Research

Original Investigation

Tinzaparin vs Warfarin for Treatment of Acute Venous

Thromboembolism in Patients With Active Cancer
A Randomized Clinical Trial
Agnes Y. Y. Lee, MD, MSc; Pieter W. Kamphuisen, MD, PhD; Guy Meyer, MD; Rupert Bauersachs, MD;
Mette S. Janas, MD, PhD; Mikala F. Jarner, MSc; Alok A. Khorana, MD; for the CATCH Investigators

Supplemental content at
IMPORTANCE Low-molecular-weight heparin is recommended over warfarin for the jama.com
treatment of acute venous thromboembolism (VTE) in patients with active cancer largely
based on results of a single, large trial.

OBJECTIVE To study the efficacy and safety of tinzaparin vs warfarin for treatment of acute,
symptomatic VTE in patients with active cancer.

DESIGN, SETTINGS, AND PARTICIPANTS A randomized, open-label study with blinded central
adjudication of study outcomes enrolled patients in 164 centers in Asia, Africa, Europe, and
North, Central, and South America between August 2010 and November 2013. Adult patients
with active cancer (defined as histologic diagnosis of cancer and receiving anticancer therapy or
diagnosed with, or received such therapy, within the previous 6 months) and objectively docu-
mented proximal deep vein thrombosis (DVT) or pulmonary embolism, with a life expectancy
greater than 6 months and without contraindications for anticoagulation, were followed up for
180 days and for 30 days after the last study medication dose for collection of safety data.

INTERVENTIONS Tinzaparin (175 IU/kg) once daily for 6 months vs conventional therapy with
tinzaparin (175 IU/kg) once daily for 5 to 10 days followed by warfarin at a dose adjusted to
maintain the international normalized ratio within the therapeutic range (2.0-3.0) for 6 months.

MAIN OUTCOMES AND MEASURES Primary efficacy outcome was a composite of centrally
adjudicated recurrent DVT, fatal or nonfatal pulmonary embolism, and incidental VTE. Safety
outcomes included major bleeding, clinically relevant nonmajor bleeding, and overall
mortality.

RESULTS Nine hundred patients were randomized and included in intention-to-treat efficacy
and safety analyses. Recurrent VTE occurred in 31 of 449 patients treated with tinzaparin and
45 of 451 patients treated with warfarin (6-month cumulative incidence, 7.2% for tinzaparin Author Affiliations: Department of
vs 10.5% for warfarin; hazard ratio [HR], 0.65 [95% CI, 0.41-1.03]; P = .07). There were no Medicine, University of British
Columbia, Vancouver, Canada (Lee);
differences in major bleeding (12 patients for tinzaparin vs 11 patients for warfarin; HR, 0.89
British Columbia Cancer Agency,
[95% CI, 0.40-1.99]; P = .77) or overall mortality (150 patients for tinzaparin vs 138 patients Vancouver, Canada (Lee);
for warfarin; HR, 1.08 [95% CI, 0.85-1.36]; P = .54). A significant reduction in clinically Department of Vascular Medicine,
relevant nonmajor bleeding was observed with tinzaparin (49 of 449 patients for tinzaparin University Medical Center Groningen,
University of Groningen, Groningen,
vs 69 of 451 patients for warfarin; HR, 0.58 [95% CI, 0.40-0.84]; P = .004). the Netherlands (Kamphuisen);
INSERM U 970, Hôpital Européen
CONCLUSIONS AND RELEVANCE Among patients with active cancer and acute symptomatic Georges-Pompidou, Université Paris
Descartes, Paris, France (Meyer);
VTE, the use of full-dose tinzaparin (175 IU/kg) daily compared with warfarin for 6 months did
Department Vascular Medicine,
not significantly reduce the composite measure of recurrent VTE and was not associated with Darmstadt Hospital, Darmstadt,
reductions in overall mortality or major bleeding, but was associated with a lower rate of Germany (Bauersachs); Center of
clinically relevant nonmajor bleeding. Further studies are needed to assess whether the Thrombosis and Haemostasis,
University of Mainz, Mainz, Germany
efficacy outcomes would be different in patients at higher risk of recurrent VTE.
(Bauersachs); LEO Pharma, Ballerup,
Denmark (Janas, Jarner); Taussig
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01130025 Cancer Institute, Cleveland Clinic,
Cleveland, Ohio (Khorana).
Group Information: CATCH
Investigators are listed at the end of
JAMA. 2015;314(7):677-686. doi:10.1001/jama.2015.9243 this article.

(Reprinted) 677

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Bayer HealthCare AG User on 09/30/2015

 Research Original Investigation Tinzaparin vs Warfarin for Acute VTE in Patients With Active Cancer

V
enous thromboembolism (VTE) is a major cause of mor- not in complete remission from a hematological malig-
bidity and mortality in patients with cancer.1,2 Treat- nancy. Proximal DVT was defined as thrombosis involving
ment with low-molecular-weight heparin (LMWH) is ef- the popliteal, femoral, or iliac veins. Objective confirmation
fective and is recommended over vitamin K antagonist therapy of DVT and pulmonary embolism using standard imaging
by clinical practice guidelines.3-6 These recommendations are techniques and diagnostic criteria was required.13 Patients
largely based on results from a single, large randomized trial also had an Eastern Cooperative Oncology Group (ECOG)
with supportive evidence performance status of 0, 1, or 2 prior to the index throm-
DVT deep vein thrombosis from additional smaller botic event (ie, their activity level ranged from no limitation
HIT heparin-induced studies that were con- [score 0] to being unable to work but able to perform self-
thrombocytopenia ducted over a decade ago care and remain ambulatory for at least 50% of waking
INR international normalized ratio in academic centers pri- hours [score 2]).
LMWH low-molecular-weight marily in North America Patients were excluded for any of the following: creati-
heparin and Western Europe.7-10 nine clearance of 20 mL/min/1.73 m2 or lower (to convert cre-
TTR time in the INR therapeutic These limitations may atinine clearance to mL/s/m2, multiply by 0.0167); any con-
range partly explain why vita- traindication to anticoagulation; known hypersensitivity to
VTE venous thromboembolism min K antagonists remain study medications; history of HIT; therapeutic anticoagula-
frequently used world- tion for more than 72 hours prior to randomization; thera-
wide in patients with cancer-associated thrombosis.11,12 To peutic anticoagulation at the time of thrombotic event; life
provide more contemporary and global evidence for long- expectancy less than 6 months; unlikely to comply with the
term LMWH therapy, we conducted the Comparison of protocol; participating in another interventional study;
Acute Treatments in Cancer Hemostasis (CATCH) trial to women of childbearing potential or fertile men not using
compare the efficacy and safety of tinzaparin with conven- effective contraception.
tional warfarin therapy for the treatment of VTE in patients
with active cancer. Randomization and Concealment
Randomization occurred within the first 72 hours after con-
firmation of the qualifying thrombotic event or initiation of
therapeutic anticoagulation. Prior to randomization, all
Methods patients had diagnostic imaging for both DVT and pulmo-
Study Design and Oversight nary embolism to document any additional VTE at baseline.
This phase 3, multinational, randomized, active-controlled, Treatment assignment was preplanned according to a
open-label trial was designed, conducted, and supervised computer-generated randomization schedule in a 1:1 ratio
by a steering committee of academic physicians and spon- and concealed until individual randomization using an
sor representatives. Members of a central, independent interactive voice-response system. Randomization was
adjudication committee, who were unaware of the study stratified by tumor extent (known distant metastasis, no
treatment assignments, reviewed and adjudicated all sus- distant metastasis, or hematological malignancy); geo-
pected cases of recurrent VTE, heparin-induced thrombocy- graphic region (Asia and Middle East; Eastern Europe;
topenia (HIT), bleeding events, and causes of death. An Western Europe and North America; and Central and South
independent data and safety monitoring committee regu- America); and history of VTE.
larly received data on study outcomes and adverse events.
Institutional ethics approval was obtained at each partici- Study Treatments
pating center and written informed consent was obtained Patients in the tinzaparin (Innohep, LEO Pharma A/S) group
from each participant. The trial was designed in accordance received tinzaparin (175 IU/kg) once daily by subcutaneous
with the International Conference on Harmonisation Guide- injection for 6 months. Patients in the warfarin group
lines of Good Clinical Practice and the Declaration of received warfarin for 6 months, overlapping with tinzaparin
Helsinki (trial protocol in Supplement 1). (175 IU/kg) once daily for the first 5 to 10 days and until the
Details and rationale of study methods were published pre- international normalized ratio (INR) was higher than 2.0 for 2
viously and are briefly described here.13 consecutive days. Thereafter, these patients continued on
warfarin alone at a dose adjusted to maintain the INR within
Study Population the therapeutic range (2.0-3.0). INR testing was required at
Patients 18 years or older with a diagnosis of active cancer least once every 2 weeks. Temporary interruption of the
and acute symptomatic proximal deep vein thrombosis study drug not exceeding 3 weeks was permitted for a plate-
(DVT), pulmonary embolism, or both were eligible for inclu- let count lower than 50 × 103/μL, a bleeding event, or inva-
sion (Figure 1). Active cancer was defined by histological or sive procedures.
cytological confirmation of malignancy (excluding basal cell
carcinoma or nonmelanoma skin cancer) and having any of Efficacy Outcomes
the following features: cancer diagnosis within the previous The primary efficacy outcome was the composite of symp-
6 months; recurrent, regionally advanced, or metastatic dis- tomatic DVT, symptomatic nonfatal pulmonary embolism,
ease; treatment for cancer during the previous 6 months; or fatal pulmonary embolism, incidental proximal DVT

