The main objectives of this study are(I) to compare the sensitivity of CT-venography and ultrasound for screening-detected, catheter-related thrombosis in cancer patients and (II) to assess intrinsic coagulation levels in cancer patients prior to…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
- Embolism and thrombosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome is the composite of:
1. Screening-detected, clinically relevant, ipsilateral upper extremity
deep-vein thrombosis at the discretion of the local radiologist, demonstrated
by one of the following:
- A non-compressible venous segment or abnormal flow on ultrasound;
- An adjudicated vascular filling defect, detectable in at least 50% of the
lumen around the catheter on CT-venography;
- An adjudicated vascular filling defect in the non-cannulated deep veins on
CT-venography.
Upper extremity deep veins include the brachial, axillary, subclavian,
brachiocephalic, jugular, and superior caval vein.
2. Screening-detected, clinically relevant pulmonary embolism at the discretion
of the local radiologist, demonstrated by an intraluminal filling defect in a
segmental or more proximal pulmonary artery on CT-venography.
Secondary outcome
Secondary endpoints include
- Intrinsic pathway activation at baseline and during follow-up, assessed by
levels of FXIIa:C1inh, FXIIa:AT, FXIa:C1inh, FXIa:AT, FXIa:a1AT, pKa:C1inh, and
FIXa:AT complexes, and a factor XIa-dependent thrombin generation test.
- Clinically relevant venous thromboembolism
- Non-clinically relevant thrombi
- Catheter malfunction
- Major bleeding
- Clinically relevant non-major bleeding
- All-cause mortality
- Allergic reaction to contrast agents
- Reported contrast nephropathy
- Initiation of anticoagulant therapy in patients with screening-detected
upper-extremity deep-vein thrombosis and/or pulmonary embolism.
Background summary
Catheter-related thrombosis, defined as mural or occlusive upper-extremity
deep-vein thrombosis (DVT) within the cannulated vein or a contiguous vein, is
a common and burdensome complication in patients with central venous catheters,
in particular in those with cancer. Sequelae of catheter-related thrombosis are
loss of vascular access, post-thrombotic syndrome of the upper extremity, vena
cava superior syndrome, or pulmonary embolism. PICCs have been reported to
double the risk of thrombosis compared to other CVCs.
Patients with catheter-related thrombosis may present with symptoms (e.g.
ipsilateral upper-extremity edema, redness, pain), but they may also remain
asymptomatic. Therefore, screening for catheter-related thrombosis is
frequently used to assess the efficacy of anticoagulants in clinical studies,
under the assumption that the number of asymptomatic screening-detected events
is a reflection of the number of symptomatic events. Currently, the diagnostic
modality of choice for catheter-related thrombosis screening is duplex
ultrasound of the upper extremity, ideally combined with compression.
Advantages of ultrasound as compared to other diagnostic modalities include its
widespread clinical utility, portability, non-invasive nature without exposure
to ionizing radiation, and that it provides information on the flow direction.
However, it is a rather operator dependent modality, and also central veins are
less accessible using ultrasound, leading to lower accuracy. In a recent
meta-analysis, the sensitivity for ultrasound in detection of symptomatic upper
extremity DVT was reported to be 85%, indicating that 15% of the clots are
missed. Data on the sensitivity of ultrasound for screening-detected events are
scarce. Upper extremity CT-venography is another diagnostic modality that may
be used for catheter-related thrombosis-screening. Although CT-venography is a
procedure involving ionizing radiation, recent advances in CT technology enable
imaging with a low effective dose equivalent to background radiation.
Accumulating evidence on CT-venography for detection of lower extremity
thrombosis suggests that CT-venography is as accurate as ultrasound for
detection of thrombosis and may additionally reveal thrombi in more central
veins such as the brachiocephalic and superior caval vein. In addition, the
small amount of contrast in the pulmonary arteries may allow for occasional
detection central emboli. Furthermore, CT-venography images allow for central
adjudication, with the ability to achieve more consistent, independent, and
unbiased results in clinical trials. Despite these potential benefits, data on
the accuracy of CT-venography for catheter-related thrombosis or
upper-extremity thrombosis in general are lacking, which hampers its use for
screening in clinical studies.
