Scintigraphic Imaging of Acute DVT

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Advances in the Diagnosis of Venous
Thromboembolism

• Scintigraphic Imaging of Acute DVT
• Using
• Tc-99m Apcitide (AcuTect)
• Hani A. Nabi, M.D.,Ph.D., F.A.C.N.P.
• Professor of Clinical Nuclear Medicine
• University at Buffalo

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Advances in the Diagnosis ofVenous
Thromboembolism

• Venous Thromboembolism
• Clinical Importance
• Diagnosis and Treatment
• Tc-99m Apcitide
• Mechanism of Action
• Clinical Results
• Clinical Applications

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Venous Thromboembolism

• Acute Deep Vein Thrombosis (DVT)
• Pulmonary Embolism (PE)

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Prevalence (USA) of Venous Thromboembolism

• Deep Vein Thrombosis
• estimated 5,000,000 cases per year1
• Pulmonary Embolism
• estimated 600,000 cases per year2

1. Moser KM. Am Rev Respir Dis 1990 141235-249.
2. Dalen JE et al. Prog Cardiovasc Dis 1975
17259-270.
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Deep Vein Thrombosis (DVT) Natural History
Acute
Non-Acute
flow
or
platelets thrombus propagation
embolization organization
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Acute DVT

• Originates in the deep veins of the lower
  extremities
• Signs and symptoms are non-specific
• Only 20-50 of symptomatic patients have
  confirmed acute DVT1,2
• As many as 90 originate in the calves3,4

1. Wells RD et al. Lancet 1995 3451326-1330. 2.
Stamatakis JD et al. Br J Radiol 1978
65449-451. 3. Nicolaides AN et al. Br J Radiol
1971 44653-663. 4. Stein PD et al. Circulation
1967 35671-681.
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Conditions Associated with Acute DVT

• Cancer
• Major surgery
• Immobilization
• Prior history of DVT
• Trauma
• Oral contraceptives, obesity, heart disease,
  pregnancy, advanced age

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Acute DVT in the Calf

• Why is it Important?
• 20 of calf vein thrombi propagate above the
  knee1
• calf vein thrombi may lead to post-phlebitic
  syndrome2
• as many as 23 of PE can derive from calf DVT3

1. Philbrick JT et al. Arch Intern Med 1988
1482131-2138. Prandoni P et al. Ann Intern
Med 1996 125 1-7. 3. Saeger W et al. Pathol Re
Pract 1994 190394-399.
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Complications of Acute DVT

• Post-Phlebitic Syndrome
• Pulmonary Embolism

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Post-Phlebitic Syndrome

• 25-65 of patients with acute DVT develop
  post-phlebitic syndrome1,2
• painful, debilitating
• venous valves damaged leading to chronic venous
  insufficiency
• patients may develop recurrent acute DVT - hard
  to diagnose by ultrasonography or venography

1. Strandness DE et al. JAMA 1983
2501289-1292. 2. Prandoni P et al. Ann Intern
Med 1996 125 1-7.
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DIAGNOSTIC METHODS FOR DVT

• CLINICAL FINDINGS
• CONVENTIONAL X-RAY CONTRAST VENOGRAM
• DUPLEX DOPPLER ULTRASOUND
• D-DIMER (BLOOD TEST)
• RADIONUCLIDE METHODS

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ALL METHODS HAVE STRENGTHS AND WEAKNESSESIDEAL
EXAM

• NON-INVASIVE
• NON-MORBID
• PERFORMED IN REASONABLY SHORT TIME FRAME
• RELATIVELY CHEAP
• STUDY ALL PERTINENT SEGMENTS
• DEMONSTRATE AGE AND SIZE OF CLOT

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DIAGNOSTIC METHODS

• CLINICAL FINDINGS
• CONTRAST VENOGRAM
• DOPPLER
• D-DIMER
• NUCLEAR

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CLINICAL FINDINGS

• LEG PAIN/SWELLING
• POSITIVE HOMANS SIGN (PAIN ON DORSIFEXION OF
  FOOT)
• PALPABLE CORD SUPERFICIAL
  THROMBOPHLEBITIS
• 1/3 OF DVTS ASYMPTOMATIC
• OF DVTS FOUND AT AUTOPSY ABOVE CALF, ONLY 19
  HAD SYMPTOMS/SIGNS

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CLINICAL CONTD.

