Introduction
Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary
embolism (PE), is a frequent cause of morbidity and mortality in patients with cancer
and is associated with a high economic burden.[1 ]
[2 ] The therapeutic management of VTE in cancer patients is challenging because of the
increased risk for thromboembolic recurrences and anticoagulant-associated bleedings.[3 ]
[4 ] Several risk factors related to cancer, anticancer treatment, and patient features
contribute to both the thrombotic and bleeding risk in these patients.[5 ] For more than a decade, low-molecular-weight heparin (LMWH) has been the gold standard
for the treatment of cancer-associated VTE. In the general population, direct oral
anticoagulants (DOACs), including apixaban, dabigatran, edoxaban, and rivaroxaban,
have emerged as the preferred treatment strategy for the treatment of acute VTE.[6 ] Beyond their favorable efficacy and safety profile, these agents have the advantage
of a predictable effect, the ease of administration, and no need for laboratory monitoring.
Recent randomized controlled trials (RCTs) have assessed the efficacy and safety of
edoxaban and rivaroxaban in comparison with dalteparin for the treatment of VTE in
cancer patients.[7 ]
[8 ] Based on the results of these studies, international guidelines have suggested the
use of edoxaban and rivaroxaban for the treatment of cancer-associated VTE in selected
patients.[6 ]
[9 ]
[10 ]
[11 ]
[12 ] More recently, apixaban was compared with dalteparin in a pilot safety study in
287 cancer patients.[13 ] Finally, the results of the Caravaggio study on the efficacy and safety of apixaban
in the treatment of VTE in cancer patients were recently published.[14 ]
We performed an updated meta-analysis of RCTs to assess the efficacy and safety of
DOACs compared with LMWH for the treatment of cancer-associated VTE.
Methods
This systematic review and meta-analysis was conducted in accordance with the “Cochrane
Handbook for Systematic Review of Interventions” and reported according to the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses statement.[15 ]
[16 ] The study protocol was registered in PROSPERO (CRD42020175589).
Search Strategy
We performed an unrestricted search in MEDLINE and CENTRAL (Cochrane Controlled Trials
Registry) and EMBASE from inception to March 30, 2020. Additional studies were identified
by hand searching bibliographies of the review articles and retrieved articles. Search
terms included: “Cancer” OR “Tumor” OR “Neoplasms” AND “Anticoagulants” OR “Factor
Xa Inhibitors” OR “Heparinoids” OR “Dabigatran” OR “Rivaroxaban” OR “Edoxaban” OR
“Apixaban” OR “Heparin, Low-Molecular-Weight” AND “Venous Thromboembolism” OR “Pulmonary
Embolism” OR “Venous Thrombosis” AND “Randomized Controlled Trial” OR “Controlled
Clinical Trial.” The research strategy is reported in the [Supplementary Material ] (available in the online version).
Two authors (M.G. and C.B.) independently performed the literature search using an
unblinded standardized approach. Study selection was initially performed by review
of title and candidate abstracts were then reviewed. Disagreements between reviewers
were resolved through revision by senior authors and by discussion.
Study Selection
Studies were considered potentially eligible for this meta-analysis if they met the
following predefined criteria: (1) were RCTs, (2) included only adult cancer patients
with acute VTE, (3) compared DOACs with LMWH, and (4) reported on objectively confirmed
VTE recurrences and bleedings in each treatment group. For duplicate publications,
only the most recent one was considered. To assess agreement between reviewers for
study selection, we used the kappa statistic, which measures agreement beyond chance.[17 ]
Study Outcomes
Two coprimary outcomes were identified for the meta-analysis: recurrent VTE and major
bleeding at 6 months. Study outcomes were considered according to the definition used
in the individual studies ([Table 1 ]). Secondary efficacy outcomes were recurrent PE, recurrent DVT, and fatal PE. Secondary
safety outcomes were clinically relevant nonmajor bleeding (CRNMB), clinically relevant
bleeding (CRB) (the composite of major bleeding and CRNMB), and fatal bleeding. All-cause
death was also reported.
