VOLUME 36 • NUMBER 20 • JULY 10, 2018

JOURNAL OF CLINICAL ONCOLOGY R A P I D C O M M U N I C A T I O N

Comparison of an Oral Factor Xa Inhibitor With Low

Molecular Weight Heparin in Patients With Cancer With
Venous Thromboembolism: Results of a Randomized
Trial (SELECT-D)
Annie M. Young, Andrea Marshall, Jenny Thirlwall, Oliver Chapman, Anand Lokare, Catherine Hill, Danielle
Hale, Janet A. Dunn, Gary H. Lyman, Charles Hutchinson, Peter MacCallum, Ajay Kakkar, F.D. Richard Hobbs,
Stavros Petrou, Jeremy Dale, Christopher J. Poole, Anthony Maraveyas, and Mark Levine

Author affiliations and support information

(if applicable) appear at the end of this A B S T R A C T
article.
Purpose
Published at jco.org on May 10, 2018.
Venous thromboembolism (VTE) is common in patients with cancer. Long-term daily subcutaneous
Processed as a Rapid Communication low molecular weight heparin has been standard treatment for such patients. The purpose of this
manuscript.
study was to assess if an oral factor Xa inhibitor, rivaroxaban, would offer an alternative treatment for
Written on behalf of the SELECT-D VTE in patients with cancer.
Collaborative Group.
Patient and Methods
The opinions, results, and conclusions
reported here are those of the authors and
In this multicenter, randomized, open-label, pilot trial in the United Kingdom, patients with active
are independent of the funding sources. cancer who had symptomatic pulmonary embolism (PE), incidental PE, or symptomatic lower-
Clinical trial information:
extremity proximal deep vein thrombosis (DVT) were recruited. Allocation was to dalteparin (200 IU/kg
ISRCTN86712308; EudraCT 2012- daily during month 1, then 150 IU/kg daily for months 2-6) or rivaroxaban (15 mg twice daily for 3 weeks,
005589-37. then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months.
Corresponding author: Annie M. Young, Safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB). A sample
PhD, Warwick Clinical Trials Unit, size of 400 patients would provide estimates of VTE recurrence to within 6 4.5%, assuming a VTE
Warwick Medical School University recurrence rate at 6 months of 10%.
of Warwick, Coventry, CV4 7AL, UK;
e-mail: annie.young@warwick.ac.uk. Results
A total of 203 patients were randomly assigned to each group, 58% of whom had metastases.
© 2018 by American Society of Clinical
Oncology
Twenty-six patients experienced recurrent VTE (dalteparin, n = 18; rivaroxaban, n = 8). The 6-month
cumulative VTE recurrence rate was 11% (95% CI, 7% to 16%) with dalteparin and 4% (95% CI, 2%
0732-183X/18/3620w-2017w/$20.00
to 9%) with rivaroxaban (hazard ratio [HR], 0.43; 95% CI, 0.19 to 0.99). The 6-month cumulative rate
of major bleeding was 4% (95% CI, 2% to 8%) for dalteparin and 6% (95% CI, 3% to 11%) for
rivaroxaban (HR, 1.83; 95% CI, 0.68 to 4.96). Corresponding rates of CRNMB were 4% (95% CI, 2%
to 9%) and 13% (95% CI, 9% to 19%), respectively (HR, 3.76; 95% CI, 1.63 to 8.69).
Conclusion
Rivaroxaban was associated with relatively low VTE recurrence but higher CRNMB compared with
dalteparin.

J Clin Oncol 36:2017-2023. © 2018 by American Society of Clinical Oncology

in patients with cancer compared with patients

INTRODUCTION
without.2 For more than a decade, low molecular
weight heparin (LMWH) for at least 6 months has
Venous thromboembolism (VTE) is a common been the standard treatment for acute VTE in
ASSOCIATED CONTENT occurrence in patients with malignant disease. patients with cancer.3,4 In cancer-associated throm-
Appendix Acute VTE is treated with anticoagulant therapy bosis, there is limited evidence on the duration of
DOI: https://doi.org/10.1200/JCO. to prevent recurrent thrombosis, including po- anticoagulant therapy beyond 6 months. Guidelines
2018.78.8034
tentially fatal pulmonary embolism (PE). The risk recommend that treatment continue as long as the
Data Supplement
of recurrent thrombosis is increased at least two- cancer is active.5
DOI: https://doi.org/10.1200/JCO.
2018.78.8034 fold in patients with cancer compared with pa- Over the last decade, a new class of antico-
DOI: https://doi.org/10.1200/JCO.2018.
tients without cancer.1 Furthermore, there is an agulant, which directly inhibits a clotting factor
78.8034 increased risk of anticoagulant-induced bleeding and is not a vitamin K antagonist (VKA), has

