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INTRODUCTION
In 1997 the British Thoracic Society (BTS) published advice entitled “Suspected acute pulmonary embolism: a practical approach”.1 It was recognised that it would need updating within a few years. Subsequent publications in several areas (CT pulmonary angiography, d-dimer, clinical probability, low molecular weight heparin) now provide sufficient evidence to allow this advice to be updated as guidelines.
All the relevant literature published from January 1997 to December 2002 was located by searching the Medline and EmBase databases; some were meta-analyses and some were evidence based practice guidelines. Relevant papers published before 1997 not referenced in the earlier document were also retrieved.
As before, the text was compiled by members of the BTS on behalf of its Standards of Care Committee, with feedback from experts recommended by specialist societies and, as with the previous guideline, we approached international authorities who all readily agreed to comment on the drafts. We are indebted to these advisors.
These guidelines supersede the 1997 document, but many of the earlier concepts remain relevant. Where allusions are made to the previous document, this is shown as the page number in curly brackets {S18}. Papers from that document are not cited in the reference list, which therefore refers almost exclusively to publications from 1997 onwards. A similar structure to that in the previous guideline has been used, comprising a reference section, summary of recommendations, and a practical section for junior doctors.
It was decided that the updated guidelines would concentrate on suspected pulmonary embolism (PE) and only include deep vein thrombosis (DVT) where relevant, even though both are part of venous thromboembolism (VTE). Compared with DVT alone, PE is potentially more serious and has a differential diagnosis of other serious conditions; many hospitals have established local protocols for the diagnosis and treatment of DVT but not for suspected PE. Although VTE is common in hospitalised patients, recommendations on prophylaxis are beyond the scope of these guidelines.
Each section of these guidelines is followed by recommendations, graded according to standard criteria.2,3 The Appendix contains charts (with notes) designed to be modified, according to local consensus and facilities, for inclusion in hospital handbooks.
Each acute hospital should consider implementing the recommendations summarised in the box. Suggested topics for local audit are:
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adherence to agreed hospital protocol
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appropriate use of d-dimer, particularly in the emergency department
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adequacy of clinical information provided with imaging requests
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patient outcomes.
RISK FACTORS
Predisposing factors for VTE are summarised in table 1, derived from previous {S4} and subsequent information.4–15 However, the previous association with cigarette smoking has not been confirmed.16 The risk of VTE rises exponentially with age,10,13 but it is unclear to what extent this is an independent risk factor. The widespread use of prophylaxis in orthopaedic17 and general surgery has substantially reduced the incidence of postoperative VTE.
Risk factors for venous thromboembolism
VTE associated with travel is a topical issue; while the case remains to be proved,18 it is likely that air and road travel, particularly with longer journeys, is associated with a 2–4-fold increased risk.19–22
The increased risk with oestrogen therapy {S5} has been confirmed,23–25 especially with “third generation” agents.8,26,27 Three large studies28–30 showed PE in 1–2 of 7000 pregnancies, less than previously supposed; the majority occurred post-partum, particularly with pre-eclampsia, Caesarean section, and multiple births.
Testing for thrombophilia (which may be inherited or acquired) will identify haemostatic abnormalities (especially antiphospholipid syndrome and deficiencies of antithrombin III, factor V Leiden, protein C, or protein S) in 25–50% of patients with VTE.24,31,32 Usually these need to interact with acquired risk factors before thrombosis occurs,6 being otherwise uncommonly associated with idiopathic VTE.33 For example, the factor V (Leiden) defect, present in 5% of the population and 20% of patients presenting with thrombosis, in isolation increases the risk of VTE by 3–5-fold but, in conjunction with oestrogen therapy, this rises to 35-fold. However, the number to test to prevent an episode of VTE would be very high and, following such an event, oestrogens would be discontinued anyway. Secondly, screening for thrombophilia in pregnancy has been advocated, but even though factor V Leiden mutation is common in pregnant patients with VTE,34 its presence leads to VTE in less than 1 in 400 pregnancies.28 Thirdly, detecting one of the common thrombophilias does not predict a higher rate or earlier recurrence of VTE.35–37 For these reasons there are few situations in which testing for thrombophilia can be clearly recommended38,39; however, it may be worthwhile in (a) patients aged under 50 years presenting with recurrent idiopathic PE since half will be positive,40 and (b) where symptomatic VTE has been proved in several family members in more than one generation.
