Page 328 - Haematologica March 2020

C. Becattini et al.
continued from the previous page
Author, year
Khorana, 201729
Khorana, 2019*11
Carrier, 201912
D-B
No
Yes
Yes
N. of patients
98
809
563
Eligible cancers
Lung, stomach, pancreas, lymphoma, gynecological, genitourinary (excluding prostate)
Solid tumor or lymphoma
Newly diagnosed cancer or progression of known cancer after complete or partial remission
Main inclusion criteria
Histological diagnosis of malignancy, planned initiation
of a new systemic CHT regimen (either initial or after progression on CHT), age ≥18 years
Age >18 years, Khorana score >2, expected survival >6 months, plan to start a new systemic regimen within 1 week
Initiating a new course of CHT with a minimum treatment intent of
3 months, Khorana score >2,
age >18 years
Study treatments
Dalteparin (5000 IU o.d.) vs. No dalteparin
Rivaroxaban (10 mg o.d.) vs. Placebo
Apixaban (2.5 mg t.d.) vs. Placebo
Primary outcome
Symptomatic lower extremity DVT, PE and upper extremity thrombosis, unsuspected DVT and PE detected by lower extremity ultrasonography and CT
Objectively confirmed symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper-extremity or distal lower-extremity DVT, symptomatic or incidental PE and VTE–related death
Duration of prophylaxis
12 weeks
180 (± 3) days
First objectively documented symptomatic or incidentally detected proximal DVT
of the lower or upper limbs, any nonfatal symptomatic or
incidental PE, and PE–related death
180 days
Enrolled patients underwent bilateral lower-extremity venous duplex compression ultrasonography to exclude pre-existing proximal deep-vein thrombosis based on prior studies in high-risk patients demonstrating a high rate of baseline thrombosis for which prophylactic anticoagulation would be inadequate. CHT: chemotherapy; INR: International Normalized Ratio; DVT: deep vein thrombosis; PE: pulmonary embolism;CVL:central venous line;TE:thromboembolism;GI:gastrointenstinal;IU:international units;o.d.:once daily;WHO:World Health Organization;ASA:acetylsalicylic acid;Rd:induction with lenalidomide plus low-dose dexamethasone; MPR: melphalan–prednisone-lenalidomide;VTE: venous thromboembolism; KPS: Karnofsky performance status scale; CT: computed tomography; UNL: upper normal limit; RT: radiotherapy; MR: magnetic resonance; ECOG= Eastern Cooperative Oncology Group; t.d.: twice daily..
was found in the analysis of studies with oral agents, which disappeared after the removal of a dose-ranging study from the analysis.
Anticoagulant prophylaxis reduced symptomatic VTE (OR=0.48, 95% CI: 0.39-0.60) but not fatal VTE (OR=0.52, 95% CI: 0.25-1.08) in studies with VTE as the primary outcome (Table 3; Figure 2).
In the eight studies with death as the primary endpoint, prophylaxis was associated with a reduction of VTE (8 studies, 3,727 patients; OR=0.61, 95% CI: 0.47-0.81; I2=0%)
When all studies were pooled in a single analysis, anti- coagulant prophylaxis was confirmed to reduce the inci- dence of VTE (22 studies, 11,953 patients; OR=0.51, 95% CI: 0.43-0.61; I2=2.4%) (Figure 1) and of symptomatic VTE (17 studies, 10,374 patients; OR=0.49, 95% CI: 0.39- 0.61; I2= 0%) with no heterogeneity (Figure 2).
The reduction in the incidence of VTE with the use of anticoagulant prophylaxis was confirmed in patients with lung cancer (3 studies, 1,991 patients; OR=0.42, 95% CI: 0.26-0.67; I2=0%), pancreatic cancer (4 studies, 740 patients; OR=0.26; 95% CI: 0.14-0.48; I2=21%), in patients at estimated high risk according to the Khorana score (5 studies, 2,167 patients; OR=0.48; 95% CI: 0.34- 0.68; I2=0%) and in high-quality studies (OR=0.47, 95% CI: 0.36-0.60), all from studies with VTE as the primary outcome (Table 3, Figure 3).
No evidence of publication bias was found in individual comparisons at visual inspection of funnel plots.
Safety of anticoagulant prophylaxis
For the analysis of safety, the results from studies with VTE or death as the primary outcome were pooled in a single analysis. Overall, 24 studies reported on the inci- dence of major bleeding in patients randomized to antico- agulant prophylaxis or no prophylaxis. The pooled inci-
dence of major bleeding was 2% in patients randomized to prophylaxis or to no prophylaxis, with significant het- erogeneity (95% CI: 0.17-0.31; I2>50%). Heterogeneity persisted after removal of outlier studies and disappeared when the analysis was limited to high-quality studies.
Anticoagulant prophylaxis was not associated with an increase in the risk of major bleeding (24 studies, 12,014 patients; OR=1.30, 95% CI: 0.98-1.73; I2=0%) (Figure 4). Similar results were obtained in studies with parenteral anticoagulants (21 studies, 10,713 patients; OR=1.27, 95% CI: 0.93-1.73; I2=0%) or oral anticoagulants (3 stud- ies, 1,494 patients; OR=1.78, 95% CI: 0.83-3.83; I2=0%).
When the analysis was limited to high-quality studies or those with VTE as the primary outcome, the use of anticoagulant prophylaxis was associated with a margin- ally significant increase in major bleeding (Table 3).
Discussion
This meta-analysis in ambulatory cancer patients treat- ed with chemotherapy shows that anticoagulant prophy- laxis, with either oral or parenteral agents, is associated with a 50% reduction in the incidence of VTE and no sig- nificant increase in major bleeding. The efficacy of pro- phylaxis in reducing VTE was consistent in studies with VTE or death as the primary outcome and in all sensitiv- ity analyses.
Anticoagulant prophylaxis is currently used to prevent VTE in patients undergoing major cancer surgery as well as in cancer patients admitted to hospital for an acute ill- ness.40 Despite the results of individual studies and previ- ous meta-analyses, antithrombotic prophylaxis remained controversial and is still not recommended in ambulatory cancer patients treated with chemotherapy.8,9 The main concerns regarding the use of antithrombotic prophylaxis
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