Prospective evaluation of
Innovance D-dimer in the
exclusion of venous
thromboembolism [VTE].
Robert Gosselin, CLS
Department of Clinical Pathology and Laboratory Medicine
University of California, Davis Health System
Sacramento, CA
• D-dimer
– Indicates clot formation
– Indicates clot degradation
• D-dimer test commonly used for
exclusion:
– Pulmonary embolism
– Deep vein thrombosis
– Consumptive coagulopathy
– Aortic dissection
• Innovance D-dimer and Stratus CS
D-dimer new test from Siemen
Healthcare
• Prospective study in the US to validate
cut-off for excluding PE and DVT
• 3 sites in US
– Duke University
– Cleveland Clinic
– UC Davis
• Total enrollment all sites
– 550 PE
– 480 DVT
• Inclusion criteria
– First clinically suspected PE and/or DVT
– Objective testing
• Diagnostic algorithms
• Radiographic studies
– Capable of giving informed consent
– Agree to 3 month follow-up for patients
with negative imaging studies.
• Exclusion criteria
– Under 18 years of age
– Pregnant
– Previous Hx of PE or DVT
– Resolved symptoms >72 hours before
presenting to ED
– Oral anticoagulation
– 3 month f/u not available
– Inpatient
– Prisoners
Clinical Probability for DVT
Active cancer
+1
Paralysis, paresis, recent casting of leg
+1
Bedridden (>3 days) or major (>12 weeks)
+1
Entire leg swollen
+1
Calf swelling (>3cm) compared to other leg
+1
Pitting edema greater in symptomatic leg
+1
Collateral nonvaricose superficial veins
+1
Localized tenderness along deep venous system +1
Previously documented DVT
+1
Alternative Dx as or more likely than DVT
-2
Score:
DVT unlikely <2
DVT likely >2
Wells PS, et al Lancet 1997; 350:1795-98; N Engl J Med 2003;349: 1227-35
Clinical Probability for PE
Clinical signs and symptoms of DVT
Heart rate >100/min
Hemoptysis
Active cancer
Bedridden (>3 days) or major (>12 weeks)
Previously history of DVT or PE
PE most likely diagnosis
Score:
Low <2
Moderate 2-6
Wells PS, et al Thromb Haemost 2000; 83:416-20.
+3
+1.5
+1
+1
+1.5
+1.5
+3
High >6
DVT
Compression US
Positive
Negative
Serial CUS
(5-8 days)
Positive
Negative
Positive VTE
DVT Positive
Algorithm
Low prob
Mod or High Prob
3 month f/u
Negative VTE
DVT Negative
PE
Spiral CT or Angiogram
Positive
Algorithm
Negative
3 month f/u
Positive VTE
PE Positive
Negative VTE
PE Negative
• After informed consent
– Blood collected
• 3.2% sodium citrate
• Lithium heparin (Stratus only)
– If testing within 4 hours of collection
• Whole blood heparin on Stratus
• Plasma testing on other analyzers
– If testing not completed within 4 hours of
collection
• Samples processed and refrigerated
• Testing completed within 24 hours of collection
Testing performed on:
Sysmex analyzers
CA560
CA1500
CA7000
BCS
Stratus
(heparin and citrate testing)
[Delayed testing---CS2000i]
• As of May 11, 2009
– 381 patients enrolled
– 353 with demographics complete
– 284 with 3 mo f/u
• 2 withdrawn
– One patient declined participation after testing
completed [1 month later]
– One patient had imaging studies canceled after
enrollment
• 4 pending 3 month f/u