Summary of recommendations
Clinical
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All patients with possible PE should have clinical probability assessed and documented. [C]
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An alternative clinical explanation should always be considered at presentation and sought when PE is excluded. [C]
d-dimer
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Blood d-dimer assay should only be considered following assessment of clinical probability. [B]
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d-dimer assay should not be performed in those with high clinical probability of PE. [B]
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A negative d-dimer test reliably excludes PE in patients with low (SimpliRED, Vidas, MDA) or intermediate (Vidas, MDA) clinical probability; such patients do not require imaging for VTE. [B]
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Each hospital should provide information on sensitivity and specificity of its d-dimer test. [C]
Imaging
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CTPA is now the recommended initial lung imaging modality for non-massive PE. [B]
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Patients with a good quality negative CTPA do not require further investigation or treatment for PE. [A]
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Isotope lung scanning may be considered as the initial imaging investigation providing (a) facilities are available on site, and (b) chest radiograph is normal, and (c) there is no significant symptomatic concurrent cardiopulmonary disease, and (d) standardised reporting criteria are used, and (e) a non-diagnostic result is always followed by further imaging. [B]
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Where isotope lung scanning is normal, PE is reliably excluded [B] but a significant minority of high probability results are false positive. [B]
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In patients with coexisting clinical DVT, leg ultrasound as the initial imaging test is often sufficient to confirm VTE. [B]
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A single normal leg ultrasound should not be relied on for exclusion of subclinical DVT. [B]
Massive PE
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CTPA or echocardiography will reliably diagnose clinically massive PE. [B]
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Thrombolysis is the first line treatment for massive PE [B] and may be instituted on clinical grounds alone if cardiac arrest is imminent [B]; a 50 mg bolus of alteplase is recommended. [C]
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Invasive approaches (thrombus fragmentation and IVC filter insertion) should be considered where facilities and expertise are readily available. [C]
Treatment
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Thrombolysis should not be used as first line treatment in non-massive PE. [B]
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Heparin should be given to patients with intermediate or high clinical probability before imaging. [C]
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Unfractionated heparin (UFH) should be considered (a) as a first dose bolus, (b) in massive PE, or (c) where rapid reversal of effect may be needed. [C]
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Otherwise, low molecular weight heparin (LMWH) should be considered as preferable to UFH, having equal efficacy and safety and being easier to use. [A]
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Oral anticoagulation should only be commenced once VTE has been reliably confirmed. [C]
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The target INR should be 2.0–3.0; when this is achieved, heparin can be discontinued. [A]
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The standard duration of oral anticoagulation is: 4–6 weeks for temporary risk factors [A], 3 months for first idiopathic [A], and at least 6 months for other [C]; the risk of bleeding should be balanced with that of further VTE. [C]
Other
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Imaging should be performed within 1 hour in massive PE, and ideally within 24 hours in non-massive PE. [C]
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Testing for thrombophilia should be considered in patients aged under 50 with recurrent PE or in those with a strong family history of proven VTE. [C]
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Investigations for occult cancer are only indicated in idiopathic VTE when it is suspected clinically, on chest radiography, or on routine blood tests. [C]
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Current organisation for outpatient management of DVT should be extended to include stable patients with PE. [C]
There is an increased risk of cancer being detected within 6–12 months of a first episode of VTE, particularly in those with no other risk factors and/or recurrent episodes.41–45 Previously unrecognised cancer, present in 7–12% of those with idiopathic VTE, can usually be detected by a combination of careful clinical assessment, routine blood tests, and chest radiography41,46,47 and, if these are satisfactory, the current consensus is that it is not appropriate to proceed to tests such as ultrasound, CT scanning, or endoscopy. Moreover, in one large study the 1 year survival of patients with occult cancer was only 12% because most had regional or distant spread at diagnosis48 (the occurrence of VTE in patients already known to have cancer is similarly a poor prognostic factor49).
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Testing for thrombophilia should be considered in patients aged under 50 with recurrent PE or in those with a strong family history of proven VTE. [C]
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Investigations for occult cancer are only indicated in idiopathic VTE when it is suspected clinically, on chest radiography, or on routine blood tests. [C]
CLINICAL FEATURES
Large community studies show that the overall annual incidence of PE is 60–70 cases/100 000.10,50 Half of these patients develop VTE while in hospital or in long term care, and the rest are equally divided between idiopathic cases and those with recognised risk factors.51 In both these and in less representative series,52–56 in-hospital mortality rates ranged from 6% to 15%. In the most comprehensive and representative cohort,57 of the 814 who initially survived, 7% died within 1 week, 13% within 1 month, and 18% by 3 months. All found that a high proportion of early deaths are directly due to PE in spite of standard treatment. Adverse prognostic factors include clinically major embolism, cancer, congestive cardiac failure, and previous or current DVT.57,58 Non-fatal recurrence, particularly in the first year, is common in those with disabling neurological disease and cancer, and least likely in those with temporary risk factors.59
