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D-Dimers: Clinical Utility in the Diagnosis of PE. Resident Grand Rounds November 19, 2002 Heather M. Powers, MD Wake Forest University Medical Center Department of Internal Medicine. Overview. Case presentation Clinical questions Epidemiology VTE D-dimers – pathophysiology Assays

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D dimers clinical utility in the diagnosis of pe l.jpg

D-Dimers:Clinical Utility in the Diagnosis of PE

Resident Grand Rounds

November 19, 2002

Heather M. Powers, MD

Wake Forest University Medical Center

Department of Internal Medicine


Overview l.jpg
Overview

  • Case presentation

  • Clinical questions

  • Epidemiology VTE

  • D-dimers – pathophysiology

  • Assays

  • Evidence

  • Conclusions


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Case Presentation

  • 45 yo obese WF presenting to ED

    • PMHx significant for asthma

    • Complaints of SOB and right sided chest pain x 1 day

    • Reports recent travel

    • Medication  OCP’s

    • Soc HX  nonsmoker, works at desk job

    • Fam Hx

  • PE: VVS 92% pulse ox RA

    • Lungs: few scattered wheezes, LE: no asymmetry

    • CV: RRR w/o m/r/g


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Case (cont’d)

Would a D-dimer be useful in ruling out PE in this patient with a low pretest probability without doing diagnostic imaging?


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Clinical Questions

  • How sensitive and specific are D-dimers at detecting VTE?

  • In what patient population is it appropriate to use D-dimers in helping rule out VTE?

  • Can you safely withhold anticoagulation in patients with a negative D-dimer result?

  • Can D-dimers be used as the sole test to rule out VTE?


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VTE

  • refers to spectrum of PE and DVT

  • Annual incidence of VTE

    • 125,000-400,000 cases/year (some as high as 2 million)

    • PE responsible for 200,00 deaths in US /year

  • preventable condition associated with substantial morbidity and mortality if untreated

    • Untreated 30% (23-87%)

    • Treated 2-8%

  • 65-90% of PE’s arise from LE


Vte risk factors l.jpg

Age > 40

Immobilization

Obesity

h/o CVA

Recent surgery (within the last 3 months)

Estrogen use

Lower extremity fractures

Myocardial Infarction

VTE - Risk Factors

40 years old

CVA


Vte risk factors9 l.jpg

CHF

Varicose veins

Pregnancy/postpartum

Antiphospholipid Ab

Prior history of VTE

OCP’s

Hypercoagulable state (i.e. Factor V Leiden)

VTE - Risk Factors

DVT

PE

FACTOR

V

CHF


Clinical predictors of pe l.jpg

Signs

tachypnea (70%)

rales (51%)

tachycardia (30%)

fourth heart sound (24%)

accentuated P2 (23%)

fever (14%)

Symptoms

dyspnea (73%)

pleuritic pain (66%)

cough (37%)

hemoptysis (13%)

Clinical Predictors of PE?

  • Caveat

    • frequency of these symptoms and signs similar to the 843 PIOPED cohort patients w/o PE


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Diagnostic Dilemmas

  • History and physical exam

  • Objective tests

  • Gold standard tests

  • V/Q scanning

  • Empiric anticoagulation


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What are D-Dimers?

  • degradation product from a specific region of cross-linked fibrin


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What are D-Dimers?

  • Degradation product from a specific region of cross-linked fibrin

  • Sensitive markers for thrombosis but not specific

    • commonly elevated in patients with malignancy, infection, CHF, renal failure, SS crisis, and recent surgery

  • Levels elevated 8 fold after VTE compared with controls

  • Levels normalize within 15-20 days

  • Levels increase linearly with age


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Effects of age on D-dimer performance

%

Age(yrs)

Adapted from Righini et al, 2000


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Relationship between D-dimer levels and Embolus Location

  • De Monye demonstrated that the accuracy of the D-dimer measurement to exclude PE depends strongly on embolus location

  • D-dimer may miss subsegmental PE’s

Adapted from de Monye et al, Amer J of Resp Crit Care Med 2002


Assays l.jpg

ELISA

Microplate ELISA gold standard

VIDAS ELISA with reported sensitivity 100%

Typically more time consuming but newer tests more rapid

Less specific

Agglutination

Second generation kits have higher sensitivity and are more clinically useful (i.e. SimpliRED)

More rapid

More specific

Assays

  • Correlation between different assays is poor



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Performance of various D-dimer assays in suspected PE

