Adjustments in the diagnostic work-up, treatment and prognosis of pulmonary embolism van Es, Josien

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1 UvA-DARE (Digital Academic Repository) Adjustments in the diagnostic work-up, treatment and prognosis of pulmonary embolism van Es, Josien Link to publication Citation for published version (APA): van Es, J. (2013). Adjustments in the diagnostic work-up, treatment and prognosis of pulmonary embolism 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: 02 Dec 2017

2 1 Introduction and outline of the thesis J. van Es S. Middeldorp P.W. Kamphuisen

3 Chapter 1 General introduction Pulmonary embolism (PE) is a potentially fatal condition, in which an embolism, usually a thrombus originating from one of the deep veins of the legs, blocks one or more pulmonary arteries, causing impaired blood flow and increased pressure of the right cardiac ventricle. PE and deep vein thrombosis (DVT) are considered two entities of the same disease: venous thromboembolism. The clinical presentation of patients with suspected acute PE is nonspecific and varies widely, from only limited symptoms, to severe shortness of breath, pain on exertion, syncope, cardiogenic shock and death. As PE is a frequently occurring disease, with an incidence of 1-2 per 1000 to nearly 8 per 1000 in older-aged patients per year, it is the third most common cardiovascular disorder in Western society (1;2). The first step in the diagnostic work-up of suspected PE consists of clinical history taking and physical examination, in order to determine the clinical probability of PE. Information regarding clinical signs and symptoms can be used to classify patients in probability categories, by either using implicit judgement or validated clinical decision rules. Although four clinical decision rules have been proven to perform equally (3), the most commonly used clinical decision rule is the Wells score (4). This score consists of items obtained from clinical history such as risk factors for PE, physical examination such as increased heart rate and signs of DVT, and a subjective item, where the physician judges whether an alternative diagnosis is more likely than PE (5). When the low clinical probability (Wells score 4 points) is combined with a normal D-dimer test result, PE is safely excluded in 20 to 40% of the patients with suspected PE, without the need for imaging techniques (6). Fibrin D-dimer is the final product of the plasmin-mediated degradation of cross-linked fibrin and D-dimer levels are typically elevated in patients with acute venous thromboembolism. The sensitivity of the D-dimer, using a cut-off value of 500 µg/l, is nearly 100% (7). In contrast, since D-dimer levels can be elevated in other clinical conditions, e.g. malignancy, increased age, infection, postoperative states and pregnancy, the specificity for acute venous thromboembolism is only between 30% and 40% (7-9), and further decreases with advancing age. As aging increases the risk of PE, it is likely that a higher D-dimer cut-off results in higher specificity without a relevant fall in sensitivity in older patients (10;11). Indeed, in a retrospective analysis the use of an age-adjusted cut-off of the D-dimer (patient s age x 10 µg/l) in combination with an unlikely clinical decision rule greatly increased the number of patients above 50 years in whom PE could safely be excluded (12). These results need to be confirmed in a 10

4 Introduction and outline prospective study where patients are managed according to their age-adjusted D-dimer level. If the clinical probability of PE is likely or the D-dimer test is abnormal, further imaging is necessary to confirm or exclude the diagnosis. Next to the clinical decision rule-d-dimer strategy, computed tomography (CT-) scan has increasingly become the most preferred imaging test to either confirm or exclude PE (13). With the introduction of multi-detector row CT-scan, the sensitivity of the CT-scan has greatly improved, ranging from 83% to 100% with specificity ranging from 96% to 100% (14;15), and even small subsegmental emboli can now be visualized (16). Besides, compared to the previous reference standard, i.e. ventilation perfusion scintigraphy (if necessary followed by pulmonary angiography), advantages of CT-scan are that the CT-scan is easily accessible, quickly performed and non-invasive. Another potential advantage of the CT-scan is the capability of detecting other findings supporting an explanation for the patient s complaints or symptoms when PE is excluded (17). On the other hand, the newer generation of CT-scans increases the rate of subsegmental filling defects and the clinical relevance of these subsegmental emboli is a topic of debate (18). Besides, despite the improvement of diagnostic yield with the clinical decision rule-d-dimer strategy, of the patients with an indication for CT-scan only 20% to 30% indeed has a diagnosis of PE (19). This proportion is even lower in the United States, where it is approximately 10% (20). Additionally, CT-scan can also cause adverse effects, such as an increased lifetime risk of (breast) cancer from radiation exposure, especially in young women, and the risk of contrast nephropathy (21;22). These concerns force physicians to use a diagnostic strategy, which results in fewer CT-scans and the lowest possible false negative rates. Regarding the treatment and prognosis of PE, important questions have surfaced. Although most hemodynamically stable patients with PE benefit from standard anticoagulant treatment, the rates of residual thrombosis at the end of anticoagulant therapy and the short-term clot resolution with anticoagulant treatment is not well known. Nowadays, although without solid evidence for clinical relevance, physicians often perform repeat CT-scans after six months of anticoagulant treatment, as the presence of residual thrombotic obstruction appears to have two important implications. First, repeat scans after discontinuation of anticoagulant therapy may aid in the differentiation between residual and recurrent thrombi in the diagnostic workup of patients with suspected recurrent PE. This is of importance given the therapeutic consequences of prolonged or even lifelong anticoagulant treatment after a recurrence 11