As reported before {S8}, the many abnormalities observed on clinical examination and routine investigations, particularly in the more severe cases, are of limited value in confirming a diagnosis of PE.60–70 Even in those with confirmed proximal DVT, respiratory symptoms are a poor predictor of concurrent PE.71
A new observation is that acute right heart strain in major PE can be detected by the release of cardiac troponin72–78 due to right ventricular muscle damage79,80; although such measurements may give prognostic information,77,78 their role in decision making is limited and they are of no diagnostic value in non-massive PE.81
The value of making an assessment of clinical probability was highlighted previously {S7} because it encourages good clinical assessment and allows better interpretation of isotope scan results; a new advantage is that, in combination with d-dimer assay, it can substantially reduce the need for imaging. The PIOPED observation that PE is only present in 9% of those with low clinical probability has, with two exceptions,82,83 been confirmed in several large studies,84–91 giving a negative predictive value of 89–96%. All these surveys involved experienced clinicians using defined criteria for assessing clinical probability under a research protocol. This is very different from the emergency room situation where decisions are often made by junior doctors whose ability to make an accurate estimate of the likelihood of PE is much less than that of their seniors.92 A simple and effective method of assigning clinical probability is therefore desirable. The method previously recommended {S17} has the advantage of simplicity. It was based on principles introduced successfully for DVT by a Canadian group who have since shown it to be equally valid and reproducible in PE,84,93,94 and it has independently been suggested elsewhere.95 It requires that the patient has clinical features compatible with PE—namely, breathlessness and/or tachypnoea, with or without pleuritic chest pain and/or haemoptysis {S6}. Two other factors are sought: (a) the absence of another reasonable clinical explanation, and (b) the presence of a major risk factor. Where (a) and (b) are both true the probability is high; if only one is true the probability is intermediate; and if neither is true the probability is low. Some hospitals prefer a scoring system that places patients into one of only two categories—PE likely and PE unlikely. Several such attempts have been made,87,93,96,97 but these are either inaccurate or require a complex scoring system that is difficult to remember, a criticism of other recent85,89,98 and previous such approaches; their superiority over simpler clinical assessment may also be marginal.89,91
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All patients with possible PE should have clinical probability assessed and documented. [C]
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An alternative clinical explanation should always be considered at presentation and sought when PE is excluded. [C]
INVESTIGATIONS
d-dimer
Following previous uncertainty {S11}, evidence is accumulating that d-dimer assays may have an important role in accurately excluding PE. On the other hand, raised levels of d-dimer do not infer the presence of VTE because such results are commonly found in hospitalised patients,83,99 obstetrics,100 peripheral vascular disease, cancer, and many inflammatory diseases, as well as increasing age. Several new systems offer improved sensitivities and a low incidence of false negatives; not surprisingly, false negative results are more common in those with subsegmental than larger emboli.101 A meta-analysis of studies looking at the newer second generation rapid d-dimer tests found sensitivities of 87–98%,102 but all have poor specificity—that is, a substantial number of false positives.
Three systems have been studied in large clinical studies of PE. A qualitative red cell agglutination (SimpliRED) test was used in 1177 patients103 with a test specificity of 68%. The overall negative predictive value (85%) was much higher (97%) in those with low clinical probability, and the combination of low clinical probability and negative SimpliRED d-dimer occurred in 44% of the cohort. Furthermore, a negative test also proved useful in patients with intermediate clinical probability and an indeterminate isotope lung scan. The value of combining clinical probability assessment and SimpliRED assay has been confirmed recently.104 Although a rapid test, it should be performed in the laboratory and not by the bedside.105
A second investigation used the rapid quantitative ELISA (Vidas) test in 918 patients with suspected PE (n=444) or DVT.106 Only those with a positive test were subsequently investigated, and treatment was withheld in the remaining 280; two had objectively confirmed VTE in the subsequent 3 months. This test, one of the most sensitive in head-to-head comparisons,107 has the potential advantage over SimpliRED in that it is also useful in those with intermediate clinical probability, but its lower specificity meant that imaging became unnecessary in only 29%, similar to the results of another group.83 As with all such tests, sensitivity and specificity need to be considered in conjunction with prevalence of disease in the population being studied108,109 which, in studies of PE, varies between 15% and 40%. With a PE prevalence of 20%, it can be excluded by negative d-dimer in one patient for every 1.8 tested using SimpliRED (if low clinical probability) or 3.0 using Vidas (if low/intermediate clinical probability).
Unlike previous latex tests {S11}, the MDA d-dimer test seems promising because, as well as having a specificity of 45%, a negative test excludes VTE in those with both intermediate and low clinical probability.110 Other tests appear potentially useful.83,111–113 The Medical Devices Agency is currently comparing 10 d-dimer assays in patients with suspected VTE, and other studies in Europe and North America are likely to clarify which are the most useful and reliable in limiting the number of imaging tests needed to exclude PE and in avoiding unnecessary hospital admissions. The assay chosen must have a high negative predictive value, have been validated in a management study, and take into account pre-test probability.
