Updated Meta-Analysis of Randomized Controlled Trials on Primary Outpatient Thromboprophylaxis (POTP) in Patients with Advanced Pancreatic Cancer (APC) Receiving Chemotherapy

Introduction: APC is as a highly thrombogenic cancer where the score of 2 is assigned per Khorana score (KS). POTP is currently suggested to patients with KS of 2 and above by recent clinical practice guidelines. We conducted an updated meta-analysis to demonstrate the benefit of POTP with low-molecular weight heparins (LMWH) and direct oral anticoagulants (DOAC) in patients with APC receiving chemotherapy.

Methods: Comprehensive literature across MEDLINE and EMBASE databases were searched from inception through June 30, 2022, using search terms 'thromboprophylaxis’ OR 'anticoagulation’ OR 'low-molecular-weight heparin’ OR 'direct oral anticoagulants’ AND 'pancreas cancer'. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in venous thromboembolism (VTE) as a primary or secondary endpoint were incorporated in the analysis. The primary meta- analytic approach was a random effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). I² statistic and Cochran's Q- statistic were used to assess heterogeneity among the studies.

Results: Two RCTs and a subgroup of another four RCTs including 1,091 patients with APC were included. The prophylactic, intermediate and therapeutic doses of LMWH and prophylactic doses of DOAC (rivaroxaban and apixaban) were used in the trials. The duration of anticoagulation ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I² statistic for heterogeneity was 35, suggesting some heterogeneity among RCTs. The VTE incidence was 30 (5.4%) in ATP group and 71 (13.2%) in control group with a RR of 0.42 (95% CI: 0.23 to 0.74, P = 0.003). The absolute RD was -0.08 (95% CI: -0.11 to -0.04, P < 0.0001) with an estimate of the number needed to treat (NNT) of 13 to prevent one VTE event. In a subset of patients treated with LMWH (n= 740, 4 studies), the pooled RR was significant at 0.32 (95% CI: 0.15 to 0.69, P = 0.003) whereas in patients who received DOACs (n=351, 2 studies), RR was statistically non-significant at 0.66 (95% CI: 0.36 to 1.22, P = 0.19).

Conclusions: Although POTP in APC statistically significantly decreases VTE events (approximately with relative risk reduction of 59% and a NNT of 13), the VTE reduction seemed only statistically significantly observed in patients who had received "LMWH vs control” compared to patients who were treated with "DOAC vs control". One hypothesis could be that in the trials with LMWH, higher doses (therapeutic dose in FRAGEM and intermediate dose in CONKO-004) were utilized compared to the studies with DOAC where only prophylactic doses were utilized. Another possibility is that the compliance rates were poor in the CASSINI trial. More randomized trials are required to further define the high-risk subsets who may benefit from POTP as well as the optimal dosing and types of anticoagulation in such population.

Oo:Thein Hlaing Oo served on the advisory board of Bristol-Myers Squibb.: Other: Thein Hlaing Oo served on the advisory board of Bristol-Myers Squibb..