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The diagnosis and prognosis of venous thromboembolism : variations on a
theme
Gibson, N.S.
Publication date
2008
Document Version
Final published version
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Citation for published version (APA):
Gibson, N. S. (2008). The diagnosis and prognosis of venous thromboembolism : variations
on a theme.
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The diagnosis and prognosis of
venous thromboembolism
The diagnosis and prognosis of venous thromboembolism Thesis, University of Amsterdam, the Netherlands ISBN 978 90 902 3385 7 Copyright © 2008 N.S. Gibson, Amsterdam, the Netherlands No part of this thesis may be reproduced, stored in a retrieval system or transmitted in any way or by any means, without written permission of the author. Financial support for the printing of this thesis was provided by: Stichting tot Steun Promovendi Vasculaire Geneeskunde, AMSTOL stichting, the Federatie van Nederlandse Trombosediensten, Pfizer, sanofi‐aventis, Actelion, Bayer, Schering‐ Plough, Boehringer Ingelheim, Merck Sharp & Dome B.V. and the Universiteit van Amsterdam.
The diagnosis and prognosis of
venous thromboembolism
Variations on a theme
ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof.dr. D.C. van den Boom ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Aula der Universiteit op woensdag 8 oktober 2008, te 12.00 uur door Nadine Suryanti Gibson geboren te LeidenP
ROMOTIECOMMISSIE
Promotor: Prof.dr. H.R. Büller Co‐promotores: Dr. V.E.A. Gerdes Dr. M. Söhne Overige leden: Dr. D.P.M. Brandjes Prof.dr. M.M. Levi Prof.dr. M.H.H. Kramer Prof.dr. P.M.M. Bossuyt Prof.dr. E.H.D. Bel Faculteit der Geneeskunde
The study described in this thesis was supported by a grant of the Netherlands Heart foundation (NHF‐2001B205). Financial support by the Netherlands Heart Foundation for the publication of this thesis is gratefully acknowledged.
Aan Jan‐Joost en de kinderen
C
ONTENTS
Chapter 1 9 General introduction and outline of the thesis Part I ‐ DIAGNOSIS OF VENOUS THROMBOEMBOLISM Chapter 2 17 Pulmonary embolism; a review Chapter 3 37
Further validation and simplification of the Wells clinical decision rule in pulmonary embolism Chapter 4 55 Validity and clinical utility of the simplified Wells rule for assessing clinical probability of pulmonary embolism Chapter 5 67
Implementation of a decision rule and a D‐dimer assay in the diagnosis of pulmonary embolism
Chapter 6 83
The importance of clinical probability assessment in interpreting a normal D‐dimer in patients with suspected pulmonary embolism
Chapter 7 95
Clinical usefulness of prothrombin fragment 1+2 in patients with suspected pulmonary embolism
Chapter 8 105
Safety and sensitivity of two ultrasound strategies in patients with clinically suspected deep venous thrombosis; a prospective management study
Chapter 9 123 Prognostic value of echocardiography and spiral computed
tomography in patients with pulmonary embolism Chapter 10 137 Is screening for chronic thromboembolic pulmonary hypertension in patients with a previous pulmonary embolism indicated? Chapter 11 149 Treatment of pulmonary embolism in the Netherlands; a survey Summary 159 Samenvatting 165 Dankwoord 171
General introduction and
outline of the thesis
NADINE S. GIBSON AND HARRY R. BÜLLER
10
G
ENERAL INTRODUCTION
Venous thromboembolism is a possibly fatal disease that has been recognized since the middle ages. Since then, numerous researchers have studied this theme to accomplish advances with new variations on the existing practice of the diagnosis, prevention, treatment and prognosis of this disease.
It was the 19th century German pathologist Rudolf Virchow, who created the concept
that pulmonary embolism and deep venous thrombosis are both manifestations of a single disease entity, called venous thromboembolism. He stated: ‘The detachment of larger or smaller fragments from the end of the softening thrombus which are carried along by the current of blood are driven into remote vessels. This gives rise to the very
frequent process on which I have bestowed the name of Embolia.’1
In the 1960’s the diagnostic work‐up of patients with clinically suspected pulmonary embolism changed significantly when imaging tests, such as contrast venography,
pulmonary angiography and perfusion lung scanning were introduced2‐5. This major
step forward in the diagnosis of venous thromboembolism was characterized by the possibility to (in)directly visualize thrombi. However, what was not well realized until that moment, was that only a quarter of clinically suspected patients appeared to have the disease. Moreover, the availability of these tests was limited and together with the reluctance of many physicians to perform invasive tests resulted often in an incomplete diagnostic work‐up and anticoagulant treatment without a definitive diagnosis. Despite these limitations, physicians had no alternative diagnostic methods. In the 1980’s, the introduction of ultrasonography, that could non‐invasively
image the deep veins in the leg significantly changed the diagnostic approach6.
Nevertheless to refute the diagnosis, all patients with suspected venous thromboembolism had to undergo one or more of these imaging tests. This has led to a revival of the use of information from the medical history, physical examination, and simple blood tests to guide the diagnostic process. With the introduction of clinical decision rules and the D‐dimer test (a laboratory assay that indirectly measures blood coagulation), a powerful strategy was created to safely exclude the disease in one third to half of the patients, without the need for imaging tests.
Albeit well validated, these clinical decision rules are sometimes difficult to compute and simplification may increase the broader implementation in daily clinical practice. Also the D‐dimer assay has gained an important place in the diagnosis of patients with suspected pulmonary embolism. Due to its moderate specificity, it should not be used as a screening test, and perhaps other coagulation tests, more specifically
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measuring thrombin generation may be helpful to compensate for this shortcoming. On the other hand, how often false negative D‐dimer results occur, and what the reasons are, remains unclear.