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 Young et al

emerged for the prevention and treatment of acute VTE. The direct stratification by stage of disease (early or locally advanced disease v
oral anticoagulants (DOACs) are dabigatran, inhibiting activated metastatic disease for solid tumors v hematologic malignancy), baseline
factor II (thrombin), and rivaroxaban, apixaban, and edoxaban, platelet count (# 350,000 v . 350,000/mL), type of VTE (symptomatic
VTE v incidental PE), and risk of clotting by tumor type (high v low risk).
inhibiting activated factor X. These agents are noninferior to VKAs
Trial staff, participants, and investigators were not blinded to treatment
in patients with acute VTE.6-10 allocation.
LMWH requires daily subcutaneous injection; DOACs are For patients assigned to dalteparin, 200 IU/kg was administered
taken orally and do not require laboratory monitoring. In patients with subcutaneously once daily for the first 30 days of treatment, and then
anorexia and vomiting, oral administration can be problematic.11 150 IU/kg was administered subcutaneously once daily for an additional
In the EINSTEIN trials (ClinicalTrials.gov identifiers: 5 months. The LMWH was supplied by the National Health Service. The
NCT00440193 and NCT00439725) , which compared rivaroxaban total daily dose was not to exceed 18,000 IU. The dose was also adjusted or
discontinued for low platelet count and significant renal failure until
with LMWH followed by a VKA in patients with acute symp- recovery.
tomatic deep vein thrombosis (DVT) or acute PE,9,10 only 5.5% of For patients assigned to rivaroxaban, 15-mg tablets were administered
patients had active cancer at baseline.12 The comparator to the orally with food twice daily for the first 3 weeks, followed by 20-mg tablets
DOAC was a VKA, whereas the standard treatment in cancer is once daily for a total of 6 months. If platelet counts were , 50,000/mm3,
long-term LMWH.3 Because the generalizability to patients with rivaroxaban was to be discontinued until the platelet count recovered
active cancer was unclear, we conducted a trial to assess VTE to . 50,000/mm3. A dose reduction or discontinuation was specified for
different levels of renal impairment.
recurrence rates in patients with active cancer, treated with either
After approximately 5 months of receiving study medication, patients
rivaroxaban or dalteparin. The trial provided an opportunity to with an index DVT underwent CUS of the lower limbs. If the CUS showed
address the question of the duration of anticoagulant therapy residual DVT or patients had presented with a PE, they were eligible to be
beyond 6 months, based on the premise that the presence of re- randomly assigned to 6 months of rivaroxaban or placebo. Patients had to
sidual DVT on compression ultrasound (CUS) after 5 months of still be receiving trial treatment, be without a VTE recurrence, and satisfy
anticoagulant therapy is a marker for increased risk of recurrent the baseline inclusion criteria to be approached for the second random
VTE.13 The comparison of dalteparin and rivaroxaban over assignment.
6 months is reported.
Follow-Up
All patients were assessed at 3-month intervals until month 12 and
PATIENTS AND METHODS then at 6-month intervals until month 24. Physical examination (as
clinically indicated) and routine hematology and biochemistry were
Design performed at each visit. Computed tomography scans and venous ul-
Anticoagulation Therapy in Selected Cancer Patients at Risk of trasonography of upper and lower limbs were performed if clinically
Recurrence of Venous Thromboembolism (SELECT-D) was a randomized, indicated.
open-label, multicenter pilot trial.

Outcomes
Patient Population The primary outcome of the trial was VTE recurrence. Recurrent
The inclusion criteria were patients with active cancer (solid and proximal DVT (definition listed in Appendix Table A1, online only) was
hematologic malignancies) presenting with a primary objectively con- confirmed using CUS. Recurrent PE, either symptomatic or incidental PE,
firmed VTE, either symptomatic lower-extremity proximal DVT, symp- and fatal PE were defined as listed in Appendix Table A1. In addition, other
tomatic PE, or incidental PE. Active cancer was defined as a diagnosis of sites of venous thrombosis (eg, subclavian vein, hepatic vein, and inferior
cancer (other than basal-cell or squamous-cell skin carcinoma) in the vena cava) were counted as primary outcome events. Although the study
previous 6 months, any treatment for cancer within the previous 6 months, protocol did not specify central adjudication of suspected VTE events,
recurrent or metastatic cancer, or cancer not in complete remission reported VTE events were subsequently adjudicated by a central committee
(hematologic malignancy). In addition, patients had to be age $ 18 years of unaware of treatment allocation after the study was completed.
age; weigh $ 40 kg; have an Eastern Cooperative Oncology Group per- Secondary outcomes were major bleeding and clinically relevant
formance status of # 2; and have adequate hematologic, hepatic, and renal nonmajor bleeding (CRNMB9; Appendix Table A2, online only).14
function. Bleeding events were adjudicated by an independent committee of ex-
The exclusion criteria included taking any previous treatment dose of perienced clinicians unaware of treatment allocation. Adverse events ex-
anticoagulant or . 75 mg aspirin per day (planned start time of study perienced from trial entry until 30 days after the end of trial treatment were
therapy was . 96 hours after starting anticoagulant for this VTE), having recorded according to the National Cancer Institute Common Termi-
a history of VTE, clinically significant liver disease, bacterial endocarditis, nology Criteria for Adverse Events (version 4.0).15
active bleeding or high risk of bleeding, or uncontrolled hypertension, and
inadequate contraceptive measures if of childbearing potential. Con-
comitant use of strong cytochrome P- 450 3A4 inhibitors or inducers or
P-glycoprotein inhibitors or inducers was not permitted. After approval by Statistics
ethics committees in the United Kingdom and by the Medicines and We conducted a pilot trial to obtain estimates of recurrent VTE rates
Healthcare Products Regulatory Agency, each center approved the study to gauge the feasibility of recruiting to a phase III trial and assess the
protocol. All patients provided written informed consent. assumptions for the second random assignment. A target sample size of
530 patients would provide estimates of VTE recurrence rates at 6 months
to within an 8% width of the 95% CI, assuming a VTE recurrence rate at
Random Assignment and Study Interventions 6 months of 10%.3 In addition, it would ensure that the sample size would
Patients were randomly assigned centrally by telephoning Warwick be large enough to allow sufficient numbers for the second random
Clinical Trials Unit. Consenting patients were randomly assigned at assignment—a total of 300 patients randomly assigned (150 to each arm)
a one-to-one ratio using a computer-based minimization algorithm with to provide estimates for a future definitive duration study.