A potentially important study found that, if d-dimer levels are normal following cessation of anticoagulation, recurrence of idiopathic VTE is very unlikely.114
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Bloodd-dimer assay should only be considered following assessment of clinical probability. [B]
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d-dimer assay should not be performed in those with high clinical probability of PE. [B]
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A negatived-dimer test reliably excludes PE in patients with low (SimpliRED, Vidas, MDA) or intermediate (Vidas, MDA) clinical probability; such patients do not require imaging for VTE. [B]
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Each hospital should provide information on sensitivity and specificity of itsd-dimer test. [C]
Imaging
Isotope lung scanning
The PIOPED finding that PE can only be diagnosed or excluded reliably in a minority of patients by isotope lung scanning {S7} has been confirmed,115,116 and continuing attempts to refine technology117 and to redefine interpretative criteria118,119 will not materially improve this. Hence, the proposition {S9, 14} that further imaging is mandatory in all those with either an indeterminate lung scan or discordant clinical and lung scan probability continues to be emphasised.120 Nevertheless, clinicians frequently ignore such advice121–123 and, where in doubt, consider that it is better to treat than not.116,124–128 In a recent Dutch study PE was adequately confirmed or excluded in only 11% until an agreed national consensus was introduced but, even so, this figure then rose only to 55%129 and overall improvements nationally were also disappointing.122
It is still not universally realised that a normal scan reliably excludes PE.122,130–132 On the other hand, it is commonly concluded that a high probability lung scan is diagnostic of PE, although the PIOPED investigation showed this to be incorrect {S7} (some false positives were found in those with previous rather than current PE) and this has recently been confirmed.132 An indeterminate result is very common in those with symptomatic co-existing cardiopulmonary disease {S9}133—including acute or chronic airways disease and conditions causing intrapulmonary shadowing on the chest radiograph—and in the elderly87; it is also in these categories where interobserver variability is highest.134 This partly accounts for the finding that half of patients with an abnormal chest radiograph need further imaging133,135; this is much less likely when the chest radiograph is normal, but this only applies to a small number of those investigated for possible PE.135,136
Although national guidelines have been published on technical aspects of isotope lung scanning,137 there is no agreed consistent terminology for reporting, particularly in those of low and “intermediate” probability, and clinicians may reach erroneous conclusions.126,130,138 A valid interpretation is only possible when the following principles are followed139:
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a contemporaneous good quality erect chest radiograph should be available so that other clinical conditions that can cause ventilation/perfusion defects are not overlooked; and
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in abnormal lung scans knowledge of clinical probability is essential in interpreting the report’s meaning but must not influence its description.
The practice of 25 nuclear medicine departments in south-east England over a 1 year period (1999–2000) has been analysed140; there were 200 isotope lung scans per 100 000 population. In spite of a survey 5 years earlier which generated agreed guidelines, a third of units did not always have a current chest radiograph available, a third were unable to complete and report the test within 24 hours of request, three quarters did not have clinical probability included on the request form, and few had an out-of-hours emergency service. Similar variations are likely to be present nationally. Although most district general hospitals in the British Isles have access to isotope lung scanning, over a third do not have this available on site.121
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Isotope lung scanning may be considered as the initial imaging investigation providing (a) facilities are available on site, and (b) chest radiograph is normal, and (c) there is no significant symptomatic concurrent cardiopulmonary disease, and (d) standardised reporting criteria are used, and (e) a non-diagnostic result is always followed by further imaging. [B]
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Where isotope lung scanning is normal, PE is reliably excluded [B] but a significant minority of high probability results are false positive. [B]
Leg ultrasound
Because 70% of patients with proven PE have proximal DVT {S4}, leg ultrasound has been used in suspected PE (a) as an initial test in those with a clinical DVT, (b) as an initial test in all patients to reduce the need for lung imaging, and (c) after lung imaging, particularly isotope lung scanning, has given inconclusive information. Identification of DVT precludes the need for further tests. However, there seems to be insufficient awareness of the limited accuracy of compression ultrasound in detecting asymptomatic proximal DVT. In four recent studies proximal clot was found in only 23–52% of patients with confirmed PE.141–144 This compares with a figure of 60% using venography,145 with distal thrombus in a further 22%. A study of patients with non-diagnostic isotope lung scans and a single negative leg ultrasound scan found that one third did have PE on pulmonary angiography146; similar results were reported in those with a low probability lung scan.147 Although it is safe to withhold anticoagulation in patients with suspected DVT and a single negative leg ultrasound scan, these results cannot yet be extrapolated to those presenting with possible PE.
An attractive justification for considering leg imaging in patients with suspected PE is that, if negative, anticoagulation to prevent recurrence might be unnecessary, as has been shown for patients presenting with suspected DVT and a single negative leg ultrasound scan.148 In suspected PE, a 3 month VTE rate of only 0.5% has been found in such patients with negative leg imaging,84,149 but the protocol required serial studies which has major resource implications. Using one time leg ultrasound scanning in those with low clinical probability and a non-diagnostic isotope lung scan, the recurrence rate in untreated patients was higher at 1.7%.86 A negative single examination by ultrasound does not reliably exclude VTE in such patients, except in the few with no major risk factors and also no clinical DVT.150 An alternative strategy is to perform both computed tomographic pulmonary angiography (CTPA) and leg ultrasound in all patients with suspected PE, as in a recent large French multicentre study where 7% of those without confirmed PE had proximal DVT only.91 Such an approach has major resource implications.
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In patients with co-existing clinical DVT, leg ultrasound as the initial imaging test is often sufficient to confirm VTE. [B]
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A single normal leg ultrasound should not be relied on for exclusion of subclinical DVT. [B]
Conventional pulmonary angiography
The above approaches were devised because of the very limited use of conventional pulmonary angiography due to a combination of patchy availability, limited radiological experience, and the perception of clinicians that this invasive test is potentially dangerous. It has been seen as the gold standard against which other imaging modalities have been historically evaluated, but it is not always recognised that, with subsegmental clot, interobserver disagreement {S10} occurs in up to one third of cases151 and animal models that mimic this clinical situation have found sensitivity and positive predictive values of only 87–88% compared with necropsy.152 A few centres have developed facilities and expertise for selective angiography and catheter fragmentation of large emboli.
