A Prospective Algorithm incorporationg Limited and whole- Leg
Assessment of the Deep venous system In symptomatic Outpatients
(the PALLADIO study)
on behalf of:
Paolo Prandoni (Padua) and Walter Ageno (Varese)
Introduction and Rationale of the Study
Compression ultrasonography (CUS) plays a central role in the diagnostic
approach to patients with clinically suspected deep vein thrombosis (DVT) of
the lower limbs. Investigation of the deep veins with CUS can be extended to
the entire venous system (whole-leg CUS), from the iliac veins to the distal
veins in the calf (1-4), or it can be limited to the proximal veins only (limitedCUS). When limited-CUS is performed, patients with an initially negative test
usually require repeat CUS after 5 to 7 days (5-7), unless the results of
additional tests, such as pre-test clinical probability (8-11) or D-dimer (10-13)
allow to safely rule-out DVT with no need for repeat CUS, as it was
consistently shown by the results of clinical trials published over the last years
(14,15).
Limited-CUS has a number of advantages over whole-leg CUS. These
advantages include greater simplicity, greater reproducibility, and broader
availability. Its major drawback is represented by the frequent need for
additional tests. On the other hand, whole-leg CUS may have the advantage
to rule in or to rule out DVT in a single evaluation, though this requires the
presence of an experienced operator and the availability of more advanced
scanners.
Two
recent
studies
have
directly
compared
the
two
ultrasonographic strategies, which resulted to be substantially equivalent
(16,17).
1
The availability of a safe and effective algorithm that combines limited
and whole-leg investigation could offer clinicians the advantages of both
strategies while eliminating the need for repeat CUS and, at the same time,
the risk of diagnosing a number of small distal thrombi that would very likely
expose patients to an often unnecessary anticoagulant treatment.
The Palladio study is designed as an international, multicenter trial
aimed to assess the accuracy of a new diagnostic algorithm in a consecutive
cohort of outpatients with clinically suspected DVT. In all patients, DVT will be
ruled-out with a single evaluation based on routine limited-CUS, that will be
extended to whole-leg CUS only in those patients with concomitant high pretest clinical probability and a positive D-dimer.
Inclusion criteria
- outpatients with clinically suspected DVT
- signed informed consent
Exclusion criteria
- concomitant signs or symptoms of pulmonary embolism (PE)
- previous DVT of the affected leg
- referral for superficial vein thrombosis or bilateral DVT
- ongoing or planned anticoagulant therapy
- need for pharmacological thromboprophylaxis (e.g. recent surgery or
medical disease)
- inpatient status
- unavailability to follow up
- pregnancy
- age < 18 years
Methods
2
All eligible patients will undergo D-dimer measurement and a formal
assessment of pre-test clinical probability by means of the Wells score (10)
(appendix 1). Patients with unlikely PTP and negative D-dimer will have DVT
ruled out and will undergo a 3-month clinical follow-up. If at least one of the
two tests will result positive, patients will undergo CUS of the proximal vein
system investigating at least the common femoral vein at the groin, the
superficial femoral at the mid thigh and the popliteal vein(s) in the popliteal
fossa – for the investigation of the popliteal vein(s) see appendix 2). A
positive CUS will adjudicate proximal DVT. In the case of negative CUS of the
proximal vein system, patients with either negative D-dimer or unlikely PTP
will have DVT ruled out and will undergo a 3-month follow up. Only patients
with concomitant likely PTP and positive D-dimer will undergo whole-leg
ultrasonography to complete the test below the popliteal veins. A positive test
will adjudicate distal DVT. Patients with negative test will undergo a 3-month
clinical follow up.
Procedure for interrogating the calf vein system
See appendix 2. A quality control under the supervision of Sebastian
Schellong will be performed, and will be essential for participation in the
study.