Finally, a dilemma in the diagnostic process has arisen with the ability of new technology in ultrasonography allowing full visualization of all deep veins in the leg, as compared to the traditional method of compression ultrasonography in the groin and popliteal fossa. Regarding the themes prognosis and treatment three pertinent questions have surfaced. The first concerns the significance and therefore the need to detect, by either echocardiography or spiral CT, the presence of right ventricular dysfunction in patients who are otherwise hemodynamically stable. This is relevant since the treatment may have to be more aggressive in these patients. Another long term complication of pulmonary embolism that has caught medical attention recently is the occurrence of chronic thromboembolic pulmonary hypertension. Although the disease is rare in consecutive patients with pulmonary embolism the question is whether screening for this important disease is indicated, in particular in view of the recent advances in the treatment of this disease. Thirdly, the introduction of low molecular weight heparins without their need for laboratory monitoring has made out
of hospital treatment for venous thromboembolism feasible7. Although it is widely
accepted that patients with primary deep venous thrombosis receive out of hospital treatment in the majority of cases this is largely unknown for patients with primary pulmonary embolism.
Taken together, ‘Variations on a Theme’ can be used as a metaphor for the different aspects of venous thromboembolism that are discussed below, to further improve our understanding of the diagnosis, prognosis and treatment of this disease entity.
O
UTLINE OF THE THESIS
This thesis consists of two parts. The first focuses on the diagnosis of venous thromboembolism and in the second part prognostic and therapeutic aspects are addressed.
In Chapter 2 an overview of pulmonary embolism is presented, consisting of the various diagnostic strategies that have been evaluated, as well as the etiology, best prevention and treatment and finally prognosis of this disease. The Wells clinical decision rule, probably one of the best rules for assessing the clinical probability was further validated in Chapter 3, together with the derivation of a simplified variation of
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this rule. Chapter 4 focuses on the validation of this simplified clinical decision rule in another large cohort of patients with suspected pulmonary embolism. To what degree decision rules and D‐dimer assays are really integrated in the daily clinical routine and whether physicians are influenced by the information of an abnormal D‐dimer result when scoring the decision rule is evaluated by means of a questionnaire in Chapter 5. In Chapter 6 we assessed how often false negative D‐dimers occur in all‐ comers with pulmonary embolism, and in those with a likely clinical probability for the disease. Chapter 7 focuses on the clinical usefulness of the measurement of the prothrombin fragment 1+2 in patients presenting with clinically suspected pulmonary embolism, and whether this test had additional diagnostic utility to the widely applied D‐dimer assay. The findings of a large partly randomized clinical follow‐up study in patients with suspected deep venous thrombosis are presented in Chapter 8. After exclusion with the help of an unlikely clinical probability and a normal D‐dimer, patients were randomized to undergo either the clinical two point compression ultrasound in the groin and popliteal fossa, or a single full assessment, from the groin down to the distal veins in the calf.
The second part of this thesis evaluates aspects of the prognosis and treatment of venous thromboembolism. Chapter 9 is a review on the prognostic value of right ventricular dysfunction diagnosed with echocardiography and spiral CT. In particular, it focuses on the diagnostic utility of these methods and calculates the possible advantages and disadvantages with more aggressive treatment. Whether screening for chronic thromboembolic pulmonary hypertension in consecutive patients with previous pulmonary embolism is useful is evaluated in Chapter 10. In the last chapter, Chapter 11, the treatment strategies employed by Dutch internists and pulmonologists in daily clinical practice investigated by chart review of consecutive patients in fourteen hospitals in the Netherlands are described.
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R
EFERENCE LIST
1. Virchow RLK. Cellular Pathology. London: John Churchill; 1978:204-7.
2. Sasahara AA, Stein M, Simon M, Littmann D. Pulmonary angiography in the diagnosis of thromboembolic disease. N Engl J Med. 1964;270:1075-1081.
3. Haeger K. Problems of acute deep venous thrombosis. I. The interpretation of signs and symptoms. Angiology. 1969;20:219-223.
4. Wagner HN, Jr., Sabiston DC, Jr., McAfee JG, Tow D, Stern HS. Diagnosis of massive pulmonary embolism in man by radioisotope scanning. N Engl J Med. 1964;271:377-384. 5. Williams JR, Wilcox C, Andrews GJ, Burns RR. Angiography in pulmonary embolism.
JAMA. 1963;184:473-476.
6. Lensing AW, Prandoni P, Brandjes D et al. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med. 1989;320:342-345.
7. Othieno R, Abu AM, Okpo E. Home versus in-patient treatment for deep vein thrombosis. Cochrane Database Syst Rev. 2007;CD003076.
P
ART
I
Pulmonary embolism; a review
NADINE S. GIBSON AND HARRY R. BÜLLER
E.E. VAN DER WALL, F. VAN DER WERF AND F. ZIJLSTRA. CARDIOLOGIE. 2ND ED. HOUTEN; BOHN STAFLEU VAN LOGHUM: 435‐442
18
I
NTRODUCTION
The mechanism behind venous thrombus formation has already been formulated in the nineteenth century in the Virchows’ triad, which describes three major elements playing a fundamental role in developing thrombosis: venous stasis, a hypercoagulable state of blood and injury of the vessel wall1.
However, it is not well‐known that Rudolf Virchow, a German pathologist, was also the creator of the theory that pulmonary embolism and deep venous thrombosis are manifestations of a single disease entity, venous thromboembolism. Embolism is derived from the Greek verb emballein, which means toss. A bloodclot is ‘tossed’ from a deep vein and runs via the heart through the pulmonary artery, to end up in one or more of the smaller vessels of the pulmonary artery tree. In 70% of the patients with pulmonary embolism, a deep venous thrombosis is found in the leg or pelvic veins, whereas 50% of patients with deep venous thrombosis have (asymptomatic) pulmonary embolism.
Figure 1. Rudolf Ludwig Karl Virchow (1821, Schivelbein - 1902, Berlin) was a German doctor, anthropologist, pathologist, biologist and politician.
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B
ACKGROUND
Epidemiology
Pulmonary embolism is a common disease, with a yearly incidence of 1‐2 per 10002.