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 Rivaroxaban Versus LMWH for VTE in Patients With Cancer

Assessed for eligibility

Enrollment
(n = 2060)

Excluded (n = 1654)
Did not meet inclusion criteria (n = 1105)
Declined to participate (n = 264)
Other reasons (n = 285)

Randomly assigned
(n = 406)

Allocation
Allocated to Rivaroxaban (n = 203)
Allocated to Dalteparin (n = 203) Received allocated intervention (n = 202)
Received allocated intervention (n = 200) Did not receive allocated intervention because (n = 1)
Did not receive allocated intervention (n = 3) of a bleed before to starting trial treatment
because withdrew consent for trial

Treatment
Discontinued intervention (n = 90) Discontinued intervention (n = 86)

Death (n = 33) Death (n = 28)

VTE recurrence (n = 11) VTE recurrence (n = 5)
Participant decision (n = 10) Participant decision (n = 7)
Bleed (n = 2) Bleed (n = 18)
Other adverse event (n = 9) Other adverse event (n = 12)
Withdrew consent (n = 11) Withdrew consent (n = 5)
Clinical decision (n = 8) Clinical decision (n = 7)
Other (n = 1) Other (n = 2)
Unknown (n = 5) Unknown (n = 2)

Withdrawal
Withdrawal (n = 20) Withdrawal (n = 16)
Patient choice (n = 19) Patient choice (n = 11)
Clinical decision (n = 1) Clinical decision (n = 3)
Ineligible (n = 1)
Lost to follow-up (n = 1)

Analysis
VTE recurrence (n = 203) VTE recurrence (n = 203)
Overall survival (n = 203) Overall survival (n = 203)

Fig 1. CONSORT diagram, including enrollment and outcomes. VTE, venous thromboembolism.

On September 1, 2016, based on a recommendation from the data and estimated using the complement of the Kaplan-Meier estimates, and the
safety monitoring committee (DSMC), the second random assignment was VTE recurrence rate at 6 months and 95% CIs were obtained. Kaplan-
closed, with only 92 patients recruited, because it was considered futile to Meier estimates were also obtained for bleeding and survival. A Cox model
continue. At the same time, the sample size for the trial was reduced to a total was used to obtain hazard ratios (HRs) and associated 95% CIs and to
of 400 patients (200 patients in each arm), because recruitment was slower evaluate independent prognostic factors for VTE recurrence. A competing
than anticipated. This would still allow estimates of the primary outcome to risk analysis was performed using the cumulative incidence competing risk
be within a 95% CI of 9%, instead of 8% as originally planned. method to account for death as a competing risk.16
A safety analysis was planned for the first 220 patients (110 in each
arm). This would be sufficient to detect an excess of 10% in major bleeding
and CRNMB rates (80% power; 5% one- sided significance level, assuming
a 5% rate in the control arm). RESULTS
Because of censoring, VTE recurrence was analyzed using the time to
a VTE recurrence, which was calculated from the date of random as-
signment to the date of first VTE recurrence event or censored at the Patient Population
analysis date of 6 months or date last known to be VTE recurrence free, if Between September 6, 2013, and December 22, 2016, a total
earlier. Cumulative incidence curves for the time to VTE recurrence were of 2,060 patients were screened, and 670 eligible patients were

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 Young et al

Table 1. Patient Baseline Characteristics by Trial Arm (continued)

Table 1. Patient Baseline Characteristics by Trial Arm
No. (%)
No. (%)
Dalteparin Rivaroxaban
Dalteparin Rivaroxaban Characteristic (n = 203) (n = 203)
Characteristic (n = 203) (n = 203)
Prostate 8 (4) 13 (7)
Male sex 98 (48) 116 (57) Sarcoma 0 2 (1)
Age, years Other 5 (3) 6 (3)
Median 67 67 Unknown 3 (2) 1 (1)
Range 34-87 22-87
BMI, kg/m2 Abbreviations: BMI, body mass index; DVT, deep vein thrombosis; ECOG PS,
Median 26.6 26.7 Eastern Cooperative Oncology Group performance status; IQR, interquartile
Range 15.1-50.4 14.9-46.2 range; PE, pulmonary embolism; VTE, venous thromboembolism.
*One patient with incidental DVT.
ECOG PS
†Six patients had an incidental PE but were also found to have a DVT (dalteparin,
0 61 (30) 58 (29) n = 2; rivaroxaban, n = 4).
1 95 (47) 90 (44) ‡One patient was on anticoagulation for 97 hours.
2 43 (21) 52 (26) §Patients could receive more than one treatment.
White ethnicity 197 (96) 192 (94)
Stage of disease
Early/locally advanced 79 (39) 81 (40)
Metastatic 118 (58) 118 (58)
Hematologic malignancy 6 (3) 4 (2) The baseline characteristics were reasonably comparable between
Platelet count # 350,000/mL 168 (83) 168 (83)
Qualifying VTE
treatment arms (Table 1). The qualifying event was a symptomatic
Symptomatic VTE 98 (48) 95 (47) DVTor PE in 193 patients (48%) and an incidental PE in 213 patients
PE 38 (18) 40 (19) (52%). Fifty-eight percent of patients presented with metastatic
DVT* 57 (28) 53 (25)
disease (Table 1). Colorectal cancer was the primary in approximately
PE and DVT 2 (1) 2 (1)
Unknown 1 (1) 0 (0) 25% of patients (Table 1), and 282 patients (69%) were receiving
Incidental PE† 105 (52) 108 (53) anticancer treatment at the time of their VTE, a majority of whom
VTE high-risk tumor type 170 (84) 169 (83) (83%) were receiving chemotherapy (n = 233; Table 1).
Anticoagulation for qualifying VTE 162 (80) 158 (78)
before random assignment
Of the 406 patients randomly assigned, 11 were subsequently
Time on anticoagulant before found to be ineligible as a result of lower-extremity distal DVT (n = 5),
starting study treatment, hours jugular vein DVT (n = 2), unconfirmed PE (n = 1), previous DVT
Median 48 48
Range 17-96 16-97‡
(n = 1), incidental DVT (n = 1), or started trial treatment late because
Time since diagnosis of primary of pharmacy issues (n = 1). These 11 patients who were allocated
tumor to random assignment, dalteparin (n = 7) or rivaroxaban (n = 4) were included in the analysis
months
Median 6.0 6.4
on the basis of an intention to treat. A total of 216 patients (54%)
IQR 3.3-19.8 3.3-21.9 completed 6 months of trial treatment. The main reason for not
Currently receiving cancer treatment§ 142 (70) 140 (69) completing the study treatment in both arms was death (Fig 1).
Chemotherapy 120 (85) 113 (81) The median duration of treatment was 5.8 months (interquartile
Radiotherapy 10 (7) 6 (4)
Targeted therapy 22 (15) 21 (15) range, 3.0-6.0 months) for dalteparin and 5.9 months (interquartile
Endocrine therapy 15 (11) 15 (11) range, 2.5-6.0 months) for rivaroxaban. A total of 99 patients
Primary tumor type (24%) reported missing doses, 44 (22%) of whom were receiving
Bladder 4 (2) 10 (5)
dalteparin and 55 (27%) of whom were receiving rivaroxaban.
Brain 2 (1) 1 (1)
Breast 20 (10) 20 (10) The main reasons were requiring surgery or a procedure or patient
Cancer unknown primary 3 (2) 3 (1) decision.
Chronic lymphoid leukemia 2 (1) 1 (1)
Colorectal 47 (23) 55 (27)
Gallbladder 2 (1) 2 (1) Safety Analysis
Gastric 7 (3) 4 (2)
Gynecologic 7 (3) 6 (3) The DSMC reviewed the results of the safety analysis of the
Kidney 5 (3) 2 (1) first 220 patients. The data did not cross the safety boundary of
Lung 25 (12) 22 (11) 10% excess in major bleeding or CRNMB. The DSMC also noted
Lymphoma 12 (6) 11 (5)
a nonsignificant difference in major bleeding between arms in the
Multiple myeloma 3 (2) 2 (1)
Esophageal/gastroesophageal 19 (9) 11 (5) 19 patients with cancer of the esophagus or gastroesophageal
Ovarian 18 (9) 12 (6) junction. These cancers were subsequently excluded from en-
Pancreatic 11 (5) 19 (9) rollment as a precautionary measure.
(continued in next column)

