Diagnostic strategy for excluding pulmonary embolism in primary care Lucassen, W.A.M.

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1 UvA-DARE (Digital Academic Repository) Diagnostic strategy for excluding pulmonary embolism in primary care Lucassen, W.A.M. Link to publication Citation for published version (APA): Lucassen, W. A. M. (2013). Diagnostic strategy for excluding pulmonary embolism in primary care General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 26 Nov 2017

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4 DIAGNOSTIC STRATEGY FOR EXCLUDING PULMONARY EMBOLISM IN PRIMARY CARE Wim Lucassen

5 Diagnostic strategy for excluding pulmonary embolism in primary care Thesis, University of Amsterdam ISBN: , W.A.M. Lucassen, Amsterdam Cover idea: W. Lucassen Cover design and lay-out: R.C.B. Kreuger Printed by: Ridderprint, Ridderkerk

6 DIAGNOSTIC STRATEGY FOR EXCLUDING PULMONARY EMBOLISM IN PRIMARY CARE 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 Agnietenkapel op donderdag 11 april 2013, te 14:00 uur door Wilhelmus Arnoldus Maria Lucassen geboren te Hilversum

7 Promotiecommissie Promotoren: Prof. dr. H.C.P.M. van Weert Prof. dr. H.R. Büller Overige leden: Prof. dr. P.E.J. Bindels Prof. dr. G.J. Dinant Prof. dr. D.A. Legemate Prof. dr. S. Middeldorp Prof. dr. A.H. Zwinderman Faculteit der Geneeskunde

8 Het tot de derde macht verheffen van amen en samen. Amen, amen, amen. Amen, amen, samen. Amen, amen, samen. Amen, amen, samen. Amen, samen, samen. Amen, samen, samen. Amen, samen, samen. Samen, samen, samen. Gerard Lucassen

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10 CONTENTS page Chapter 1 General Introduction 9 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Excluding pulmonary embolism in primary care using the Wells-rule in combination with a point of care D-dimer test: a scenario analysis. 27 BMC Family Practice 2010 Sep 13; 11:64. Clinical decision rules for excluding pulmonary embolism: a meta-analysis. 39 Annals of Internal medicine 2011; 155(7): Safe exclusion of pulmonary embolism using the Wells rule and qualitative D-dimer testing in primary care: prospective cohort study. 83 BMJ 2012; 345:e6564. Alternative diagnoses of pulmonary embolism in primary care. 103 Submitted. The additional value of the CRP-test in patients in whom the primary care physician excluded pulmonary embolism. 117 Accepted European Journal of General Practice. Concerns in using multi-detector computed tomography for diagnosing pulmonary embolism in daily practice. A cross-sectional analysis using expert opinion as reference standard. 135 Thrombosis Research 2013; Feb; 131(2): Chapter 8 Discussion. 149 Accepted (in Dutch) Huisarts en Wetenschap. Samenvatting 167 Summary 175 Nawoord 183 Curriculum Vitae 187 Portfolio 188

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12 CHAPTER 1 GENERAL INTRODUCTION AND OUTLINE OF THE THESIS 9

13 CHAPTER I 10

14 General introduction and outline of the thesis Pulmonary embolism (PE) is more common than is usually supposed and is often overlooked because not considered in differential diagnosis was written in The Lancet in Nowadays, more than 100 years after the publication in this journal, the statement is still true and PE remains a frequently missed or delayed diagnosis in particular because the diagnosis is not even considered. 2 In 2009 the omission of the diagnosis resulted in a warning at the Dutch medical disciplinar y council. An obese woman was progressively short of breath and complained of chestpain two weeks after a varicose vein operation. The general practitioner considered cardial, pleural effusion or panic as possible explanations, as he wrote down in his report. His most probable diagnosis hyper ventilation appeared wrong. The woman died of pulmonar y embolism 5 days after the first consultation. 3 In 2010 a missed diagnosis resulted again in a warning at the tribunal. A 43 year old, healthy prisoner complained of chestpain, decreased exercise tolerance and tachycardia. He had never experienced those complaints before. Repeatedly and with different physicians he was diagnosed with hyper ventilation. Three weeks after his first complaint he died of massive pulmonar y embolism. His persistent symptoms were based on (small) multiple pulmonary emboli. 4 In an analysis of disciplinary law verdicts concerning family physicians, Gaal and colleagues concluded that most incidents with serious health consequences were related to missing potentially severe diagnoses and they stressed the importance of an increase in quality of diagnosing potentially serious diseases in primary care. 5 Pulmonary embolism in primary care In patients consulting their primary care physician (PCP) with symptoms suggestive of pulmonar y embolism, such as sudden unexplained (or deterioration of existing) dyspnoea, pain on inspiration or unexplained cough symptoms, the PCP can not do anything but refer to secondar y care for further evaluation. In secondar y care only 10-20% of these referred patients are diagnosed with pulmonary embolism. A large proportion of the remaining patients have alternative diagnoses that the PCP herself/himself could have treated. Referral of all patients with suspected PE to secondary care is not only a burden for patients and unsatisfactory for PCPs but is also 11

15 CHAPTER I not a ver y cost-effective strategy. To increase the effectiveness and management of patients suspected of PE PCPs require accurate diagnostic tools that enables them to discriminate between patients who need a referral for further diagnostic work-up and patients in whom PE can be safely excluded and do not need to be referred. Incidence of pulmonary embolism in primary care The incidence of pulmonar y embolism correlates strongly with age. It is extremely uncommon in childhood (0.0 per 1000 inhabitants yearly) but increases to 1.0 per 1000 in elderly people (above 75 years) with hardly any difference between women and men. 6 In an average Dutch general practice (2350 patients) about 0.5 patients will be diagnosed with PE yearly. Because the suspicion of PE will arise about 8 times more often a Dutch general practitioner will see approximately 4 patients with suspected PE annually. PE is a potentially lethal disease if left untreated. Mortality rates up to 30% of untreated PE are based on historical studies, which were small and methodologically flawed. 7 Analysis of untreated or missed PE in ambulator y patients reveals a more realistic mortality rate of approximately 5%. 8 Pulmonary embolism in secondary care Clinical presentation The clinical presentation of pulmonar y embolism can var y greatly depending on the extent of obstruction of the vascular bed. In case of massive PE, patients might present with a circulator y collapse (hypotensive shock) but to the other extreme, a person with small peripheral emboli may have few or even not any symptoms at all. The classical presentation of PE is of one with acute shortness of breath, pleuritic chestpain and haemoptysis, but this patient is hardly ever seen. Knowledge of the clinical characteristics of patients with acute PE derives from secondar y care studies. History Dyspnoea is the most common symptom; it occurs in 3 out of four patients with PE. Dyspnoea is usually present at rest but one in six patients complains of dyspnoea with exertion only. Orthopnoea, often associated with heart failure, exists in one third of PE- 12