The incidence correlates strongly with age, and is 0.05 per 1000 in adolescents, whereas an incidence of 8 per 1000 is observed in the age category older than 80. The number of patients with a clinical suspicion of pulmonary embolism will be five times higher, since only 20% of these patients will have the disease.
Natural course
In 1960 a randomized trial was performed, which would not be thinkable nowadays. In this trial patients with pulmonary embolism were randomised into heparin treatment or no treatment to evaluate whether the bleeding risk would
counterbalance the possible positive effect of heparin treatment3. Of the 19 patients
that received no treatment, 5 developed a fatal pulmonary embolism and 5 developed a non fatal pulmonary embolism during the first month of observation, versus no events in the patients that were treated with heparin.
With the current anticoagulant therapy the mortality due to pulmonary embolism has
decreased from 25% to 2‐3%4. The actual figures may possibly be higher than
generally accepted, since patients that die directly after the acute onset of symptoms are usually not included in clinical studies.
The total mortality after one year is 20%, despite treatment. This is mainly due to comorbid diseases, like malignancy, cardiac disease or other pulmonary disorders. It is difficult to identify patients with a bad prognosis, but both cardiogenic shock at presentation and right ventricular dysfunction on echocardiography have a distinct correlation with mortality.
The development of right ventricular dysfunction is the result of a chain reaction of hemodynamic components. Obstruction of a thrombus in the pulmonary artery tree causes an elevated after load in the right ventricle which can lead to right ventricular dilatation. The dilatation will counteract the movement of the right ventricle which may result in hypokinesia. Furthermore the ventricular septum will bulge into the left ventricle, which interferes with the filling of the left ventricle. Finally, this will cause hypoxemia and vasoconstriction with an increase of the pulmonary vascular resistance.
20
and not because of embolic obstruction of the pulmonary arteries.
After three months of treatment, half of the patients will have a normal perfusion scan. Restoration of the perfusion will be mainly due to natural fibrinolysis and recanalisation of the obstructed blood vessels.
Clinical presentation
The classic patient with pulmonary embolism will present with acute dyspnoea, chest pain while taking a deep breath, coughing and hemoptysis. However, patients with pulmonary embolism usually have a wide variety of complaints, with non‐specific symptoms that match many diseases.
The occurrence of some common signs and symptoms of pulmonary embolism is as follows: dyspnoea 73%, pleuritic pain 44%, cough 34%, hemoptysis 13%, tachypnoea
54% and tachycardia 24%5.
The combination of complaints is mainly due to the extent of thrombus obstruction in the pulmonary artery tree. Large thrombi at the bifurcation of the main pulmonary artery or the lobar branches may cause hemodynamic instability or even circulatory collapse. Smaller thrombi that are localized more distal are more likely to produce pleuritic chest pain or no complaints at all. Altogether, symptoms and signs of pulmonary embolism are highly variable, nonspecific, and common among patients with and without pulmonary embolism.
Because of the above mentioned pattern of complaints, the physical examination will be of little help in the majority of the patients. Crepitation or crackles can be heard with auscultation, caused by pleurital friction rub. Moreover, a loud pulmonary component of the second heart sound may indicate pulmonary hypertensions and an elevated central venous pressure is a sign of right ventricular overload. If the physical examination shows a red, swollen, tender leg, or if other signs of deep venous thrombosis are present, the diagnosis of venous thromboembolism will be very likely.
Risk factors
The causes of pulmonary embolism are diverse. Both hereditary and acquired factors can contribute to an elevated risk for pulmonary embolism (Table 1).
Patients with cancer have a hypercoagulable state, and pulmonary embolism can signal the first appearance of a malignancy. However, a routine aggressive search for malignancy in all patients does not appear to be warranted.
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Table 1. Risk factors for pulmonary embolism.
Oral contraceptives are the most important cause of pulmonary embolism in young
women, due to their widespread use6. Within the first months of use the risk of
pulmonary embolism is especially increased, but the risk does persist after this period. Second generation contraceptives have a more favorable thrombosis risk profile than third generation products, but all are associated with an increased risk for pulmonary embolism.
The expression trombophilia can be used for inherited and acquired changes in the coagulation cascade that increase the risk of pulmonary embolism (Figure 2). Trombophilia means a tendency for developing venous thromboembolism, which can be caused by either physiological coagulation inhibitors, prothrombotic mutations and acquired prothrombotic changes.
Deficiencies of the naturally occurring anticoagulants protein C and protein S decrease the inhibition of factors Va en VIIIa, which causes a hypercoagulable state. Antithrombin is a major inhibitor of thrombin and factor Xa, and deficiency leads to less down regulation of thrombin and factor Xa generation.
The Factor V Leiden and prothrombin mutation are prothrombotic mutations. The first is an autosomal dominant condition that prevents efficient inactivation of factor V. When factor V remains active, it facilitates overproduction of thrombin leading to excess fibrin generation and excess clot formation. In patients with a prothrombin mutation an elevated plasma level of the clotting protein prothrombin has been described. Malignancy Surgery Immobilisation Trauma Oral anticonceptives
Hormon ereplacement therapy History of VTE
Pregnancy
Post partum period Increasing age
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Figure 2. A survey of the coagulation cascade in the human body.
XIa
Xa (+Va) IIa (trombine) Fibrine Tissue factor + VIIa
Antitrombine
IXa (+VIIIa) Geactiveerd proteïne-C(+ proteïne S)
If a defect appears in the vascular wall, subendothelial tissue factor will be exposed to blood which is the primary physiological event in initiating clotting. Tissue factor than complexes with factor VII, and activates factor X into factor Xa. Factor Xa converts prothrombin into thrombin with the help of factor Va, and thrombin converts fibrinogen into fibrin (thick arrows).
A first positive feed back loop consists of indirect factor X activation, via factor IXa with the help of factor VIIIa (triangle of arrows). The second feed back loop consist of factor XI activation by thrombin, which leads tot further factor IX and factor X activation (circle of arrows)
Negative feed back is established by activated protein C, in association with protein S that inactivates factors VIIIa and Va. Furthermore, antithrombin inactivates factors IIa and Xa (dotted arrows).