678 JAMA August 18, 2015 Volume 314, Number 7 (Reprinted) jama.com

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Bayer HealthCare AG User on 09/30/2015

 Tinzaparin vs Warfarin for Acute VTE in Patients With Active Cancer Original Investigation Research

Figure 1. Patient Screening, Enrollment, Follow-up, and Analysis of the CATCH Trial

1035 Patients assessed for eligibility

135 Excluded
14 Did not meet eligibility criteria
121 Refused participation

900 Patients randomized

449 Randomized to receive tinzaparin 451 Randomized to receive warfarin

449 Received tinzaparin as randomized 451 Received warfarin as randomized

140 Discontinued tinzaparin before day 180 a 172 Discontinued warfarin before day 180 a
39 Progressive cancer 35 Progressive cancer
24 Adverse events 30 Contraindication for anticoagulation
24 Patient or physician preference 23 Patient or physician preference
17 Withdrew consent 22 Adverse events
17 Contraindication for anticoagulation 18 Target INR not achieved
12 Protocol violation 17 Withdrew consent
3 Lost to follow-up 16 Protocol violation
4 Reason not specified 5 Lost to follow-up
3 Unable to obtain blood sample for INR
3 Reason not specified

416 Completed scheduled follow-up 401 Completed scheduled follow-up

5 Lost to follow-up 9 Lost to follow-up
28 Other 41 Other

449 Included in ITT primary analysis 451 Included in ITT primary analysis
449 Included in safety analysis 451 Included in safety analysis

351 Included in per-protocol analysis 307 Included in per-protocol analysis

98 Excluded 144 Excluded
8 Did not meet inclusion criteria 16 Did not meet inclusion criteria
5 Tinzaparin interrupted >3 wk 16 Warfarin interrupted >3 wk
1 Met exclusion criteria 4 Met exclusion criteria
84 Discontinued tinzaparin before day 180 a 108 Discontinued warfarin before day 180 a
21 Patient or physician preference 20 Contraindication for anticoagulation
15 Withdrew consent 18 Patient or physician preference
12 Progressive cancer 15 Withdrew consent
11 Contraindication for anticoagulation 14 Progressive cancer
9 Protocol violation 13 Adverse events
9 Adverse events 11 Target INR not achieved INR indicates international
3 Lost to follow-up 8 Protocol violation normalized ratio; ITT,
4 Reason not specified 4 Lost to follow-up intention-to-treat.
3 Unable to obtain blood sample for INR a
Study drug was stopped for reasons
2 Reason not specified
other than death or a thrombotic
event.

(popliteal vein or anatomic ally more proximal), and events diagnosed between randomization and the day 180
incidental proximal pulmonary embolism (segmental arter- visit that were validated by central adjudication were
ies or larger). Each component was a secondary efficacy included in the efficacy analyses.
outcome.
Incidental VTE was defined as DVT or pulmonary embo- Safety Outcomes
lism detected during imaging performed for other reasons Principal safety outcomes were major bleeding, clinically
(eg, cancer staging).14 relevant nonmajor bleeding, and all-cause mortality. Major
Recurrent DVT and nonfatal pulmonary embolism were bleeding events included those that were fatal; occurred in a
objectively confirmed using standard imaging techniques, critical area or organ (eg, intracranial); or caused a fall in
including venous ultrasonography, contrast venography, hemoglobin of 2 g/dL or more or led to a transfusion of 2
computer tomography venography, or magnetic resonance or more units of whole blood or red cells.15 All nonmajor
venography for DVT; and ventilation-perfusion scintigra- bleeding events that required any medical or surgical inter-
phy, standard pulmonary angiography, or computer tomog- vention were classified as clinically relevant nonmajor
raphy angiography for pulmonary embolism. Fatal pulmo- bleeding. Only those bleeding events that occurred within
nary embolism was defined as proven on objective imaging, 24 hours after the last dose of study drug and confirmed
autopsy, or as the most probable cause of a sudden and by adjudication were included in the bleeding outcome
unexplained death according to central adjudication. Only analyses.

jama.com (Reprinted) JAMA August 18, 2015 Volume 314, Number 7 679

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Bayer HealthCare AG User on 09/30/2015

 Research Original Investigation Tinzaparin vs Warfarin for Acute VTE in Patients With Active Cancer