Computed tomographic pulmonary angiography (CTPA)
Our previous advice that conventional pulmonary angiography should be much more widely used {S14–15} has been rendered largely obsolete by the advent of CTPA. This has led to a revolution in diagnostic strategies and, in the UK, almost all hospitals currently lacking this technology121 are being funded to acquire the latest generation of fast multi-slice scanners (in order to meet national targets for cancer diagnosis and staging). Technical aspects are fully described in recent textbooks.153,154 CTPA is increasingly being used as an adjunct and, more recently, as an alternative to other imaging modalities, and is clearly superior in specificity to ventilation-perfusion isotope scanning.132,133,155–159 It also allows a quantitative assessment which correlates well with clinical severity160,161 and all investigators have found that, when PE is excluded, the true alternative diagnosis may be recognised. Interobserver agreement is good even with relatively inexperienced assessors155,162–167 and in patients with co-existing cardiorespiratory disease.168
Although studies comparing CTPA with conventional pulmonary angiography published before 2000 have been criticised on methodological grounds,169–171 they are more numerous and robust than the studies which led to isotope lung scanning becoming an accepted diagnostic tool. Most early investigators used 5 mm collimation and single detector CT scanning which limited their accuracy,172 but it is clear that results are better using defined protocols, thin section collimation, images being viewed at work stations, and familiarity with pitfalls in interpretation.165,173,174 The main disadvantage of CTPA compared with conventional pulmonary angiography is that subsegmental clot is less likely to be seen. However, most patients also have more proximal clot that can be reliably identified—94–96% in four studies151,175–177 although in a fifth it was only 78%178—findings corroborated in an animal model.152 Latest CT technology and techniques allow better identification of peripheral thrombus.177,179,180 Meticulous attention to technique—for example, in the timing of contrast—is necessary to achieve results comparable to those in published series, in all of which a small proportion of examinations are technically unsatisfactory. As well as directly demonstrating intra-vascular thrombus, CTPA may show secondary effects such as wedge shaped opacities or characteristic right ventricular changes.181,182
There has been a recent trend to analyse the accuracy of CTPA using clinical outcome measures rather than comparison with conventional angiography, and data are accumulating that it is safe to withhold anticoagulation when PE is excluded on CTPA. Early evidence came from reports in which it was used in conjunction with other imaging modalities,183–186 but three recent studies using CTPA alone found subsequent PE in only nine of 854 such patients (1.1%) by 3 months187–189; none of these studies used multi-slice scanners. This compares favourably with 3 month recurrence figures of 0.9% (7/796) for those with negative conventional pulmonary angiograms190–193 and 0.5% (6/1246) in patients with a normal isotope scan.149,150,187,193 It is likely to be better with the latest generation of scanners and may approach the figure of 0.4% (4/993) found in a very large study using electron beam CT, a third of whom had PE.194 In cancer patients with a high risk of PE, a negative CTPA is sufficient to exclude the diagnosis.195
In a large multicentre study in which all patients were investigated by both CTPA and leg ultrasound,91 those with negative tests and low or intermediate clinical probability of PE were not anticoagulated and in the following 3 months only one of 507 (0.2%) had definite PE. The 76 patients with negative tests but high clinical probability of PE underwent further lung imaging which identified PE in four (5%), but none had major intrapulmonary clot, the effect of withholding anticoagulation was not assessed, and multi-slice CTPA was not used. Using the latter technology another French group reported only one recurrence by 3 months in 91 patients with a negative test who were not anticoagulated, and that was in an elderly patient known to have a DVT.177
Multi-slice scanners also allow the option of imaging leg veins during the same procedure. Comparison has mainly been made with ultrasound rather than venography and results have been mixed.196–204 In a cohort of 541 patients with suspected PE the combined approach identified an additional 18% of patients where only the DVT could be identified,196 whereas in two later studies this figure was under 8%.204,205 Disadvantages include an increased radiation dose, particularly to the gonads,206 and longer scanning time, and currently few UK radiology departments routinely perform such a combined examination.
