Epidemiology and diagnostic tests for venous thromboembolism Edwin

Epidemiology and diagnostic tests for venous thromboembolism Edwin JR van Beek, MD Ph. D FRCR Section of Academic Radiology University of Sheffield, UK

Personal background 1980 -87 Medical School, Rotterdam, NL 1987 MD Rotterdam, NL 1987 -90 Surgical jobs, UK and NL 1994 Ph. D Amsterdam, NL (Pulmonary embolism) 1994 -99 Radiology training, NL 1999 FRCR, London, UK

Venous thromboembolism (VTE) * Consists of two clinical pictures: 1. Deep vein thrombosis (DVT) 2. Pulmonary embolism (PE) * Intimately related in etiology, treatment and outcome. * 50% of proven DVT also have PE * 70% of proven PE also have DVT

Incidence of Venous thromboembolism * Clinical suspicion PE: 2 -3 per 1000/ year * Proven PE: 0. 5 per 1000/year * Clinical suspicion DVT: 2 -3 per 1000/year * Proven DVT: 1 per 1000/year * Japan: 50 to 100 -fold less common

Risk factors: congenital * Deficiencies: antithrombin, protein C, protein S, plasminogen, factor XII * Mutations: factor V Leiden (APC-R), prothrombin 20210 A * Congenital dysfibrinogenemia * Hyperhomocysteinemia * Thrombomodulin disorders * Dysplasminogenemia * Anticardiolipin antibodies * Excessive plasminogen activator inhibitor

Risk factors: acquired * * * * Surgery (incl. Orthopaedics, trauma, neurosurgery) Immobilisation: fractures, stroke Malignancy, chemotherapy, central venous catheters Heart failure, chronic venous insufficiency Pregnancy, puerperium, oral contraceptives Albumin loss: Crohn’s disease, nephrotic syndrome Hyperviscosity (Polycythemia, Waldenstrom’s macroglobulinemia) * Platelet abnormalities

Importance of Diagnosis * 70% of patients with clinical suspicion will not have diagnosis confirmed * Anticoagulants may have serious adverse (haemorrhagic) effects: - 1 per 100 treatment years: fatal bleeding - 4%-16% serious hemorrhagic events

Risk of Missed Diagnosis * 30% of patients with untreated PE will suffer fatal second event * 30% of patients with untreated PE will suffer non-fatal second event: - pulmonary hypertension risk increase? - post-thrombotic syndrome risk increase?

Role of diagnostic strategy * Balance between missed/over-diagnosis * Initial risk of recurrent PE: physicians will be likely to treat patients * Diagnostic tests are there to: 1. Offer alternative diagnosis 2. Exclude VTE 3. Prove VTE (this affects management least)

Main diagnostic aids in suspected PE * * Clinical diagnosis (history, examination) ECG, chest X-ray Traditional tests: lung scintigraphy, angiography Newer tests: US, CT, D-dimer, cardiac US, MRA

Clinical signs VTE * Dyspnea (often sudden onset) * Haemoptysis * Collapse * “Fear of dying” * Redness of leg * Pleural chest pain * Tachycardia * Cyanosis (subclinical) * Coughing * Leg swelling * Tenderness of calf

Points of interest in clinical history * Onset of symptoms * Previous VTE * Family history * Risk factors (increasing number known!)

Chest X-ray findings suggestive for PE * Normal * Peripheral consolidation (“Hampton’s hump”) * Pleural effusion * Radiolucency (“Westermakr sign”)

ECG findings suggestive for PE * Right bundle branch block * Right axis shift * Tachycardia or new onset atrial fibrillation * S 1 Q 3 T 3 pattern

Pulmonary angiography * Gold standard * Normal angiogram effectively rules out PE * Physicians are reluctant to use it: - fear, “invasive”, availability * Major changes: contrast agents, catheters, guide wires, DSA