In addition, cases of suspected HIT were centrally The safety population included all patients who received
adjudicated based on the Warkentin 4T score and laboratory at least 1 dose of study drug. Similar to efficacy analyses, com-
confirmation. peting risk time-to-event analysis was performed for first ma-
All deaths were adjudicated centrally and a cause jor bleeding event and for first clinically relevant nonmajor
of death was assigned as due to pulmonar y embo - bleeding.
lism, bleeding, c ancer progression, or other known Overall mortality was summarized with Kaplan-Meier es-
conditions. timates and compared between treatment groups using a strati-
fied log-rank test.
Study Follow-up The significance threshold for secondary analyses was not
Follow-up visits occurred on days 7, 14, 30, and then every adjusted for multiple comparisons. All analyses were con-
30 days until day 180. Telephone contacts were made 2 ducted using SAS (SAS Institute), version 9.3, and Stata
weeks after the monthly visits. Each scheduled visit and (StataCorp), version 13.1.
telephone contact included a standardized assessment of
the signs and symptoms of recurrent thrombosis and bleed-
ing and a reminder to patients to notify the research staff if
they developed signs and symptoms between scheduled
Results
assessments. Appropriate objective testing was performed Patient Enrollment and Baseline Characteristics
in patients with symptoms to confirm or exclude VTE. If From August 2010 to November 2013, 1035 patients were
recurrent VTE was confirmed, end-of-treatment assess- screened and 900 patients were enrolled from 164 centers in
ments were conducted and therapy for recurrent thrombo- 32 countries; 449 were randomized to receive tinzaparin
sis was initiated according to local practice. and 451 to receive warfarin (Figure 1 and Table 1). The
All patients were followed for the primary composite ef- median number of patients enrolled per site was 4 (range,
ficacy outcome and for all-cause mortality up to day 180 or 1-38; interquartile range, 2-7). Of these, 23 patients did not
death, whichever occurred first. Patients were followed up for have a qualifying episode of thrombosis (eg, incidental or
safety outcomes and serious adverse events until 1 month fol- distal thrombosis) and 1 patient did not have histological
lowing the last dose of study treatment. confirmation of cancer. These 24 patients received study
treatment and were followed up according to protocol. All
Statistical Analyses 900 patients received assigned study treatment and 817
The trial was designed to demonstrate superiority of tinzapa- patients (91%) completed scheduled follow-up.
rin over warfarin in reducing the risk of recurrent VTE. Based The demographic data, clinical status, and medical his-
on published data, we estimated a 6-month cumulative event tory of the patients were well balanced at baseline between the
rate of 12.6% in the warfarin group (statistical analysis in 2 treatment groups and within each stratum (Table 1). Over-
Supplement 2).7-10 Assuming a relative risk reduction of 50% all, 89.6% of the patients had solid tumors (54.7% had meta-
with tinzaparin and using a time-to-event analysis with a static disease) and 10.4% had hematological malignancy; 52.9%
2-sided significance level of P = .05 and an overall power of were receiving anticancer therapy and 6.3% of the patients had
90%, a sample size of 847 patients was required. Incorporat- previous VTE. The qualifying symptomatic thrombotic event
ing an expected dropout rate of 5%, the target sample size was was DVT in 683 patients (75.9%) and pulmonary embolism with
900 patients. A prespecified sample size reestimation was con- or without DVT in 194 patients (21.6%). Additional thrombo-
ducted on blinded composite data when approximately 25% sis was found with baseline testing in 194 patients (21.6%). The
of patients had completed the treatment period, died, or been most common primary tumor sites were gynecologic, colo-
lost to follow-up. This analysis supported maintaining the origi- rectal, upper gastrointestinal, and lung.
nal sample size.
The efficacy population included all randomized Anticoagulant Treatment
patients. Comparisons between groups were based on time The study treatment duration was longer in the tinzaparin
to first recurrent VTE and accounted for deaths not due to group (median, 168 days [range, 1-216]) than in the warfarin
fatal pulmonary embolism as a competing risk. The cumula- group (median, 127 days [range, 1-209]). Study treatment was
tive incidence functions and the corresponding 95% CIs interrupted for a median of 5 days (range, 2-40) in 21% of pa-
were estimated in a competing risk regression model16 and tients. Of these, 10 discontinued study drug permanently af-
the cumulative incidence functions were compared between ter an interruption lasting longer than 3 weeks. In patients
the 2 treatment groups using a Wald test. For each time-to- treated with warfarin, the mean time in the INR therapeutic
event analysis, the components not defined as the event of range (TTR) was 47.0%.17 The percentage of time below the
interest were considered a competing risk. A per-protocol therapeutic range was 26.1% and time above was 26.9%. In pa-
efficacy analysis was also prespecified, which excluded tients treated with tinzaparin, 86% received an injection for
patients if they had a major protocol violation (eg, did not at least 75% of the treatment days.
have eligible VTE or active cancer) or discontinued the study
drug prior to day 180 for more than 3 consecutive weeks or Efficacy Outcomes
for any other reason except for death or having a recurrent Recurrent VTE occurred in 31 patients in the tinzaparin
thrombotic event. group and 45 patients in the warfarin group (cumulative

680 JAMA August 18, 2015 Volume 314, Number 7 (Reprinted) jama.com

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Bayer HealthCare AG User on 09/30/2015

 Tinzaparin vs Warfarin for Acute VTE in Patients With Active Cancer Original Investigation Research

risks, 7.2% for the tinzaparin group vs 10.5% for the

Table 1. Baseline Characteristics of Patients in the CATCH Trial
warfarin group; hazard ratio [HR], 0.65 [95% CI, 0.41-1.03];
P = .07; Figure 2, left panel). Symptomatic DVT occurred in No. (%)
12 patients in the tinzaparin group and in 24 patients in the Tinzaparin Warfarin
(n = 449) (n = 451)
warfarin group. Symptomatic nonfatal pulmonary embo-
Age, mean (SD), y 59.7 (12.7) 58.8 (12.5)
lism occurred in 3 patients in the tinzaparin group and 2
Sex
patients in the warfarin group and fatal pulmonar y
Women 262 (58.4) 273 (60.5)
embolism occurred in 17 patients in each group. Incidental
VTE occurred in 2 patients; both were in the warfarin Men 187 (41.6) 178 (39.5)

group. Table 2 summarizes the results of the efficacy Location

outcomes. Asia and Middle East 196 (43.7) 195 (43.2)
Eastern Europe 94 (20.9) 96 (21.3)
Safety Outcomes Western Europe and North America 75 (16.7) 75 (16.6)
Major bleeding events occurred in 12 patients assigned to Central and South America 84 (18.7) 85 (18.8)
tinzaparin and 11 patients assigned to warfarin (HR, 0.89 Weight, mean (SD), kg 67.3 (17.3) 67.1 (16.3)
[95% CI, 0.40-1.99]; P = .77; Figure 2, right panel, and
Creatinine clearance, mL/min/1.73 m2
Table 2). Clinically relevant nonmajor bleeding occurred in
<30 8 (1.8) 2 (0.4)
49 patients in the tinzaparin group compared with 69
30–<60 59 (13.1) 60 (13.3)
patients in the warfarin group (HR, 0.58 [95% CI, 0.40-
0.84]; P = .004). ≥60 355 (79.1) 378 (83.8)

There were no confirmed cases of HIT. Noncalculable due to missing data 27 (6.0) 11 (2.4)
Death occurred in 150 patients in the tinzaparin group Primary tumor site
and 138 patients in the warfarin group (cumulative risk, Gynecologic 101 (22.5) 102 (22.6)
34.7% for the tinzaparin group vs 32.2% for the warfarin Colorectal 66 (14.7) 53 (11.8)
group; HR, 1.08 [95% CI, 0.85-1.36]; P = .54; Figure 3). No Upper gastrointestinal 56 (12.5) 49 (10.9)
differences in cause of death were observed between the Lung 48 (10.7) 56 (12.4)
treatment groups. Progression of cancer was the most fre-
Genitourinary 53 (11.8) 41 (9.1)
quent cause of death (69%), followed by other known
Hematologic 44 (9.8) 50 (11.1)
causes (16.4%), fatal pulmonary embolism (12.5%), and
Breast 37 (8.2) 47 (10.4)
bleeding (2.1%). All cases of fatal pulmonary embolism were
deaths adjudicated by central adjudication; none except 1 Other 44 (9.8) 53 (11.8)

case had objective imaging or autopsy confirmation. Known metastases 247 (55.0) 245 (54.3)
Cancer therapya 228 (50.8) 248 (55.0)
Additional Adverse Events Systemic medical therapyb 189 (42.1) 193 (42.8)
Adverse events led to study drug discontinuation in 5.3% of Radiation 51 (11.4) 41 (9.1)
patients assigned to the tinzaparin group and in 5.1% of pa- Surgery 24 (5.3) 38 (8.4)
tients assigned to the warfarin group. Serious adverse events Hospitalization 3 d or longerc 140 (31.2) 146 (32.4)
occurred in 49.2% of the tinzaparin group and 43.2% of the war- c
Immobility 33 (7.3) 45 (10.0)
farin group, with progression of disease as the most common
ECOG performance status
reason.
0 or 1 343 (76.4) 348 (77.2)
2 106 (23.6) 103 (22.8)
Per-Protocol Efficacy Analysis
A total of 658 patients (tinzaparin, 351; warfarin, 307) were in- Previous history of VTE 27 (6.0) 30 (6.7)
cluded in the per-protocol analysis (Figure 1). The cumula- Qualifying thrombotic event
tive incidence of recurrent VTE in the per-protocol set was 8.3% Symptomatic DVT 252 (56.1) 259 (57.4)
in the tinzaparin group compared with 12.7% in the warfarin Symptomatic DVT with incidental PE 82 (18.3) 90 (20.0)
group (HR, 0.62 [95% CI, 0.38-1.00]; P = .05). Symptomatic PE 48 (10.7) 44 (9.8)
Symptomatic PE with incidental DVT 11 (2.4) 11 (2.4)
Symptomatic PE and symptomatic DVT 48 (10.7) 32 (7.1)
Discussion No qualifying VTE 8 (1.8) 15 (3.3)