Compared with isotope scanning, CTPA (a) is quicker to perform, (b) rarely needs to be followed by other imaging, (c) may provide the correct diagnosis when PE has been excluded, (d) is now available in most hospitals, and (e) is easier to arrange urgently out of hours. Although most clinicians and radiologists recognise that CTPA should be the preferred initial imaging modality in suspected PE, current resources make this impracticable. The pressure on CTPA examinations can be substantially alleviated by prior measurements of clinical probability and d-dimer and/or selective use of isotope scanning. In a recent British study of 779 patients with suspected PE (present in a quarter), perfusion lung scans were performed in those with both a normal chest radiograph and no significant chronic respiratory disease; since this was normal in 231, CTPA was unnecessary in 30% of the whole cohort and only 13% required both investigations.136
There are very few studies of imaging in patients with chronic cardiorespiratory disease, those who are already inpatients, and those with underlying critical illness. These pose a major diagnostic problem because few can be confidently classified as low clinical probability, d-dimer is often positive,83,168 and isotope scans are usually non-diagnostic. Since isolated subsegmental thrombus could be dangerous in many of these patients, conventional angiography rather than CTPA has been advocated.207 However, a recent report of patients with a high incidence of symptomatic cardiorespiratory conditions (one third with proven PE) showed that, of the 81 patients not anticoagulated following a negative CTPA, a proven non-fatal PE occurred within 3 months in only two and another two died of unknown causes.168 In another similar study in 135 patients with chronic respiratory disease, two cases of presumed PE (both fatal) occurred by 3 months.208 Neither group used multi-slice CTPA which gives good image quality in patients with chronic obstructive pulmonary disease, including down to the subsegmental level.177
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CTPA is now the recommended initial lung imaging modality for non-massive PE. [B]
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Patients with a good quality negative CTPA do not require further investigation or treatment for PE. [A]
Other imaging modalities
Echocardiography
Echocardiography is diagnostic in massive PE52,54,209,210 but allows a firm diagnosis in only a minority of others.52,211,212 Although it can give prognostic information, it is of less value in predicting mortality than clinical features or the presence of acidosis.213 Use of the transoesophageal route improves diagnostic accuracy by more reliably demonstrating intrapulmonary and intracardiac thrombus and has been used during cardiopulmonary resuscitation,214 but other advantages over the transthoracic approach are marginal215–218 and availability is limited.
Transthoracic ultrasound
Transthoracic ultrasound219–221 accurately identifies peripheral wedge-shaped opacities due to focal pulmonary haemorrhage or infarction,222,223 particularly in patients with pleuritic pain. This technique should be considered as an adjunct rather than an alternative to other imaging; it is not widely used.
Magnetic resonance angiography
Magnetic resonance angiography appears promising both in human224,225 and animal models.226–229 It avoids ionising radiation but has poor sensitivity for subsegmental clot225,230 and limited access is likely to continue for several years.
Emergency imaging
Our previous recommendation that in “each acute hospital a strategy is developed for arranging urgent investigations in patients with life threatening PE” {S15} has been shown to be achievable.231 We previously advocated transthoracic echocardiography {S18} which can be performed at the bedside. CTPA is now widely available and, in some hospitals, may be quicker to arrange out of hours. In major PE it reliably demonstrates both proximal thrombus and acute right ventricular dilatation181 and, occasionally, interventricular septal displacement.232 Should major PE be excluded, the correct diagnosis is usually evident with either test.
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CTPA or echocardiography will reliably diagnose clinically massive PE. [B]
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Imaging should be performed within 1 hour in massive PE, and ideally within 24 hours in non-massive PE. [C]
TREATMENT
The pathophysiological processes occurring in acute PE have recently been described.233 Supportive therapy {S12} includes oxygen and, in some patients, analgesia. In hypotensive patients it is common practice to use plasma expanders and inotropic support.213 The effects of acute PE on right heart function due to arterial obstruction by thrombus are exacerbated by concomitant pulmonary vasoconstrictors, and animal studies on the effect of antagonists to these and of direct pulmonary vasodilators suggest that such agents have a potential future role in massive PE.234
Thrombolysis and embolectomy
If there has been a massive PE—that is, one so severe as to cause circulatory collapse—recommended practice is to use thrombolysis, the earlier the better.235 Evidence for reduction in mortality is sparse; two meta-analyses236,237 found a single randomised controlled trial of thrombolysis versus heparin which was terminated when all four patients given thrombolysis survived while all four given heparin died.238 Since massive non-fatal PE is uncommon and those who survive long enough to have imaging proof have a low mortality,56 it is unlikely that robust evidence for reduced mortality with thrombolysis will materialise. In patients with right heart thrombus—in itself an ominous finding {S11}—mortality with thrombolysis is a third of that with heparin.239