16 General introduction and outline of the thesis patients. Pleuritic pain is present in less than half of all patients. Twofifths of patients complain of lower limb pain. Haemoptysis occurs in only a minority of patients (<10%). Physical examination Tachypnoea (>20/min.) exists in more than half of the patients and tachycardia (>100/min) in more than a quarter of patients. Fever above 38.5 is rarely seen. Examination of the lungs identifies abnormalities in about one third of both suspected patients finally diagno-sed with PE and in suspected patients finally not diagnosed with PE. 9;10 Chest pain that is reproduced by palpation is thought to be caused by pathology of the musculoskeletal chest wall and may prompt physicians to discard PE as the cause. However Le Gal and colleagues showed that in suspected PE-patients chest pain with palpation is not associated with a lower prevalence of PE. 11 One third of all PE-patients show calf swelling plus pain with palpation of the deep veins. Oxygen saturation measurement is not of great value. A normal oxygen saturation does not exclude pulmonar y embolism but a low saturation puts the physician on the track of lung pathology. In conclusion The broad range (of severity) of clinical findings in patients with pulmonary embolism makes it a difficult and an easy to miss diagnosis. 9 Both history and physical examination are neither specific nor sensitive for PE. There is no individual clinical sign or even a combination of these that can be used to confirm or safely exclude the diagnosis. Diagnosing pulmonary embolism In the second half of the last century ventilation-perfusion lung scanning was usually performed as a first step in patients suspected of having pulmonar y embolism. A normal scan was considered to rule out the diagnosis of PE and a high-probability scan confirmed the diagnosis. However more than 50% of the patients had a so called non-high probability scan. In these patients a pulmonar y angiography, at that time being the gold standard diagnostic test, was required but this technique is invasive, expensive and labor intensive. 12 Moreover, as PE was only present in 20% of suspected 13

17 CHAPTER I patients, unnecessary imaging occurred in a large number of patients without PE. 13 Therefore, Wells and colleagues incorporated the clinical probability of PE into the diagnostic work up. They showed that only 0.5% of patients with a low or moderate clinical probability and a non-high-probability scan, who received no anticoagulant treatment, had PE in a three month follow-up period. Incorporating the clinical probability increased significantly the specificity of ventilation-perfusion lung scanning. 14 As the diagnostic strategy using clinical assessment of PE-probability and ventilation-perfusion scanning was rather complicated Wells and colleagues simplified the strategy and showed that combining probability assessment using their clinical decision rule and D-dimer testing could safely exclude PE in secondar y care patients without the need for additional ventilation-perfusion scanning or other imaging tests. In 46% of patients with a negative strategy PE occurred in only 1.7% of patients during a three month follow-up period. 15 A large Dutch secondar y care management study showed that in 32% of suspected patients with a negative strategy, not treated with anticoagulants, PE occurred in only 0.5% of patients during a three month follow-up period. 16 Several prospective studies confirmed the safety of withholding additional diagnostic testing and treatment in patients (either inpatients or outpatients) with suspected PE if they had the combination of a low clinical probability (as assessed with different clinical decision rules or with the unstructured clinical estimate) and a negative D-dimer test. All these studies were performed in secondary care Hence, the first step in the diagnostic work-up of patients with suspected PE is assessment of the clinical probability. If the probability is high (or likely) additional investigation is required. If the probability is low/intermediate (or unlikely), D-dimer testing is the next step. If the D-dimer test is positive additional investigation is required. If the D-dimer test is negative PE is considered safely excluded (Figure 1.1). In the last decade of the previous centur y computed tomography pulmonar y angiography (CTPA) was introduced and is currently the first line imaging test in patients with a high (or likely) clinical probability or a positive D-dimer test. 14

18 General introduction and outline of the thesis Figure 1.1. Diagnostic work-up in suspected PE-patients in secondary care Assessment of PE-probability using clinical gestalt or using a clinical decision rule Physicians are able to stratify patients in different groups of clinical probability using empirical clinical assessment ( clinical gestalt ). 20 However such empirical assessment depends on the physician s subjective judgement and experience, thereby showing considerable interobser ver variability. To objectify and standardize this clinical probability assessment various decision rules have been developed. Wells and colleagues developed a decision rule using logistic regression (Table 1.1a). 15 The rule only contains clinical variables which makes the rule also suitable for primary care. One of 7 items is the physician s judgment of whether PE is more likely than an alternative diagnosis. This criterion however is subjective and therefore submitted to inter-doctor variation. Therefore other rules contain- 15