• CONVERSELY, VENOGRAMS () FOR DVT IN ONLY 46 OF
  CLINICALLY SUSPECTED CASES
• DDX
• CELLULITIS
• BAKER CYST (ESPECIALLY WITH RUPTURE)
• HEMATOMA
• ETC.
• CLINICAL FINDINGS UNRELIABLE

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DIAGNOSTIC METHODS

• CLINICAL
• CONTRAST VENOGRAM
• DOPPLER
• D-DIMER
• NUCLEAR

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Contrast Venography

• Gold Standard for imaging DVT - when
  technically adequate
• can image entire lower extremities
• sensitive in asymptomatic patients
• Limitations
• painful
• technically inadequate/difficult to interpret in
  10-30 of cases1,2

1. Hirsh J et al. Circulation 1996 932212-2245.
2. Anand SS et al. JAMA 1998 2791094-1099.
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DVT
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DVT
21
DVT
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CONTRAST VENOGRAPHY CONTD.COMPLICATIONS OF
CONTRAST VENOGRAM

• DVT CAUSED BY DYE IN PT WITHOUT DVT
• IONIC CONTRAST - UP TO 25
• NONIONIC CONTRAST - UP TO 7
• NON ISOSMOLAR, NONIONIC - STUDIES PENDING
• ALLERGIC REACTION
• RENAL AND OTHER TOXICITIES
• DEATH

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DIAGNOSTIC METHODS

• CLINICAL
• CONTRAST VENOGRAM
• DOPPLER
• D-DIMER
• NUCLEAR

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DUPLEX DOPPLER ULTRASOUND

• ONLY RELIABLE FROM INGUINAL LIGAMENT TO TAKE-OFF
  OF TIBIAL VEINS
• MULTIPLE TRIALS
• 92 SENSITIVITY (FOR ALL CLOT IN LEG, EVEN THOUGH
  CALF VESSELS NOT SEEN)
• 99 SPECIFIC

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DOPPLER CONTD. METHOD

• PULSED DOPPLER/BETTER WITH COLOR
• COMPRESSION AT EVERY LEVEL FROM UPPER COMMON
  FEMORAL TO LOWER POPLITEAL (EVEN IF CLOT NOT
  SEEN, INCOMPLETE COMPRESSABILITY SUGGESTS
  PRESENCE OF CLOT)

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NORMAL WITHOUT COMPRESSION
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NORMAL WITH COMPRESSION
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PARTIALLY OBSTRUCTING THROMBUS
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Ultrasonography

• Advantages
• high sensitivity (82-100) for proximal DVT
  (thighs and knees) in patients with localizing
  signs and symptoms1
• fast
• low cost per procedure

1. Rose SC. RSNA Categorical Course in Vascular
Imaging. 1998139-156.
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DRAWBACKS TO VENOUS DOPPLER

• HEAVILY OPERATOR-DEPENDENT
• SOME SEGMENTS MAY BE BLIND TO SAMPLING
• CALF VEINS USUALLY NOT STUDIED, BUT WITH NEW
  GENERATION EQUIPMENT CALF VEINS CAN BE RELIABLY
  SEEN IN 60-90 IF SEEN, DOPPLER 90 SENSITIVE
  AND SPECIFIC FOR CLOT IN THEM.

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Anatomic Imaging Modalities

• Contrast Venography and Ultrasonography
• not specific for acute DVT
• cannot reliably differentiate acute from
  non-acute DVT

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DIAGNOSTIC METHODS

• CLINICAL
• CONTRAST VENOGRAM
• DOPPLER
• D-DIMER
• NUCLEAR

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D-DIMER BLOOD TESTING FOR ACUTE THROMBOSIS

• DEGRADATION PRODUCT OF CIRCULATING CROSS-LINKED
  FIBRIN
• ELEVATED LEVELS IN ACUTE THROMBOSIS

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RECENT LITERATURE REVIEW (BECKER, et al
ARCHIVES INT MED, MAY 96

• VARIOUS ASSAYS NOT STANDARDIZED (ELISA, LATEX,
  IMMUNOFILTRATION)
• STUDIES HAVE NOT LOOKED FOR PRESENCE OR ABSENCE
  OF BOTH DVT AND P.E.
• (I.E. PTS CONSIDERED FREE OF P.E. MAY HAVE HAD
  SILENT DVT, AND VICE VERSA)

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DIAGNOSTIC METHODS

• CLINICAL
• VENOGRAPHY
• DOPPLER
• D-DIMER
• NUCLEAR MEDICINE

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NUCLEAR VENOGRAPHY

• 99MTc-MAA
• SENSITIVITY 94/SPECIFICITY 92 (SIEGEL, USC)
• PROS
• LUNG PERFUSION ILIACS/IVC
• CONS
• CALF VEINS NONOBSTRUCTING CLOT WITHOUT
  COLLATERALS

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Tc-99m Apcitide Scintigraphy

• Specific for Acute DVT

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Tc-99m Apcitide

• a small synthetic peptide
• 13 amino acids, mol. wt. 1392 Da
• binding region for the platelet GPIIb/IIIa
  receptor
• radiolabeled with Tc-99m

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Binding to Platelet GPIIb/IIIa Receptors
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GPIIb/IIIa Receptor