Recurrent VTE
Twenty-six patients treated with dalteparin (n = 18) or
approached for participation; 264 patients declined random assign- rivaroxaban (n = 8) experienced a recurrent VTE within the first
ment (Fig 1). A total of 406 patients were recruited from 58 sites across 6 months after random assignment, including two patients with
the United Kingdom; 203 patients were allocated to each trial arm. symptomatic PE and six with incidental PE receiving dalteparin,

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 Rivaroxaban Versus LMWH for VTE in Patients With Cancer

Table 2. Recurrent VTE 40 Dalteparin

35 Rivaroxaban
No. (%)*

Recurrence (%)
Dalteparin Rivaroxaban 30
Thrombosis (n = 203) (n = 203)
25

VTE
VTE recurrence 18 8
20
Location of recurrence
Lower extremity 7 (39) 3 (38)† 15
Femoral vein 5 2
10
Popliteal vein 3 1
Iliac vein 2 2 5
IVC 0 1
PE 9 (50) 4 (50)
Other 2 (11) 2 (25) 0 1 2 3 4 5 6
Brachial, subclavian, or jugular 1 1 Time Since Trial Entry (months)
Renal plus IVC 1 0 No. at risk:
Extrahepatic portal vein 0 1 Dalteparin 203 171 139 115
Type of PE
Rivaroxaban 203 174 149 134
Symptomatic 2 (11) 2 (25)
Incidental 6 (33) 1 (13) Fig 2. Time to venous thromboembolism (VTE) recurrence within 6 months.
Fatal PE 1 (6) 1 (13)

Abbreviations: IVC, inferior vena cava; PE, pulmonary embolism; VTE, venous
thromboembolism.
*Percentages are out of the total with VTE recurrence.
†One patient had deep vein thrombosis and PE. DISCUSSION

The primary goal of our trial was to obtain estimates of the VTE
recurrence rates in patients with cancer treated with rivaroxaban or
compared with two symptomatic and one incidental PE in those dalteparin. The 6-month cumulative risk of recurrent VTE in the
receiving rivaroxaban. There was one fatal PE in each arm patients receiving dalteparin was consistent with what had been
(Table 2). The cumulative VTE recurrence rate at 6 months was postulated based on the trial, Low-Molecular–Weight Heparin Versus
11% (95% CI, 7% to 16%) for patients receiving dalteparin and 4% a Coumarin for the Prevention of Recurrent Venous Thromboem-
(95% CI, 2% to 9%) for patients receiving rivaroxaban (HR, 0.43; bolism in Patients with Cancer (CLOT) .3 Given that rivaroxaban was
95% CI, 0.19 to 0.99; Fig 2). A competing risk analysis showed noninferior to initial LMWH followed by a VKA in the EINSTEIN
similar results (Appendix Fig A1, online only). Site of primary trials,9,10 and that in CLOT, dalteparin reduced recurrent VTE by 50%
tumor (stomach or pancreas v other; HR, 5.55; 95% CI, 1.97 to compared with LMWH followed by a VKA,3 we estimated that the
15.66; lung, lymphoma, gynecologic, or bladder v other; HR, 2.69; 6-month cumulative risk of recurrent VTE in patients receiving
95% CI, 1.11-6.53) and VTE type (symptomatic VTE v incidental rivaroxaban would be 10% at best. In fact, the observed 6-month
PE; HR, 2.78; 95% CI, 1.20 to 6.41) predicted for VTE recurrence. recurrent VTE risk with rivaroxaban was only 4%. It is unlikely that
this reduction in recurrent VTE risk in favor of rivaroxaban was by
Bleeding chance, because the 95% CI of the HR did not include 1.0.
Six patients receiving dalteparin had major bleeds, compared Most of the cases of recurrent PE in the dalteparin arm were
with 11 patients in the rivaroxaban arm (Table 3). The cumulative incidental, related to computed tomography imaging for tumor
major bleed rate at 6 months was 4% (95% CI, 2% to 8%) for status. This did not seem to be the case for the rivaroxaban arm. It
dalteparin and 6% (95% CI, 3% to 11%) for rivaroxaban (HR, is conceivable that the increased detection of incidental PE was
1.83; 95% CI, 0.68 to 4.96; Fig 3). Most major bleeding events were a chance occurrence.
GI, and there were no CNS bleeds (Table 3). Patients with An important secondary objective of our trial was to assess
esophageal or gastroesophageal cancer tended to experience more rates of major bleeding and CRNMB. The rates of major bleeding
major bleeds with rivaroxaban than with dalteparin—four (36%) in both trial arms were relatively low and consistent with previously
of 11 versus one (11%) of 19 (Appendix Table A3, online only). observed rates.3,4 Most major bleeding events were GI. Upper GI
An additional seven patients receiving dalteparin had CRNMB bleeding is a challenge in patients with atrial fibrillation receiving
compared with 25 patients in the rivaroxaban arm (Table 3). The cu- rivaroxaban.17 There was a signal that cancer of the esophagus and
mulative rate of CRNMB at 6 months was 4% (95% CI, 2% to 9%) for gastroesophagus was associated with rivaroxaban-associated major
dalteparin and 13% (95% CI, 9% to 19%) for rivaroxaban (HR, 3.76; bleeding. CNS bleeding is a concern in patients with cancer re-
95% CI, 1.63 to 8.69). Most CRNMBs were GI or urologic (Table 3). ceiving anticoagulant therapy, and there were no such bleeds in the
trial.
There was a three-fold relative increase in CRNMB with
Survival rivaroxaban compared with dalteparin. Such bleeds were not
A total of 104 patients died within 6 months (dalteparin, n = trivial, because they had to satisfy at least one of the following
56; rivaroxaban, n = 48). Overall survival at 6 months was 70% criteria: requiring medical intervention, unscheduled contact with
(95% CI, 63% to 76%) with dalteparin and 75% (95% CI, 69% to a physician, interruption or discontinuation of study drug, or
81%) with rivaroxaban (Appendix Fig A2, online only). discomfort or impairment of activities of daily life.