To our knowledge, CATCH is the largest trial to study the Abbreviations: DVT, deep vein thrombosis; ECOG, Eastern Cooperative
Oncology Group; PE, pulmonary embolism; VTE, venous thromboembolism.
efficacy and safety of LMWH relative to warfarin for the
SI conversion factor: To convert creatinine clearance to mL/s/m2, multiply by
treatment of acute VTE in patients with active cancer.
0.0167.
Tinzaparin did not significantly reduce the composite pri- a
Patient may be receiving more than 1 type of cancer treatment.
mary outcome of recurrent VTE and was not associated b
Includes cytotoxic, hormonal, targeted, and immunoregulatory therapy.
with reductions in overall mortality or major bleeding, but c
Present within 3 months of randomization.
reduced the risk of clinically relevant nonmajor bleeding.

jama.com (Reprinted) JAMA August 18, 2015 Volume 314, Number 7 681

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Bayer HealthCare AG User on 09/30/2015

 Research Original Investigation Tinzaparin vs Warfarin for Acute VTE in Patients With Active Cancer

Figure 2. Cumulative Incidence Among Patients With Active Cancer According to Treatment With Tinzaparin vs Warfarin

Recurrent venous thromboembolism Major bleeding

12 12
Wald test P = .07 Warfarin Wald test P = .77
10 10
Cumulative Incidence of

Cumulative Incidence of
Major Bleeding, %
Recurrent VTE, %

8 8
Tinzaparin
6 6

4 4
Warfarin
2 2
Tinzaparin
0 0
0 30 60 90 120 150 180 0 30 60 90 120 150 180
Time Since Randomization, d Time Since Randomization, d

No. at risk No. at risk

Tinzaparin 449 357 294 254 Tinzaparin 449 330 257 163
Warfarin 451 347 279 249 Warfarin 451 308 230 142

VTE indicates venous thromboembolism. Source: The left panel of Figure 2 was reproduced with permission from the American Society of Hematology.24

Table 2. Primary and Secondary Efficacy and Safety Outcomes in the CATCH Trial

No. (%)
Tinzaparin Warfarin
(n = 449) (n = 451) HR (95% CI) P Value
Primary Efficacy Outcome
Recurrent VTE 31 (6.9)a 45 (10.0) 0.65 (0.41-1.03) .07
Secondary Efficacy Outcomes
Symptomatic DVTb 12 (2.7) 24 (5.3) 0.48 (0.24-0.96) .04
Symptomatic nonfatal PE 3 (0.7) 2 (0.4) NA
Fatal PEc 17 (3.8) 17 (3.8) 0.96 (0.49-1.88) .89
Incidental proximal DVT 0 1 (0.2) NA
Incidental PE 0 1 (0.2) NA
Recurrent VTE, per protocol, 29/351 (8.3) 39/307 (12.7) 0.62 (0.38-1.00) .05
No./total patients (%)
Safety Outcomes
Major bleedingd 12 (2.7) 11 (2.4)
Noncritical site 5 (1.1) 10 (2.2)
0.89 (0.40-1.99) .77
Critical site 7 (1.6) 1 (0.2)
Fatal bleedinge 0 0
Clinically relevant nonmajor bleeding 49 (10.9) 69 (15.3) 0.58 (0.40-0.84) .004
All bleeding 114 (25.4) 110 (24.4) NA
All-cause death 150 (33.4) 138 (30.6)
Progression of cancer 105 (23.4) 93 (20.6)
Fatal PE 17 (3.8) 19 (4.2)f 1.08 (0.85-1.36) .54
Fatal bleedingg 3 (0.7) 3 (0.7)
Other 25 (5.6) 23 (5.1)
d
Abbreviations: DVT, deep vein thrombosis; HR, hazard ratio; NA, not available; Three patients had more than 1 major bleeding event during study period.
PE, pulmonary embolism; VTE, venous thromboembolism. Only the first event is included in the safety outcome analysis.
a e
One patient had a symptomatic nonfatal DVT and a symptomatic nonfatal PE Fatal bleeding events included in the safety outcome of major bleeding
on the same day. occurred from first dose of study drug to 24 hours after last dose of study
b
Of the 36 recurrent DVT events, 34 were proximal and 2 were distal. Both drug.
f
cases of distal recurrent DVT occurred in the warfarin group. Two patients had a fatal PE after a recurrent DVT or PE and so there were 2
c
The cause of death in all fatal PE cases was assigned by the central more fatal PE cases included here than in the efficacy outcome.
g
adjudication committee based on available data. None of the events had Fatal bleeding events occurring any time during study period from
confirmatory imaging or autopsy results. randomization to death.

682 JAMA August 18, 2015 Volume 314, Number 7 (Reprinted) jama.com

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Bayer HealthCare AG User on 09/30/2015

 Tinzaparin vs Warfarin for Acute VTE in Patients With Active Cancer Original Investigation Research

The signific ant reduc tion in symptomatic DVT and

Figure 3. All-Cause Mortality Among Patients With Active Cancer
results of other secondary analyses should be considered According to Treatment With Tinzaparin vs Warfarin
hypothesis-generating and exploratory because we did
not adjust for multiple comparisons. Study strengths 40

include the international nature of the trial, with significant Wald test P = .54
Tinzaparin
patient enrollment from countries outside of Europe and

Probability of Death, %
30
Warfarin
North America. Tinzaparin is available in 44 countries in
Africa, Asia, Europe, Central, South and North America
(except the United States) for the prevention and treatment 20