19 CHAPTER I ing only objective items were developed. Both the Geneva-rule and (revised) Pisa-rules require the result of either a chest X-ray, blood gas analysis or ECG-interpretation and are therefore less feasible for use in primary care The revised Geneva-rule, containing 8 only clinical variables was constructed and can also be used in primary care (Table 1.1b). 24 The clinical decision rules all assign different weights to the variables. To facilitate computation of the scores the Wells rule and the revised Geneva-rule have recently been simplified, assigning one point to all items (except for heart-rate in the simplified revised Geneva). 25;26 Both the Wells rule and the revised Geneva might stratify patients into two levels (low and high) or three levels of probability (low, intermediate and high). No clinical decision rule is considered sensitive enough to exclude pulmonary embolism safely without additional D-dimer testing and none of these clinical decision rules was validated in primary care. Before implementing a clinical decision rule in primary care it needs to be validated in the proper setting of primary care. Owing to differences in spectrum of disease, symptoms and doctors experience encouraging results from secondary care may not be applicable in primary care. 27;28 D-dimer tests The process of thrombosis is physiologically accompanied by fibrinolysis with the aim to degrade the clot. D-dimers are degradation products of cross-linked fibrin and are generated during fibrinolysis. D-dimer is not a single entity in plasma but a mixture of heterogeneous fibrin degradation products. The D-dimer test is based on the complex formation of an antibody against the D-dimer molecule. Different assays use different types of monoclonal anti-d-dimerantibodies. 29 The D-dimer test is used to exclude venous thromboembolism. A negative D-dimer test has a high sensitivity (low false negative rate) and a high negative predictive value for the presence of venous thromboembolism. The specificity however is rather low due to the fact that increased levels of D-dimers are not only found in venous thromboembolism but also in many other conditions such as pregnancy, cancer and infections. D-dimer levels are also age-dependent (higher in the elderly)

20 Table 1.1.a/b Clinical decision rules suitable for use in primary care a. Wells rule General introduction and outline of the thesis Variable Points 1. Clinical signs and symptoms of DVT (minimum of leg swelling 3 0 and pain with palpation of the deep veins) 2. Alternative diagnosis less likely than PE Heart rate>100/min Immobilization (>3days) or surgery in the previous 4 weeks Previous PE or DVT Haemoptysis Malignancy 1 0 (receiving treatment, treated in the last 6 months or palliative) Clinical probability of PE: Unlikely 4 points Likely >4 points Low Intermediate High <2 points 2-6 points >6 points Abbreviations: DVT,deep venous thrombosis; PE, pulmonary embolism. b. revised Geneva-rule Variable Score 1. Age>65 y 1 2. Previous DVT or PE 3 3. Surgery (under general anaesthesia) 2 or fracture (of the lower limbs) within 1 month 4. Active malignant condition (solid or hematologic malignant 2 condition, currently active or considered cured <1y) 5. Unilateral lower-limb pain 3 6. Haemoptysis 2 7. Heart rate beats/min 3 95 beats/min 5 8. Pain on lower-limb deep venous palpation and unilateral oedema 4 Clinical probability for PE: Unlikely 5 points Likely >5 points Low Intermediate High <4 points 4-10 points >10 points 17

21 CHAPTER I D-dimer tests are available as laboratory based and as point of care tests. These point of care or near patient-tests can be performed during the consultation and results are ready available within minutes. For some point of care tests no additional equipment is necessar y, which makes these tests easily accessible for use in the primar y care setting. Two major groups of D-dimer tests are available: quantitative tests in which the result is expressed in a number and qualitative tests in which the result is expressed in a positive or negative score. Computed tomography for PE In computed tomography a motorized table moves the patient through the CT imaging system. At the same time a source of x-rays rotates within the circular opening and a set of x-ray detectors rotates in synchrony on the far side of the patient. After intravenous administration of ml of iodinated contrast medium an image is produced by irradiating the patient from several directions with a narrow beam of X-rays. The intensity of transmitted X-rays will be measured with detectors. With a spiral CT-scan the X-ray tube continuously makes circular movements while the patient is moved slowly through the centre of the CT scanner (Figure 1.2).The X-ray tube describes a spiral movement around the patient hence the name spiral CT or helical CT. All the data are processed by a computer to produce a series of image slices representing a three-dimensional view of the chest. 34 To reduce scanning time and improve resolution current CT-machines typically have multiple rows of detectors operating side by side, so that many slices (currently up to 64) can be imaged simultaneously. The negative predictive value of a normal multi-slice CT-scan is regarded high enough to exclude PE without the need for additional imaging. 35 In the Christopher-study the three months incidence of venous thromboembolism in patient with a normal CT-scan not treated with anticoagulants was 1.3% 16, Perrier et al found an incidence of 1.7%. 19 With the increase in the number of detectors one is increasingly able to detect even small pulmonar y emboli. Since the introduction of multi-detector CTPA the incidence of pulmonary embolism increased significantly. The suggestion is that these additional cases are often 18

22 General introduction and outline of the thesis Figure 1.2. Spiral CT-scan (Reproduced with permission 34 Copyright Massachusetts Medical Society) small, subsegmental emboli. 36 The clinical significance of these small emboli is not entirely clear. They can be a precursor to larger emboli and might have more impact in patients with a poor cardiopulmonary status. 37 Alternatively the trapping of smaller emboli could be an important physiological function of the lung. 38 In the past these emboli would have remained untreated and probably would not have led to complications. Further research is needed to determine the need for treatment of these small emboli. An important disadvantage of CT-scanning is the contrast-induced nephropathy in 2-5% of patients. 39 Another major disadvantage of CT-scanning is the relatively high radiation exposure and the increased (though small) risk for radiation induced carcinogenesis, 19

23 CHAPTER I which emphasizes the importance of excluding PE with the combination of an unlikely Wells decision rule and a negative D-dimer test in particular in younger women thereby reducing the number of patients undergoing unnecessary imaging. 34 Compression ultrasonography of the legs in patients with suspected PE Pulmonar y embolism usually arises from deep venous thrombosis (DVT) of the lower extremities. 40;41 Compression ultrasonography of the leg veins could provide indirect evidence for the presence of PE in patients with clinically suspected PE. 42 The detection of DVT would anyhow provide a rationale for anticoagulant treatment without the requirements of further diagnostic investigation. However bilateral compression ultrasound has been demonstrated to have a relatively low sensitivity (many false-negatives) for the diagnosis of asymptomatic DVT in patients presenting with symptoms of pulmonary embolism. Given that the prevalence of PE may be only 10% to 30% in the evaluation of suspected patients, this further reduces the utility of screening all patients initially with bilateral ultrasonography. The exception may be the patient with suspected PE with clinical signs of DVT in which case the likelihood of detection of DVT with ultrasonography is increased about 4-fold. 43;44 Outline of this thesis The previous AMUSE-1 (Amsterdam, Maastricht, Utrecht, Study on thrombo-embolism) showed that primar y care physicians can safely exclude deep vein thrombosis with a clinical decision rule and D- dimer testing, thereby reducing the need for referral to secondar y care of patients with clinically suspected DVT by almost 50%. 45 Many participating physicians asked whether a similar approach could also be possible for their patients with suspected PE. This thesis aims to evaluate the safety of a strategy to exclude pulmonar y embolism in primar y care patients with clinically suspected pulmonar y embolism using the Wells PE-decision rule and a qualitative point of care D-dimer test. If the safety of this strategy is confirmed the primar y care physician can distinguish between suspected PE-patients she/he can safely manage in primar y care 20