The risk of developing a first event of pulmonary embolism in patients with an antithrombin deficiency, or a protein C or S deficiency, is 8 to 10 fold increased, and 3
to 5 fold in patients with a factor V Leiden or prothrombin mutation7. In those
patients with a combination of two or more trombophilia defects (double hit), the risk for developing pulmonary embolism increases even more. The risk for developing a recurrent pulmonary embolism after a first pulmonary embolism is not or only weakly related to the presence of thrombophilia.
An acquired form of thrombophilia is the anti phospholipid syndrome. This syndrome occurs when autoimmune antibodies are produced against phospholipids and cardiolipin. These antibodies are often seen in patients with auto‐immune
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Table 2. Differential diagnosis of pulmonary embolism.
Pulmonary causes Cardiac causes Thoracic causes Others
Pneumothorax Angina pectoris Musculoskeletal pain Stomach complaints Pneumonia Myocardial infarction Rib fracture Hyperventilation Atelectasis Pericarditis Costochondritis
Astma Aneurysma dissecans
COPD Heart failure
Pulmonary oedema Pericard tamponade Malignancy Pulmonary hypertension
disorders like systemic lupus erythematodes (SLE), but may also be observed in patients without these disorders.
A definite diagnosis of the antiphospholipid syndrome can be made when the antibodies are present on a minimum of two occasions in combination with (recurrent) arterial or venous thrombosis or recurrent miscarriages. To date the exact mechanism is unknown.
D
IAGNOSIS
A correct diagnosis or exclusion of pulmonary embolism is of utmost importance, because pulmonary embolism is associated with a substantial morbidity and mortality if untreated, whereas anticoagulant treatment is associated with an increased bleeding risk (Table 2).
Electrocardiography, chest radiograph and arterial blood gas
Electrocardiography (ECG), chest radiograph and arterial blood gas are often performed in patients with acute chest pain that are suspected of pulmonary embolism. However, the value of these tests in diagnosing pulmonary embolism are restricted.
ECG is especially of importance for the diagnosis or exclusion of an alternative
diagnosis, for example a myocardial infarction or pericarditits8. Abnormalities on
ECG that can be seen in patients with pulmonary embolism, are nonspecific signs of right ventricular dysfunction and tachycardia. The abnormalities most commonly observed are nonspecific ST‐segment and T‐wave changes, which are also seen in patients with right ventricular strain due to other causes.
24
Radiographic abnormalities resembling cardiomegaly, atelectasis or parenchymal abnormalities are similarly common in patients with pulmonary embolism as in those
without the disease9. However, chest radiograph is of value for diagnosing an
alternative diagnosis, such as a pneumothorax or pneumonia.
Arterial blood gas analysis usually shows hypoxemia, hypocapnia, and respiratory alkalosis in patients with pulmonary embolism. However, in patients with massive pulmonary embolism hypotension and respiratory collapse can cause hypercapnia and a respiratory and metabolic acidosis.
An arterial blood gas analysis can be of use in deciding whether or not supplemental oxygen should be administered.
Taken together, ECG, chest X‐ray and arterial blood gas are of use for drawing up a differential diagnosis, but additional testing is necessary to diagnose or exclude the disease.
Ventilation-perfusion scan and pulmonary angiography
A ventilation‐perfusion scan evaluates the circulation of air and blood in the lungs of a patient. The perfusion scan depicts how well the blood circulates within the lungs, whereas the ventilation scan estimates the ability of air to reach all parts of the lungs. If after intravenous injection of radioactive labelled albumin a perfusion defect is shown, the ventilation scan has to be performed, upon which the patients inhales a gaseous radionuclide xenon or technetium. With a normal perfusion scan, a pulmonary embolism can be safely excluded. However, if a mismatch is shown on the
lobar or segmental levels of the lungs, a pulmonary embolism is diagnosed10.
A disadvantage of this test is that besides the limited availability, more than half of the patients will have a non‐diagnostic test result. The test is non‐diagnostic if only subsegmental defects are shown, or if perfusion and ventilation defects are matched, which can be observed by consolidation caused by an infection. The prevalence of pulmonary embolism in the patients with a non‐diagnostic scan is still 25%, therefore, additional testing is necessary to exclude or diagnose the disease in this subgroup of patients. To date, pulmonary angiography is assumed to be the gold standard for diagnosing pulmonary embolism. Due to its invasive character and the expertise that is required for performing this test, it is usually only performed in patients in whom the ventilation‐perfusion scan is non‐diagnostic, and in whom ultrasound of the venous
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system of the legs does not show a deep venous thrombosis. Angiography is performed by injection of intravenous ionic contrast material in the pulmonary artery via a catheter, to view intraluminal filling defects, caused by thrombi in the
pulmonary artery tree11.
Among diagnostic algorithms that include previously mentioned imaging tests, it usually takes over 72 hour to diagnose or exclude the disease. In the last decade a great deal of effort has been invested, to improve the diagnostic procedure. With the combination of a clinical probability test, a D‐dimer test and a spiral CT‐scan, a safe and efficient diagnostic strategy has been developed that can be completed within 24
hours12.
Clinical probability test, D-dimer and spiral CT
Nowadays, the diagnostic strategy for patients that present with signs and symptoms of pulmonary embolism consists of an estimation of the probability for having the disease, based on the history and the physical examination. In case of a low or an unlikely clinical probability, an additional blood test is performed, the D‐dimer assay. The estimation of the probability is also called, the pre‐test probability, and can be measured by a clinical decision rule. A widely excepted decision rule is the ‘Wells rule’, which assigns points to seven elements, to generate a score that resembles the
pre‐test probability (Figure 3)13.
