Page 325 - Haematologica March 2020

Prevention of VTE in cancer patients
mended in ambulatory cancer patients treated with chemotherapy.8,9 On this background, the current avail- ability of oral anticoagulants that can be used with no lab- oratory monitoring reopens the issue of practicality of antithrombotic prophylaxis in ambulatory cancer patients.10-12 Three clinical trials on the use of new oral anticoagulants for this indication have recently been pub- lished.
We performed a meta-analysis of randomized studies to assess the clinical benefit of antithrombotic prophylax- is in ambulatory cancer patients receiving chemotherapy.
Methods
The methods for this meta-analysis are in accordance with “Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA)” (http://www.prisma-statement.org/).13
Study objectives and outcomes
The primary objective of this meta-analysis of randomized controlled studies was to assess the efficacy of anticoagulant prophylaxis in preventing VTE in ambulatory cancer patients treated with chemotherapy. The secondary objective was to assess the safety of anticoagulant prophylaxis in these patients.
The primary outcome of the study was objectively confirmed VTE, defined as the composite of pulmonary embolism and/or deep vein thrombosis adjudicated according to the criteria and procedures of the individual studies. The secondary outcome was major bleeding defined according to the criteria of the indi- vidual studies. Ancillary outcomes were symptomatic VTE and fatal VTE.
Search strategy and study inclusion criteria
We performed unrestricted searches in MEDLINE and Scopus using the terms “cancer AND venous thromboembolism AND prevention” and “cancer AND venous thromboembolism AND prophylaxis”. Studies were independently selected by two authors (CB and MV) using predetermined criteria (detaied in the Online Supplementary Data).
Randomized controlled trials on the prevention of VTE in ambulatory cancer patients treated with chemotherapy were included in this meta-analysis and results pooled into two groups: (i) studies with VTE as the primary endpoint; and (ii) studies with death as the primary endpoint.
The kappa statistic was used to assess the agreement between reviewers regarding the studies selected.14
Statistical analysis
We determined pooled incidences of study outcomes in patients randomized to anticoagulant prophylaxis or no prophy- laxis and the pooled odds ratios (OR) with 95% confidence intervals (95% CI). We planned cumulative and separate analy- ses for studies with VTE or mortality as the primary outcome.
Sensitivity analyses were performed concerning (i) parenteral or oral anticoagulants; (ii) symptomatic VTE; (iii) fatal VTE; (iv) subgroups of patients based on the primary cancer site (lung, pancreas and breast); (v) patients considered as being at high-risk of VTE; and (vi) high-quality studies.
Study quality was evaluated using the Jadad score and the Cochrane risk assessment tool.15
Data were pooled by the Mantel-Haenszel method;16 results are reported according to a fixed-effects model in the absence of significant heterogeneity and to a random-effects model in the presence of significant heterogeneity.17,18 The Cochran χ2 test and
the I2 test for heterogeneity were used to assess between-study heterogeneity.16,17 Significant heterogeneity was considered pres- ent at P<0.10 and I2>50%.18
Correction for zero cells was performed. Publication bias was assessed visually by the use of funnel plots.
Statistical analyses were conducted using Review Manager release 5.3 (The Cochrane Collaboration, Oxford, England) and StatsDirect 3.0.
Results
Overall, 22 papers were found reporting on 23 studies fulfilling the inclusion criteria (flow diagram in Online Supplementary Figure S1).11-12,19-38 After discussion among the authors, a randomized double-blind phase II study with apixaban compared to placebo was included in the analysis despite the main outcome being major bleed- ing.10 The reasons for inclusion were high-quality, appro- priate study population and the potential to increase the power of the meta-analysis with respect to the efficacy and safety of oral anticoagulants. The main features of included studies are reported in Tables 1 and 2. The pri- mary outcome was VTE in 16 studies and death in eight. The agreement between reviewers regarding study selec- tion was good (kappa statistic: 0.88).
Among the 15 studies with VTE as the primary out- come, eight were double-blind studies with placebo as the comparator.10-12,19,21-22,24-25 In five studies the comparator was no treatment and in one it was aspirin. One paper was composed of two ‘twin-studies’, one including patients with breast cancer and the other including patients with lung cancer. With regards to the study pop- ulations, these were limited to patients with a single pri- mary site of cancer in eight studies (breast and pancreas in two studies each,19,24,26-27 acute lymphatic leukemia,20 multiple myeloma,23 glioma22 and lung24 cancer in one study each) while multiple cancers were included in seven studies. In three studies patients were eligible in the case of an estimated increased risk for VTE assessed by the Khorana score.11-12,29 The number of study patients var- ied from a minimum of 34 to a maximum of 3,212. Asymptomatic or incidental VTE accounted for a study outcome event in nine studies.11-12,24-26,29 All but one of the studies were conducted in adult patients. A systematic assessment of thrombosis by screening tests was sched- uled in three studies12,20,29 and was aimed at the diagnosis of lower limb deep vein thrombosis in two studies and to assess upper-body and cerebral vein thrombosis in one study (Table 1).
Among the studies with death as the primary outcome,30- 38 two were double-blind studies with placebo as the com- parator. In seven studies the comparator was no treatment. Patients were eligible in the case of a diagnosis of advanced cancer in four studies.31,33-34,36 No systematic assessment of thrombosis was scheduled (Table 1).
According to the Jadad scale, nine studies10-12,19,21-22,24-25 were classified as good quality (Onlne Supplementary Table S1).
Efficacy of anticoagulant prophylaxis
In the 14 studies with VTE as the primary outcome and data available for the efficacy analysis (8,226 patients), the pooled incidence of symptomatic or asymptomatic (incidental) VTE was 2% in patients randomized to anti- coagulant prophylaxis (95% CI: 2-3; I2=85%) and 6% in
haematologica | 2020; 105(3)
839