5 Chapter 1 (23). Second, patients with residual thrombotic occlusion may be at increased risk of recurrent PE or chronic thromboembolic pulmonary hypertension (24). Finally, little attention has been paid to the quality of life in patients after PE. Outline of the thesis This thesis consists of two parts. The first part focuses on the diagnosis of PE. In chapter 2, an age-adjusted cut-off point (patient s age x 10 µg/l) of D-dimer levels was validated in four recently introduced and widely used clinical decision rules, which all four showed to perform equally well. In chapter 3, the performance of these four clinical decision rules was investigated in patients with cancer and suspected PE. An alternative diagnostic strategy, in which women younger than 50 years of age with a high risk of PE are investigated with the combination of a chest X-ray and perfusion scintigraphy, in order to avoid CT-scanning and thereby radiation exposure to the breasts, is prospectively evaluated in chapter 4. In chapter 5, the accuracy of the D-dimer test is tested in patients with zero, one or two items of the Wells score, and additionally, in chapter 6 we designed a new clinical decision rule that includes the D-dimer as a first step, with the aim to further lower the number of unnecessary CTscans. Next, in chapter 7 we studied whether alternative diagnoses observed on CTscans, ordered for PE, have diagnostic or therapeutic consequences. In chapter 8, we investigated whether the level of prothrombin fragments in serum and urine in patients with venous thromboembolism and myocardial infarction is elevated compared to healthy volunteers. Part II of this thesis focuses on the treatment and the prognosis of PE. An overview of the current treatment and the potential of the new oral anticoagulants in PE patients is presented, as well as the treatment in special populations, such as patients with obesity or severe renal failure, in chapters 9 and 10. Chapter 11 focuses on the resolution of the pulmonary clots in patients with acute PE, diagnosed with either a CT-scan or a perfusion-scan, and followed up by a similar scan after three weeks of anti-coagulant treatment. Furthermore, in chapter 12, residual pulmonary thrombi are investigated with a CT-scan after six months of anticoagulant treatment, by two independent radiologists. Chapter 13 investigated the clinical outcome of patients with subsegmental PE versus more proximal PE (segmental 12