The blood test that is used in patients with a low pre‐test‐probability to exclude the disease is a D‐dimer assay. It measures fibrin degradation products that are produced by fibronolysis. These degradation products can be observed in increased concentrations in patients with thrombosis, but as well in numerous other situations, for example in patients with malignancy or an infection, after an operation, during pregnancy, or in the elderly. Therefore this assay is especially sufficient to exclude pulmonary embolism, but not to diagnose the disease, since an abnormal D‐dimer is a non‐specific test result14. In about 30% of the patients the combination of an unlikely clinical probability and a normal D‐dimer test result is observed. In these patients pulmonary embolism can be safely excluded, and the use of extensive imaging tests can be restrained. In patients
26
Signs and symptoms of pulmonary embolism (PE) Clinical decision rule (CDR)
CDR ≤ 4 CDR > 4
D-dimer (DD) DD ≤ 0.5 mg/l DD > 0.5 mg/l
No PE Spiral CT Spiral CT
Figure 3. The diagnostic strategy for patients with clinically suspected pulmonary embolism.
with a likely clinical probability or with an abnormal D‐dimer, additional imaging testing has to be performed. The strength of this diagnostic strategy lies in the combination of high efficiency together with ease of use in daily clinical practice. In those patients that require additional testing, usually a spiral CT‐scan is performed. Non‐ionic contrast material is injected, and pulmonary embolism is diagnosed if the contrast material outlines an intraluminal filling defect or if a vessel is totally occluded by low‐attenuation material on at least two adjacent slices. An advantage of the spiral CT‐scan is the possibility of imaging an alternative diagnosis.
The spiral CT‐scan had gained widespread popularity in the last decades for diagnosing pulmonary embolism, at the expense of the pulmonary angiography. As a consequence the expertise to perform an angiography with sufficient experience will decline.
The seven items of the Wells clinical decision rule Score Clinical signs & symptoms deep venous thrombosis 3
Tachycardia (>100/min) 1.5
Immobilization or surgery in the previous four weeks 1.5 Previous deep venous thrombosis/pulmonary embolism 1.5
Hemoptysis 1 Malignancy 1 An alternative diagnosis is less likely than pulmonary embolism 3
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T
REATMENT
The patient’s clinical status has to be taken into account when choosing the appropriate treatment. Those patients with a normal blood pressure should initially be treated with low molecular weight heparin (LMWH), a pentasaccharide, or unfractionated heparin, followed by vitamin K antagonists. In patients with massive pulmonary embolism, that present with cardiogenic shock thrombolytic therapy is
indicated15.
Anticoagulant therapy
The initial therapy with (low molecular weight) heparin, or a pentasaccharide should be administered for at least 5 days, and preferably until the vitamin K antagonist has reached a therapeutic level. With unfractionated heparin treatment, frequent monitoring of the activated partial thromboplastin time (APTT) is necessary to accomplish a therapeutical range, which is 1.5 to 2 times the control value of the APTT.
Heparin is an indirect thrombin inhibitor which complexes with antithrombin and converts it into a 1000 fold more rapid inactivor of several coagulation factors, especially factor Xa and IIa (thrombin).
Nowadays low molecular weight heparin (LMWH) is often preferred above unfractionated heparin. Due to the stable farmacokinetic profile, monitoring by means of the anti‐factor Xa, is only necessary in those patients with an altered metabolism (severe renal insufficiency, morbid obesity or pregnancy). Furthermore the subcutaneous delivery makes treatment at home possible, although outpatient therapy for pulmonary embolism is not well established. The dosage of LWMH is
based on the patient’s weight16.
Vitamin K antagonists, coumarin derivates, inhibit the production of vitamin K‐ dependent coagulation factors prothrombin, factor VII, IX and X. The therapeutic range is measured by the International Normalized Ratio (INR), based on the partial‐ thromboplastin time. In the Netherlands the Thrombotic Services are responsible for maintaining the INR in the therapeutic range, and adjusting the dosage, if necessary. Vitamin K antagonists are contraindicated in patients with liver or renal insufficiency, hemorrhagic diathesis, severe thrombopenia, severe hypertension, recent bleeding events and hypersensitivity for coumarin derivates. During the first term of pregnancy there is a risk of developing teratogenic abnormalities with vitamin K
28
antagonist treatment, and after 36 weeks bleeding complications during and after the delivery may occur. Therefore LMWH is a safe alternative in pregnant patients. Vitamin K antagonists are not contraindicated during lactation, since they have no anticoagulant effect on the infant. Moreover, in the Netherlands all neonates receive
vitamin K suppletion17.
A complication of unfractionated heparin and in small amounts of LMWH, is the development of a heparin induced thrombocytopenia (HIT). At least five days after initiating heparin therapy, antibodies appear, that cause platelet aggregation, with thrombocytopenia as a consequence. These aggregates increase the risk of venous and arterial thrombosis. In patients suspected of HIT, the heparin treatment should be stopped and HIT antibodies have to be measured. Treatment with vitamin K antagonists may cause worsening of thrombotic complications, including venous limb gangrene and skin necrosis, and should therefore not be initiated. Patients should be treated with alternative anticoagulant therapy, for example danaparoid, a
pentasaccharide or the direct thrombin inhibitors bivalirudin and lepirudin18.
Thrombolytic therapy
Vitamin K antagonists and heparin are non thrombolytic agents. They prevent further thrombus deposition and establish thrombus stabilization and endogenous lysis. In patients with massive pulmonary embolism and cardiogenic shock, a rapid lysis of the clot by thrombolytic therapy is necessary. Thrombolytic agents activate plasminogen to form plasmin, resulting in the accelerated lysis of thrombi. Examples are streptokinase, alteplase or urokinase, which increase the endogenous fibrinolysis considerably. The restraint for using thrombolytic therapy is caused by a high bleeding risk, with a risk of severe bleeding of 6 to 8%. In case of severe bleeding, the thrombolytic therapy should be discontinued immediately, and fresh frozen plasma, fibrinogen, and cryoprecipitate in high dosage should be administered.