Follow-up
All patients in whom DVT will be ruled out will be monitored for 3 months
(either by clinical visit or by telephone contact) after the enrolment in the
study. Patients with clinical symptoms of DVT or PE during follow up will
undergo objective diagnostic testing (venous ultrasound for suspected DVT
and spiral CT-scan or VQ scan for suspected PE). All source documents will
be sent out to an independent adjudication committee. In case of death, PE
diagnosis will be adjudicated by means of autopsy, if available. If autopsy is
3
not available, clinical documentation should be collected if possible for central
adjudication.
D-dimer
All quantitative D-dimer tests available at each center will be acceptable for
the purpose of this study. D-dimer will be considered negative according to
the cut-offs provided by the manufacturer.
Study outcomes
Primary outcome of the study is the safety of the proposed diagnostic
algorithm, defined as the incidence of objectively documented venous
thromboembolic events occurring during follow up in patients in whom DVT
was ruled out after a single evaluation.
Secondary outcomes of the study are the rate of patients requiring whole-leg
CUS and the incidence of distal DVT in this subgroup of patients.
Sample size
We expect that in every 100 symptomatic outpatients DVT will be excluded
without the need for objective testing in approximately 30%, while
approximately 20% will have a CUS-detected proximal DVT, approximately
15% will have negative CUS and unlikely PTP in spite of positive D-Dimer (no
need for further investigation), approximately 15% will have negative CUS
and negative D-Dimer in spite of likely PTP (no need for further investigation),
and approximately 20% will have negative CUS and both likely PTP and
positive D-Dimer (thus requiring interrogation of the calf vein system).
We hypothesize that the incidence of venous thromboembolic events during
follow up in patients reputed as not having DVT will not exceed 1% with the
application of the proposed algorithm, and that the upper limit of the 95%
4
confidence intervals around this proportion will not exceed 2%. In order to
have a power of 80%, 1100 patients need to be included.
Data collection and management
Data will be collected in an electronic database that will be accessible on the
web. Data from each center will be protected by means of individual
passwords and only anonymous data will be available at the coordinating
center.
Original
documents
or
copies
of
documents
of
venous
thromboembolic events will be requested and sent to the independent
adjudication committee.
References
1. Elias A, Mallard L, Elias M, et al. A single complete ultrasound investigation
of the venous network for the diagnostic management of patients with a
clinically suspected first episode of deep venous thrombosis of the lower
limbs. Thromb Haemost 2003;89:221-7.
2. Schellong SM, Schwarz T, Halbritter K, et al. Complete compression
ultrasonography of the leg veins as a single test for the diagnosis of deep
vein thrombosis. Thromb Haemost 2003;89:228-34.
3. Stevens SM, Elliott CG, Chan KJ, Egger MJ, Ahmed KM. Withholding
anticoagulation after a negative result on duplex ultrasonography for
suspected
symptomatic
deep
venous
thrombosis.
Ann
Intern
Med
2004;140:985-91.
4. Johnson SA, Stevens SM, Woller SC, et al. Risk of Deep Vein Thrombosis
Following a Single Negative Whole-Leg Compression Ultrasound: A
Systematic Review and Meta-analysis. JAMA 2010;303:438-45.
5. Heijboer H, Büller HR, Lensing AW, Turpie AG, Colly LP, ten Cate JW. A
comparison of real-time ultrasonography with impedance plethysmography
5
for the diagnosis of deep-vein thrombosis in symptomatic outpatients. N Engl
J Med 1993;329:1365-9.
6.
Cogo
A,
Lensing
AWA,
Koopman
MMW,
et
al.
Compression
ultrasonography for diagnostic management of patients with clinically
suspected
deep
vein
thrombosis:
prospective
cohort
study.
BMJ
1998;316:17-20.
7. Birdwell BG, Raskob GE, Whitsett TL, et al. Predictive value of
compression ultrasonography for deep vein thrombosis in symptomatic
outpatients: clinical implications of the site of vein noncompressibility. Arch
Intern Med 2000;160:309-13.
8. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest
probability of deep-vein thrombosis in clinical management. Lancet
1997;350:1795-8.