Table 1
Description of the included studies according to the PICO criteria
Source
Study design
No. of patients
Participants
Intervention
Comparator
Treatment duration
Primary outcome
Raskob et al, 2018[7 ]
Randomized, open-label, noninferiority trial with blinded central outcome adjudication
1,046
Patients with active cancer or cancer diagnosed within 2 y before study inclusion
Therapeutic-dose of LMWH for at least 5 d, followed by edoxaban 60 or 30 mg[a ] once daily
Dalteparin at 200 IU/kg daily for 1 mo, followed by 150 IU/kg daily
6 up to 12 mo
Composite of recurrent VTE (symptomatic and incidental DVT or PE and fatal PE) and
major bleeding defined according to the ISTH criteria
Young et al, 2018[8 ]
Randomized, open-label, pilot trial with blinded central outcome adjudication
406
Patients with active cancer
Rivaroxaban 15 mg twice daily for 3 wk, followed by 20 mg once daily
Dalteparin 200 IU/kg daily for 1 month, followed by 150 IU/kg daily
6 mo
Recurrent VTE which included proximal DVT, PE (symptomatic, incidental or fatal),
other sites of thrombosis (e.g., subclavian vein, hepatic vein, and inferior caval
vein)
McBane et al, 2020[13 ]
Randomized, open-label, superiority trial with blinded central outcome adjudication
287
Patients with active cancer
Apixaban 10 mg twice daily for 7 d, followed by 5 mg twice daily
Dalteparin 200 IU/kg daily for 1 mo, followed by 150 IU/kg daily
6 mo
Major bleeding defined according to the ISTH criteria
Agnelli et al, 2020[14 ]
Randomized, open-label, noninferiority trial with blinded central outcome adjudication
1,155
Patients with active cancer or cancer diagnosed within 2 years before study inclusion
Apixaban 10 mg twice daily for 7 d, followed by 5 mg twice daily
Dalteparin 200 IU/kg daily for 1 month, followed by 150 IU/kg daily
6 mo
Primary efficacy outcome: Recurrent VTE which included proximal DVT of lower limbs
(symptomatic or incidental), symptomatic DVT of upper limbs and PE (symptomatic, incidental
or fatal)
Primary safety outcome: Major bleeding defined according to the ISTH criteria + bleeding
requiring surgical intervention
Abbreviations: DVT, deep vein thrombosis; ISTH, International Society of Thrombosis
and Haemostasis; LMWH, low molecular weight heparin; PE, pulmonary embolism; PICO,
Patient, Intervention, Comparison, Outcome; VTE, venous thromboembolism.
a According to study dose reduction criteria.
Data Extraction
For each study, the following data were independently extracted by two authors: (1)
general data (study design, year of publication), (2) characteristics of trials participants
(number, mean age, gender, number of patients with active cancer, metastatic cancer,
solid or hematological disease at presentation), (3) type of intervention (type of
anticoagulant, dose, duration, and frequency), and (4) type of outcome measure and
number of patients with study outcomes in each treatment arm.
Risk of Bias in Individual Studies
To explore the validity of eligible randomized trials, two reviewers (M.G. and C.B.)
independently determined the appropriate generation of random allocation sequence,
allocation concealment, blinding of patients and personnel, blinding of outcomes assessment,
incomplete outcome data, selective reporting, and other bias. Risk of bias was defined
as high, medium, or low. We resolved disagreements by opinion of senior authors or
by discussion. The risk of bias and strength of evidence were assessed by using the
Cochrane Collaboration's tool and the GRADE system, respectively.[15 ]
[18 ]
Statistical Analysis
The statistical analyses, forest plots, and publication bias analyses were produced
with Review Manager release 5.3 (The Cochrane Collaboration, Oxford, United Kingdom)
and the influence analysis with R software. Meta-analyses were performed by using
the Mantel–Haenszel with a random effects model to estimate pooled effect sizes. Relative
risk ratios (RRs) were reported with 95% confidence intervals (CIs). Cochran's test
and the I
2 test were used to assess between-study heterogeneity.[19 ]
[20 ]
[21 ] Statistically significant heterogeneity was considered present at p < 0.10 and I
2 > 50%. Forest plots were created for each outcome. Publication bias was assessed
visually by the use of funnel plots.