24 General introduction and outline of the thesis and patients who need referral to secondar y care for further testing. Chapter 2 describes a scenario-analysis that calculates the expected results of such a management strategy. The Wells rule at different cutoff values in combination with a qualitative point of care D-dimer test is applied in secondar y care outpatients suspected of PE. Chapter 3 presents the results of a meta-analysis that compares the test-characteristics of gestalt (physicians unstructured estimate) and different clinical decision rules for suspected PE-patients and assesses failure-rates (missed cases) when used in combination with D-dimer testing. Chapter 4 shows the results of AMUSE-2 (Amsterdam, Maastricht, Utrecht, Study on thrombo-embolism), a prospective validation study performed in primar y care evaluating a diagnostic strategy using the Wells clinical decision rule and a point of care qualitative D-dimer test. Chapter 5 describes the alternative diagnoses in patients in whom pulmonar y embolism was rejected. In patients in whom the PCP excluded PE using a negative Wells rule and a negative D-dimer test the PCP still faces a diagnostic dilemma. Are these patients suffering from any other clinically relevant disease? Chapter 6 answers this question and assesses the additional value of the CRP-test in these patients. In patients referred to secondar y care CTPA is the preferred imaging test. Chapter 7 looks at the accuracy of the CTPA with the assessment of three expert radiologists as the reference standard. The general discussion (Chapter 8) follows a 35 year old female patient suspected of having pulmonar y embolism in the process of applying the diagnostic strategy using clinical probability assessment and the D-dimer test. Reference List 1 Anonymous. The diagnosis of pulmonary embolism. Lancet 175, Schiff GD, Hasan O, Kim S, Abrams R, Cosby K, Lambert BL et al. Diagnostic error in medicine: analysis of 583 physician-reported errors. Arch Intern Med 2009; 169(20):

25 CHAPTER I 3 Crul BVM, van de Meer HCP. Ook verworpen diagnose noteren. Medisch Contact Rijksen WP, Crul BVM. Hyperventilatie blijkt longembolie. Medisch Contact Gaal S, Hartman C, Giesen P, van WC, Verstappen W, Wensing M. Complaints against family physicians submitted to disciplinary tribunals in the Netherlands: lessons for patient safety. Ann Fam Med 2011; 9(6): van der Linden MW, Westert GP, de Bakker DH, Schellevis FG. Tweede nationale studie naar ziekten en verrichtingen in de huisartspraktijk. Nivel Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1960; 1(7138): Calder KK, Herbert M, Henderson SO. The mortality of untreated pulmonary embolism in emergency department patients. Ann Emerg Med 2005; 45(3): Stein PD, Beemath A, Matta F, Weg JG, Yusen RD, Hales CA et al. Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am J Med 2007; 120(10): Le Gal GG, Righini M, Roy PM, Meyer G, Aujesky D, Perrier A et al. Differential value of risk factors and clinical signs for diagnosing pulmonary embolism according to age. J Thromb Haemost 2005; 3(11): Le Gal GG, Testuz A, Righini M, Bounameaux H, Perrier A. Reproduction of chest pain by palpation: diagnostic accuracy in suspected pulmonary embolism. BMJ 2005; 330(7489): Stein PD, Athanasoulis C, Alavi A, Greenspan RH, Hales CA, Saltzman HA et al. Complications and validity of pulmonary angiography in acute pulmonary embolism. Circulation 1992; 85(2): van Beek E.J.R., Buller HR, van Royen E.A.van Everdingen J.J.E., ten Cate J.W. Het diagnostisch beleid bij vermoeden van longembolie: resultaten van een enquete onder Nederlandse internisten en longartsen. Nederlands Tijdschrift voor Geneeskunde 136[7] Wells PS, Ginsberg JS, Anderson DR, Kearon C, Gent M, Turpie AG et al. Use of a clinical model for safe management of patients with suspected pulmonary embolism. Ann Intern Med 1998; 129(12): Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent 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(3): van Belle A, Buller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006; 295(2):

26 General introduction and outline of the thesis 17 Wells PS, Anderson DR, Rodger M, Stiell I, Dreyer JF, Barnes D et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer. Ann Intern Med 2001; 135(2): Runyon MS, Beam DM, King MC, Lipford EH, Kline JA. Comparison of the Simplify D-dimer assay performed at the bedside with a laboratory-based quantitative D-dimer assay for the diagnosis of pulmonary embolism in a low prevalence emergency department population. Emerg Med J 2008; 25(2): Perrier A, Roy PM, Sanchez O, Le GG, Meyer G, Gourdier AL et al. Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med 2005; 352(17): 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(20): Wicki J, Perneger TV, Junod AF, Bounameaux H, Perrier A. Assessing clinical probability of pulmonary embolism in the emergency ward: a simple score. Arch Intern Med 2001; 161(1): Miniati M, Monti S, Bottai M. A structured clinical model for predicting the probability of pulmonary embolism. Am J Med 2003; 114(3): Miniati M, Bottai M, Monti S, Salvadori M, Serasini L, Passera M. Simple and accurate prediction of the clinical probability of pulmonary embolism. Am J Respir Crit Care Med 2008; 178(3): Le Gal GG, Righini M, Roy PM, Sanchez O, Aujesky D, Bounameaux H et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med 2006; 144(3): Gibson NS, Sohne M, Kruip MJ, Tick LW, Gerdes VE, Bossuyt PM et al. Further validation and simplification of the Wells clinical decision rule in pulmonary embolism. Thromb Haemost 2008; 99(1): Klok FA, Mos IC, Nijkeuter M, Righini M, Perrier A, Le GG et al. Simplification of the revised Geneva score for assessing clinical probability of pulmonary embolism. Arch Intern Med 2008; 168(19): Knottnerus JA. Between iatrotropic stimulus and interiatric referral: the domain of primary care research. J Clin Epidemiol 2002; 55(12): Oudega R, Hoes AW, Moons KG. The Wells rule does not adequately rule out deep venous thrombosis in primary care patients. Ann Intern Med 2005; 143(2): van der Graaf F, van den Borne H, van der Kolk M, de Wild PJ, Janssen GW, van Uum SH. Exclusion of deep venous thrombosis with D-dimer testing comparison of 13 D-dimer methods in 99 outpatients suspected of deep venous thrombosis using venography as reference standard. Thromb Haemost 2000; 83(2):