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 Young et al

Table 3. Bleeding Events 20

Dalteparin
Dalteparin Rivaroxaban
Type of Bleed (n = 203) (n = 203) Rivaroxaban

Major Bleed (%)

15
Major bleeding 6 11
Criteria to define major bleeding*
Clinically overt and decrease in hemoglobin level 5 6 10
of $ 2 g/dL over 24 hours
Clinically overt and transfusion of $ 2 units of 3 10
packed red cells
Clinically overt and critical site (eg, intracranial, 0 0 5
retroperitoneal)
Clinically overt and contributes to death 1 1
Sites of major bleed*
GI 0 1 2 3 4 5 6
Esophageal 1 3
Stomach 3 2
Time Since Trial Entry (months)
No. at risk:
Lower GI 0 1
Site unknown 0 2 Dalteparin 203 176 147 122
Genitourinary Rivaroxaban 203 172 149 134
Hematuria 0 1
Fig 3. Time to major bleed within 6 months.
Other
Epistaxis 0 1
Intraoperative hemorrhage 0 1
Hematoma 1 0 perturbation of coagulation, predisposing to more bleeding. Fi-
Abdominal hematoma related to surgical clip 1 0 nally, it is recognized that in terms of GI bleeding, rivaroxaban has
CRNMB 7 25 both a local and systemic effect.20
Criteria to define CRNMB*
Overt bleeding with medical intervention 0 8
Our trial is not without limitations. Recruitment was slower
Unscheduled contact with a physician 2 15 than anticipated. Our postulates for the number of patients who
Interruption or discontinuation of a study drug 4 22 would be available to participate in the second random assignment
Discomfort or impairment of activities of daily life 2 11 were overly optimistic, there was a high mortality rate, and cli-
Site of CRNMB*
GI nicians were choosing not to randomly assign to rivaroxaban
Oral 0 1 versus placebo for many patients. Reducing the sample size re-
Upper GI 0 2 quired for the first random assignment did not substantially lower
Lower GI 1 0
the precision of the estimates of the observed outcome rates. The
Colon and rectum 2 1
Anus 0 3 results of our trial reflect only 6 months of treatment and are not
Hemorrhoidal 0 2 generalizable to longer treatment.
Genitourinary Some might consider the SELECT-D trial rather large for a ran-
Hematuria 1 9
Vagina 0 1
domized pilot study.21 However, we consider the study design in-
Menorrhagia 0 1 novative because it addressed two questions. Although we were unable
Penis 1 0 to answer the question of treatment duration beyond 6 months, we
Other were successful in meeting our primary aim, which was to obtain robust
Bronchopulmonary 0 2
Epistaxis 1 1
estimates of VTE and bleeding rates for the treatment arms.
Bruising 1 1 In VTE trials, DVT and PE are usually the primary outcome
Hematoma 1 0 events. We also counted other sites of DVT as primary events. It is
Subconjunctival 0 2 not unreasonable to expect anticoagulant therapy to have an effect
Joint effusion 0 1
on such sites. In an exploratory analysis, when only DVT and PE
Abbreviation: CRNMB, clinically relevant nonmajor bleeding. were considered, the rates of recurrent VTE at 6 months were
*Patients could have more than one reason or site of bleed; one patient
receiving rivaroxaban had two CRNMBs. consistent with those in other trials.3,4,22
In the recently published Hokusai trial (ClinicalTrials.gov
identifier: NCT02073682), patients with cancer with VTE were
randomly assigned to either LMWH for at least 5 days followed by
In our trial, there were fewer episodes of recurrent VTE as- the DOAC edoxaban or dalteparin for at least 6 months.22 The
sociated with rivaroxaban, but there was an increase in bleeding. primary outcome was a composite of either recurrent VTE or major
LMWH accelerates the inhibition by antithrombin of activated bleeding. Edoxaban was found to be noninferior to dalteparin. Over
factor X in the conversion of prothrombin to thrombin.18 the first 6-month period, the recurrent VTE rate was 6.5% with
Rivaroxaban binds directly and reversibly to factor Xa and com- edoxaban and 8.8% with dalteparin, but rates were 5.6% and 3.2%
petitively inhibits factor Xa. It is 10,000-fold more selective for for major bleeding and 12.3% and 8.2% for CRNMB, respectively.
factor Xa than other related serine proteases, and it does not re- Although there are limitations to between-study comparisons, the
quire cofactors (eg, antithrombin) to exert its anticoagulant effect. results of our trial are consistent with those of this study.
Rivaroxaban also inhibits both free and clot-bound factor Xa, as The results of our trial provide evidence that rivaroxaban is an
well as prothrombinase activity.19 It is plausible that the enhanced effective alternative to LMWH for the treatment of VTE in cancer.
antithrombotic effect of rivaroxaban is associated with a greater Rivaroxaban reduced the rate of recurrent VTE compared with