The case fatality rate of recurrent VTE and major bleeding was also calculated. Case
fatality rate was expressed as a percentage, computed from the number of fatal events
divided by the number of fatal plus nonfatal events.
Prespecified subgroup analyses were performed according to features of study outcome:
major bleeding in specific sites such as gastrointestinal, genitourinary, and intracranial;
or according to the characteristics of trials participants at randomization: (1) initial
clinical presentation (only DVT or PE ± DVT); (2) symptomatic and incidental VTE;
(3) active cancer; (4) metastatic or locally advanced cancer; (5) solid cancer and
hematological malignancy; (6) Eastern Cooperative Oncology Group (ECOG) performance
status of two or more; (7) age of 65 years or lower; (8) study outcomes in the overall
study treatment period; (9) use of apixaban; and (10) single drug approach. Data of
the HOKUSAI VTE Cancer Study refer to the 12-month study period in case of unavailability
of 6-month data.
Results
The literature search provided a total of 1,282 citations (March 30, 2020). After
adjusting for duplicates, 1,046 articles remained. Of these, 1,013 were excluded because
they did not meet the inclusion criteria as described. After a full review of the
remaining articles, four RCTs enrolling 2,894 cancer patients with acute VTE were
included in the meta-analysis.[7 ]
[8 ]
[13 ]
[14 ] The flow diagram of literature search is shown in [Fig. 1 ]. The agreement between reviewers for initial study selection was good (kappa statistic
0.87).
Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow
diagram.
Of the included studies, three were designed to assess noninferiority[7 ]
[8 ]
[14 ] and one was a safety trial designed to assess superiority.[13 ] The duration of study treatment was 6 months in three studies[8 ]
[13 ]
[14 ] and 12 months in one.[7 ] For the purpose of this meta-analysis, the results of HOKUSAI Cancer Study at 6
months were considered. Patients received apixaban in two studies,[13 ]
[14 ] and edoxaban[7 ] and rivaroxaban[8 ] in one study each. As dabigatran was not used in any study, the wording DOACs refer
to apixaban, edoxaban, or rivaroxaban. Dalteparin was the comparator in all four studies,
therefore the wording LMWH refers to dalteparin. The primary outcome differed among
the trials. [Table 1 ] shows the main characteristics of the studies according to the Patient, Intervention,
Comparison, Outcome criteria. Study cohorts varied from 287 to 1,170 patients ([Table 2 ]). Two studies included patients with both active cancer and history of cancer (cancer
not fulfilling the criteria for active cancer but diagnosed within 2 years from randomization).[7 ]
[14 ] Mean age varied from 64 to 67 years, and similar proportions of women and men were
included in the studies. More than half of included patients had locally advanced
or metastatic cancer and about a quarter had an ECOG score of two or more ([Table 2 ]).
Table 2
Main clinical features of the included studies
Source
Mean age (y)
Male sex
Active cancer
Metastatic cancer
ECOG status of 2
Solid tumor
Hematological malignancy
Creatinine clearance 30–50 mL/min
Platelet count 50–100.000/mm3
Incidental PE at diagnosis
Anticoagulant dose reduction
Raskob et al, 2018[7 ]
I
64.3
53.1%
98.3%
52.5%
23.6%
89.1%
10.7%
7.3%
6.1%
32.0%[a ]
Reduction if creatinine clearance 30–50 mL/min or body weight ≤60 kg or concomitant
treatment with potent P-glycoprotein inhibitors
C
63.7
50.2%
97.5%
53.4%
23.7%
89.1%
10.5%
6.5%
4.4%
33.0%[a ]
Temporary reduction if platelet count < 100,000/mm3
Young et al, 2018[8 ]
I
67
57%
100%
58%
26%
96%
2%
NR
NR
53%
Reduction if creatinine clearance 30–50 mL/min and patient's risk for bleeding outweighs
the risk for recurrent VTE
C
67
48%
100%
58%
21%
94%
3%
NR
NR
52%
Dose adjustment if platelet count < 100,000/mm3 or significant renal failure
McBane et al, 2020[13 ]
I
64.4
48.0%
100%
65.3%
13.3%
89.3%
8.6%
9.3%
6.7%
NR
Reduction if concomitant treatment with strong CYP3A4 and/or P-glycoprotein inhibitors.