of VTE.
The CATCH trial and previous LMWH trials in cancer- 10
associated thrombosis share many study design char-
acteristics. Like the Randomized Comparison of Low-
0
Molecular-Weight Heparin vs Oral Anticoagulant Therapy 0 30 60 90 120 150 180
for the Prevention of Recurrent Venous Thromboembolism Time Since Randomization, d
in Patients with Cancer (CLOT) trial, which was previously No. at risk
the largest trial and established dalteparin as more effica- Tinzaparin 449 364 303 268
Warfarin 451 371 305 273
cious than vitamin K antagonist therapy, 9,18 CATCH also
used a prospective randomized open blinded endpoint
(PROBE) design19 and warfarin as the control comparator.
Both studies used the same definition for active cancer, treatment groups, although it was slightly more common in
required the same eligible thrombotic events, and treated CATCH than in CLOT. The low number of incidental throm-
patients for 6 months. Unlike the CLOT trial, in which botic events in CATCH demonstrates the efficacy of antico-
dalteparin was administered at a reduced dose after the agulation.
first month, CATCH used tinzaparin at a full dose through- The efficacy result difference between the CATCH and
o u t t h e s t u d y p e r i o d a n d i n c l u d e d i n c i d e nt a l V T E CLOT trials was unlikely due to differences in the degree of
in its composite primary outcome. The rationale for simi- anticoagulation from warfarin therapy. The TTR was 47% in
larities and differences in design features have been CATCH and 46% in CLOT and the time above INR therapeu-
described.13 tic range was 27% in CATCH and 24% in CLOT. Although a
Lower than anticipated thrombotic event rates in the TTR of 47% was low compared with trials in patients
warfarin group of the CATCH trial may explain the differ- without cancer, it is consistent with the published lit-
ences in findings regarding the ability of LMWH to reduce erature and appears to be the achievable range for
the primary outcome in the CLOT trial vs the CATCH trial. warfarin in patients with cancer who are susceptible to
Although we had expected a recurrence rate of 12.6% with gastrointestinal toxic ities, poor nutrition, and drug
warfarin, the observed rate was only 10.5%. This potentially interactions.8,10,20,21
affected the power of the trial to detect a benefit associated CATCH found a low risk of major bleeding in both treat-
with tinzaparin. The lower risk may reflect critical differ- ment groups. Tinzaparin significantly reduced the risk of
ences in the patient populations between the CATCH vs clinically relevant nonmajor bleeding compared with warfa-
CLOT trials. In the CATCH trial, fewer patients had meta- rin. Together with the adverse events data, CATCH demon-
static disease (55% for CATCH vs 67% for CLOT), fewer had strated that tinzaparin, even when given at a full therapeu-
an ECOG performance status of 2 (23% for CATCH vs 36% for tic dose for up to 6 months, is safe in a broad oncology
CLOT), fewer were receiving anticancer therapy (53% for population.22
CATCH vs 78% for CLOT), and fewer had a previous history The trial did not study the newer direct oral anticoagu-
of thrombosis (6% for CATCH vs 11% for CLOT). The lants because they were not available when the study was de-
6-month mortality was also lower in CATCH compared with signed. Our study results are still relevant because these agents
CLOT (32% for CATCH vs 39% for CLOT). Consequently, the are currently not recommended for use in patients with can-
CATCH population had fewer risk factors for thrombosis and cer by evidence-based consensus guidelines and warfarin re-
recurrent thrombosis than the CLOT population. It is pos- mains the most commonly used anticoagulant worldwide for
sible that a significant reduction in recurrent VTE might be the treatment of cancer-associated thrombosis.5,23 Further re-
observed with tinzaparin in a higher-risk population. Differ- search is needed.
ences in geographic distribution, primary tumor sites, and The trial has limitations. First, the sample size was
associated anticancer treatments and the 10-year time gap insufficient because the incidence of recurrent VTE was
between the 2 trials (during which cancer treatments have lower than expected. Second, the open-label design is a
evolved) might also contribute to the discrepant findings. In source of potential bias. This design was chosen over
both trials, the primary composite efficacy outcome was double-blinding to avoid sham INR testing and sham injec-
primarily comprised of symptomatic recurrent DVT, with a tions, which increase patient anxiety. Providing realistic
risk reduction of 52% in CATCH and 62% in CLOT. Fatal pul- sham INR values is particularly challenging in an oncology
monary embolism was also evenly distributed between population that may be affected by nutritional deficiencies,

jama.com (Reprinted) JAMA August 18, 2015 Volume 314, Number 7 683

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Bayer HealthCare AG User on 09/30/2015

 Research Original Investigation Tinzaparin vs Warfarin for Acute VTE in Patients With Active Cancer

chemotherapy treatment, and other comorbidities. Blinding

might also compromise patient safety during episodes of Conclusions
thrombocytopenia and invasive procedures, and assess-
ment of quality of life.13 We attempted to minimize bias by Among patients with active cancer and acute symptomatic
using structured interviews during follow-up and blinded VTE, the use of full-dose tinzaparin (175 IU/kg) daily com-
central adjudication. Third, approximately 5% of patients pared with warfarin for 6 months did not significantly reduce
withdrew consent or were lost to follow-up. This is unavoid- the composite measure of recurrent VTE and was not associ-
able in a population with advanced cancer. Fourth, this ated with reductions in overall mortality or major bleeding, but
study was not designed to address potential differences in was associated with a lower rate of clinically relevant nonma-
relative efficacy and safety of tinzaparin vs warfarin in sub- jor bleeding. Further studies are needed to assess whether the
groups of patients with cancer (eg, patients with different efficacy outcomes would be different in patients at higher risk
types of cancer). of recurrent VTE.