Pts (n) PE (n)

Sensitivity Specificity

Classical ELISA

Rapid ELISA

Classical latex tests

Microlatex

WBL test

Adapted from Task Force Report Eur Heart Journal, 2000


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Evidence

  • Basic EBM concepts

    • Pretest probability

    • Likelihood ratios

  • Clinical Evidence


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Formulating PTP

  • Pretest Probability

    • Probability that a patient has the disease before undergoing a test

      PTP + LR = posttest prob

    • LR > 10 or < 0.1 significantly changes post-test probability


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Low <2

Moderate 2-6

High >6

Modified Wells CriteriaAdapted from Wells et al., 1998

Clinical FeaturesScore

Clinical signs and symptoms of DVT 3.0

HR>100 beats/min 1.5

Immobilization (for >3 consecutive days) 1.5

Surgery in previous 4 weeks 1.5

Previous dx of DVT or PE 1.5

Hemoptysis 1.0

Cancer 1.0

PE as likely or more likely

than any other diagnosis 3.0


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ROC Curve for Plasma D-dimerELISA

Adapted from Perrier in American Journal of

Respiratory Critical Care Medicine, 1997


Bates et al a latex d dimer reliably excludes venous thromboembolism 2001 l.jpg
Bates et al, “A latex D-Dimer reliably excludes venous thromboembolism” 2001

  • Question

    • Does the MDA- D-dimer assay have a high sensitivity and NPV for VTE and does it have the specificity to make the test clinically useful?

  • Design

    • Retrospective cohort study

  • Population

    • 595 (60% women) unselected outpatients with clinically suspected DVT (317) or PE (278) referred to 4 tertiary care centers in Canada


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Bates et al

  • Methods

    • Pts assigned pretest probability of VTE based on previously validated model

    • Blood drawn for testing with MDA D-dimer assay (negative <0.5µg FEU/ml)

    • Evaluated with objective testing per consulting physician

    • Pts with low PTP and (–) D-dimer assay had no further testing

    • Anticoagulation held in all patients with (-) objective test results

    • Classified as VTE + or – according to the objective test results and followed for 3 mo.


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Bates et al

  • Results

    • Prevalence of VTE was 19%(113/595)

      • 48 pts (17.3%) with suspected PE classified as PE+

    • 34.5% (205) had a low PTP of VTE

      prevalence of VTE in low PTP group 5.9% and 16.9% in moderate PTP group

    • MDA D-dimer has 97% sensitivity and 99% NPV when low and moderate PTP groups combined

    • LR(-) was 0.07 in this subgroup of patients




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Bates et al VTE

  • Conclusions

    • First study to demonstrate that a D-Dimer assay has the potential to be used as the sole diagnostic test to exclude VTE

    • 96% sensitivity and 98% NPV for all comers with suspected VTE

      • NPV compares favorably with widely accepted diagnostic tests for VTE

    • D-dimer result of <0.5µg FEU/ml excludes VTE in patients with a low or moderate pretest probability (80% of population in this study)

    • Promising results but need further testing to determine safety of withholding anticoagulation in patients with low/mod pretest probability and (-) MDA D-dimer test


Bates et al32 l.jpg

Strengths VTE

Specificity of this latex assay higher than ELISA

Evaluated subgroup of pts with cancer with low/ mod PTP of VTE and found 97% sensitivity and 94% NPV

Limitations

Did not perform gold standard

Results cannot be extrapolated to other assays

Funded by Organon Teknika, manufacturer of MDA assay

Bates et al


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Ginsberg, et al VTE“Sensitivity and specificity of a rapid whole blood assay for D-dimer in the diagnosis of pulmonary embolism” 1998

  • Question

    • How accurate is a D-dimer assay in patients with suspected PE? Can a (-) D-dimer be of value in excluding PE in patients with low probability, non-diagnostic lung scans, or both?

  • Design

    • prospective cohort with blinded comparison of D-dimer assay results, V/Q scanning, and bilateral CUS with watchful waiting (3mo)

    • 4 tertiary care centers from Sept ‘93-May ’96


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Ginsberg et al VTE

  • Population

    • 1177 consecutive adults >18 yrs of age referred for suspected PE.