Temporary reduction if platelet count < 50,000/mm3
C
64.0
48.7%
100%
66.0%
8.0%
88.6%
10.0%
9.3%
8.7%
NR
Dose adjustment if > 10% change in body weight; acute kidney injury (creatinine clearance
15–30 mL/min) or platelet count < 50,000/ mm3
Agnelli et al, 2020[14 ]
I
67.2
50.7%
97.0%
67.5%
18.9%
94.3%
5.7%
8.9%
3.6%
20.1%[a ]
None
C
67.2
47.7%
97.6%
68.4%
22.8%
91.0%
9.0%
10.5%
3.8%
19.7%[a ]
Temporary reduction if platelet count < 100,000/mm3
Abbreviations: C, comparator; DVT, deep vein thrombosis; ECOG, Eastern Cooperative
Oncology Group; I, intervention; NR, not reported; PE, pulmonary embolism; VTE, venous
thromboembolism.
a Incidental PE and DVT.
Three of the included trials had an overall low risk of bias, with the exception of
performance bias due to the absence of blinding of participants and personnel.[7 ]
[13 ]
[14 ] The SELECT-D trial had a high risk of bias for selection and detection bias.[8 ] The risk of bias is reported in [Supplementary Fig. S1 ] (available in the online version).
Recurrent VTE and Major Bleeding
Data on 6-month recurrent VTE and major bleeding were reported for all the trials
([Table 3 ], [Fig. 2 ]).
Table 3
Primary and secondary study outcomes
Outcomes
DOACs
% (95% CI)
Dalteparin
% (95% CI)
RR
95% CI
I
2
Recurrent VTE
5.2% (4.2–6.5)
8.2% (6.9- 9.8)
0.62
0.43–0.91
30%
Major bleeding
4.3% (3.4–5.5)
3.3% (2.5–4.4)
1.31
0.83–2.08
23%
Recurrent PE
3.2% (2.4–4.2)
4.6% (3.6–5.8)
0.71
0.49–1.03
0%
Recurrent DVT
2.2% (1.6–3.1)
3.8% (2.9–4.9)
0.60
0.36–1.00
16%
Fatal PE
0.3% (0.2–0.8)
0.3% (0.1–0.7)
1.25
0.34–4.67
0%
CRNMB
10.4% (8.912.1)
6.4% (5.2–7.7)
1.65
1.19–2.28
29%
CRB
13.7% (12.0–15.6)
9.3% (7.8–10.9)
1.51
1.09–2.09
49%
Fatal bleeding[a ]
0.2% (0.07–0.6)
0.3% (0.2–0.8)
0.37
0.07–2.00
0%
All-cause death
23.9% (21.8–26.2)
24.2% (22.1–26.5)
0.99
0.83–1.18
37%
Abbreviations: CI, confidence interval; CRB, clinical relevant bleeding; CRNMB, clinically
relevant nonmajor bleeding; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis;
PE, pulmonary embolism; RR, relative risk; VTE, venous thromboembolism.
a For HOKUSAI Cancer data at 12 months were considered.
Fig. 2 Forest plot of the main study outcomes comparing direct oral anticoagulants (DOACs)
and low-molecular-weight heparin (LMWH).
Recurrent VTE occurred in 75 of 1,446 patients (5.2%) treated with DOACs and in 119
of 1,448 patients (8.2%) treated with dalteparin. DOACs were associated with a significant
reduction in VTE recurrence (RR 0.62; 95% CI 0.43–0.91; I
2 , 30%).