ARTICLE INFORMATION The decision to submit the manuscript for Group, Ismailia); Ezzat Safwat Saad, MD (Kasr El
Author Contributions: Dr Lee had full access to all publication and the contents of the manuscript lay Ainy Hospital, Cairo); Sabry El Kady Mohamed, MD
of the data in the study and takes responsibility for solely with the CATCH Steering Committee and the (Ain Shams University Hospital, Cairo). Germany:
the integrity of the data and the accuracy of the 2 coauthors from the sponsor. Bauersachs Rupert, MD (Darmstadt Hospital,
data analysis. Group Information: CATCH Investigators. Darmstadt), Bacchus Liza, MD (Robert-Bosch-
Study concept and design: Lee, Kamphuisen, Meyer, Argentina: Bella Santiago Rafael, MD (Clinica Krankenhaus GmbH, Stuttgart); Beyer-Westendorf
Bauersachs, Janas, Khorana. Universitaria Privada Reina Fabiola, Cordoba); Jan, MD (Universitätsklinikum Carl Gustav Carus,
Acquisition, analysis, or interpretation of data: All Cerana Susana, MD (Sanatorio Británico, Santa Fe); Dresden); Kamphausen Ulrich, MD
authors. Zarbá Juan José, MD (Centro Médico San Roque, (Gemeinschaftspraxis für Gefäßmedizin,
Drafting of the manuscript: Lee, Kamphuisen, Tucumán). Austria: Johannes Andel, MD Mönchengladbach); Niederwieser Dietger, MD
Meyer, Bauersachs, Janas, Khorana. (Landeskrankenhaus Steyr, Steyr). Brazil: Barrios (Universitätsklinikum Leipzig, Leipzig); Ostermann
Critical revision of the manuscript for important Carlos Henrique, MD (Hospital São Lucas, Porto Helmut, MD (Klinikum Großhadern, Medizinische
intellectual content: All authors. Alegre, Rio Grande do Sul); Borba Reiriz André, MD Klinik III, Munchen); Sosada Markus, MD (Klinikum
Statistical analysis: Jarner. (IPCEM, Caxias do Sul, Rio Grande do Sul); Cesario Region Hannover, Hannover). Greece:
Administrative, technical, or material support: Fabiane, MD (Centro Especializado em Oncologia e Anagnostopoulos Nikolas, MD (General Hospital of
Janas, Jarner. Hematologia, Taguatinga Distrito Federal); Athens, Athens); Fountzilas George, MD (General
Study supervision: Lee, Kamphuisen, Meyer, de Azevedo Sérgio, MD (Hospital de Clínicas de Hospital of Thessaloniki “Papageorgiou,”
Bauersachs, Janas, Khorana. Porto Alegre, Port Alegre, Rio Grande do Sul); Thessaloniki); Ioannou Christos, MD (University
Ferreira Filho Antonio Fabiano, MD (Oncosinos, General Hospital of Heraklion, Heraklion); Liapis
Conflict of Interest Disclosures: All authors have Christos, MD (University General Hospital of
completed and submitted the ICMJE Form for Novo Hamburgo, Rio Grande do Sul); Franke Fábio
André, MD (Hospital São Lucas, Ijui, Rio Grande do Athens, Athens). Guatemala: Barrios Schaeffer
Disclosure of Potential Conflicts of Interest. Dr Lee Francisco José, MD (Instituto De Cancerología Dr
reports receiving honoraria from Avivia, LEO Sul); Padilha Sergio, MD (Instituto de Oncologia do
Paraná, Curitiba, Paraná); Paiva Queiroz Renata, MD Bernardo Del Valle S. [INCAN], Guatemala). India:
Pharma, Pfizer, and sanofi-aventis and research or Atilli Suresh, MD (Bibi General and Cancer Hospital,
consultancy funding from LEO Pharma and Pfizer. (Centro Brasileiro de Radioterapia Oncologia e
Mastologia, Goiania, Goiás); Pimenta Alex, MD Hyderabad); Balsubramanian Sivanesan, MD
Dr Kamphuisen reports receiving payment for (G. Kuppuswamy Naidu Memorial Hospital,
research and consultancy funding from LEO (Assistencia Multidisciplinar em Oncologia,
Salvador, Bahia); Rerin Júlio, MD (Clínica de Coimbatore); Bondarde Shailesh, MD (Shatabdi
Pharma. Dr Meyer reports receiving research Hospital, Nashik); Desai Sanjay C, MD (Ramaiyah
funding from LEO Pharma, Boehringer-Ingelheim, Oncologia de Porto Alegre Clinionco Ltda, Porto
Alegre, Rio Grande do Sul); Rigo Rodrigo, MD Memorial Hospital, Bangalore); Deshmukh Chetan,
Bayer, sanofi-aventis; travel accommodations from MD (Deenanath Mangeshkar Hospital, Pune); Singh
Daichii Sankyo; and having board membership with (Instituto Sul Brasileiro de Oncologia, Curitiba,
Paraná); Rocha Van Eyll Sylvie Brigitte, MD Dharam Pal, MD (SMS Medical College Hospital,
Bayer, Bristol-Meyers Squibb-Pfizer, Daichii Sankyo, Jaipur); Gharami Firoz, MD (Netaji Subhash Chandra
and sanofi-aventis. Dr Bauersachs reports receiving (Instituto do Câncer Arnaldo Vieira de Carvalho,
Sao Paulo); Santos Borges Giuliano, MD (Clínica de Bose Cancer Research Institute, Kolkata); Goyal
honoraria for consultation from Novartis, Pfizer, Lovenish, MD (OP Jindal Institute of Cancer and
and LEO Pharma. Dr Khorana reports receiving Neoplasias Litoral, Itajaí, Santa Catarina); Vacaro
Giovana, MD (Hospital São Vicente de Paulo, Passo Research, Hisar); Gupta Seema, MD (Chhatrapati
research funding and payment for consultancy Shahuji Maharaj Medical University, Lucknow);
from LEO Pharma and personal fees from LEO Fundo, Rio Grande do Sul). Bulgaria: Anastasov
Vasil, MD (UMHAT “Sveti Georgi” EAD, Plovdiv); Gupte Smita, MD (Cancer Clinic, Nagpur);
Pharma, sanofi-aventis, Janssen, Boehringer- Mukherjee Kalyan Kusum, MD (Chittaranjan
Ingelheim, Genentech, Daichii Sankyo, Dragneva Tanya, MD (MHAT Sveta Anna, Varna);
Georgiev Georgi, MD (MHAT, Ruse). Canada: National Cancer Institute, Kolkata); Krishnan
Angiodynamics, Halozyme, and Pfizer. Srinivasan, MD (Dr Rai Memorial Medical Centre,
Champion Philip, MD (Queen Elizabeth Hospital,
Funding/Support: The study was sponsored and Charlottetown, Prince Edward Island); Kuruvilla Chennai); Kumar Kriushna, MD (Meenakshi Mission
funded by LEO Pharma and had research support Philip, MD (William Osler Health Centre, Brampton Hospital and Research Centre, Madurai); Mehta
from the Sondra and Stephen Hardis Endowed Memorial Hospital Campus, Brampton, Ontario). Ajay, MD (Central India Cancer Research Institute,
Chair in Oncology Research and the Scott Hamilton Chile: Gonzalez Carolina, MD (Hospital Regional de Nagpur); Mishra Kshitish, MD (Hitech Medical
CARES Initiative (Dr Khorana). Talca, Talca). Czech Republic: Ditl Pavel, MD College and Hospital, Bhubneswar); Naik
Role of the Funder/Sponsor: LEO Pharma had a (Hospital Na Bulovce, Prague); Förster Jiří, MD Radheshyam, MD (Bangalore Institute of Oncology
role in the design and conduct of the study; (Oblastní nemocnice Jičín, Jičín); Lubomir Buncek, Specialty Centre, Bangalore); Pawar Suraj, MD
collection, management, analysis, and MD (Krajska nemocnice Pardubice, Pardubice); (Kolhapur Cancer Centre, Kolhapur); Rajnish Vasant
interpretation of the data; preparation, review, and Vydra Jan, MD (Institut Onkologie a Rehabilitace Na Nagarkar, MD (Curie Manavata Cancer Care
approval of the manuscript. It is committed to Plesi, Prague). Egypt: Abo El Hassan Rasha, MD Hospital, Nashik); Warrier Narayanankutty, MD
pursue publication of all phase 3 studies in (Nasser Institute Oncology Centre, Cairo); Sabri (Malabar Institute of Medical Sciences, Calicut).
peer-reviewed journals in order to ensure Sherif, MD (Bein Suef University Hopsital, Beni Israel: Brenner Benjamin, MD (Rambam Medical
scientific disclosure and comply with regulatory Suef); Allahloubi Nasr, MD (National Cancer Center, Haifa); Gavish Israel, MD (HaEmek Medical
requirements on public access and transparency. Institute, Cairo); Elzawawy Ahmed, MD (Suez Canal Center, Afula); Lugassy Gilles, MD (Barzilai Medical
Regional Oncology and Hematology Research Center Ashkelon, Ashkelon); Kolin Maya, MD
(Western Galilee Hospital-Nahariya, Nahariya).

684 JAMA August 18, 2015 Volume 314, Number 7 (Reprinted) jama.com

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Bayer HealthCare AG User on 09/30/2015

 Tinzaparin vs Warfarin for Acute VTE in Patients With Active Cancer Original Investigation Research