However, thrombolytic therapy is justified in those patients with cardiogenic shock, since the risk of dying of the disease counterbalances the bleeding risk. There is insufficient evidence that hemodynamic stable patients with signs of right ventricular dysfunction should be treated with thrombolysis.
Duration of treatment
The duration of treatment with vitamin K antagonists depends on the circumstances in which the embolism was formed, the presence of risk factors or if it is a first or recurrent episode. Three to six months of treatment is adequate for patients with a
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first provoked episode of pulmonary embolism, with the presence of an apparent temporary risk factor.
In those patients with pulmonary embolism without risk factors, an idiopathic pulmonary embolism, treatment of 6 to 12 months is advised. In high risk patients, with recurrent spontaneous venous thromboembolism, long term treatment is advised, provided the increased risk of bleeding is counterbalanced by the positive effect of treatment. Therefore the patient’s opinion on the bleeding‐ and recurrence risk should be taken into account in the decision of treatment duration. After one year of treatment 2 to 8% of patients have major bleeding events, which will lead to a fatal bleeding in 0.25% of the patients.
In patients with malignancy, treatment should be given for an indefinite period if metastatic disease is present or the patient is receiving chemotherapy, or until the cancer is resolved. It is advisable to re‐evaluate frequently the risk‐benefit ratio of ongoing anticoagulant therapy in individual patients, taking into consideration the overall clinical status of the patient and the quality of life.
New anticoagulants
Although pulmonary embolism can be treated efficiently and safe with the current therapy, some aspects of the treatment are still open for improvement, especially those aspects which make the administration of the therapy more convenient for the patient. With the improved understanding of the coagulation system down to the molecular level, new anticoagulants have been developed in the last decade. The aim was to develop a novel anticoagulant which is suitable both for the initial as well as for the chronic treatment phase, and which requires no laboratory monitoring. The patient can then be treated with just one agent, and does not need INR monitoring. These new antithrombotic agents can be divided into the direct thrombin inhibitors, and the factor Xa inhibitors. The most important similarity in these new agents is the
absence of the need to monitor the effect of the agent with laboratory tests19.
Thrombin inhibitors bind direct to the active part of thrombin. Ximelagatran was the most promising drug of the direct thrombin inhibitors, with an effective reduction of the risk of a new venous thromboembolism episode. Furthermore, the bleeding complications were comparable to the treatment with vitamin K antagonists. Unfortunately there was a high incidence of hepatotoxicity, which resulted in withdrawal of this agent from the market.
30
The orally active factor Xa inhibitors inhibit factor Xa directly by binding to its active site without requiring the action of antithrombin. Due to the ease of use of these agents, they may be a good substitute drug for the vitamin K antagonists.
Pentasaccharides are indirect factor Xa inhibitors. They consist of at least five saccharide units, and have a sequence derived from the minimal antithrombin binding region of heparin. When the pentasaccharide binds on this region a conformational change in antithrombin increases the ability of antithrombin to inactivate factor Xa. The pentasaccharide fondaparinux appeared to be as effective
and safe in the initial treatment of pulmonary embolism as heparin20. With a half life
of 17 hours, fondaparinux is administered once daily. Idraparinux is a longer acting analogue of fondaparinux, and can be administered once a week because of the half life of 80 to 130 hours. A disadvantage of this longer half life is the difficulty of counteracting the anticoagulant effect of the drug when a bleeding event occurs, due to the absence of a reversing agent.
The future will tell which of these agents offers the most favourable balance between effectiveness, safety, convenience and cost‐effectiveness.
Inferior vena caval filter
Inferior vena caval filters allow blood to pass through the caval vein while preventing large emboli from traveling from the pelvis or lower extremities to the lung. Patients at high risk for recurrence pulmonary embolism in
whom anticoagulant treatment is
contraindicated, due to an increased bleeding risk, and those with recurrent pulmonary embolism, despite adequate anticoagulant therapy are eligible for a caval filter insertion. Disadvantages of the caval filter are the increased risk for deep venous thrombosis, and the possibility of developing of a vena cava
31 C HAPTER 2
P
ROGNOSIS
The natural course of pulmonary embolism differs widely. Therefore, it is of utmost importance to identify those patients in the acute phase that are at risk for severe morbidity or even mortality. These patients may benefit from more aggressive therapy, such as thrombolysis or surgical removal of the thrombus (thrombectomie). Persistent hypotension or a cardiogenic shock are widely accepted indications for thrombolytic therapy.
Right ventricular dysfunction and biomarkers
Studies in normotensive and hypotensive patients have shown that right ventricular dysfunction, with a prevalence of 30 to 40%, is associated with a two‐fold increased risk of pulmonary embolism related mortality. However, the impact of right ventricular dysfunction on the mortality in only normotensive patients appears to be modest, with a pulmonary embolism related mortality of 4 to 5%.
The biomarkers BNP, troponin I and troponin T appear to have prognostic value in patients with pulmonary embolism. The elevated pressure in the pulmonary artery and the right ventricle can cause micro infarctions in the right ventricular wall and myocardial cell damage. Troponin may leak out of the cells within 12 hours after the onset of pulmonary embolism and the rise of BNP appears already after a few hours
due to ventricular myocyte stretch22.
There is no sufficient evidence that more aggressive therapy will improve the prognosis of normotensive patients with right ventricular dysfunction or elevated biomarkers. Future studies have to show, whether a strategy can be designed with, for example, the combination of right ventricular dysfunction and several biomarkers for a risk stratification for poor prognosis.
Recurrent thrombosis
The highest risk for recurrent venous thromboembolism occurs directly after the acute onset of pulmonary embolism, and is mainly influenced by the circumstances that led to pulmonary embolism. The recurrent risk after an idiopathic pulmonary embolism is 12 to 18% within two years of the diagnosis, whereas this risk after pulmonary embolism due to surgery or a temporary risk factor is very low.32
than for recurrent pulmonary embolism, and is therefore limited in predicting the recurrence risk.