Pulmonary angiography: Safety * Studies before 1990: * 2203 patients * 5 deaths (0. 2%) * 42 compl (1. 9%) * Studies after 1990 * 3613 patients * 1 death (0. 03%) * 17 compl (0. 47%)

Lung scintigraphy: PIOPED Classification * Normal (<1% PE) * Very low probability (<10% PE) * Low probability (<19% PE) * Intermediate probability (20 -79% PE) * High probability results (>80% PE)

Lung scintigraphy: Classification discussions * How low is low probability? * PIOPED: very low: 10% PE; low: 16% PE * Clinicians do not realize this!! * Suggested: normal, high probability and non -diagnostic

Lung scintigraphy: Normal perfusion scan * Obtained in 20 -30% of ? PE patients * 3 studies with 693 patients: anticoagulants withheld and follow-up 3 -6 months * Risk of recurrence: 0. 3% (95%CI 0. 2 -0. 4%)

Lung scintigraphy: High probability VQ scan * Obtained in 20 -30% of ? PE patients * 9 studies with 350 patients compared with pulmonary angiography * Pos. Pred. Value: 88% (95%CI 84 -91%)

Lung scintigraphy: Non-diagnostic (V)Q scan * Obtained in 40 -60% of ? PE patients * 12 studies with 1529 patients compared with pulmonary angiography * PE present: 25% (95%CI 24 -28%)

Ultrasonography of the deep venous system * Direct visualization of thrombus in PE and DVT * Based on 70 -90% prevalence of DVT in proven PE. * Repeated ultrasonography over 7 -10 day period: - replaces venography in suspected DVT - may be able to replace angiography in suspected PE

Ultrasonography of the deep venous system in suspected PE * Single investigation: sens 30%, spec 97% * Only to prove PE! * Problem: false positive leads to treatment. * Cost-effectiveness in doubt.

Plasma D-dimer * Break-down product of cross-linked fibrin. * Only ELISA and recent rapid unitary ELISA reach sensitivity approaching 100%. * Able to safely exclude >35% of suspected patients in A&E department. * Comorbid conditions increase D-dimer levels (specificity approximately 50%).

Helical CT pulmonary angiography: studies * * * 12 studies CT vs scintigraphy/angiography 1171 patients, prevalence PE 39% Sensitivity 88%, Specificity 92% Problem 1: high prevalence Problem 2: poor results in subsegmental PE

Anatomical distribution of PE * * 3 studies using pulmonary angiography. 1 retrospective and 2 prospective. 15 -30% isolated subsegmental PE In all with suspected PE: 5 -8% isolated subsegmental PE.

Helical CT: two management studies * * * * Study 1: 164 patients: N-D lung scan, normal US. Prevalence PE 24%, follow-up only in 109 patients Recurrent VTE: 6 (5. 5%; 95% CI 2 -12%) Fatal PE: 1 (1%; 95% CI 0. 02% - 4. 3%) Study 2: 398 h. CT, 285 normal (72%) Follow-up only in 198 (70%) Recurrent PE: 2 (1%; 95% CI 0. 12 -3. 57 %) Fatal PE: 1 (0. 5%; 95% CI 0. 01 -2. 75%)

Echocardiography for suspected PE * * * Direct visualization of (central) thrombus Assessment of right ventricular function Measurement of pulmonary arterial pressure Useful in suspected massive PE Potentially useful for therapy monitoring

Magnetic Resonance Angiography * No ionizing radiation, non-invasive. * Promising new technology, fast developments. * Pulmonary perfusion studies possible. * Early results show similar problems to helical CT: subsegmental PE difficult!

Management strategies for suspected PE: clinical factors * Massive PE: hemodynamic instability. * Sub-massive PE: echocardiographic signs of RV dysfunction only. * Non-massive PE: no hemodynamic effects detectable.

Management issues * Pregnancy * Children * Suspected recurrent PE * Chronic Thromboembolic Pulmonary Hypertension