individualized prediction in pulmonary embolism; novel ...individualized prediction in pulmonary...
TRANSCRIPT
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Individualized prediction in pulmonary embolism; novel concepts and future ideas.Geert-Jan Geersing, MD PhDFamily Medicine specialist
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Our thrombosis research
R.Oudega, et.al. Ann Int Med 2005;143:100-107
Since then: 50+ papersGuidelines primary care
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And beyond …
Mild thrombosis Severe thrombosis
SVT distal DVT proximal DVT atrial fib PE AF + …
DIAGNOSIS, PROGNOSIS AND TREATMENT?!
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Management of (acute) pulmonary embolism
Primary Care
Talk of today
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Pulmonary embolism
Europe: 500.000+ deaths per year
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Our patient of today
Home visit:82 yearsHeavy smokerCOPD, HT
Shortness of breath‘not like it usually is, doc …’
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Our patient of today
SuspicionTesting
Reference
Rx
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Suspected of PE…
COPD exacerbation?Heart failure?“not like usually…” PE…
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Misdiagnosis is common
G.Schiff, et.al. Arch Intern Med 2009;169(20):1881-7
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Not a new problem
BMJ 1949
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Common; estimates 30-50%
Higher age/comorbidity Non-specific symptomsMay increase mortality
What do we know
J. Alonso-Martinez, et.al. Eur.J.Int.Med. 2010;278-82J. Torres-Macho, et.al. Am.J.Emerg.Med. 2013;1646-50
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Determinants in primary careConsequencesEvaluate awareness strategies
More research needed
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Our patient of today
SuspicionTesting
Reference
Rx
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TestingClinical Probability Assessment, e.g.
Wells-rule
Low High
D-dimer CTPA
Negative:rule-out
Positive
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Good news: Wells-rule
Variable PointsSigns of DVT 3.0PE most likely 3.0Heart rate > 100 1.5Immobilization 1.5Previous PE or DVT 1.5Hemoptysis 1.0Cancer 1.0
Score ≤ 4 defines low risk
Score >4 defines high risk
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Add D-dimer
Good for rule-outYet, low specificity
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More good news
W. Lucassen, et.al. Ann Int Med 2011; 155:448-60
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Also true for primary care
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Point-of-care D-dimer
+-
Clearview Simplify®, Inverness Medical, Bedford, UK
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Sensitivity lower (around 90%)Good NPV combined with CDRCost-effective
More POC tests
G.J. Geersing, et.al. BMJ; 2009:b2990J. Hendriksen, et.al. Expert Rev Mol Diagn; 2015:125-36
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Back to our patient
30
40
50
60
70
80
90
100
40 50 60 70 80
% D-dimer positive
Age
Probability positive D-dimer > 90%!
H. Schouten, et.al. BMJ; 2013:346; f2492R. Douma, et.al. BMJ; 2010:340; c1475
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423 nursing home patients 322 ‘high risk’ 39% of those: not referred
H. Schouten, et.al. PloS one;2014: e90395
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126 non-referred: mean age: 82 years75% blind initiation of anticoagulants (!)Mortality at 3 months: 31%
199 referred: mean age: 82 years60% confirmed VTE (!)Mortality at 3 months: 17%
Mortality non-referred
adjusted OR mortality 1.99 (1.09-3.62)
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Qualitative approach“In many of my years of
started this.”
“In many of my years of experience, I have seen so much misery: people going to the hospital and either dying there, tremendously delirious, tied up to the bed, or returning in a condition that makes you say: “Oh my, I wish we had never started this.”
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Getting a suspicion difficult …… but if we do:
- Validated prediction rules- (POC) D-dimer testing- Often false-positive = frustrating- Leads to: non-referral in nursing homes
Interim summary
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Improve “rule-in”(serial) ultrasound testing
Improve “rule-out”Age-adjusted D-dimer: cut-off = age x 10 if age > 50 years
Better tools needed
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Age-adjusted D-dimer
R. Douma, et.al. BMJ; 2010:340; c1475
Cut-off:Age x 10
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Back to our patient
30
40
50
60
70
80
90
100
40 50 60 70 80
Traditional cut-off
Age-adjusted cut-off
% D-dimer positive
H. Schouten, et.al. BMJ; 2013:346; f2492R. Douma, et.al. BMJ; 2010:340; c1475
Age
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Fewer false-positives D-dimer
Still: ≈70% positive if age > 80 years
Not incorporated: gender, comorbidity, cancer, etc.
Age-adjusted D-dimer
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The next step
Personalized threshold based on age, gender, comorbidity, frailty, PTP, etc.
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Database ≈ 15.000 patientsGroup: Canada-USA-Netherlands-Others?
Advanced updating techniqueInteraction terms into the modelMultilevel structureSo aim ≠ “new rule”!
IPD meta-analysis
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Many advantages
Efficient use of existing dataGain in subgroup analysesRobust models, multiple validation option
IPD meta-analysis
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Our patient of today
SuspicionTesting
Reference
Rx
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CTPA
- High sensitivity- Easy to do- Other diagnosis- …
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Flipside: Overdiagnosis
Ann Int Med 1977
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Flipside: Overdiagnosis
Finding small clotsRx treatment benefit?
V. Prasas, et.al. Arch Int Med; 2012:172(12) 955-8
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Our patient of today
SuspicionTesting
Reference
Rx
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Risk-benefit ratio:Risk of recurrent event
versusRisk of bleeding
Both for recurrence and bleedingIndividualized Prediction models
Treatment duration
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Provoked: low risk of recurrence
Unprovoked: recurrences, yetheterogeneous
Bleeding: in elderly, HT, history of bleeding, etc.
What we know
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Risk of recurrence
S. Eichinger, et.al. Circulation; 2010:121: 1630-6
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Several validation and impact studies ongoing (e.g. VISTA, VALID, REVERSE)
Validation bleeding risk scores
Future challenge: incorporate bleeding and recurrence in one (bivariate?) model
Research agenda
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PE challenging disease
Suspicion Testing Reference Rx
In all steps: Prediction=personalized medicine(one size does not fit all)
Take home messages
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On behalf of my colleagues:
Prof. K.G.M. Moons, PhDProf. A.W. Hoes, MD PhDF.H. Rutten, MD PhDR. Oudega, MD PhDJ.M.T. Hendriksen, MD PhDS. Van Doorn, MDA.E.C. Kingma, MDC. Van den Dries, MDL.P.T. Joosten, MD
Thanks for your attentionContact information:[email protected]
www.gjgeersing.nl