Page 330 - Haematologica March 2020

C. Becattini et al.
Table 3. Results of sensitivity analyses. Sensitivity analyses of efficacy
Symptomatic VTE
Fatal VTE
High-risk patients High-quality studies10-12,19,21-22,24-25
Sensitivity analyses of safety
Parenteral anticoagulants19,21-22,24-25
Oral anticoagulants10-12 High-quality studies10-12,19,21-22,24-25
VTE as primary outcome
Death as primary outcome
N of studies; n of patients OR
12 studies; 7,578 patients 0.48
6 studies; 4,705 patients 0.52* 5 studies**; 2,167 patients 0.48 9 studies; 7,268 patients 0.47
N of studies; n of patients OR*
21 studies; 10,488 patients 1.27
3 studies; 1,526 patients 1.78 9 studies; 7,268 patients 1.50 15 studies; 8,258 patients 1.43 9 studies; 4,004 patients 1.16
95% CI
0.39 -0.60
0.25 -1.08 0.34-0.68 0.36-0.60
95% CI
0.93-1.73
0.83-3.83 1.00-2.25 1.01-2.04 0.70-1.92
I2
0%
0% 0% 15%
I squared
0%
0% 0% 0% 0%
*after correction for zero cells. **This analysis included three studies in full and the subgroups of patients estimated to be at high risk of venous thromboembolism from two additional studies. OR: odds ratio; 95% CI: 95% confidence interval;VTE: venous thromboembolism.
for this specific indication were firstly the relatively low incidence of VTE in these patients. In our analysis, the incidence of VTE in studies in ambulatory cancer patients treated with chemotherapy varied from 2.3% to over 30% without anticoagulant prophylaxis. Such a huge variation is probably related to different study designs concerning populations (single primary site of cancer vs. multiple sites, high risk for VTE vs. all-comers), anticancer therapies (asparaginase vs. others, old vs. new regimens) and methods for VTE detection (screening vs. sympto- matic events). In clinical practice, this heterogeneity is perceived by clinicians as uncertainty concerning the actual need for prophylaxis of VTE in each individual can- cer patient. In fact, the risk of VTE correlates with the type of solid or hematologic cancer, the presence of metastatic disease, the use of chemotherapy or radiother- apy, surgery or hospitalization and, according to more recent research, to genetic cancer rearrangements (ALK and ROS1 in lung cancer).41-43 A clinical model was pro- posed to categorize ambulatory cancer patients treated with chemotherapy according to their risk of VTE.44 A meta-analysis of 55 cohorts (34,555 ambulatory cancer patients) recently showed that although this model is able to identify categories of patients at different risk of VTE, most VTE events occur outside the high-risk group.45 Further studies should be performed to improve the selec- tion of ambulatory cancer patients who are candidates for anticoagulant prophylaxis. Personalized medicine and big data technology could have a role in this process.
The second concern about the use of prophylaxis in cancer patients treated with chemotherapy is the incon- venience of prolonged parenteral therapy. A not negligi- ble number of patients in the context of the selected clin- ical studies discontinued anticoagulant prophylaxis for reasons other than thrombosis or bleeding (about 30%). Hence, it may be problematic for large numbers of patients to tolerate longer durations of prophylaxis. In this scenario, the availability of oral anticoagulants that can be used with no laboratory monitoring and with the potential for few drug-drug interactions could solve at least the issue of parenteral administration and make pro- phylaxis acceptable also for extended periods. Three ran- domized studies have assessed the efficacy and safety of apixaban (2 studies)10-11 and rivaroxaban (1 study)12 for the
prevention of VTE in cancer patients and provided prom- ising results. In particular, our meta-analysis found similar risk reductions with parenteral or oral agents. Direct oral anticoagulants could make prophylaxis feasible for ambu- latory cancer patients receiving chemotherapy as they will be more acceptable than parenteral agents for those at high risk of VTE.
An additional concern regards the risk-to-benefit ratio of anticoagulant prophylaxis. The pooled incidence of major bleeding was 2% in patients randomized to antico- agulant prophylaxis, with high variability across individ- ual studies as shown by significant heterogeneity. Differences in study populations across individual studies could have had a major role as determinants of hetero- geneity. No significant increase in the risk of major bleed- ing in patients randomized to receive anticoagulant pro- phylaxis, compared to the risk in controls, was found in this meta-analysis when all studies were pooled together. This finding is reassuring as cancer patients are known to have an increased risk of bleeding, mainly related to the primary site of the cancer, the need for invasive proce- dures and thrombocytopenia. However, the analysis on risk of major bleeding in high-quality studies and that in studies with VTE as the primary outcome showed a mar- ginally significant increase in the risk of major bleeding by about 50%. Additional evidence on risk factors for major bleeding in ambulatory cancer patients receiving chemotherapy could help decision-making concerning the use of prophylaxis.
Fatal VTE was not significantly reduced by anticoagu- lant prophylaxis. This result should be considered taking into account the low rates of death deemed to be due to VTE in patients with advanced cancer. Indeed, previous studies failed to show an effect of heparin, given at either therapeutic or prophylactic doses, in improving survival in cancer patients. However, it should be taken into account that a diagnosis of new VTE in cancer patients may affect quality of life and lead to the interruption of anticancer treatment. In this view, preventing VTE can be a relevant clinical goal.
Among the sensitivity analyses, we included one on patients at ‘high-risk’ of VTE, which confirmed the effi- cacy of anticoagulant prophylaxis in this setting. The Khorana score was used to identify this population of
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