• 8 patients expired
– 0/8 with normal D-dimer levels
37% males [91/248]
Median age 51.5 years [range 19-81 years]
Patients with PE studies
• Probability scores
–
–
–
–
Low probability 62% [154/248]
Moderate probability 33% [82/248]
High probability 3% [7/248]
No score performed 2% [5/248]
Patients with DVT studies
• Probability scores
– Unlikely 64.4% [94/146]
– Likely 30.8% [45/146]
– No score performed 4.7% [7/146]
• Of the 353 patients with demographics:
– 70.2% [248/353] tested for PE
• 238 with spiral CT
• 12 with V/Q scan
• 25 with PE [10.5%]
– 41.4% [146/353] CUS for DVT
• 13 with DVT [9.6%]
37 patients evaluated for PE and DVT
–
–
–
–
30 with CT and CUS
6 with VQ and CUS
1 with CUS, CT and VQ
3 patients with both DVT and PE
4
3.7
Innovance D-dimer mg/L
3.5
3
2.5
2
1.5
1
0.8
0.5
0
No VTE
VTE
Innovance D-dimer, mg/L
PE Probability
DVT Probability
5.00
4.50
4.00
3.50
3.00
2.50
2.00
1.50
1.00
0.50
0.00
Low
Mod
High
Unlikely
Likely
Data for all patients enrolled
BCS CA1500 CA7000 CA560 SCS-H SCS-C
Neg VTE <0.5 mg/L 110
101
119
115
118
138
>0.5 mg/L 247
256
238
240
236
218
Pos VTE <0.5 mg/L
1
1
2
2
1
1
>0.5 mg/L
36
36
35
34
35
36
SCS-H Heparin sample on Stratus
SCS-C Citrate sample on Stratus
Innovance D-dimer in all VTE
BCS
CA1500 CA7000 CA560 SCS-H
SCS-C
Sens 97.3%
97.3%
94.6%
94.4%
97.2%
97.3%
Spec 30.8%
28.3%
33.3%
32.4%
33.3%
38.8%
NPV 99.1%
99.0%
98.3%
98.3%
99.2%
99.3%
PPV 12.7%
12.3%
12.8%
12.4%
12.9%
14.2%
SCS-H Heparin sample on Stratus
SCS-C Citrate sample on Stratus
Patients evaluated for PE
N=248
BCS CA1500 CA7000 CA560 SCS-H SCS-C
Neg PE <0.5 mg/L 79
69
84
81
86
93
>0.5 mg/L 144
154
139
142
135
129
1
1
2
2
1
1
>0.5 mg/L 24
24
23
23
23
24
Pos PE <0.5 mg/L
SCS-H Heparin sample on Stratus
SCS-C Citrate sample on Stratus
Innovance D-dimer in PE
BCS
CA1500 CA7000
CA560
SCS-H SCS-C
Sens
96.0%
96.0%
92.0%
92.0%
95.8%
96.0%
Spec
35.4%
30.9%
37.7%
36.3%
38.9%
41.9%
NPV
98.8%
98.6%
97.7%
97.6%
98.9%
98.9%
PPV
14.3%
13.5%
14.2%
13.9%
14.6%
15.7%
SCS-H Heparin sample on Stratus
SCS-C Citrate sample on Stratus
Patients evaluated for DVT
N=146
BCS CA1500 CA7000 CA560 SCS-H SCS-C
Neg DVT <0.5 mg/L 31
32
35
34
32
45
>0.5 mg/L 103
102
99
98
101
89
Pos DVT <0.5 mg/L 0
0
0
0
0
0
>0.5 mg/L 12
12
12
11
12
12
SCS-H Heparin sample on Stratus
SCS-C Citrate sample on Stratus
Innovance D-dimer in DVT
BCS
CA1500
CA7000 CA560
SCS-H
SCS-C
Sens
100.0%
100.0%
100.0% 100.0%
100.0%
100.0%
Spec
23.1%
23.9%
26.1%
25.8%
24.1%
33.6%
NPV
100.0%
100.0%
100.0% 100.0%
100.0%
100.0%
PPV
10.4%
10.5%
10.8%
10.6%
11.9%
SCS-H Heparin sample on Stratus
10.1%
SCS-C Citrate sample on Stratus
• Summary
– Poor positive predictive value of D-dimer
with VTE
– Acceptable negative predictive value for
Innovance D-dimer in excluding VTE in
outpatients
– Need more data for PE sensitivity
– Weakness
• Few positive samples in subset analysis
• Fellow collaborators at UC Davis
– Edward Panacek, MD, MPH
– Abhi Gorhi, MS, CCRP
– Shari Nichols, CCRP
– Allyson Sage, RN
– Leslie Freeman, CLS
– Andrea Picazo, CCRP