Italy: Enrico Breda, MD (Ospedale San Giovanni OUSA a TU, Bratislava); Szentivanyi Miroslav, MD interpretation, or any publication of the trial results.
Calibita Fatebenefratelli Isola Tiberina, Rome); (Interne oddelenie, Vseobecna nemocnica s Central Adjudication members were Martin Prins,
Mazzucconi Maria Gabriella, MD (Azienda poliklinikou Lucenec, Lucenec). Spain: Barón MD, PhD (chairman) (Academic Hospital
Policlinico Umberto I di Roma, Rome); Visani Francisco, MD (Hospital Clínico Universitario, Maastricht, Maastricht, the Netherlands); Harry
Giuseppe, MD (Ospedale San Salvatore, Div. Santiago de Compostela); Gallardo Enrique, MD Büller, MD, PhD (Academic Medical Centre,
Ematologica di Muraglia, Pesaro). Jordan: Awidi (Corporació Sanitaria Parc Taulí, Barcelona); Amsterdam, the Netherlands); Hans-Martin Otten,
Abdalla, MD (Jordan University Hospital, Amman). Jiménez David, MD (Hospital Universitario Ramon y MD, PhD (Slotervaart Ziekenhuis, Amsterdam, the
Latvia: Novikovs Nikolajs, MD (Daugavpils Regional Cajal, Madrid); Remedios Otero, MD (Virgen Del Netherlands); Ton Slagboom, MD (Ooserpark,
Hospital, Daugavpils); Miscuks Jurijs, MD (Rezekne Rocio University Hospital, Seville); Sanchez Amsterdam, the Netherlands); and Annelise
Regional Hospital, Rezekne). Lebanon: Abigerges Antonio, MD (Hospital Puerta de Hierro Seegers, MD (ICTOM BV, Amsterdam, the
Dany, MD (Middle East Institute of Health, Bsalim); Majadahonda, Madrid). South Africa: Engelbrecht Netherlands). Data Monitoring Committee
Farhat Fadi, MD (Hammoud Hospital University Johannes, MD (Vergelegen MediClinic, Cape Town); members were Frederick Rickles, MD, FACP
Cancer, Saida); Khoueiry Paul, MD (Centre Jonas Natalie, MD (Langenhoven Drive Oncology (chairman) (George Washington University,
Hospitalier, Jbeil); Makarem Jawad, MD (Ain Wazein Centre, Port Elizabeth); McAdam Georgina, MD Washington, DC); Carsten Bokemeyer, MD, PhD
Hospital, Ain Wazein). Mexico: Alvarez Ordorica (Rondebosch Oncology Centre, Rondebosch); Patel (Universitätsklinikum Hamburg Eppendorf,
Oliver, MD (Instituto Biomédico de Investigación, Moosa, MD (Chris Hani Baragwanath Hospital, Hamburg, Germany); Joerg Hasford, MD, PhD
Aguascalientes); Anaya Santacruz Ernesto, MD Johannesburg); Rapoport Bernardo, MD (Medical (University of Munich, Germany); Martin Rimmer,
(Hospital Medica Sur Cif Biotec, Mexico City); Oncology Centre of Rosebank, Johannesburg); BSc, PhD (Biostatistician, INC Research, Lewes,
Calderillo Ruiz German, MD (Instituto Nacional de Robertson Barbara, MD (Groote Schuur Hospital, United Kingdom). Helene Wellington (Mudskipper
Cancerología, Mexico City); De la Concha Ureta Dept. of Radiation Oncology, Cape Town). South Business Limited) provided editorial assistance, but
Humberto Jesus, MD (Instituto de Corazón de Korea: Doyeun Oh, MD (CHA Bundang Medical did not draft or edit the manuscript for important
Querétaro SA de CV, Querétaro). Peru: Pantigoso Center, Seongnam-si); Hawk Kim, MD (Ulsan intellectual content. All of the additional
Wuilbert Sabino Rodriguez, MD (Instituto de University Hospital, Ulsan); Hoon-Kyo Kim, MD contributors listed received funding from the
Oncologia y Radioterapia de la Clinica Ricardo (Catholic University of Korea St Vincent Hospital, sponsor.
Palma, Lima); Philco Manuel, MD (Instituto Gyeonggi-Do); Hyo Jung Kim, MD (Hallym
Oncológico de Lima, Lima); Romero Pineda Atilio, University Sacred Heart Hospital, Dongan-gu); Hyo REFERENCES
MD (Instiruto de Ginecologia y Reproducción, Song Kim, MD (Severance Hospital, Yonsei 1. Khorana AA, Francis CW, Culakova E, Kuderer
Lima); Vargas Queszada Ernesto Andres, MD University Health System, Seoul); Jin Seok Ahn, MD NM, Lyman GH. Thromboembolism is a leading
(Instituto Regional de Enfermedades Neoplasicas, (Samsung Medical Center, Seoul); Jooseop Chung, cause of death in cancer patients receiving
Arequipa). Poland: Gawrychowski Krzysztof, MD MD (Pusan National University Hospital, Busan); outpatient chemotherapy. J Thromb Haemost.
(Centrum Onkologii—Instytut im. Marii JoungSoon Jang, MD (Chung-Ang University 2007;5(3):632-634.
Sklodowskiej-Curie w Warszawie, Warsaw); Medical Center, Seoul); Keon Uk Park, MD
Witkiewicz Wojciech, MD (Wojewódzki Szpital (Keimyung University Dongsan Medical Center, 2. Sørensen HT, Mellemkjaer L, Olsen JH, Baron JA.
Specjalistyczny we Wroclawiu, Wrocław). Portugal: Joong-gu); Sang-Won Shin, MD (Korea University Prognosis of cancers associated with venous
Macias Emilio, MD (Hospital São Sebastião, Anam Hospital, Seoul); Se Hyung Kim, MD thromboembolism. N Engl J Med. 2000;343(25):
Santa Maria de Feira); Teixeira Encarnação, MD (Soonchunhyang University Bucheon Hospital, 1846-1850.
(Hospital de Santa Maria, Lisbon). Romania: Bucheon-si); Sung-Soo Yoon, MD (Seoul National 3. National Comprehensive Cancer Network.
Ciuleanu Tudor-Eliade, MD (Institutul Oncologic University Hospital, Seoul); Yang-Ki Kim, MD NCCN Clinical Practice Guidelines in Oncology
“Prof. Dr. I. Chiricuta,” Cluj-Napoca); Ligia Cebotaru (Soonchunhyang, University Seoul Hospital, Seoul). (NCCN Guidelines): venous thromboembolic
Cristina, MD (Institutul Oncologic Cluj, Taiwan: Chang-Fang Chiu, MD (China Medical disease. http://www.nccn.org/professionals
Cluj-Napoca); Lungulescu Dan, MD (Oncolab SRL, University Hospital, Taichung); Cheng-Shyong /physician_gls/pdf/vte.pdf. Accessed July 24, 2015.
Craiova); Manolescu Irina Gabriela, MD (Spitalul Chang, MD (Changhua Christian Hospital, 4. Kearon C, Akl EA, Comerota AJ, et al.
Judetean de Urgenta Braila, Braila); Rodica Anghel, Changhua); Jin-Hwang Liu, MD (Veterans General Antithrombotic therapy for VTE disease:
MD (Institutul Oncologic Professor Doctor Hospital, Taipei); Kun-Ming Rau, MD (Chang Gung antithrombotic therapy and prevention of
Alexandru Trestioreanu, Bucharest); Volovat Memorial Hospital, Kaohsiung); Shang-Wen Chen, thrombosis, 9th ed: American College of Chest
Constantin, MD (Centrul de Oncologie Medicala, MD (Chi Mei Hospital, Liouying, Tainan). Thailand: Physicians evidence-based clinical practice
Iasi). Russia: Burov Yury, MD (Municipal medical Chittima Sirijerachai, MD (Srinagarind Hospital, guidelines. Chest. 2012;141(2 suppl):e419S-e494S.
institution “1st Municipal Clinical Hospital,” Saratov); Khon Kaen); Ekkapong Tharavichitkul, MD (Chiang
Katelnitsky Ivan, MD (Rostov State Medical Rai Prachanukroh Hospital, Chiang Rai); Nonglak 5. Lyman GH, Bohlke K, Khorana AA, et al;
University, Rostov-on-Don); Svistov Dmitriy, MD Kanitsap, MD (Thammasat Hospital, American Society of Clinical Oncology. Venous
(SM Kirov Military Medical Academy—Ministry of Prathumthanee); Pantep Angchaisuksiri, MD thromboembolism prophylaxis and treatment in
Defense of Russia, Saint Petersburg). Saudi Arabia: (Ramathibodi Hospital, Bangkok); Pramook patients with cancer: American Society of Clinical
Ahmad Khadega, MD (King Abdul Aziz Medical City, Mutirangura, MD (Siriraj Hospital, Bangkok); Oncology clinical practice guideline update 2014.
Riyadh); Algahtani Farjah, MD (King Khalid Thanakrit Somprasertkul, MD (Chonburi Hospital, J Clin Oncol. 2015;33(6):654-656.
University Hospital, Riyadh); Al-Zahrani Hazaa, MD Chonburi); Patrapim Sunpaweravong, MD 6. Mandalà M, Falanga A, Roila F; ESMO Guidelines
(King Faisal Speciality Hospital and Research (Songklanagarind Hospital, Songkhla); Sumitra Working Group. Management of venous
Center, Riyad); Qari Mohamad, MD (King Abdul Aziz Thongprasert, MD (Maharaj Nakorn Chiang Mai thromboembolism (VTE) in cancer patients:
University Hospital, Jeddah. Serbia: Jovanovic Hospital, Chiang Mai); Udomluck Chenbhanich, MD ESMO Clinical Practice Guidelines. Ann Oncol. 2011;
Darjana, MD, Oncology Institute of Vojvodina, (Buddhachinaraj Hospital, Phitsanulok). Ukraine: 22(suppl 6):vi85-vi92.
Sremska Kamenica; Milanovic Nenad, MD, Institute Kobza Ihor, MD (Lviv Regional, Lviv); Nykonenko 7. Akl EA, Labedi N, Barba M, et al. Anticoagulation
for Oncology and Radiology of Serbia, Belgrade; Olexan, MD (Municipal institution “Zaporizhzhia for the long-term treatment of venous
Perin Branislav, MD, Institute for Pulmonary Regional Clinical Hospital,” Zaporizhzhya); Prasol thromboembolism in patients with cancer.
Diseases of Vojvodina, Sremska Kamenica); Vitaliy, MD (State Institution “Zaycev V. T. Institute Cochrane Database Syst Rev. 2011;(6):CD006650.
Stojanovic Vesna, MD (Clinical Centre Nis, Clinic of of General and Urgent Surgery of National Academy
Oncology, Nis); Tomasic Ljiljana, MD (Clinical of Medical Sciences Of Ukraine,” Kharkiv); 8. Hull RD, Pineo GF, Brant RF, et al; LITE Trial
Hospital Center Zemun, Belgrade). Slovakia: Vladychuk Iaroslav, MD (Central District Outpatient Investigators. Long-term low-molecular-weight
Chovanec Jozef, MD (NsP Sv. Jakuba, no, Bardejov, Hospital of Desnyanskiy District of Kiev, Kiev). heparin vs usual care in proximal-vein thrombosis
Poko); Herman Oto, MD (Interne oddelenie, patients with cancer. Am J Med. 2006;119(12):1062-
Additional Contributions: James Cassidy, MD, 1072.
Fakultna nemocnica Trencin, Trencin); Kissova MSc, MBChB, was a member of the Steering
Viera, MD (Interna klinika, Fakultna nemocnica Committee until June 2011. Luis Paz-Ares 9. Lee AY, Levine MN, Baker RI, et al; Randomized
Nitra, Nitra); Sasvary Ferdinand, MD (COR Clinical Rodriguez, MD, PhD, was a member of the Steering Comparison of Low-Molecular-Weight Heparin vs
Research, Sahy); Špánik Stanislav, MD (Onkologický Committee from September 2012 to November Oral Anticoagulant Therapy for the Prevention
Ustav Sv. Alzbety sro Interna onkologicka klinika, 2012. Neither was involved with data analysis, of Recurrent Venous Thromboembolism in