  • Exclusion criteria

    • Suspected UE DVT

    • No symptoms within previous 48hrs

    • Receipt of anticoagulation for 72hrs

    • Limited life expectancy

    • Contraindication for contrast media


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Ginsberg et al VTE

  • Methods

    • Classified as high, moderate, or low pretest probability. All patients underwent V/Q scanning and CUS within 24 hours of presentation

    • D-dimer tests using SimpliRED assay done concurrently with other diagnostic testing

    • All patients followed for 3 months


Ginsberg et al36 l.jpg
Ginsberg et al VTE

  • Results

    • Overall prevalence of PE 17% (197)

    • No patient classified as PE (-) died of PE during follow up

    • For all patients, D-dimer assay had a sensitivity of 84.8% and a specificity of 68.4%

    • Subgroup analysis based on PTP

      • 703 classified as low PTP and 3.4% PE(+)

      • 521 had (-) D-dimer, 5 of which were PE(+)

      • LR (-) = 0.27


Ginsberg et al37 l.jpg
Ginsberg et al VTE

PE in low PTP

Sens = 79%

Spec = 76%

NPV = 99.7%

LR (-) = 0.27

D- Dimer


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Ginsberg et al VTE

  • Conclusions

    • D-dimer testing has a high sensitivity and moderate specificity for PE

    • D-dimers should not be used as a stand alone test

    • Not to be used to exclude PE in patients with mod/high pretest probability unless combined with other objective testing

    • Further testing and anticoagulant therapy may be with held in patients with a normal D-dimer if patients have a low pretest probability


Ginsberg et al39 l.jpg
Ginsberg et al VTE

  • Limitations

    • Gold standard not performed

    • Results apply only to

      SimpliRED assay

    • Outpatients only

    • Did not give details

      of follow up data


Perrier a et al non invasive diagnosis of venous thromboembolism in outpatients 1999 l.jpg
Perrier A. et al VTE“Non-invasive diagnosis of venous thromboembolism in outpatients”, 1999

  • Design

    • Prospective cohort study with 3mo. follow up

  • Population

    • 918 consecutive patients presenting to ED or outpatient clinic with suspected PE or DVT

  • Methods

    • Clinical probability assigned based on RF, signs and sxs, likelihood of alternative diagnosis, bld gas and CXR results in case of PE


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Perrier et al VTE

  • Methods (cont’d)

    • Low, moderate, and high probability defined as 0-20%, 21-79%, and 80-100% respectively

    • Pts then entered algorithm

      • D-dimer testing (VIDAS ELISA) performed on all pts

      • D-dimer <500µg/L deemed to r/o VTE

      • Pts with (+) dimer results went further testing according to the algorithm

      • Pts followed at 3mo for determination of bleeding or thromboembolic events


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Perrier et al VTE

  • Primary outcome

    • Efficiency of their diagnostic strategy in terms of the number of patients in whom a definite diagnosis can be made without invasive workup


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Perrier et al VTE

  • Results

    • Prevalence of VTE was 23% and similar in both DVT and PE subgroups

    • D-dimer normal in 31% of cohort therefore excluding VTE

    • 2 FN tests resulting in NPV of 99.3%

    • D-dimer and ultrasound established diagnosis in 48% of cohort

    • Overall a noninvasive dx of VTE achieved in 99% of pts


Perrier et al44 l.jpg
Perrier et al VTE

  • Prevalence of DVT and PE in low probability subgroup was 2% and 9% respectively

  • 10 of the 703 pts not on anticoagulation had confirmed events during 3 mo F/U

    • None of these 10 pts had a normal D-Dimer

    • Overall 3 month thromboembolic risk was 1.8%


Perrier et al45 l.jpg
Perrier et al VTE

PE / DVT

Sens =99.1%

Spec = 41.1%

NPV = 99.3%

LR (-) = .02

D-Dimer


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Perrier et al VTE

  • Conclusions

    • High sensitivity in all pts using VIDAS ELISA

    • Noninvasive workup feasible in a large proportion of patients

    • Low thromboembolic risk at 3 months

    • Large cohort and therefore easily applied to outpatient population presenting with suspected DVT or PE


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Perrier et al VTE

  • Limitations

    • Applies only to outpatient population

    • Gold standard not performed in all patients

    • Did not follow a clinical prediction rule


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Wells et al, “ VTEExcluding PE at the bedside without diagnostic imaging: Management of patients with suspected PE presenting to the ED by using a simple clinical model and D-dimer” 2001

  • Question

    • How safe is using a clinical model combined with D-dimer assay to manage patients presenting to the ED with suspected PE?

