SEMINAR
`
`Seminar
`
`Pulmonary embolism
`
`Samuel Z Goldhaber
`
`Pulmonary embolism (PE) is a common illness that can cause death and disability. It is difficult to detect because
`patients present with a wide array of symptoms and signs. The clinical setting can raise suspicion, and certain
`inherited and acquired risk factors predispose susceptible individuals. D-dimer concentration in blood is the best
`laboratory screening test, and chest CT has become the most widespread imaging test. Treatment requires rapid and
`accurate risk stratification before haemodynamic decompensation and the development of cardiogenic shock.
`Anticoagulation is the foundation of therapy. Right-ventricular dysfunction on echocardiography and higher than
`normal concentrations of troponin identify high-risk patients who might need escalation of therapy with thrombolysis
`or embolectomy even if the blood pressure is normal on presentation. When patients are admitted to medical wards or
`when patients undergo surgery, their physicians should prescribe prophylactic measures to prevent PE. After hospital
`discharge, prophylaxis should continue for about a month for patients at high risk of thromboembolism.
`
`Pulmonary embolism (PE) is a common, potentially life-
`threatening cardiopulmonary illness that has only recently
`attracted the attention of the general public, when a
`healthy young woman died of PE shortly after a flight
`from Australia to the UK. Although PE can be difficult to
`diagnose, early recognition is important because prompt
`medical or surgical
`intervention can be
`life-saving.
`Therefore, physicians, health-care providers, and the
`public need to understand the rapidly progressing
`advances in PE epidemiology, pathophysiology, diagnosis,
`treatment, and prevention strategies. The interdisciplinary
`nature of PE means that knowledge about this disease can
`no longer be consigned to the domain of specialists.
`
`Epidemiology
`Although PE and deep venous thrombosis (DVT) can be
`notoriously difficult to diagnose,1 hospital admission rates
`for venous thromboembolism (VTE) increased in the UK
`in the 1990s.2 Despite challenges in detection of VTE,
`cohort studies show consistency in incidence estimates
`among western populations. In the Brest district of
`France, the annual incidence was 1·83 per 1000.3 In
`Olmsted County, MN, USA, the most recent annual
`incidence estimate was 1·22 per 1000 among adults.4 In
`the Longitudinal Investigation of Thromboembolism
`Etiology, which combined two separate US cross-
`sectional studies totalling 148 054 person-years, the
`annual incidence was 1·45 per 1000.5 If the annual
`incidence of recognised VTE is 1·50 per 1000, and if only
`one of every three cases of VTE is detected, the USA,
`with a population of almost 300 million, has about
`450 000
`recognised
`incident cases and 900 000
`unsuspected incident cases, totalling about 1 350 000
`VTE cases each year.
`Mortality from recognised PE is higher than generally
`acknowledged. In a population-based cohort study from
`
`Lancet 2004; 363: 1295–305
`
`Cardiovascular Division, Brigham and Women’s Hospital, Harvard
`Medical School, Boston, MA 02115, USA (S Z Goldhaber MD)
`Correspondence to: Dr Samuel Z Goldhaber, Brigham and Women’s
`Hospital, 75 Francis Street, Boston, MA 02115, USA
`(e-mail: sgoldhaber@partners.org)
`
`Olmsted County, the 30-day mortality rate after PE or
`DVT was 28%.6
`In the International Cooperative
`Pulmonary Embolism Registry of 2454 consecutive
`patients from 52 institutions in seven countries, the
`3-month mortality rate was 17·4 %.7 In a Japanese registry
`of 533 patients with PE, the in-hospital mortality rate was
`14·0%.8 Many patients die from underlying comorbid
`disorders,
`especially
`cancer
`and
`cardiorespiratory
`diseases.9 The mortality from PE in registries such as the
`international one mentioned above, which enrol
`consecutive patients without any exclusions, is far higher
`than that in selective registries such as the Prospective
`Investigation of Pulmonary Embolism Diagnosis, in which
`the 1-year mortality rate from PE was 2·5%.10 In an
`overview of 1302 patients in five clinical studies of PE, 19
`died of PE and there were 11 other sudden deaths, giving
`a low overall mortality rate of only 2·3%.11
`
`Risk factors
`Understanding of risk factors for VTE12,13 will increase the
`likelihood that DVT and PE can be diagnosed and
`prevented. These factors include environmental, natural,
`and hormonal influences (panel 1).