Major bleeding occurred in 62 of 1,446 patients (4.3%) treated with DOACs and in 48
of the 1,448 patients (3.3%) treated with LMWH (RR 1.31; 95% CI 0.83–2.08; I
2 , 23%).
Funnel plot inspection showed no evidence of publication bias ([Supplementary Fig. S2 ], available in the online version). The certainty in evidence according to the GRADE
system was high for recurrent VTE and moderate for major bleeding. Influence analysis
for recurrent VTE and for major bleeding is reported in [Supplementary Fig. S3 ] (available in the online version).
Secondary Outcomes
Overall, 46 of 1,446 DOAC-treated patients (3.2%) and 66 of 1,448 LMWH-treated patients
(4.6%) had recurrent PE (RR 0.71; 95% CI 0.49–1.03; I
2 , 0%). A total of 32 of 1,446 DOAC-treated patients (2.2%) and 55 of 1,448 LMWH-treated
patients (3.8%) had recurrent DVT (RR 0.60; 95% CI 0.36–1.00; I
2 , 16%) ([Table 3 ]). Fatal PE occurred in 5 of 1,446 patients treated with DOACs and in 4 of 1,448
patients treated with LMWH (RR 1.25, 95% CI 0.34–4.67, I
2 , 0%). Case fatality rate of recurrent VTE was 6.7% (5 out of 75 events) in the DOACs
arm and 3.4% (4 out of 119 events) in the LMWH arm (RR 2.12, 95% CI 0.53–8.47, I
2 , 0%).
CRNMB occurred in 150 of 1,446 patients treated with DOACs and in 92 of 1,448 patients
treated with LMWH (10.4% vs. 6.4%; RR 1.65; 95% CI 1.19–2.28; I
2 , 29%). Risk of CRB was also higher in patients treated with DOACs (RR 1.51; 95% CI
1.09–2.09, I
2 , 49%). One of 1,446 DOAC-treated patients (0.2%) and 5 of 1,448 LMWH-treated patients
(0.3%) had a fatal bleeding (RR 0.37, 95% CI 0.07–2.00, I
2 , 0%). Case fatality rate of major bleeding was 1.6% (1 out of 62 events) in the DOACs
arm and 10.4% (5 out of 48 events) in the LMWH arm (RR 0.21, 95% CI 0.04–1.12, I
2 , 0%). All-cause death occurred in 346 of 1,446 (23.9%) DOACs-treated patients and
in 351 of 1,448 (24.2%) LMWH-treated patients (RR 0.99, 95% CI 0.83–1.18, I
2 , 37%) ([Table 3 ]).
Subgroup Analyses
Overall, 39 of 1,446patients (2.7%) treated with DOACs and 20 of 1,448 patients (1.4%)
with LMWH had a gastrointestinal bleeding (RR 1.91, 95% CI 0.96–3.82, I
2 , 35%) ([Supplementary Fig. S3 ], available in the online version). Major bleeding occurred at the genitourinary
site in 10 of 1,446 DOACs patients (0.7%) and in 1 of 1,448 LMWH patients (0.01%)
(RR 4.99, 95% CI 1.08–23.08, I
2 , 0%). Two of 1,446 patients (0.1%) and 7 of 1,448 patients (0.5%) had intracranial
hemorrhage in the DOACs and LMWH arm, respectively (RR 0.37, 95% CI 0.10–1.49, I
2 , 0%).
Subgroup analyses according to the initial clinical VTE presentation (only DVT or
PE ± DVT; symptomatic or incidental) and characteristics of trials participants at
randomization (active cancer, metastatic or locally advanced cancer, solid tumor,
and hematological malignancy), ECOG of 2 or more, study outcomes in the overall study
treatment period, use of apixaban, and single drug approach are reported in [Table 4 ].
