Burden of venous thromboembolism in patients with pancreatic cancer

Table 2 Studies assessing the clinical benefit of anticoagulants for the prevention of venous thromboembolism in ambulatory pancreatic cancer patients

	PROTECHT	SAVE ONCO	FRAGEM	CONKO-0004	CASSINI
	Agnelli et al[58], 2009	Agnelli et al[59], 2012	Maraveyas et al[54], 2012	Pelzer et al[55], 2015	Khorana et al[61], 2019 and Vadhan-Raj et al[41], 2020
Population	Ambulatory patients > 18 yr on chemotherapy with metastatic or locally advanced lung, gastrointestinal, breast, ovarian, or head and neck cancer	Patients with metastatic or locally advanced lung, pancreatic, gastric, colorectal, bladder, and ovarian cancer beginning to receive a course of chemotherapy	Patients aged 18 yr or older; Histologically/cytologically confirmed advanced or metastatic pancreatic cancer; KPS: 60-100	Patients with histologically proven advanced pancreatic cancer were randomly assigned to ambulant first-line chemotherapy	Adult ambulatory patients with various cancers initiating a new systemic regimen and at increased risk for VTE (defined as Khorana score ≥ 2)
Study design	Randomized, placebo-controlled, double-blind, multicenter study	Randomized, placebo-controlled, double-blind, multicenter study	Randomized, controlled Phase 2b study	Prospective, open label, randomized, multicenter and group-sequential 2b trial	Double-blind, randomized, placebo-controlled, parallel-group, multicenter study
Intervention	Arm A: nadroparin 3800 IU/d; Arm B: placebo; For duration of chemotherapy (up to 4 mo maximum)	Arm A: Semuloparin, 20 mg/d; Arm B: placebo; For duration of chemotherapy (median: 3.5 mo)	Arm A: Gemcitabine + Dalteparin 200 IU/kg s.c., o.d., for 4 wk, followed by a step-down regimen to 150 IU/kg for a further 8 wk); Arm B: Gemcitabine alone; For up to 12 wk	Arm A: Enoxaparin 1 mg/kg per day; Arm B: No enoxaparin	Arm A: rivaroxaban 10 mg o.d. up to day 180; Arm B: placebo up to day 180
Number of patients analyzed	Overall population: Arm A: 769 patients; Arm B: 381 patients. PC subgroup: Arm A: 36 patients; Arm B: 17 patients	Overall population: Arm A: 1608 patients; Arm B: 1604 patients. PC subgroup: Arm A: 126 patients; Arm B: 128 patients	Arm A: 59 patients; Arm B: 62 patients	Arm A: 160 patients; Arm B: 152 patients	Overall population: Arm A: 420 patients; Arm B: 404 patients. PC patients: Arm A: 135 patients; Arm B: 138 patients
Follow-up	120 d	3 mo	3 mo	3 mo	6 mo
Thromboembolic endpoint events	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: 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. At 3 mo: Arm A: 2/59 (3%); Arm B: 14/62 (23%); RR 0.145 (95%CI: 0.035-0.612); P = 0.002	At 3 mo: Arm A: 2/160 (1.25%); Arm B: 15/152 (9.8%); HR 0.12 (95%CI: 0.03-0.52); P = 0.001. Entire study: Arm A: 7/59 (12%); Arm B: 17/62 (28%); RR 0.419 (95%CI: 0.187-0.935); P = 0.039	Cumulative incidence rates: Arm A: 6.4%; Arm B: 15.1%; HR 0.40 (95%CI: 0.19-0.83); P = 0.01	Overall population: Up-to-day-180 observation period: Arm A: 25/420 (5.95%); Arm B: 37/421 (8.79%); HR 0.66 (95%CI: 0.40-1.09); P = 0.101; NNT =3 5. Intervention 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: Up-to-day-180 observation period: Arm A: 13/135 (9.6%); Arm B: 18/138 (13.0%); HR 0.70 (95%CI: 0.34-1.43); P = 0.329. Intervention period: Arm A: 5/135 (3.7%); Arm B: 14/138 (10.1%); HR 0.35 (95%CI: 0.130-0.96); P = 0.043; NNT = 16
Bleeding	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 = not significant. PC subgroup: P = not significant	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: P = not significant	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%)	Major bleeding: Arm A: 8.3%; Arm B: 6.9%; HR 1.23 (95%CI: 0.54-2.79); P = 0.63	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. CRNMB: 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: 2/130 (1.5%); Arm B: 3/131(2.3%); HR 0.67 (95%CI: 0.11-3.99); P = 0.654. CRNMB: Arm A: 3/131(2.3%); Arm B: 2/130 (1.5%); HR 2.47 (95%CI: 0.48-12.72); P = 0.264
Survival	Overall population: Arm A: 33/769 (4∙3%); Arm B: 16/381 (4.2%); P = not significant. PC subgroup: not significant	Not significant	Arm A: 8.7 mo; Arm B: 9.7 mo	Arm A: 8.2 mo; Arm B: 8.51 mo; HR 1.01 (95%CI: 0.87-1.38); P = 0.44	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: Arm A: 34/135 (25.2%); Arm B: 33/138 (23.9%)

CI: Confidence interval; CRNMB: Clinically relevant non-major bleeding; HR: Hazard ratio; ISTH: International society of thrombosis and haemostasis; KPS: Karnofsky performance status; o.d.: Once daily; NTT: Number needed to treat; OR: Odds ratio; PC: Pancreatic cancer; RR: Risk ratio.