27 CHAPTER I 30 Francalanci I, Comeglio P, Liotta AA, Cellai AP, Fedi S, Parretti E et al. D- dimer concentrations during normal pregnancy, as measured by ELISA. Thromb Res 1995; 78(5): Di Nisio NM, Sohne M, Kamphuisen PW, Buller HR. D-Dimer test in cancer patients with suspected acute pulmonary embolism. J Thromb Haemost 2005; 3(6): Tardy B, Tardy-Poncet B, Viallon A, Lafond P, Page Y, Venet C et al. Evaluation of D-dimer ELISA test in elderly patients with suspected pulmonary embolism. Thromb Haemost 1998; 79(1): Righini M, Goehring C, Bounameaux H, Perrier A. Effects of age on the performance of common diagnostic tests for pulmonary embolism. Am J Med 2000; 109(5): Brenner DJ, Hall EJ. Computed tomography-an increasing source of radiation exposure. N Engl J Med 2007; 357(22): Mos IC, Klok FA, Kroft LJ, DE RA, Dekkers OM, Huisman MV. Safety of ruling out acute pulmonary embolism by normal computed tomography pulmonary angiography in patients with an indication for computed tomography: systematic review and meta-analysis. J Thromb Haemost 2009; 7(9): Carrier M, Righini M, Wells PS, Perrier A, Anderson DR, Rodger MA et al. Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies. J Thromb Haemost 2010; 8(8): Hull RD, Raskob GE, Pineo GF, Brant RF. The low-probability lung scan. A need for change in nomenclature. Arch Intern Med 1995; 155(17): Gurney JW. No fooling around: direct visualization of pulmonary embolism. Radiology 1993; 188(3): Lencioni R, Fattori R, Morana G, Stacul F. Contrast-induced nephropathy in patients undergoing computed tomography (CONNECT) - a clinical problem in daily practice? A multicenter observational study. Acta Radiol 2010; 51(7): Girard P, Musset D, Parent F, Maitre S, Phlippoteau C, Simonneau G. High prevalence of detectable deep venous thrombosis in patients with acute pulmonary embolism. Chest 1999; 116(4): Kruit WH, de Boer AC, Sing AK, van RF. The significance of venography in the management of patients with clinically suspected pulmonary embolism. J Intern Med 1991; 230(4): Anderson DR, Barnes D. The use of leg venous ultrasonography for the diagnosis of pulmonary embolism. Semin Nucl Med 2008; 38(6):

28 General introduction and outline of the thesis 43 Girard P, Sanchez O, Leroyer C, Musset D, Meyer G, Stern JB et al. Deep venous thrombosis in patients with acute pulmonary embolism: prevalence, risk factors, and clinical significance. Chest 2005; 128(3): Righini M, Le GG, Aujesky D, Roy PM, Sanchez O, Verschuren F et al. Diagnosis of pulmonary embolism by multidetector CT alone or combined with venous ultrasonography of the leg: a randomised non-inferiority trial. Lancet 2008; 371(9621): Buller HR, Ten Cate-Hoek AJ, Hoes AW, Joore MA, Moons KG, Oudega R et al. Safely ruling out deep venous thrombosis in primary care. Ann Intern Med 2009; 150(4):

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30 CHAPTER 2 EXCLUDING PULMONARY EMBOLISM IN PRIMARY CARE USING THE WELLS RULE IN COMBINATION WITH A POINT OF CARE D-DIMER TEST: A SCENARIO ANALYSIS WAM Lucassen, RA Douma, DB Toll, HR Büller, HCPM van Weert BMC Family Practice 2010 Sept 13; 11:64 27

31 CHAPTER 2 ABSTRACT Background In secondary care the Wells clinical decision rule (CDR) combined with a quantitative D-dimer test can exclude pulmonary embolism (PE) safely. The introduction of point of care (POC) D-dimer tests facilitates a similar diagnostic strategy in primary care. We estimated failure-rate and efficiency of a diagnostic strategy using the Wells CDR combined with a POC-D-dimer test for excluding PE in primary care. We considered ruling out PE safe if the failure rate was <2% with a maximum upper confidence limit of 2.7%. Methods We performed a scenario-analysis on data of 2701 outpatients suspected of PE. We used test characteristics of two qualitative POC D-dimer tests, as derived from a meta-analysis and combined these with the Wells CDR-score. Results In scenario 1 (SimpliRed-D-dimer sensitivity 85%, specificity 74%) PE was excluded safely in 23.8% of patients but only by lowering the cutoff value of the Wells rule below 2. (failure rate: 1.4%, 95% CI %) In scenario 2 (Simplify-D-dimer sensitivity 87%, specificity 62%) PE was excluded safely in 12.4% of patients provided that the Wells cutoff value was set at 0. (failure rate: 0.9%, 95% CI %) Conclusion Theoretically a diagnostic strategy using the Wells CDR combined with a qualitative POC D-dimer test can be used safely to exclude PE in primary care albeit with only moderate efficiency. 28