Table 4
Results of subgroup analyses on recurrent VTE and major bleeding for the comparison
between DOACs and LMWH
Patients' characteristics at presentationa
N studies; N patients
Recurrent VTE
RR
(95% CI, I
2 %)
Major bleeding
RR
(95% CI, I
2 %)
Active cancer
4 studies; 2,841 patients
0.61 (0.44–0.86, I
2 23%)
1.40 (0.87–2.27, I
2 30)
Metastatic cancer
2 studies; 1,388 patients
0.78 (0.56–1.10, I
2 0%)
1.28 (0.82–2.02, I
2 0)
Solid tumor
2 studies; 2,000 patients
0.68 (0.51–0.91, I
2 0%)
1.38[b ] (0.86–2.20, I
2 33)
Hematological malignancy
2 studies; 196 patients
0.81 (0.23–2.83, I
2 0%)
0.98 (0.21–4.66, I
2 not estimable)
Age < 65 y
2 studies; 916 patients
0.46 (0.18–1.18, I
2 74%)
0.97 (0.38–2.44, I
2 54)
ECOG ≥2
2 studies; 488 patients
0.70 (0.37–1.31, I
2 0%)
1.48 (0.63–3.46, I
2 39)
Incidental PE or incidental DVT
2 studies; 570 patients
0.45 (0.23–0.89, I
2 0%)
1.57 (0.77–3.18, I
2 12)
Symptomatic PE or DVT
2 studies; 1,631 patients
0.77 (0.56–1.06, I
2 0%)
1.20 (0.74–1.93, I
2 0)
DVT only
2 studies; 906 patients
0.72 (0.49–1.05, I
2 0%)
1.08 (0.56–2.10, I
2 0)
PE ± DVT
2 studies; 1,295 patients
0.67 (0.43–1.03, I
2 0%)
1.48 (0.85–2.56, I
2 25)
Study outcome during overall treatment period
4 studies; 2,894 patients
0.62 (0.44–0.87; I
2 26)
1.33 (0.84–2.11, I
2 27)
Single drug approach
3 studies; 1,848 patients
0.63 (0.48–0.84, I
2 0%)
1.31 (0.82–2.08, I
2 34)
Use of apixaban
2 studies; 1,442 patients
0.36 (0.06–2.13, I
2 68%)
0.88 (0.49–1.57, I
2 3)
Abbreviations: CI, confidence interval; DOAC, direct oral anticoagulant; DVT, deep
vein thrombosis; ECOG, Eastern Cooperative Oncology Group; LMWH, low molecular weight
heparin; PE, pulmonary embolism; RR, relative risk; VTE, venous thromboembolism.
a All analyses include HOKUSAI Cancer results at 12 months.
b Three studies, 2,386 patients.
A reduction in recurrent VTE with DOACs compared with dalteparin was seen in active
cancer, solid tumor, age < 65 years, and incidental PE or incidental DVT ([Table 4 ]). When used according to the single drug approach, that is, with apixaban or rivaroxaban
only, DOACs showed a significant 46% reduction in the risk of VTE recurrence with
no increase in major bleeding compared with dalteparin.
Discussion
This meta-analysis of RCTs for the treatment of acute VTE in cancer patients shows
that, in comparison to the LMWH dalteparin, oral factor Xa inhibitors significantly
reduced the risk of recurrent VTE and nonsignificantly increased the risk of major
bleeding.
The superiority of DOACs over dalteparin for the prevention of recurrent VTE is reinforced
by our meta-analysis in cancer patients. Of note, DOACs were already shown to be noninferior
to initial LMWH followed by vitamin K antagonists in the general population of patients
with VTE.[22 ] Reasons for superiority of DOACs compared with LMWH could be related to a better
adherence to oral agents compared with parenteral agents and to the label-based regimen
of dalteparin, consisting of a 25% dose reduction after the first month of treatment.
The improvement in efficacy is a very relevant clinical finding for a fragile patient
population at particular high risk for recurrent VTE. The finding of a reduced risk
of recurrent VTE was consistent for both recurrent PE and DVT, although the definition
of recurrent VTE differed slightly across the studies. Indeed, the Caravaggio study
included symptomatic DVT of the upper limb as recurrent VTE and the ADAM-VTE study
included unusual site VTEs (subclavian vein, hepatic vein, and inferior vena cava).