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 Rivaroxaban Versus LMWH for VTE in Patients With Cancer

LMWH, but at the cost of more bleeding. Oral administration is

AUTHOR CONTRIBUTIONS
more convenient than daily subcutaneous injections. It should be
used with particular caution in patients with esophageal cancer. At
Conception and design: Annie M. Young, Andrea Marshall, Oliver
the end of the day, a patient’s preference for a specific anticoagulant
Chapman, Anand Lokare, Janet A. Dunn, F.D. Richard Hobbs, Stavros
is based on a careful discussion between patient and physician Petrou, Jeremy Dale, Christopher J. Poole
about the benefits and risks of the treatment alternatives. Collection and assembly of data: Jenny Thirlwall, Catherine Hill, Danielle
Hale, Anthony Maraveyas
Data analysis and interpretation: Andrea Marshall, Oliver Chapman,
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS Anand Lokare, Gary H. Lyman, Charles Hutchinson, Peter MacCallum,
OF INTEREST Ajay Kakkar, Anthony Maraveyas, Mark Levine
Manuscript writing: All authors
Disclosures provided by the authors are available with this article at Final approval of manuscript: All authors
jco.org. Accountable for all aspects of the work: All authors

7. Agnelli G, Buller HR, Cohen A, et al: Oral medicinal products in non-surgical patients. J Thromb
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3. Lee AY, Levine MN, Baker RI, et al: Low- Practical considerations for the management of pa- controlled trials. Int J Stroke 12:589-596, 2017
molecular-weight heparin versus a coumarin for tients with nausea or vomiting. Oncologist [epub 18. Hirsh J, Bauer KA, Donati MB, et al: Parenteral
the prevention of recurrent venous thromboem- ahead of print on April 12, 2018] anticoagulants: American College of Chest Physi-
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349:146-153, 2003 Oral rivaroxaban versus enoxaparin with vitamin K edition). Chest 133:141s-159s, 2008 (suppl)
4. Lee AYY, Kamphuisen PW, Meyer G, et al: antagonist for the treatment of symptomatic ve- 19. Samama MM, Contant G, Spiro TE, et al:
Tinzaparin vs warfarin for treatment of acute nous thromboembolism in patients with cancer Laboratory assessment of rivaroxaban: A review.
venous thromboembolism in patients with ac- (EINSTEIN-DVT and EINSTEIN-PE): A pooled sub- Thromb J 11:11, 2013
tive cancer: A randomized clinical trial. JAMA group analysis of two randomised controlled trials. 20. Cheung KS, Leung WK: Gastrointestinal
314:677-686, 2015 Lancet Haematol 1:e37-e46, 2014 bleeding in patients on novel oral anticoagulants:
5. Lyman GH, Khorana AA, Kuderer NM, et al: 13. Napolitano M, Saccullo G, Malato A, et al: Optimal Risk, prevention and management. World J Gastro-
Venous thromboembolism prophylaxis and treat- duration of low molecular weight heparin for the treat- enterol 23:1954-1963, 2017
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6. Schulman S, Kakkar AK, Goldhaber SZ, et al: Control of Anticoagulation of the Scientific and 22. Raskob GE, van Es N, Verhamme P, et al:
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Affiliations
Annie M. Young, Andrea Marshall, Jenny Thirlwall, Catherine Hill, Danielle Hale, Janet A. Dunn, and Stavros Petrou, Warwick
Clinical Trials Unit, University of Warwick; Oliver Chapman and Christopher J. Poole, University Hospitals Coventry and Warwickshire;
Charles Hutchinson and Jeremy Dale, Warwick Medical School, University of Warwick, Coventry; Anand Lokare, Heart of England
National Health Service Foundation Trust, Birmingham; Peter MacCallum, Queen Mary University of London; Ajay Kakkar, Thrombosis
Research Institute, London; F.D. Richard Hobbs, University of Oxford, Oxford; Anthony Maraveyas, Hull York Medical School, Hull,
United Kingdom; Gary H. Lyman, Fred Hutchinson Cancer Research Center, Seattle, WA; and Mark Levine, McMaster University,
Hamilton, Ontario, Canada.
Support
Supported by an unrestricted educational grant from Bayer AG, which also provided rivaroxaban and placebo tablets.
Prior Presentation
Presented orally at the American Society of Hematology Annual Meeting, Atlanta, GA, December 9-12, 2017.