32 Excluding PE, a scenario analysis Background Pulmonar y embolism (PE) has an estimated annual incidence of 23 cases per persons. 1 Because PE is potentially life-threatening, immediate diagnosis and management is essential. As primar y care physicians lack accurate diagnostic tools, all patients have to be referred, often with all due speed to secondary care in case PE is suspected. However in 75-95% of these referred patients PE subsequently is excluded. 2-4 Several management-studies in secondary care have demonstrated that PE can be excluded safely in patients with a low (<2) or unlikely ( 4) clinical probability according to the clinical decision rule (CDR) as developed by Wells et al.(table 2.1), combined with a normal D-dimer test result (both quantitative and qualitative D-dimer tests). 5-8 The introduction of easy-to-use rapid point of care (POC) D-dimer tests makes it possible to exclude PE safely in the primary care setting, using a diagnostic work-up similar to that in secondar y care thereby avoiding unnecessar y referrals. Qualitative POC D-dimer tests do not need additional equipment or calibration, are ready to use, cheap, utilize capillar y or venous blood and can be done in-and outside the clinic. They can be interpreted within 10 minutes as either positive or negative which make the tests suitable for use in primar y care. Questions have been raised however about the sensitivity of the tests ranging from % in different studies. 7;9-13 To our knowledge a management-study with a diagnostic strategy using a CDR in combination with POC D-dimer test for excluding PE has not been performed in primary care although this approach was successfully used in the setting of suspected deep vein thrombosis (DVT). 14 We performed a scenario-analysis to calculate the expected results of such a management strategy in patients referred by their primar y care physician for suspected PE. Because exclusion of PE is based on the probability score of the Wells rule combined with the result of a qualitative D-dimer test we aimed to calculate a safety-threshold by var ying the cutoff value of the Wells rule. 29

33 CHAPTER 2 Table 2.1. Wells clinical decision rule Variable Points Clinical signs and symptoms of DVT 3.0 (minimum of leg swelling and pain with palpation of the deep veins) Alternative diagnosis less likely than PE 3.0 Heart rate>100/min 1.5 Immobilization (>3days) or surgery in the previous 4 weeks 1.5 Previous PE or DVT 1.5 Haemoptysis 1.0 Malignancy 1.0 (receiving treatment, treated in the last 6 months or palliative) Clinical probability of PE: Unlikely 4 points Likely >4 points Low Intermediate High <2 points 2-6 points >6 points Abbreviations: DVT,deep vein thrombosis; PE, pulmonary embolism. Methods For the present analysis we used data from a large prospective management study, the Christopher-study, including 3306 consecutive in-and outpatients, suspected of pulmonary embolism. 8 This study was performed in secondar y care in the Netherlands between November 2002 and September It evaluated the safety of excluding PE by a sequential diagnostic work-up consisting of the dichotomous Wells CDR (cutoff 4), a quantitative D-dimer test and helical computer tomography (CT). Patients with a CDR indicating PE unlikely underwent D-dimer testing. Either the Vidas ELISA D-dimer test or the Tinaquant D-dimer test was used (cutoff 500µg/l, combined sensitivity 97.8% and specificity 56.9%) and when normal, the diagnosis of PE was considered excluded. All other patients underwent helical CT. All patients were followed up for a period of 3 months to document the occurrence of subsequent symptomatic venous thromboembolism (VTE). 30

34 Excluding PE, a scenario analysis We used test characteristics of two qualitative POC D-dimer tests from a meta-analysis on the diagnostic accuracy of POC D-dimer tests for excluding VTE. 15 SimpliRed D-dimer (sensitivity 85%, specificity 74%) is a semi qualitative test performed by mixing capillary or venous blood with a drop of test reagent in the test well. A positive result is defined as any visible agglutination within two minutes. Simplify D-dimer (sensitivity 87%, specificity 62%) is a qualitative test and is performed by mixing 35µl of capillary or venous blood with two drops of test reagent. A positive result is indicated by a visible pink-purple coloured line that forms at the test zone. The test can be read within 10 minutes. To mimic a primary care setting we excluded all inpatients from the original cohort for the present analysis. As would be the case in primary care all patients with Wells CDR >4 needed imaging regardless of the D-dimer test result. Hence in these patients no additional D- dimer testing was performed. Using the original Christopher-study data, we divided the remaining patients into groups according to their individual Wells CDR scores with different cutoff values (Table 2.2). Within each group PE was excluded in patients with the combination of a Wells CDR below the cutoff value and a negative D-dimer test result. Combining the prevalence of PE in each group with the sensitivity and specificity of the D-dimer test we calculated the theoretical failure-rate and the efficiency of the combined strategy in each clinical probability group. Efficiency was defined as the proportion of all study patients, in whom PE was excluded (and thus would not need referral) based on a Wells CDR below various cutoff values and a negative D-dimer test. The failure rate was defined as the proportion of patients in whom PE was excluded based on a Wells CDR below various cutoff values and a negative D-dimer test, with symptomatic and proven VTE during 3 months follow-up. We considered ruling out PE safe if the failure rate was <2% with a maximum upper confidence limit of 2.7%, being the upper confidence limit of the three-month thromboembolic rate of patients suspected of PE but with a normal pulmonary angiography. 16 The 95% confidence intervals (CI) were calculated using Confidence Inter val Analysis (CIA, version 1.0; Gardner MJ). 31

35 CHAPTER 2 Table 2.2. Results of failure-rate and efficiency in 2 scenarios at different cutoff values of the Wells-rule in comparison with results of the Christopher-study SimpliRed: Simplify: Wells N= Prevalence Sens 85% Sens 87% Christopher 2006 PE Spec 74% Spec 62% Tinaquant/Vidas Failure-rate Efficiency Failure-rate Efficiency Failure-rate Efficiency (95% CI) (95% CI) (95% CI) 12.0% 2.7% 46.5% 2.8% 38.9% 0.5% 35.0% (226/1876) ( %) ( %) ( %) 11.3% 2.5% 44.2% 2.6% 37.0% 0.4% 34.1% (201/1772) ( %) ( %) ( %) 6.3% 1.4% 23.9% 1.5% 20.1% 0.2% 19.8% (58/919) ( %) ( %) ( %) 6.3% 1.4% 23.8% 1.5% 20.0% 0.2% 19.8% <2 915 (58/915) ( %) ( %) ( %) 4.6% 0.9% 16.1% 1.1% 13.5% 0.0% 14.5% (28/611) ( %) ( %) ( %) 4.3% 1.0% 14.8% 0.9% 12.4% 0.0% 13.8% (24/559) ( %) ( %) ( %) Legend: N = Number of outpatients in different Wells clinical probability groups. CI = Confidence interval. 32