9. Wells PS, Anderson DR, Bormanis J, et al. Application of a diagnostic
clinical model for the management of hospitalized patients with suspected
deep-vein thrombosis. Thromb Haemost 1999;81:493-7.
10. Wells PS, Anderson DR, Rodger M, et al. Evaluation of D-dimer in the
diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003;349:122735.
11. Tick LW, Ton E, van Voorthuizen T, et al. Practical diagnostic
management of patients with clinically suspected deep vein thrombosis by
clinical probability test, compression ultrasonography, and D-dimer test. Am J
Med 2002;113:630-5.
12. Bernardi E, Prandoni P, Lensing AW, et al. D-dimer testing as an adjunct
to ultrasonography in patients with clinically suspected deep vein thrombosis:
prospective cohort study. BMJ 1998;317:1037-40.
13. Kraaijenhagen RA, Piovella F, Bernardi E, et al. Simplification
of the diagnostic management of suspected deep vein thrombosis. Arch
Intern Med 2002;162:907-11.
6
14. Ten Cate-Hoek AJ, Prins MH. Management studies using a combination
of D-dimer test result and clinical probability to rule out venous
thromboembolism: a systematic review. J Thromb Haemost 2005;3:2465-70.
15. Büller HR, Ten Cate-Hoek AJ, Hoes AW, et al. Ruling out deep venous
thrombosis in primary care. Ann Intern Med 2009;150:229-35.
16. Bernardi E, Camporese G, Büller HR, et al. Serial 2-point ultrasonography
plus D-dimer vs whole-leg color-coded Doppler ultrasonography for
diagnosing suspected symptomatic deep vein thrombosis: a randomized
controlled trial. JAMA 2008;300:1653-9.
17. Gibson NS, Schellong SM, El Kheir DY, et al. Safety and sensitivity of two
ultrasound strategies in patients with clinically suspected deep venous
thrombosis; a prospective management study. J Thromb Haemost 2009;
7:2035-41.
7
Appendix 1
Pre-test clinical probability of DVT
• Active cancer
1
• Previous thromboembolism
1
• Paralysis, paresis or recent plaster
1
• Recently bedridden and/or major surgery
1
• Localized tenderness along the distribution
of the deep venous system
1
• Entire leg swollen
1
• Calf swelling 3 cm > asymptomatic side
1
• Pitting oedema (greater in the symptom. leg)
1
• Collateral superficial veins (non varicose)
1
• Alternative diagnosis
-2
_____________________________________________________
• DVT LIKELY:
> 2 points
• DVT UNLIKELY:
1 point or less
8
Appendix 2
Examination protocol for distal veins
(Complete compression ultrasound – CCUS)
Patient sitting, legs dangling over the edge of the examination table, feet on a
stool, in order to maximize venous filling of lower leg veins
Linear transducer, 5 MHz included
Transverse planes only, B-mode only. Colour Doppler only in order to
anatomically identify the posterior tibial artery and peroneal artery,
respectively.
Hollow of the knee (confirmatory)
Identification of popliteal artery
Identification of undivided popliteal vein
Compresson maneuvers in 1 cm intervals from the femoro-popliteal junction
down to the beginning of the paired calf veins. This segment includes the
undivided popliteal vein, the peroneal confluens segment and the posterior
tibial confluens segment. However, a DVT in these segments would be
considered as proximal DVT.
Calf
Transducer from a 45°medio-dorsal position, rear edges of the lower leg
bones forming a transverse plane
Identification of paired peroneal veins
Compression maneuvers in 1 cm intervals from the proximal calf down to the
ankle.
Identification of paired posterior tibial veins
Compression maneuvers in 1 cm intervals from the proximal calf down to the
ankle
9
Identification of lateral gastrocnemial veins in the hollow of the knee
Compression maneuvers in 1 cm intervals down to the end of the lateral GC
head
Identification of medial gastrocnemial veins in the hollow of the knee
Compression maneurvers in 1 cm intervals down to the end of the medial GC
head
Identification of soleus veins at the proximal calf level
Compression maneuvers in 1 cm intervals down to the distal third of the lower
leg
10