• expressed only on platelets
• key in platelet aggregation
• mediates the binding of fibrinogen to platelets
• only binds fibrinogen when platelets are activated

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Tc-99m Apcitide

• How It Works
• Activated platelets are present in acute thrombi
• The GPIIb/IIIa receptor is expressed on activated
  platelets
• Tc-99m apcitide binds to the GPIIb/IIIa receptor
• Unbound Tc-99m apcitide clears rapidly

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Advances in the Diagnosis ofVenous
Thromboembolism

• Venous Thromboembolism
• Clinical Importance
• Diagnosis and Treatment
• Tc-99m Apcitide
• Mechanism of Action
• Clinical Results
• Clinical Applications

46
Imaging Acute DVT with Tc-99m Apcitide

• Standard Procedure
• 20 mCi Tc-99m, 100 ?g peptide
• Antecubital vein injection
• Standard nuclear medicine gamma camera
• Anterior and posterior planar images starting at
  10 min and 60-90 min
• In some cases
• SPECT or delayed (3 h) planar images useful

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Imaging Acute DVT with Tc-99m Apcitide

• Image Interpretation Criteria
• asymmetric, linear Tc-99m apcitide uptake
• in a deep vein segment
• that persists
• or becomes apparent on late images
• Image contrast must be optimized

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Tc-99m Apcitide Normal Biodistribution
10 min
60 min
240 min
R anterior L L posterior R
R anterior L L posterior R
R anterior L L posterior R
41 year old female
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Tc-99m Apcitide

• Biodistribution and Dosimetry
• rapid urinary excretion over 24 hours (84-99)
• hepatobiliary excretion 6 over 24 h
• blood pool approx. 10 ID at 60 min
• mean effective dose equivalent 0.034 rem/mCi
• maximum absorbed radiation dose (to urinary
  bladder wall) 0.22 rad/mCi
• estimated biological half-life 1.9 h

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Tc-99m Apcitide Negative Case
10 min
60 min

120 min
R anterior L L posterior R
R anterior L L posterior R
R anterior L L posterior R
Patient History 34y female, no prior history of
DVT or PE, 2 days from onset of signs and
symptoms in right calf, knee and thigh venogram
negative Tc-99m Apcitide Findings negative for
acute DVT
2395
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Tc-99m Apcitide Positive Case
10 min
60 min
120 min
R anterior L L posterior R
R anterior L L posterior R
R anterior L L posterior R
Patient History 66y male, prior history of DVT
and PE, 5 days from onset of signs and symptoms
in right calf and knee, on heparin and warfarin
venogram positive right calf and popliteal
veins Tc-99m Apcitide Findings acute DVT in
right calf, knee and (distal) thigh
4370
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Tc-99m Apcitide Positive Case
60 min images
R anterior
L
R anterior
L
Patient History 23y male, no history of DVT or
PE, 8 days post gunshot wound to left thigh, 3
days from onset of signs and symptoms in left
leg, on heparin and warfarin ultrasound positive
left femoral and popliteal veins Tc-99m Apcitide
Findings acute DVT in left calf, knee and thigh
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Tc-99m Apcitide Phase 3 Clinical Trials

• 2 Independent trials, 34 centers, 280 patients
  enrolled
• Entry Criteria
• Within 10 days of onset of signs and symptoms of
  acute DVT or within 10 days of high risk surgery
• Diagnostic Tests
• Contrast venography and Tc-99m Apcitide
  scintigraphy to be performed within 3 days of
  each other

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Phase 3 Clinical Trials
Investigator Results
Acute All Evaluable Patients
Cohort n 243 63 History of DV/PE
58 (24) 0 Sensitivity 75.5 90.6 Sp
ecificity 72.8 83.9 Accuracy 74.0 87.
3 PPV 70.9 85.3 NPV 77.1 89.7
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Tc-99m Apcitide Clinical Performance

• In Phase 3 Clinical Trials, Patients (n63) with
  No History of VT, Within 3 Days of Onset of
  Signs and Symptoms
• Institutional-read Tc-99m Apcitide versus
  Venography
• Sensitivity 90.6
• Specificity 83.9
• Accuracy 87.3
• PPV 85.3
• NPV 89.7

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Safety
Treatment-Related Adverse Events in Pivotal
Trials

• Tc-99m Apcitide Contrast
  Venography
• (n278)
  (n272)
• 1 (hypotension) 12
• (plt0.001)

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Tc-99m Apcitide

• Particularly Useful in These Cases
• obese patient
• patient with an orthopedic cast
• trauma
• suspected recurrent acute DVT
• acute DVT in the pelvis
• acute DVT in the calf
• equivocal ultrasonography or venography

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Tc-99m Apcitide

• Summary
• Binds to Activated Platelets
• Images Acute DVT
• Provides rapid, definitive, objective diagnosis
• Particularly useful when US is negative or
  equivocal and suspicion of acute DVT is high