6 Introduction and outline and central PE). The influence of the duration of complaints before CT-scanning on the D-dimer level and the prognosis of patients is described in chapter 14. The quality of life in patients with a history of PE is described and compared to patients with other (cardio-) pulmonary diseases in chapter 15. Reference List (1) Silverstein MD, Heit JA, Mohr DN, Petterson TM, O Fallon WM, Melton LJ, III. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998 Mar 23;158(6): (2) White RH. The epidemiology of venous thromboembolism. Circulation 2003 Jun 17;107(23 Suppl 1):I4-I8. (3) Douma RA, Mos IC, Erkens PM, Nizet TA, Durian MF, Hovens MM, et al. Performance of 4 Clinical Decision Rules in the Diagnostic Management of Acute Pulmonary Embolism: A Prospective Cohort Study. Ann Intern Med 2011 Jun 7;154(11): (4) 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 Mar;83(3): (5) 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 Dec 15;129(12): (6) The Christopher study investigators, van Belle A, Buller HR, Huisman MV, Huisman PM, Kaasjager K, et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006 Jan 11;295(2): (7) Righini M, Perrier A, de MP, Bounameaux H. D-Dimer for venous thromboembolism diagnosis: 20 years later. J Thromb Haemost 2008 Jul;6(7): (8) Gibson NS, Sohne M, Gerdes VE, Nijkeuter M, Buller HR. The importance of clinical probability assessment in interpreting a normal d-dimer in patients with suspected pulmonary embolism. Chest 2008 Oct;134(4): (9) Douma RA, van Sluis GL, Kamphuisen PW, Sohne M, Leebeek FW, Bossuyt PM, et al. Clinical decision rule and D-dimer have lower clinical utility to exclude pulmonary embolism in cancer patients. Explanations and potential ameliorations. Thromb Haemost 2010 Oct;104(4): (10) Rosendaal FR, van Hylckama Vlieg, Doggen CJ. Venous thrombosis in the elderly. J Thromb Haemost 2007 Jul;5 Suppl 1: (11) Righini M, Nendaz M, Le Gal G, Bounameaux H, Perrier A. Influence of age on the cost-effectiveness of diagnostic strategies for suspected pulmonary embolism. J Thromb Haemost 2007 Sep;5(9): (12) Douma RA, Le Gal G, Sohne M, Righini M, Kamphuisen PW, Perrier A, et al. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. BMJ 2010;340:c

7 Chapter 1 (13) Musset D, Parent F, Meyer G, Maitre S, Girard P, Leroyer C, et al. Diagnostic strategy for patients with suspected pulmonary embolism: a prospective multicentre outcome study. Lancet 2002 Dec 14;360(9349): (14) Quiroz R, Kucher N, Zou KH, Kipfmueller F, Costello P, Goldhaber SZ, et al. Clinical validity of a negative computed tomography scan in patients with suspected pulmonary embolism: a systematic review. JAMA 2005 Apr 27;293(16): (15) Stein PD, Fowler SE, Goodman LR, Gottschalk A, Hales CA, Hull RD, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 2006 Jun 1;354(22): (16) Patel S, Kazerooni EA, Cascade PN. Pulmonary embolism: optimization of small pulmonary artery visualization at multi-detector row CT. Radiology 2003 May;227(2): (17) Van Strijen MJ, Bloem JL, de Monye W, Kieft GJ, Pattynama PM, Berg-Huijsmans A, et al. Helical computed tomography and alternative diagnosis in patients with excluded pulmonary embolism. J Thromb Haemost 2005 Nov;3(11): (18) Carrier M, Righini M, Le Gal G. Symptomatic sub-segmental pulmonary embolism: what is the next step? J Thromb Haemost 2012 Jun 5. (19) Perrier A, Roy PM, Sanchez O, Le Gal G, Meyer G, Gourdier AL, et al. Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med 2005 Apr 28;352(17): (20) Penaloza A, Kline J, Verschuren F, Courtney DM, Zech F, Derrien B, et al. European and American suspected and confirmed pulmonary embolism populations: comparison and analysis. J Thromb Haemost 2012 Mar;10(3): (21) Einstein AJ, Henzlova MJ, Rajagopalan S. Estimating risk of cancer associated with radiation exposure from 64-slice computed tomography coronary angiography. JAMA 2007 Jul 18;298(3): (22) Hurwitz LM, Reiman RE, Yoshizumi TT, Goodman PC, Toncheva G, Nguyen G, et al. Radiation dose from contemporary cardiothoracic multidetector CT protocols with an anthropomorphic female phantom: implications for cancer induction. Radiology 2007 Dec;245(3): (23) Es van J, Douma RA, Gerdes VE, Kamphuisen PW, Buller HR. Acute pulmonary embolism. Part 2: treatment. Nat Rev Cardiol 2010 Nov;7(11): (24) Grifoni S, Vanni S, Magazzini S, Olivotto I, Conti A, Zanobetti M, et al. Association of persistent right ventricular dysfunction at hospital discharge after acute pulmonary embolism with recurrent thromboembolic events. Arch Intern Med 2006 Oct 23;166(19):