`
`Travel
`Long-haul air travel is a rare (0·4 cases per million
`passengers) risk factor for massive PE.14 The risk increases
`substantially with flight distances of 5000 km or more.
`
`Search strategy and selection criteria
`
`I subscribe to about 15 journals in internal medicine,
`cardiology, haematology, and pulmonary disease. I use a
`"tear and file" system to track relevant articles. To ensure
`that I have not missed important articles in other journals, I
`check the venous thrombosis articles weekly on the AMEDEO
`web page. For selection in this seminar, I searched MEDLINE
`(1993–2003) with the search terms "pulmonary embolism"
`and "clinical" and "OVID full text". I chose mostly recent
`articles published in 2000–2003. I emphasised papers from
`journals with high impact factors that add critical knowledge
`to this field. I also included 22 articles recommended by the
`reviewers of this seminar.
`
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`
`MYLAN - EXHIBIT 1019
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`SEMINAR
`
`Passengers at particularly high risk include those older
`than 50 years, and individuals with a history of previous
`VTE, thrombophilia, limitation of mobility, cancer, or
`large varicose veins.
`
`Obesity
`The magnitude of risk associated with obesity is related to
`the body-mass
`index. The Nurses’ Health Study
`identified risk factors for PE among a cohort of initially
`healthy female nurses, with 1 619 770 person-years of
`
`Panel 1: Risk factors for PE
`
`Environmental
`Long-haul air travel
`Obesity
`Cigarette smoking
`Hypertension
`Immobility
`
`Natural
`Increasing age
`
`Women’s health
`Oral contraceptives, including progesterone-only and
`especially third-generation pills
`Pregnancy
`Hormone replacement therapy
`
`Medical illness
`Previous PE or DVT
`Cancer
`Congestive heart failure
`Chronic obstructive pulmonary disease
`Diabetes mellitus
`Inflammatory bowel disease
`Antipsychotic drug use
`Chronic in-dwelling central venous catheter
`Permanent pacemaker
`Internal cardiac defibrillator
`Stroke with limb paresis
`Nursing-home confinement or current or repeated hospital
`admission
`Varicose veins
`
`Surgical
`Trauma
`Orthopaedic surgery, especially total hip replacement, total
`knee replacement, hip fracture surgery, knee arthroscopy
`General surgery, especially for cancer
`Gynaecological and urological surgery, especially for cancer
`Neurosurgery, especially craniotomy for brain tumour
`
`Thrombophilia
`Factor V Leiden mutation
`Prothrombin gene mutation
`Hyperhomocysteinaemia (including mutation in
`methylenetetrahydrofolate reductase)
`Antiphospholipid antibody syndrome
`Deficiency of antithrombin III, protein C, or protein S
`High concentrations of factor VIII or XI
`Increased lipoprotein (a)
`
`Non-thrombotic
`Air
`Foreign particles (eg, hair, talc, as a consequence of
`intravenous drug misuse)
`Amniotic fluid
`Bone fragments, bone marrow
`Fat
`Cement
`
`follow-up.15 The relative risk of PE was 1·7 (95% CI
`1·1–2·7)
`for
`those with a body-mass
`index of
`25·0–28·9 kg/m2 and 3·2 (1·7–6·0) for those with a body-
`mass index of 29·0 kg/m2 or higher. In the International
`Cooperative Pulmonary Embolism Registry,
`the
`proportion of patients with a body-mass
`index of
`29·0 kg/m2 or higher was 29%.7 Even in Japan, with a
`much
`leaner population than western countries, a
`prospective PE registry found that body-mass index was
`25·3 kg/m2 or higher in 34% of cases.8
`
`Women’s health
`Oral contraceptives, pregnancy, and postmenopausal
`hormone replacement therapy raise the risk of PE.
`Inherited prothrombotic states further increase the risk.