Difficulties in diagnosing a recurrent pulmonary embolism are frequently observed, since 50% of the patients will have residual thrombosis on imaging tests. This makes it
difficult to distinguish between old and new abnormalities23.
Chronic thromboembolic pulmonary hypertension
Chronic thromboembolic pulmonary hypertension is an important complication of pulmonary embolism, which causes progressive complaints of exertional dypsnoea. Although the exact hemodynamic evolution of the disease has not been fully established, the hypertension appears to be a result of insufficient thrombus resolution, which may cause changes in the small resistance vessels of the peripheral pulmonary vascular bed which will lead to increased pulmonary artery pressure. Pulmonary hypertension is diagnosed if pulmonary artery pressure exceeds 25mmHg at rest, or 30mmHg on exertion, observed with right heart catheterization and pulmonary angiography.
The incidence of chronic thromboembolic pulmonary hypertension appears to be below 1%. The disorder however is thought to be under diagnosed. The prognosis is poor, with a two years survival of less than 20% if not treated in those patients with a mean pulmonary artery pressure exceeding 50 mmHg.
Chronic thromboembolic pulmonary hypertension can be treated by
thromboendarterectomy, but only in the patients with emboli in the proximal pulmonary arteries. This surgical intervention has a high mortality rate of 10% in specialized clinical centers with expertise. On the other hand, the prognosis and
quality of life improve significantly if the surgery is successful24.
C
ONCLUSION
In the last decade the diagnosis of pulmonary embolism has been optimized. Diagnostic strategies have been developed that can safely diagnose or rule out pulmonary embolism within 24 hours, with a simple combination of a clinical decision rule, a D‐dimer test and a spiral CT‐scan. Furthermore it is likely that in the coming years the treatment of pulmonary embolism will consist of an oral agent, without the need for monitoring and differentiation between the initial phase and long term treatment.
33
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2
Concerning the prognosis of pulmonary embolism some issues remain unclear. Is it possible to develop a risk stratification that estimates the risk for severe morbidity and mortality? And how do we treat normotensive patients with right ventricular dysfunction?
Hopefully these questions will be answered in the future along with further optimization of treatment and implementation of improved diagnostic strategies in daily clinical practice.
34
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EFERENCE LIST
1. Virchow RLK. Cellular Pathology. 204-207. 1859. London, John Churchill. Ref Type: Generic
2. White RH. The epidemiology of venous thromboembolism. Circulation. 2003;107:I4-I8. 3. Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. A
controlled trial. Lancet. 1960;1:1309-1312.
4. Carson JL, Kelley MA, Duff A et al. The clinical course of pulmonary embolism. N Engl J
Med. 1992;326:1240-1245.
5. Stein PD, Beemath A, Matta F et al. Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am J Med. 2007;120:871-879.
6. Kujovich JL. Hormones and pregnancy: thromboembolic risks for women. Br J Haematol. 2004;126:443-454.
7. Weitz JI, Middeldorp S, Geerts W, Heit JA. Thrombophilia and new anticoagulant drugs.
Hematology Am Soc Hematol Educ Program. 2004;424-438.
8. Rodger M, Makropoulos D, Turek M et al. Diagnostic value of the electrocardiogram in suspected pulmonary embolism. Am J Cardiol. 2000;86:807-9, A10.
9. Stein PD, Terrin ML, Hales CA et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest. 1991;100:598-603.
10. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators. JAMA. 1990;263:2753-2759.
11. Stein PD, Henry JW, Gottschalk A. Reassessment of pulmonary angiography for the diagnosis of pulmonary embolism: relation of interpreter agreement to the order of the involved pulmonary arterial branch. Radiology. 1999;210:689-691.
12. van Belle A, Buller HR, Huisman MV et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006;295:172-179.
13. Wells PS, Anderson DR, Rodger M et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost. 2000;83:416-420.
14. Di Nisio M, Squizzato A, Rutjes AW, Buller HR, Zwinderman AH, Bossuyt PM. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review. J
Thromb Haemost. 2007;5:296-304.
15. Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:401S-428S.
16. Hull RD, Raskob GE, Hirsh J et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N
Engl J Med. 1986;315:1109-1114.
17. Brandjes DP, Heijboer H, Buller HR, de RM, Jagt H, ten Cate JW. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1992;327:1485-1489.
18. Warkentin TE, Levine MN, Hirsh J et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332:1330-1335.
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20. Buller HR, Davidson BL, Decousus H et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003;349:1695-1702.
21. Decousus H, Leizorovicz A, Parent F et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prevention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group. N Engl J
Med. 1998;338:409-415.
22. Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation. 2007;116:427-433.
23. Kearon C. Natural history of venous thromboembolism. Circulation. 2003;107:I22-I30. 24. Becattini C, Agnelli G, Pesavento R et al. Incidence of chronic thromboembolic pulmonary
Further validation and simplification
of the Wells clinical decision rule
in pulmonary embolism
NADINE S. GIBSON, MAAIKE SÖHNE, MARIEKE J.H.A. KRUIP, LIDWINE W. TICK, VICTOR E.A. GERDES, PATRICK M.M. BOSSUYT, PHILIP S. WELLS, HARRY R. BÜLLER
38
A
BSTRACT
Background
The Wells rule is a widely applied clinical decision rule, in the diagnostic work‐up of patients with suspected pulmonary embolism (PE). The objective of this study was to replicate, validate and possibly simplify this rule.Methods
We used data collected in 3306 consecutive patients with clinically suspected PE to recalculate the odds ratios for the variables in the rule, to calculate the proportion of patients with PE in the probability categories, the area under the ROC curve and the incidence of venous thromboembolism during follow‐up. We compared these measures with those for a modified and a simplified version of the decision rule.Results
In the replication, the odds ratios in the logistic regression model were found to be lower for each of the seven individual variables (p=0.02) but the proportion of patients with PE in the probability categories in our study group were comparable to those in the original derivation and validation groups. The area under the ROC of the original, modified and simplified decision rule was similar: 0.74 (p=0.99; p=0.07). The venous thromboembolism incidence at 3 months in the group of patients with a Wells score 4 and a normal D‐dimer was 0.5%, versus 0.3% with a modified rule and 0.5% with a simplified rule. The proportion of patients safely excluded for PE was 32%, versus 31% and 30%, respectively.