  • Design

    • prospective cohort study

  • Population

    • 930 consecutive patients with suspected PE at 4 tertiary care ED in Canada from Sept 98-Sept 99


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Wells et al VTE

  • Methods:

    • Pretest probability of PE assigned using clinical model

    • SimpliRED D-dimer testing performed in all pts after determining PTP

    • Pts with low PTP and (-) D-dimer were considered PE (-) and had no further testing

      • All other pts had V/Q scans


Modified wells criteria clinical assessment for pe l.jpg

Low <2 VTE

Moderate 2-6

High >6

Modified Wells CriteriaClinical Assessment for PE

Clinical FeaturesScore

Clinical signs and symptoms of DVT 3.0

HR>100 beats/min 1.5

Immobilization (for >3 consecutive days) 1.5

Surgery in previous 4 weeks 1.5

Previous dx of DVT or PE 1.5

Hemoptysis 1.0

Cancer 1.0

PE as likely or more likely

than any other diagnosis 3.0


Wells et al51 l.jpg
Wells et al VTE

  • Methods (cont’d)

    • Anticoagulation held in pts whom PE was excluded

    • Pts followed for 3 months for the development of thromboembolic events

  • Primary Outcome Measure

    • Proportion of patients who had a VTE event during the 3 mo. F/U period in whom PE had been previously excluded


Wells et al52 l.jpg
Wells et al VTE

  • Results

    • Prevalence of PE was 9.5% ≈ 86 pts

    • No patients in whom PE was excluded died of PE during follow up

    • PE diagnosed in 7 pts with low PTP

      • Only 1 of these that were PE (+) had a negative d-dimer

    • NPV of D-dimer of entire cohort was 97.3%

      • NPV in low PTP group was 99.5%

    • Imaging tests not done in 47% of patients


Wells et al53 l.jpg
Wells et al VTE

PE in Low PTP pts

D- Dimer

Sens = 85.7%

Spec = 83.8%

NPV 99.7%

LR (-) = 0.17


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Wells et al VTE

  • Results (cont’d)

    • Incidence of PE according to pretest prob subgroup

      • Low PTP

        • 7/527 = 1.3%

      • Moderate PTP

        • 52/339 = 15.3%

      • High PTP

        • 23/64 = 35.9%

    • In 92pts (10%) protocol not exactly followed


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Wells et al VTE

  • Conclusions

    • Combined PTP assessment and SimpliRED D-dimer testing can safely diagnose or R/O PE obviating need for further imaging studies

    • Nearly half of patients in this cohort (47%) did not require imaging tests

    • Their diagnostic algorithm based on PTP and results of D-dimer test feasible in ED setting

    • Their strategy virtually eliminates need for angiography and may limit need for spiral CT


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Limitations VTE

Gold standard not performed

Protocol not followed in about 10% of total pts

Low prevalence of PE in sample and results may not apply to population with higher prevalence of disease

Sensitivity of SimpliRED assay not that great 85.7%

Wells et al


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Summary of all studies VTEPE in low PTP subgroup


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NCBH VTE

  • The Advanced D-dimer – manufactured by Dade-Behring

    • Not designed to detect PE

    • Used in our DIC panel

  • Costs of various objective tests for PE

    • D-dimer $71.00

    • V/Q scan $480.25/$481.00

    • CT angiogram $900-$1200

    • PA gram


Summary l.jpg
Summary VTE

  • How sensitive and specific are D-dimers at detecting VTE?

    • Sensitivity and specificity varies between assays

    • ELISA’s have greatest sensitivity, some approaching 100%

    • Specifity declines with age

    • Sensitivity varies with embolus location


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Summary VTE

  • In what patient population is it appropriate to use D-dimers in helping rule out VTE?

    • Most useful in outpatient setting with patients who have few or no comorbid conditions

    • Particularly applicable in patients with low PTP

      • Studies seem to suggest can use D-dimers alone without further imaging in this subgroup of patients


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Summary VTE

  • Can you safely withhold anticoagulation in patients with a negative D-dimer result?

    • Studies show low thromboembolic risk at three months

    • No deaths from PE at follow-up


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Summary VTE

  • Can D-dimers be used as the sole test to rule out VTE?

    • Possible role for D-dimers as sole test in low PTP patients

    • Negative D-dimer using a highly sensitive assay

      obviates need for further imaging

    • Should not replace good clinical judgment

    • Test needs to be incorporated into a well validated diagnostic algorithm that is uniformly used


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THANK YOU!!!! VTE

  • Dr. Bob Preli

  • Dr. Jim Kimberly

  • Dr. Christian Sinclair

  • Dr. Brent Powers


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