36 Excluding PE, a scenario analysis * Overlapping data points Figure 2.1. Failure rate versus efficiency in 2 scenarios at different cutoff values of the Wells CDR in comparison with results from the Christopher-study Results Of the total study population of 3306 in-and outpatients, 2701 were outpatients and included in this analysis. The prevalence of PE in the group of outpatients was 20.2%. (including the 3-months followup period). The prevalence of PE among patients with an unlikely clinical probability decreased with a decreasing CDR cutoff value, ranging from 12.0% in patients with a Wells score 4 to 4.3% in patients with a Wells score of 0. Table 2.2 shows the failure-rate and the efficiency at different cutoff values of the Wells CDR in combination with the sensitivity and specificity of the D-dimer test. In the last column results of the outpatients obtained from the Christopher-study are depicted for comparison. In the Christopher-study PE could be excluded safely with a Wells CDR cutoff value of 4 in 35.0% of the patients. 33

37 CHAPTER 2 However the failure rate of 2.7% is exceeded in both quantitative POC D-dimer tests when combined with a Wells CDR cutoff value of 4. To meet the safety criteria (failure rate <2%, upper 95% CI<2.7%) the SimpliRed D-dimer test had to be combined with a Wells CDR cut off value <2 and the Simplify D-dimer test with a Wells CDRcutoff value of 0. Using this strategy, the proportion of patients in whom PE might be excluded safely decreased to 23.8% with the SimpliRed D-dimer test and 12.4% with the Simplify D-dimer test. The dramatic loss in efficiency when using a lower Wells CDR cutoff is demonstrated in Figure 2.1. Discussion The current scenario-analysis determined the theoretical failure-rate and efficiency of a diagnostic strategy using the Wells CDR at different cutoff values combined with a qualitative POC D-dimer test for excluding PE in primary care. Excluding PE safely in primary care with a CDR and a point of care D-dimer test seems feasible. However, the strategy appeared to be safe only when the cutoff value of the Wells CDR was lowered to <2 using the SimpliRed and 0 using the Simplify D-dimer test, respectively. Efficiency is considerably lower when using those cutoff values: the number of patients that need referral is 76.2% and 87.6% respectively, as compared to 65% with the Wells cutoff value of 4 in the Christopher-study. Several aspects of this analysis require comment. Firstly, we based the analysis on the test characteristics of two qualitative POC D-dimer tests as reported in a diagnostic meta-analysis. In this meta-analysis most of the studies included patients suspected of DVT. Only six studies included patients with PE. However in a covariate analysis of studies with only DVT both the sensitivity and the specificity of the SimpliRed and the Simplify D-dimer test were essentially the same as in the overall analysis. Secondly, several studies performed in secondary care (PE-prevalence ranging from %) show that a strategy using a CDR and a qualitative POC D-dimer test can be used safely to exclude PE. Moreover these studies show a good efficiency ranging from 44-66%. 7;10-13 Wells et al were the first to show that the combination of Wells 34

38 Excluding PE, a scenario analysis CDR<2 and a negative D-dimer test was safe to exclude PE (prevalence 9.5%, failure rate 0.2%, efficiency 47%). 7 According to Hogg and co-workers the Simplify D-dimer test alone was not sufficiently sensitive (sensitivity 81.8%, specificity 74.2%) to exclude PE in low-risk patients (prevalence PE 5.3%) presenting to the emergency department (ED) with pleuritic chest pain. However, when the Simplify D-dimer test was combined with a low-clinical probability Wells rule the negative predictive value of the combined test was 99.3% (CI %): high enough to exclude PE safely. 10 Kline et al showed in low-risk ED patients (prevalence PE 4.7%) that combination of a physician s unstructured estimate of pre-test probability of PE of <15% and a negative Simplify-D-dimer test excluded PE safely (sensitivity D-Dimer-test 80.6%, specificity 72.5%). 11 In a primar y care based management study sensitivity of the Simplify D- dimer test proved to be sufficient to exclude deep vein thrombosis (DVT) safely in patients with a low clinical probability. The relatively higher specificity, as compared to laborator y based quantitative D- dimer tests provided a good efficiency. 14 Although the sensitivity of the Simplify D-Dimer test in the studies of Hogg and Kline was only 81.8% and 80.6%, respectively, the negative predictive value of the combined strategy using a pre-test probability assessment and the Simplify D-Dimer test was high enough to exclude PE safely due to the low PE-prevalence in these studies. Thirdly, a weak point of the analysis is that although we have excluded all in-patients the study-population is still not really a primar y care population. The outpatients included in the Christopher-study are likely selectively biased as the primary care physician used his own judgement before referring the patient. In the Christopher-study the PE-prevalence was 20.2%. In daily practice when a primary care physician will use the Wells CDR rule combined with a POC D-dimer test the prevalence of PE in suspected patients is expected to be lower which will improve the negative predictive value (and thereby safety and efficiency) of an exclusion strategy for PE in primary care. Fourthly, we don t know how well the Wells CDR would perform in primary care. In secondary care the Wells rule is usually applied after routine blood tests, chest radiography and electrocardiography. The primar y care physician is usually lacking this information and this will clearly influence the scoring of the subjective variable pul- 35