nnn

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 Young et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results
of a Randomized Trial (SELECT-D)
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Annie M. Young Ajay Kakkar
Honoraria: Bayer AG, Helsinn Healthcare, LEO Pharma, Merck Sharp & Honoraria: Bayer, Boehringer Ingelheim, Daiichi Sankyo, Sanofi, Janssen,
Dohme Verseon
Research Funding: Bayer AG (Inst) Consulting or Advisory Role: Bayer, Boehringer Ingelheim, Daiichi
Sankyo, Sanofi, Janssen, Verseon
Andrea Marshall Research Funding: Bayer (Inst)
Research Funding: Bayer AG (Inst)
F.D. Richard Hobbs
Jenny Thirlwall Honoraria: Bayer
Research Funding: Bayer AG (Inst)
Stavros Petrou
Oliver Chapman No relationship to disclose
No relationship to disclose
Jeremy Dale
Anand Lokare No relationship to disclose
No relationship to disclose
Christopher J. Poole
Catherine Hill Honoraria: Roche, Genomic Health, AstraZeneca, Pfizer
Research Funding: Bayer AG (Inst) Consulting or Advisory Role: Roche, Genomic Health, AstraZeneca,
Danielle Hale Pfizer, Puma Biotechnology
Research Funding: Bayer (Inst) Speakers’ Bureau: Roche, AstraZeneca, Pfizer, Genomic Health
Research Funding: Roche (Inst), AstraZeneca (Inst), Aeterna Zentaris
Janet A. Dunn (Inst), AB Bioscience (Inst), Clovis Oncology (Inst), Bristol-Myers Squibb
Research Funding: Bayer AG (Inst) (Inst), Imgen (Inst), Macrogenics (Inst)
Gary H. Lyman Travel, Accommodations, Expenses: AstraZeneca
Leadership: Generex Biotechnology Anthony Maraveyas
Consulting or Advisory Role: Halozyme, G1 Therapeutics, Coherus Honoraria: Bayer AG, Bristol Myers Squibb
Biosciences Consulting or Advisory Role: Bayer AG, Bristol Myers Squibb
Research Funding: Amgen (Inst) Speaker’s Bureau: Bristol Myers Squibb, Pfizer
Charles Hutchinson Mark Levine
No relationship to disclose Honoraria: Bayer
Peter MacCallum
Honoraria: Bayer, Daiichi Sankyo

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 Rivaroxaban Versus LMWH for VTE in Patients With Cancer

Acknowledgment

We thank all the co-investigators in the United Kingdom for their commitment throughout the study period, in particular Mojid Khan
(MPharm), Robert Grieve, Martin Scott-Brown (MD), and Tom Goodfellow (MD), University Hospitals Coventry and Warwickshire;
Veronica Wilkie (FRCGP), University of Worcester; Andrew Entwistle (PhD) and Debs Smith (BA), patient and public involvement (PPI)
representatives; Peter Rose (FRCPath), Warwick Hospital; and Jo Grumett (BSc) and Jaclyn Brown (BSc), Warwick Clinical Trials Unit. We
also thank all of the patients who participated in the SELECT-D trial and their caregivers and all investigators and their teams from the
participating sites (Appendix, Table A4, online only) and members of the UK independent data and safety monitoring committee: Keith
Wheatley (PhD), University of Birmingham; Lisa Robinson (FRCPath), Hereford County Hospital; and Ganesh Radhakrishna (FRCR),
The Christie National Health Service Foundation Trust. During the trial, one of our PPI representatives, Irene Singleton (BSc), sadly died;
Irene gently advised with wise words of a patient.

Appendix

Table A1. Definition of VTE Recurrence

DVT Recurrence Symptomatic PE Recurrence Incidental PE Recurrence
Confirmed using CUS: new, noncompressible venous New intraluminal filling defect on spiral CT or Incidentally diagnosed PE on CT when imaging
segment or a substantial increase ($ 4 mm) in the pulmonary angiography, a cutoff of a vessel of performed, usually for staging of cancer
diameter of the thrombus during full compression in . 2.5 mm in diameter on pulmonary angiography, Fatal PE was based on objective diagnostic testing,
a previously abnormal segment on ultrasonography a new perfusion defect of at least 75% of autopsy, or death, which could not be attributed to
or a new intraluminal filling defect on venography a segment with corresponding normal ventilation a documented cause and for which PE could not be
(high probability), or a new non–high-probability ruled out (unexplained death)
perfusion defect associated with DVT as
documented by CUS or venography

Abbreviations: CUS, compression ultrasound; DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.

Table A2. Bleeding Definitions

Major Bleeding CRNMB
Acute, clinically overt bleeding accompanied by one or more of Acute, clinically overt episodes, such as wound hematoma,
the following findings: a decrease in the hemoglobin level of bruising, GI bleeding, hemoptysis, hematuria, or epistaxis,
$ 20 g/L over a 24-hour period, transfusion of two or more that did not meet the criteria for major bleeding but were
units of packed red cells, bleeding at a critical site (including associated with medical intervention, unscheduled contact
intracranial, intraspinal, intraocular, pericardial, or with a physician, interruption or discontinuation of study drug,
retroperitoneal bleeding), or fatal bleeding14 or discomfort or impairment of activities of daily life9

Abbreviation: CRNMB, clinically relevant nonmajor bleeding.

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 Young et al

Table A3. Bleeding Events by Primary Tumor Type

No. (%)
Dalteparin Rivaroxaban
Primary Tumor Type Total Major Bleeds CRNMB Total Major Bleeds CRNMB
Total patients 203 6 (3) 7 (3) 203 11 (5) 25 (12)
Bladder 4 (2) 0 1 (25) 10 (5) 1 (10) 5 (50)
Brain 2 (1) 0 0 1 (1) 0 1 (100)
Breast 20 (10) 1 (5) 0 20 (10) 0 2 (10)
Cancer unknown primary 3 (2) 0 0 3 (1) 0 0
Chronic lymphoid leukemia 2 (1) 0 0 1 (1) 0 0
Colorectal 47 (23) 4 (9) 1 (2) 55 (27) 4 (7) 6 (11)
Gallbladder 2 (1) 0 0 2 (1) 0 0
Gastric 7 (3) 0 0 4 (2) 0 0
Gynecologic 7 (3) 0 0 6 (3) 0 0
Kidney 5 (3) 0 0 2 (1) 0 0
Lung 25 (12) 0 2 (8) 22 (11) 1 (5) 2 (9)
Lymphoma 12 (6) 0 0 11 (5) 0 2 (18)
Multiple myeloma 3 (2) 0 0 2 (1) 0 0
Esophageal/gastroesophageal 19 (9) 1 (5) 0 11 (5) 4 (36) 0
Ovarian 18 (9) 0 2 (11) 12 (6) 0 3 (25)
Pancreatic 11 (5) 0 0 19 (9) 0 1 (5)
Prostate 8 (4) 0 1 (13) 13 (7) 0 1 (8)
Sarcoma 0 0 0 2 (1) 0 1 (50)
Other* 5 (3) 0 0 6 (3) 1 (20) 1 (20)
Unknown 3 (2) 0 0 1 (1) 0 0

Abbreviation: CRNMB, clinically relevant nonmajor bleeding.