In patients with non-massive PE opinions on thrombolysis still vary, particularly in patients with right ventricular dysfunction.54,209,213,240–242 In three multicentre registries 22–42% of patients without cardiogenic shock received thrombolysis.53–55 One recent controlled study of patients with submassive PE found that emergency intervention was less likely in those given thrombolysis in addition to heparin, but there was no survival advantage.243 Since the risk of major haemorrhage is twice that with heparin,237,244,245 the current majority view remains {S14} that thrombolysis should be reserved for those with clinically massive PE. Thrombolysis is equally effective in the elderly,246 although they have an increased risk of major bleeding, as do patients with intracranial disease or hypertension.247,248
Although expensive, alteplase has the advantages that it is widely available and, unlike streptokinase, does not worsen hypotension. The preparation of urokinase for unblocking vascular lines has a dose too low for use in PE. New synthetic compounds are being developed.249,250 The dosage and administration of alteplase is the same as that familiar to junior doctors treating myocardial infarction. Streptokinase, which in PE used to be given over 12 hours, works better in PE if given in 2 hours.251,252 Elegant experiments in dogs253 have explained the clinical finding that thrombolysis is equally effective when given peripherally as when administered through a catheter positioned adjacent to the embolus254; the latter requires femoral artery cannulation with a high incidence of local bleeding.248,255 Where there are absolute contraindications to thrombolysis—rarely an important consideration in a life threatening situation—or where it has failed and the patient is critically ill, large emboli can be successfully fragmented using mechanical techniques via a right heart catheter256–262; animal models have confirmed their efficacy.263 Few centres can offer either this option or surgical embolectomy.264
The high mortality of PE in patients with acute right heart failure53,265 is greatly increased when hypotension, acidosis, or cardiac arrest is also present.53,213,214,264,266 PE accounts for 10% of patients admitted with non-traumatic sudden death and 50% of those arriving with electromechanical dissociation or asystole on ECG.267 In spite of aggressive treatment, very few survive to discharge.268 However, should cardiac arrest occur while in hospital and massive PE is strongly suspected clinically, an immediate intravenous bolus of 50 mg alteplase administered during cardiopulmonary resuscitation may be life saving, with the pulse returning within 3–30 minutes.269 The value of extracorporeal membrane oxygenation in cardiac arrest due to PE is unclear.270
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Thrombolysis is the first line treatment for massive PE [B] and may be instituted on clinical grounds alone if cardiac arrest is imminent [B]; a 50 mg bolus of alteplase is recommended. [C]
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Invasive approaches (thrombus fragmentation and IVC filter insertion) should be considered where facilities and expertise are readily available. [C]
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Thrombolysis should not be used as first line treatment in non-massive PE. [B]
Anticoagulation
In patients with PE, low molecular weight heparin (LMWH) compares as favourably with unfractionated heparin (UFH) as it does in those with DVT,271–273 not only in efficacy and unwanted effects but also with respect to outpatient versus inpatient management.274–277 It is likely that half of patients with PE could be managed without hospitalisation.274 The frequency of major haemorrhage may be slightly higher in those managed as outpatients, but care with selection and risk factors should mitigate this possible difference in hazard.275 Whereas the Cochrane review278 concluded that “in patients with pulmonary embolism it might be prudent to await further results of new studies”, a more recent influential American consensus stated that “treatment of VTE with LMWH has come of age”.273 Three questions remain:
-
Can LMWH alone be given from the outset or should a bolus of UFH (with a quicker onset of action) also be given at the same time? In all but one of the PE studies LMWH has followed an initial period of UFH therapy; in the single exception, primarily a study of proximal DVT, only 15% of patients had symptoms and signs of PE but all had high probability lung scans.279
-
Are the various LMWHs equivalent? There is no evidence to the contrary, but all agree that comparative studies are needed.273,275,278 There is good evidence that once daily treatment is as effective as twice daily treatment regimens.280
-
Does the equivalence of LMWH to UFH in the prevention of recurrence of PE extend beyond the period of anticoagulation?
Although LMWH allows outpatient treatment without the necessity for haematological monitoring, it has to be given parenterally. Preliminary work suggests that ximelagatran, a direct thrombin inhibitor, is a promising alternative, being effective in PE when given orally.281
There is little disagreement that anticoagulation with warfarin for 4–6 weeks is enough when PE has occurred in relation to a temporary risk factor.282–284 Our previous advice {S12} that, for a first episode of idiopathic PE, treatment for 3 months is sufficient is consistent with recent findings285,286; a study recommending a longer period was somewhat atypical in design and in selection of patients.35 However, the same evidence has been interpreted by North American authorities to advise treatment for 6 months.272,273 This debate has stimulated an ongoing BTS multicentre study of a wide cross section of patients to compare anticoagulation for 3 and 6 months. In such patients decisions could be guided by a d-dimer assay after treatment.114 There are insufficient data to recommend duration of treatment in recurrent idiopathic PE where clinical variables are likely to suggest appropriate decisions. In those with persisting risk factors current opinion advises indefinite anticoagulation, although there is an increased risk of bleeding and no reduction in mortality.40,273,287,288 There are no data to suggest that duration of anticoagulation should be influenced by the severity of PE or the presence of DVT.