Conclusions
This study further validates the diagnostic utility of the Wells rule and indicates that the scoring system can be simplified to one point for each variable.
39 C HAPTER 3
I
NTRODUCTION
The diagnostic work‐up of patients with clinically suspected pulmonary embolism is challenging because of the relatively low prevalence of the disease in this population. In the past, several attempts have been made to include clinical information in the diagnostic process in order to rule out pulmonary embolism and withhold expensive and time‐consuming imaging techniques without compromising patient’s safety.
However, the majority of these attempts have not been clinically successful1‐5. The
main concern with these assessments of clinical probability involved the use of many variables including subjective elements as well as the often complicated scoring methods. Furthermore clinical judgment by the doctor, also called ‘gestalt’, is the simplest method of selecting low risk patients. Yet when this method is used, it appears that only a low percentage of patients can be withheld from additional
imaging testing6‐8.
The quantitative clinical decision rule, published by Wells and colleagues in 2000, incorporated seven items from the medical history and physical examination easily
obtained in the initial diagnostic work‐up9. Because of its relative comprehensiveness
and ease of use in a clinical setting this rule is now widely accepted in the exclusion of pulmonary embolism. It has been incorporated in several guidelines, despite certain
limitations10‐15.
The decision rule was obtained by selecting variables that were significantly associated with the presence or absence of pulmonary embolism from an extended 40 item list. These variables were initially tested in a univariate logistic regression analysis. Those variables that were also significant after a stepwise regression analysis were selected for the final rule. According to the value of the odds ratios in the regression analysis 1, 1.5 or 3 points are assigned for each feature (Table 1). The rule can be used to assign patients to one of three probability categories (low, moderate and high) or to classify them as ‘pulmonary embolism unlikely’ or ‘likely’.
There is evidence that odds ratios, calculated this way for the decision rule, show a bias upward and that replication studies produce lower values for the same variables. This mechanism has been suggested as one of the explanations for the phenomenon that many decision rules tend to loose their discriminative power in subsequent
40
Table 1. Scoring of the various variables in the original, the modified and simplified Wells rule.
If the true odds ratios in the clinical decision rule are lower than the ones reported by Wells and colleagues, there may be less need to use three different sets of points: 1, 1.5 or 3 points. It is possible that unit weights produce very similar, if not identical, results, as the original rule. If so, a much simplified rule could be used in practice, one that is easier to memorize and leads to fewer summing mistakes in the acute care setting.
The three purposes of this study were a replication of the weights in the decision rule developed by Wells and colleagues, a validation of the rule, and, if possible,
simplification. For these aims we used the data of a large management study18.
M
ETHODS
Data were obtained in a large prospective diagnostic management study that included patients with clinically suspected pulmonary embolism between November 2002 and August 2004 in 12 hospitals in the Netherlands. That study, described in detail elsewhere, demonstrated that a diagnostic management strategy with a clinical decision rule, a D‐dimer test and spiral CT, is safe in the work‐up of patients with
clinically suspected pulmonary embolism18.
Patients and management
Consecutive in‐ and outpatients with clinically suspected acute pulmonary embolism
Original Modified Simplified
1. Clinical signs & symptoms DVT 3 2 1
2. Tachycardia (>100/min) 1.5 1 1
3. Immobilization or surgery in the previous four weeks 1.5 1 1
4. Previous PE or DVT 1.5 1 1
5. Hemoptysis 1 1 1
6. Malignancy 1 1 1
7. An alternative diagnosis is less likely than PE 3 2 1
Cut-off for PE unlikely ≤ 4 ≤ 2 ≤ 1
DVT: Deep Venous Thrombosis PE: Pulmonary Embolism
41
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HAPTER
3
were eligible for this study. Patients were excluded if they had received (low molecular weight) heparin for more than 24 hours, were younger than 18 years of age, were pregnant, had a known hypersensitivity for iodinated contrast fluid or renal failure, had a life expectancy of less than three months, if there was geographic
inability for follow‐up or if no informed consent was obtained. The institutional
review boards of all participating hospitals approved the study protocol.
Eligible patients were asked for written or oral informed consent. At presentation the
clinical decision rule of Wells and colleagues was used by the treating physician9. The
physician assigned three points for clinical signs and symptoms of deep venous thrombosis (DVT), three more points when pulmonary embolism was more likely than an alternative diagnosis, one and a half points each for a heart rate greater than 100, immobilization or surgery in the previous four weeks, and a previous episode of DVT or pulmonary embolism, and one point each for hemoptysis and malignancy. The total score was obtained by summing these points. It takes values in the range from 0 to 12.5.
With a score of 4 or lower, pulmonary embolism was considered unlikely and a D‐ dimer test was performed (Tinaquant, Roche Diagnostica, Mannheim, Germany or
Vidas D‐dimer, Biomerieux, Marcy L’Etoile, France)18. The D‐dimer test was defined
as normal if the concentration was 0.5 mg/l. The combination of a score over 4 and a normal D‐dimer result was considered to rule out pulmonary embolism and anticoagulant treatment was withheld.
In all other patients a spiral CT scan was performed. The CT scan was considered positive for pulmonary embolism if contrast material outlined an intraluminal filling defect or if a vessel was totally occluded by low‐attenuation material on at least two adjacent slices. The decision on the presence or absence of pulmonary embolism was made by a trained attending radiologist. Follow‐up was performed in all patients without pulmonary embolism at baseline by the study physician, through a hospital visit, or a telephone interview at three months, and the instruction to contact the study centre or the general practitioner in case of complaints suggestive of DVT or pulmonary embolism. In case of clinically suspected DVT or pulmonary embolism during the follow‐up period, compression