39 CHAPTER 2 monar y embolism is as likely as or more likely than an alternative diagnosis. Fifthly, we know that the test characteristics of the POC D-dimer test, unlike this scenario, are not fixed but are influenced by the prevalence of PE in the different Wells groups. It is likely that the specificity of the D-dimer test will increase as the prevalence decreases. This might improve the negative predictive value of the strategy in primary care. 17;18 Sixthly, in this analysis the SimpliRED D-dimer assay was used which has certain limitations. It is known that this method may be associated with a risk for inadequate interpretation due to the fact that the results are based on a subjective interpretation of the presence or absence of agglutination. 19 This risk for inadequate interpretation will be enhanced by infrequent use of the assay. An average Dutch primary care physician will use a POC D-dimer assay for exclusion of PE only 3-5 times a year. However the physician will use the same assay also for exclusion of DVT. 14 We expect the Dutch primary care physician to apply the POC D-dimer test times a year in both suspected PE-patients as DVT-patients. We think this will justify an adequate and reliable use of the assay. Finally, although in scenario 2 (Simplify) the point estimate failure rate in Wells CDR<2 is within the safety limits, the upper confidence limit exceeds 2.7%. Confidence inter vals become larger with decreasing number of patients. It can be expected that with an increasing number of patients the proportion in the lower Wells CDR score will be higher and the confidence interval will become narrower. Therefore scenario 2 might also be safe in Wells <2. In secondar y care, in a strategy using a more sensitive, quantitative D-dimer test, a cutoff value of Wells 4 is generally accepted as safe. Although the sensitivity of the POC qualitative D-dimer test is lower, the specificity of the test is higher and as a consequence efficiency is higher at the cost of safety. Recalibration of the Wells rule for a primar y care situation might overcome the safety problems. Conclusion In this scenario-analysis we could exclude PE safely with a diagnostic strategy using the Wells CDR and a qualitative D-dimer test, 36

40 Excluding PE, a scenario analysis albeit with only a moderate efficiency. A prospective study is needed to assess safety and efficiency of this strategy in a true primary care population. Recalibration of the Wells rule or adaption of cutoff values might then be needed. Reference List 1 Anderson FA, Jr., Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151(5): Runyon MS, Webb WB, Jones AE, Kline JA. Comparison of the unstructured clinician estimate of pretest probability for pulmonary embolism to the Canadian score and the Charlotte rule: a prospective observational study. Acad Emerg Med 2005; 12(7): Perrier A, Roy PM, Aujesky D, Chagnon I, Howarth N, Gourdier AL et al. Diagnosing pulmonary embolism in outpatients with clinical assessment, D- dimer measurement, venous ultrasound, and helical computed tomography: a multicenter management study. Am J Med 2004; 116(5): Penaloza A, Melot C, Dochy E, Blocklet D, Gevenois PA, Wautrecht JC et al. Assessment of pretest probability of pulmonary embolism in the emergency department by physicians in training using the Wells model. Thromb Res 2007; 120(2): Anderson DR, Kovacs MJ, Dennie C, Kovacs G, Stiell I, Dreyer J et al. Use of spiral computed tomography contrast angiography and ultrasonography to exclude the diagnosis of pulmonary embolism in the emergency department. J Emerg Med 2005; 29(4): Goekoop RJ, Steeghs N, Niessen RW, Jonkers GJ, Dik H, Castel A et al. Simple and safe exclusion of pulmonary embolism in outpatients using quantitative D-dimer and Wells simplified decision rule. Thromb Haemost 2007; 97(1): Wells PS, Anderson DR, Rodger M, Stiell I, Dreyer JF, Barnes D et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer. Ann Intern Med 2001; 135(2): Belle van A., Buller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006; 295(2):

41 CHAPTER 2 9 Kline JA, Israel EG, Michelson EA, O Neil BJ, Plewa MC, Portelli DC. Diagnostic accuracy of a bedside D-dimer assay and alveolar dead-space measurement for rapid exclusion of pulmonary embolism: a multicenter study. JAMA 2001; 285(6): Hogg K, Dawson D, kway-jones K. The emergency department utility of Simplify D-dimer to exclude pulmonary embolism in patients with pleuritic chest pain. Ann Emerg Med 2005; 46(4): Kline JA, Runyon MS, Webb WB, Jones AE, Mitchell AM. Prospective study of the diagnostic accuracy of the simplify D-dimer assay for pulmonary embolism in emergency department patients. Chest 2006; 129(6): Toulon P, Lecourvoisier C, Meyniard O. Evaluation of a rapid qualitative immuno-chromatography D-dimer assay (Simplify D-dimer) for the exclusion of pulmonary embolism in symptomatic outpatients with a low and intermediate pretest probability. Comparison with two automated quantitative assays. Thromb Res 2009; 123(3): Runyon MS, Beam DM, King MC, Lipford EH, Kline JA. Comparison of the Simplify D-dimer assay performed at the bedside with a laboratory-based quantitative D-dimer assay for the diagnosis of pulmonary embolism in a low prevalence emergency department population. Emerg Med J 2008; 25(2): Büller HR, Ten Cate-Hoek AJ, Hoes AW, Joore MA, Moons KG, Oudega R et al. Safely ruling out deep venous thrombosis in primary care. Ann Intern Med 2009; 150(4): Geersing GJ, Janssen KJ, Oudega R, Bax L, Hoes AW, Reitsma JB et al. Excluding venous thromboembolism using point of care D-dimer tests in outpatients: a diagnostic meta-analysis. BMJ 2009; 339:b van Beek EJ, Brouwerst EM, Song B, Stein PD, Oudkerk M. Clinical validity of a normal pulmonary angiogram in patients with suspected pulmonary embolism-a critical review. Clin Radiol 2001; 56(10): Robert H.Fletcher., Suzanne W.Fletcher. Clinical epidemiology, the essentials, 4th edition. 4 ed Wolf SJ, McCubbin TR, Nordenholz KE, Naviaux NW, Haukoos JS. Assessment of the pulmonary embolism rule-out criteria rule for evaluation of suspected pulmonary embolism in the emergency department. Am J Emerg Med 2008; 26(2): Perzanowski C, Eiger G. Limited interobserver agreement in the SimpliRED D-dimer assay. J Thromb Haemost 2003; 1(4):

42 CHAPTER 3 CLINICAL DECISION RULES FOR EXCLUDING PULMONARY EMBOLISM: A META-ANALYSIS WAM Lucassen, GJ Geersing, PMG Erkens, JB Reitsma, KGM Moons, HR Büller, HCPM van Weert Annals of Internal Medicine 2011 Oct 4; 155(7):