Although current international guidelines suggest thromboprophylaxis with
low-molecular-weight heparin (LMWH) or direct oral anticoagulants (DOAC) in
cancer patients at high risk of thrombosis, routine prophylaxis for prevention
of catheter-associated thrombosis is not recommended, because of uncertainty
about the benefits and harms in cancer patients with CVCs. One of the main
pathophysiological mechanisms leading to catheter-related thrombosis is
induction of the intrinsic coagulation pathway. As the intravascular catheter
forms an artificial surface and lacks an endothelial layer, it directly
activates coagulation factor (F)XII, the initiator of the intrinsic coagulation
pathway. FXIIa will subsequently activate a series of serine proteases (FXI,
FIX, FX as well as prekallikrein [pKa]), which ultimately leads to thrombin
generation. In recent years, several drugs have been developed that target the
intrinsic coagulation pathway. An open-label phase II study in patients
undergoing knee arthroplasty demonstrated that FXI antisense oligonucleotide
(hepatic FXI synthesis inhibitor) 300 mg dosed once was more effective than
standard-of-care enoxaparin (LMWH) once daily (VTE risk 4% vs. 30%) with less
bleeding (3% vs. 8%). Given the important role of the intrinsic coagulation
pathway in the development of catheter-related thrombosis in cancer patients,
intrinsic pathway inhibitors may also be effective in this population. However,
additional data is needed on the level of intrinsic activation markers in
cancer patients to determine dosage and time of administration before catheter
placement.
The main aim of this study is to determine whether CT-venography offers an
accurate alternative to duplex ultrasound for detection of PICC-related
upper-extremity DVT and PE in asymptomatic cancer patients. Secondary aims
include to assess intrinsic coagulation marker levels in cancer patients prior
to and after PICC-placement in patients with and without thrombosis during
follow-up.
Study objective
The main objectives of this study are
(I) to compare the sensitivity of CT-venography and ultrasound for
screening-detected, catheter-related thrombosis in cancer patients and
(II) to assess intrinsic coagulation levels in cancer patients prior to and
after PICC-placement.
Other objectives include to evaluate of the proportion of patients initiating
anticoagulant therapy for treatment of screening-detected thrombi on ultrasound
and for treatment of screening-detected thrombi on CT-venography, the risk of
any symptomatic or asymptomatic VTE, the risk of catheter malfunction, the risk
of major or clinically relevant non-major bleeding according to ISTH
definitions, all-cause mortality in cancer patients at 25 days after
PICC-placement.
Study design
This is a prospective cohort study that will be performed at the Amsterdam
University Medical Center (UMC), locations AMC and VUmc (clinical part), and
the Maastricht University (laboratory part).
Intervention
Ultrasound and CT-venography for catheter-related thrombosis screening.
Study burden and risks
At baseline, patients will be assessed for signs of thrombosis and blood will
be drawn for laboratory analysis, followed by PICC placement. At day 7±3, a
second blood withdrawal will be performed (in a subset of) patients on a
voluntary basis. During a follow-up visit at day 20±5, patients will be
assessed for signs of thrombosis or bleeding, blood will be drawn, and a
screening ultrasound and CT-venography will be performed. The burden of the
study includes one additional hospital visit, two or three blood withdrawals,
an ultrasonography, and CT-venography, which exposes patients to ionizing
radiation and the risk of contrast-induced nephropathy or allergic reactions.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
- Age 18 to 80 years
- Diagnosis of solid or haematological cancer
- Planned PICC placement for administration of systemic cancer therapy or other
indications
- Ability to provide written informed consent
Exclusion criteria
- Extremity DVT within 6 months prior to catheter insertion
- Inserted central venous catheter within 12 hours prior to inclusion
- Mechanical heart valve or pacemaker
- Ongoing therapeutic anticoagulation
- Known pregnancy
- Creatinine clearance <30 mL/min (estimated using CKD-EPI equations)
- Solitary kidney (either functionally or anatomically)
- Allergy to contrast agents
- Anticipated referral to another hospital within a few days after PICC
placement
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL78101.018.21 |