambulatory patients with various cancers initiating a new systemic regimen and at increased risk for VTE (defined as Khorana score ≥ 2).	Arm A: rivaroxaban 10 mg once daily up to day 180 Arm B: placebo up to day 180	Overall population VTE at 6 months Arm A: 25/420 (5.95%) Arm B: 37/421 patients (8.79%) HR 0.66 (95% CI 0.40–1.09) p = 0.101 NNT = 35 VTE during the on-treatment period Arm A: 11/420 (2.62%) Arm B: 27/421 (6.41%) HR 0.40 (95% CI 0.20–0.80) p = 0.007 NNT = 26 PC subgroup Composite of VTE and death from VTE Arm A: 5/135 (3.7%) Arm B: 14/138 (10.1%) HR 0.35 (95% CI 0.130–0.97) p = 0.03	Overall population Major bleeding Arm A: 8/405 (1.98%) Arm B: 4/404 (0.99%) HR 1.96 (95% CI 0.59–6.49) p = 0.265 NNH = 101 Clinically relevant non-major bleeding Arm A: 2.72% Arm B: 1.98% HR 1.96 (95% CI, 0.59–6.49) p = 0.265 NNH = 101 PC subgroup Major bleeding Arm A: 2/135 (1.5%) Arm B: 3/138 (2.3%)	Overall population All-cause mortality Arm A: 20.0% Arm B: 23.8% HR, 0.83, 95% CI 0.62–1.11 p = 0.213. PC subgroup NS
AVERT Carrier et al. 2019 [98] Double-blind, randomized, placebo-controlled, multicenter study	Overall population Arm A: 288 patients Arm B: 275 patients PC patients: 77	6 months	Ambulatory cancer patients receiving chemotherapy who are at high-risk for VTE (as defined by a Khorana score of ≥2)	Arm A: apixaban 2.5 mg twice daily up to day 180 Arm B: placebo up to day 180	Overall population VTE at 6 months Arm A: 12/288 (4.2%) Arm B: 28/275 (10.2%) HR 0.41 (95% CI 0.26–0.65) p < 0.001 PC subgroup NS	Overall population Major bleeding Arm A: 10/288(3.5%) Arm B: 5/275(1.8%) HR 2.00 (95% CI 1.01–3.95) p = 0.046 Clinically relevant non-major bleeding Arm A: 21/288 (7.3%) Arm B: 15/276 (5.5%) HR, 1.28; 95% CI, 0.89–1.84 PC subgroup NS	All-cause mortality Arm A: 35/288 (12.2%) Arm B: 27/275 (9.8%) HR 1.29 (95% CI 0.98–1.71) p = ns PC subgroup NS
Ramathan et al. 2018 [99] Open-label multicenter phase 2	Arm A: 18 patients Arm B: 16 patients	Median of 8 weeks	Locally advanced ductal adenocarcinoma of the pancreas diagnosed ≤6 months prior to enrollment	Arm A: Gemcitabine +PCI-27483 1.2 mg/kg/bid Arm B: Gemcitabine alone	VTE (any grade) Arm A: 10/18 (56%) Arm B: 3/16 (19%)	Bleeding (any grade) Arm A: 1/18 (6%) Arm B: 2/16 (13%)	Arm A: 5.7 months Arm B: 5.6 months

Abbreviations: CI, confidence interval; CRNMB, clinically relevant non major bleeding; HR, hazard ratio; OR, odds ratio; NNH, number needed to harm; NNT, number needed to treat; NS, not specified; PC, pancreatic cancer; RR, relative risk; VTE, venous thromboembolism.