*Other cancers: anal cancer with major bleed (n = 1); sacral chordoma with CRNMB (n = 1). Patients with CNS tumors (n = 3).

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 Rivaroxaban Versus LMWH for VTE in Patients With Cancer

Table A4. SELECT-D Participating Site Teams

Participating Site Team Members
Basingstoke and North Hampshire Hospital Jackie Smith, Charlotte Rees
Bradford Royal Infirmary Janet Bunch, Victoria Drew, Vickie Hawkins, Sam Ackroyd
Bristol Haematology and Oncology Centre Kay Drury, Jack Teasdale, Vivek Mohan
Castle Hill Hospital Ceri Fuller, Karen Shepherd, Georgios Bozas
Chelsea and Westminster Hospital Laletha Agoramoorthy, Thomas Newsom-Davis
Christie Hospital Jonathan Archer, Jurjees Hasan
Churchill Hospital Christopher Deane, Nicola Curry
Countess of Chester Hospital Elizabeth Gallimore, Dale Vimalachandran
County Durham and Darlington National Health Service (NHS) Andrea Kay, Susan Wadd, Natalie Picozzi
Foundation Trust
Ealing Hospital Sheena Quaid, Olivia Hatcher
Furness General Hospital Karen Burns, Sarah Moon
Guy’s and St Thomas’ NHS Foundation Johanna Young, Beverley Hunt
Heartlands Hospital James Whitehouse, Neil Smith
Hereford County Hospital Janine Birch, Sara Willoughby
Hillingdon Hospital Mariam Nasseri, Amy Guppy
Imperial College Healthcare NHS Trust Amalia Saucan, Bhavesh Pratap, Alka Shah, Byiravey
Pathmanathan, Noura Mohamed, Danielle Power
James Paget University Hospital Wendy Harrison, Manzoor Mangi
Medway Maritime Hospital Suzie Reyner, Vijayavalli Dhanapal
Milton Keynes Hospital Hayley Moss, Sara Greig, Ijaz Mehdi
Mount Vernon Cancer Centre Christine Brannan, Teresa Young, Marcia Hall
New Cross Hospital Vanda Carter, Simon Grumett
Newcastle Upon Tyne Hospitals NHS Foundation Trust Phil Hope, Sophie Alderson, John Hanley
Norfolk and Norwich University Hospital Victoria License, Adele Cooper, Hamish Lyall
North Cumbria University Hospitals NHS Trust Patricia Nicholls, Jonathan Nicoll
Northumbria Healthcare NHS Foundation Trust Catherine Ashbrook-Raby, Charlotte Bomken
Poole Hospital Louise Heckford, Tamas Hickish
Queen Alexandra Hospital Sally Louise Evans, Sherilee Cook, Caroline Stemp, Ann
O’Callaghan
Queen Elizabeth Hospital Gateshead Helen Wild, Scott Marshall
Queen’s Hospital Burton Clare Mewies, Helena Cox, Manjusha Keni
Queen’s Hospital Romford Michelle McDonald, Jagadish Akula, Khalid Saja
Raigmore Hospital Seonaid Arnott, Carol Macgregor
Royal Albert Edward Infirmary Angela Power, Hiteshkumar Patel
Royal Bournemouth Hospital Luke Vamplew, Taslima Rabbi, Tom Geldart
Royal Cornwall Hospital Anne Griffiths, Anna Oakes, Nicholas Ashley, Duncan Wheatley
Royal Hampshire County Hospital Elizabeth Happle, Katherine Lowndes
The Royal Marsden NHS Foundation Trust Nadine Nadal, Helen Morgan, Mary Jane Lauigan, Katrin
Sainudeen, Ian Chau
Royal Shrewsbury Hospital Sally Potts, Abel Zachariah
Russells Hall Hospital Angela Watts, Julie Matthews, Stephen Jenkins
Salisbury District Hospital Julie Attlee, Louise Bell, Jonathan Cullis
South Tyneside District Hospital Judith Moore, Ashraf Azzabi
Southport Hospital Anna Morris, Helen Neville-Webbe
St George’s Hospital Pearl Quartey, James Uprichard
St Helens and Knowsley Teaching Hospitals NHS Trust Nicola Hornby, David Taylor
St James’s University Hospital Sam Lotfi, Michael Snee
Sunderland Royal Hospital Paula Newton, Vivienne Hullock, Ashraf Azzabi
University Hospital Coventry Linda Wimbush, Ruth Manton, Oliver Chapman
Weston General Hospital Harvey Dymond, Sandra Beech, Serena Hilman
Weston Park Hospital Aisling Robinson, Jonathan Wadsley
Wexham Park Hospital Julie-Ann Sinclair, Marcia Hall
Worcestershire Acute Hospitals NHS Trust Alison Harrison, Hayley Hodson, Helen Tranter, Mark Churn

Abbreviation: SELECT-D, Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism

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 Young et al

20
Dalteparin
Rivaroxaban

Recurrence (%)
15

VTE
10

0 1 2 3 4 5 6
Time Since Trial Entry (months)
No. at risk:
Dalteparin 203 171 139 115
Rivaroxaban 203 174 149 134

Fig A1. Competing risk analysis. The 6-month cumulative incidence for venous
thromboembolism (VTE) recurrence, allowing for the competing risk of death, was
9% (95% CI, 6% to 14%) for dalteparin and 4% (95% CI, 2% to 7%) for
rivaroxaban.

100

75
OS (%)

50

25
Dalteparin
Rivaroxaban

0 1 2 3 4 5 6
Time Since Trial Entry (months)
No. at risk:
Dalteparin 203 176 149 124
Rivaroxaban 203 177 154 138

Fig A2. Overall survival (OS) within 6 months.

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