The different definition of recurrent VTE may have led to differences in recurrence
rates and potentially in efficacy results across studies. However, the low level of
heterogeneity and the consistency of the efficacy results across studies observed
in this meta-analysis strengthen the validity and generalizability of the efficacy
of oral factor Xa inhibitors compared with dalteparin in the treatment of VTE in cancer
patients.
Although the rate of major bleeding was numerically higher in the DOAC-treated patients,
the 95% CI of the odds ratio for major bleeding included unity. Major bleeding was
defined according to the International Society of Thrombosis and Haemostasis (ISTH)
criteria in three studies. The European Medicines Agency definition was used in the
Caravaggio study[23 ] and includes all the ISTH criteria for major bleeding and bleeding requiring surgical
intervention. Rates of major bleeding in DOACs or dalteparin-treated patients differed
across studies. Whether these differences in safety profiles should be seen as agent
and regimen-specific is uncertain in absence of a direct comparison of the different
DOACs and requires further assessment.[24 ] However, we found that the overall heterogeneity contribution for major bleeding
was mainly related to the apixaban studies, the results of which may have influenced
the overall rates of major bleeding. Interestingly and importantly, in our meta-analysis,
the risk of intracranial hemorrhage as well as the case–fatality rate for major bleeding
was lower—although not statistically significant—in patients treated with DOACs compared
with those treated with LMWH. This is consistent with the lower rate of intracranial
hemorrhage in DOAC-treated patients compared with patients treated with vitamin K
antagonists in noncancer-associated VTE.[25 ] In contrast, gastrointestinal and genitourinary major bleedings were more common
in patients treated with oral factor Xa inhibitors than in those treated with dalteparin.
The association between the site of bleeding and the site of cancer is still a matter
of debate and whether a companion class effect exists remains to be defined. Indeed,
while in the Hokusai VTE Cancer and in the SELECT-D studies, patients with gastrointestinal
cancer had an increased risk of major bleeding with factor X inhibitors compared with
dalteparin, data on apixaban are currently not yet available. However, the results
of these subgroup analyses should be regarded with caution.
The higher risk of CRNMB and CRB observed with DOACs compared with dalteparin reflects
the numerical increase already seen in the individual studies. In this specific case,
the bleeding profile differs across individual agents as shown by the degree of heterogeneity.
All-cause mortality rates and fatal recurrent PE rates differed between patients treated
with DOACs or LMWH. Despite the fact that the included trials were not aimed or powered
to determine overall survival differences, the high risk of competing death due to
advanced cancer likely overrules any potential survival benefit associated with a
lower risk of recurrent VTE.
Limitations and Strengths
Several limitations of our study should be considered. First, as an aggregated data
meta-analysis, we could not assess the study outcomes in patients with different type
of cancer or baseline characteristics. However, subgroup analyses were performed and
showed consistent results with the primary study analysis, with the limits of potential
underpowering. Second, results are limited to dalteparin alone, being the comparator
in all studies. Also, according to previous studies, it is conceivable that the results
obtained with dalteparin are representative of other LMWHs.[26 ] Third, all the studies were open-label trials to avoid the use of parenteral placebo
for several months. However, in the studies considered in this analysis, all studies
used a PROBE design with suspected study outcome events being centrally adjudicated
by a committee blinded to assigned treatment. Moreover, the ethics of a double-blind
trial in this setting is questionable. Lastly, the subgroup analyses included considerable
smaller patient cohorts than the main analysis, causing wide CIs, and thus preventing
strong conclusions.
Strengths of our meta-analysis in comparison to previous ones, include the inclusion
of the Caravaggio study, thereby increasing generalizability and power of the individual
analyses.[27 ]
[28 ]
[29 ] Our findings indicate that the evaluated oral factor Xa inhibitors may replace LMWH
in the majority of patients with cancer-associated VTE. Moreover, state-of-the-art
methodology was used according to current guidelines for performing meta-analyses.