jama.com (Reprinted) JAMA August 18, 2015 Volume 314, Number 7 685

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Bayer HealthCare AG User on 09/30/2015

 Research Original Investigation Tinzaparin vs Warfarin for Acute VTE in Patients With Active Cancer

Patients with Cancer (CLOT) Investigators. Malignancy of the SSC of the ISTH. Incidental thromboembolic and bleeding complications
Low-molecular-weight heparin vs a coumarin for venous thromboembolism in oncology patients. among patients with venous thromboembolism in
the prevention of recurrent venous J Thromb Haemost. 2012;10(12):2602-2604. relation to both malignancy and achieved
thromboembolism in patients with cancer. N Engl J 15. Schulman S, Kearon C; Subcommittee on international normalized ratio: a retrospective
Med. 2003;349(2):146-153. Control of Anticoagulation of the Scientific and analysis. J Clin Oncol. 2000;18(17):3078-3083.
10. Meyer G, Marjanovic Z, Valcke J, et al. Standardization Committee of the International 21. Palareti G, Legnani C, Lee A, et al. A comparison
Comparison of low-molecular-weight heparin and Society on Thrombosis and Haemostasis. Definition of the safety and efficacy of oral anticoagulation for
warfarin for the secondary prevention of venous of major bleeding in clinical investigations of the treatment of venous thromboembolic disease
thromboembolism in patients with cancer: antihemostatic medicinal products in nonsurgical in patients with or without malignancy. Thromb
a randomized controlled study. Arch Intern Med. patients. J Thromb Haemost. 2005;3(4):692-694. Haemost. 2000;84(5):805-810.
2002;162(15):1729-1735. 16. Fine JP, Gray RJ. A proportional hazards model 22. Kleinjan A, Aggarwal A, Van de Geer A, et al.
11. Imberti D, Agnelli G, Ageno W, et al; MASTER for the subdistribution of a competing risk. J Am A worldwide survey to assess the current approach
Investigators. Clinical characteristics and Stat Assoc. 1999;94:496-509. doi:10.2307/2670170. to the treatment of patients with cancer and
management of cancer-associated acute venous 17. Rosendaal FR, Cannegieter SC, van der Meer FJ, venous thromboembolism. Thromb Haemost. 2013;
thromboembolism: findings from the MASTER Briët E. A method to determine the optimal 110(5):959-965.
Registry. Haematologica. 2008;93(2):273-278. intensity of oral anticoagulant therapy. Thromb 23. Khorona AA, Yannicelli D, McCrae K, et al.
12. Spirk D, Ugi J, Korte W, et al. Long-term Haemost. 1993;69(3):236-239. Evaluation of US prescription patterns: are
anticoagulation treatment for acute venous 18. Parpia S, Julian JA, Thabane L, Lee AY, Rickles treatment guidelines for cancer-associated venous
thromboembolism in patients with and without FR, Levine MN. Competing events in patients with thromboembolism (VTE) followed? Circ Cardiovasc
cancer: the SWIss Venous ThromboEmbolism malignant disease who are at risk for recurrent Qual Outcomes. 2015;8:A210.
Registry (SWIVTER) II. Thromb Haemost. 2011;105 venous thromboembolism. Contemp Clin Trials. 24. Lee AYY, Kamphuisen PW, Meyer G, et al.
(6):962-967. 2011;32(6):829-833. A randomized trial of long-term tinzaparin, a
13. Lee AY, Bauersachs R, Janas MS, et al; CATCH 19. Hansson L, Hedner T, Dahlöf B. Prospective low-molecular-weight heparin (LMWH), vs warfarin
Investigators. CATCH: a randomised clinical trial randomized open blinded end point (PROBE) study: for treatment of acute venous thromboembolism
comparing long-term tinzaparin vs warfarin for a novel design for intervention trials. Blood Press. (VTE) in cancer patients—the CATCH study. Blood.
treatment of acute venous thromboembolism in 1992;1(2):113-119. 2014;124(21):abst LBA-2.
cancer patients. BMC Cancer. 2013;13:284.
20. Hutten BA, Prins MH, Gent M, Ginsberg J,
14. Khorana AA, O’Connell C, Agnelli G, Liebman Tijssen JG, Büller HR. Incidence of recurrent
HA, Lee AY; Subcommittee on Hemostasis and

686 JAMA August 18, 2015 Volume 314, Number 7 (Reprinted) jama.com

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Bayer HealthCare AG User on 09/30/2015