Bleeding on treatment is common in elderly patients with co-morbidity, particularly early in treatment.289,290 A history of peptic ulcer disease is not, as previously thought {S13}, a risk factor although either a past history of gastrointestinal bleeding or concurrent use of aspirin is associated with higher bleeding rates.275,291 Where there is a significant risk of major bleeding and proximal DVT has been excluded, withholding anticoagulation may be considered,292 particularly in those with temporary risk factors. In all patients the risk of bleeding is related to both intensity and duration of anticoagulation.289,291,293 With LMWH as initial treatment and oral anticoagulation delivering an international normalised ratio (INR) of 2.0–3.0, the rate of major bleeding at 3 months is ⩽3%291 and mortality is ⩽0.5%.289,290
-
Heparin should be given to patients with intermediate or high clinical probability before imaging. [C]
-
Unfractionated heparin (UFH) should be considered (a) as a first dose bolus, (b) in massive PE, or (c) where rapid reversal of effect may be needed. [C]
-
Otherwise, low molecular weight heparin (LMWH) should be considered as preferable to UFH, having equal efficacy and safety and being easier to use. [A]
-
Oral anticoagulation should only be commenced once VTE has been reliably confirmed. [C]
-
The target INR should be 2.0–3.0; when this is achieved, heparin can be discontinued. [A]
-
The standard duration of oral anticoagulation is: 4–6 weeks for temporary risk factors [A], 3 months for first idiopathic [A], and at least 6 months for other [C]; the risk of bleeding should be balanced with that of further VTE. [C]
-
Current organisation for outpatient management of DVT should be extended to include stable patients with PE. [C]
Inferior vena caval (IVC) filters
Inferior vena caval (IVC) filters are mainly used where anticoagulation is contraindicated or unsuccessful in preventing recurrence of PE from continuing DVT. Current opinion on their use to prevent PE displays less enthusiasm than previously.273,294 The first randomised trial was published in 1998.295 Filters were effective for the first 12 days but neither short nor long term mortality was improved and at 2 years the recurrence of DVT was greater in the filter groups. A large retrospective study296 agreed that readmission for recurrent PE was unchanged and DVT was more common, as others have found.297 The presumed advantages of removable filters remain to be proven.298 If necessary—for example, in intensive care units—filters can be inserted at the bedside.299
Special situations
Pregnancy
Current obstetric practice300–302 is based on extrapolation from results in non-pregnant populations and on observational studies. Warfarin is teratogenic and should be avoided until after delivery; its use does not preclude breast feeding. Treatment during pregnancy should therefore be with therapeutic doses of LMWH303 or subcutaneous calcium heparin. Approaching delivery, UFH should be substituted because its anticoagulant effect can more easily be reversed if necessary; there are different views about whether it should be discontinued or the dose reduced 4–6 hours before the expected time of delivery. It is advised that anticoagulation should continue for 6 weeks after delivery or for 3 months after the initial episode, whichever is the longer.
Cancer
In patients with cancer304–306 initial treatment with heparin and warfarin is given in the standard manner, but the relative risk of recurrence is 3 and of bleeding is 6 compared with other patients.49,305 In the absence of evidence from randomised trials in this population, duration of treatment is arbitrary. For those with recurrence in spite of adequate anticoagulation, options include: (a) aiming for a higher INR of 3.0–3.5 (which further increases the risks of bleeding), (b) switching to long term LMWH while continuing anticoagulation, or (c) inserting an IVC filter, the value of which is questionable.307
APPENDIX: SUMMARY CHARTS AND NOTES FOR JUNIOR DOCTORS
Management of suspected non-massive pulmonary embolism (A) with isotope lung scanning off site only and (B) with isotope lung scanning available on site.
Summary notes for junior doctors
-
Most patients with PE are breathless and/or tachypnoeic >20/min; in the absence of these, pleuritic chest pain or haemoptysis is usually due to another cause.
-
Clinical probability in patients with possible PE may be assessed by asking:
-
is another diagnosis unlikely (chest radiograph and ECG are helpful)?
-
is there a major risk factor (recent immobility/major surgery/lower limb trauma or surgery, pregnancy/post partum, major medical illness, previous proven VTE)?
Low = neither; Intermediate = either; High = both. Some hospitals prefer to use a scoring system to classify into only low or high (see main document)
-
-
d-dimer is very helpful if used wisely:
-
it is not a routine “screening” test for PE;
-
it should only be considered where there is reasonable suspicion of PE (see 1 above);
-
only a negative result is of any value.
It should not be performed:
-
where an alternative diagnosis is highly likely;
-
if clinical probability is high;
-
in probable massive PE.
Validated tests that, if negative, exclude PE are:
-
SimpliRED (agglutination) for low clinical probability only
-
Vidas (ELISA) for low/intermediate clinical probability
-
MDA (latex) for low/intermediate clinical probability
-
-
Leg ultrasound is an alternative to lung imaging in those with clinical DVT.
-
Isotope lung scanning is not recommended if:
-
unavailable on site, or
-
the patient has chronic cardiac or respiratory disease, or
-
the chest radiograph is abnormal.
The clinical significance of the report is:
-
normal = no PE
-
scan + clinical probability both low = no PE
-
scan + clinical probability both high = PE present
-
any other = needs CTPA
-
-
In those with high clinical probability and negative CTPA, valid alternatives are:
-
conclude that PE has been excluded and stop heparin;
-
consider further imaging for VTE (leg ultrasound, conventional pulmonary angiography);
-
seek specialist advice.
-
-
Outpatient treatment may be considered if:
-
the patient is not unduly breathless, and
-
there are no medical or social contraindications, and
-
there is an efficient protocol in place (e.g. as for outpatient DVT management).
-
Management of probable massive pulmonary embolism.
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Footnotes
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↵* Guideline Development Group: I A Campbell (also Royal College of Physicians), A Fennerty, A C Miller (Chairman)
-
UK advisors: T Baglin (Royal College of Pathologists & British Society for Haematology), S Gibbs (British Cardiac Society), H Gray (British Nuclear Medicine Society), D Hansell (Royal College of Radiologists), J Reid (Royal College of Radiologists)
-
International advisors: H Bounameaux (Switzerland), M Remy-Jardin (France), P Wells (Canada)
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