`First-generation oral contraceptives contained more
`than 50 µg oestrogen. They were associated with an
`alarming increase in the frequency of massive PE and
`were withdrawn from the market in 1989. Second-
`generation oral contraceptives, containing less than 50 µg
`oestrogen, were introduced in the USA in 1967, but an
`excess, albeit lower, risk of VTE persisted. Third-
`generation
`oral
`contraceptives
`contain
`newer
`progestagens, such as desogestrel or gestodene, which
`improve acne and hirsutism. However, they cause adverse
`haemostatic changes, including acquired resistance to
`activated protein C16 and therefore increase the risk of
`VTE more than second-generation pills. Increasing age
`and cigarette smoking further increase the thrombotic risk
`among users of oral contraceptives.17
`Despite the increased relative risk of VTE from oral
`contraceptives, the absolute risk of fatal PE is low. In a
`New Zealand study, the absolute risk of death from PE in
`current users was estimated as one per 100 000 woman-
`years. Among the women who died, the median age was
`29 years. The risk of fatal PE was twice as high among
`women taking third-generation oral contraceptives.18
`A history of PE or DVT is an absolute contraindication
`to oral contraceptives. Relative contraindications include
`a strong
`family history of VTE or an
`inherited
`prothrombotic state, such as factor V Leiden or the
`prothrombin gene mutation. Whether women with a
`family history but no personal history of VTE should be
`screened
`for prothrombotic states
`is controversial.
`Overall, oral contraceptives are safe and effective. The
`absolute risk of VTE is very low.
`In pregnancy, the risk of PE increases with time, and
`most cases of VTE occur during pregnancy rather than
`post partum. Increasing maternal age and caesarean-
`section delivery increase the likelihood of VTE.19 Inherited
`prothrombotic states are associated with obstetric
`complications20 and with late fetal loss.21
`The Women’s Health Initiative
`is a randomised
`placebo-controlled primary prevention trial that enrolled
`16 608 women to assess the major benefits and risks of
`postmenopausal hormone replacement therapy.22 The trial
`used a combined oestrogen and progesterone preparation
`that is most commonly prescribed in the USA. Though
`the trial duration was planned to be 8·5 years, the study
`was stopped early because overall health risks exceeded
`benefits after an average of 5 years of follow-up. The
`hazard ratio for PE in the treated group was twice that for
`controls. The absolute excess risk of PE was 8·0 per
`10 000 woman-years. In a meta-analysis of 12 studies, the
`relative risk of VTE was 2·1 among current users and was
`highest (3·5) during the first year of use.23
`such as
`Selective oestrogen-receptor modulators
`raloxifene increase the risk of PE. In a study on prevention
`of breast cancer, 7705 postmenopausal women were
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`
`

`

`assigned raloxifene or placebo; by 40 months of follow-up
`the rate of PE was three times higher in patients assigned
`raloxifene than in those assigned placebo (0·3% vs 0·1%).
`The rate of DVT was also three times higher (0·7% vs
`0·2%).24
`Oestrogen agonists-antagonists such as tamoxifen are
`used to treat or prevent breast cancer. In a trial of
`7152 women randomly assigned tamoxifen or placebo,
`the VTE rate was 2·5 times greater in the tamoxifen group
`(1·20% vs 0·47%).25
`
`Cancer
`In patients with known cancer who develop VTE,
`recurrence and bleeding complications are common with
`conventional heparin followed by oral anticoagulation.26
`Low-molecular-weight heparin as monotherapy without
`oral anticoagulation can halve the rate of recurrence
`compared with oral anticoagulation.27
`Cancer, occult at the time of PE diagnosis in many
`cases, predisposes to PE. In the Swedish Cancer Registry,
`the risk of discovering a newly diagnosed cancer was
`increased for at least 2 years after the diagnosis of VTE.28
`However, when such cancers are discovered, they
`generally become apparent at an advanced stage and
`confer a poor prognosis.29 Cancer should be suspected,
`especially in patients who have idiopathic VTE and
`recurrence during follow-up.30
`
`Thrombophilia
`Inherited and acquired risk factors for PE commonly
`interact. In most inherited thrombophilias, impaired
`neutralisation of thrombin or failure to control thrombin
`generation causes VTE.31 To help define the role of
`heritability of the prethrombotic state, quantitative
`genetic-model fitting for hypercoagulability was done
`among participants in the St Thomas’ UK Adult Twin
`Registry.32 There was a high degree of heritability for
`markers of coagulation and inhibition of fibrinolysis,
`indicating substantial genetic control over fibrin formation
`and fibrinolysis.
`Factor V Leiden is an autosomal dominant single point
`mutation (G→A) that brings about resistance to activated
`protein C and an increased predisposition to VTE
`(roughly three times). The carrier frequency ranges from
`3% to 7%, and the mutation is especially prevalent in
`northern European people.33 Among participants in the
`Physicians’ Health Study, the carrier frequency was 5·3%
`for white Americans, 2·2% for hispanic Americans, 1·2%
`for African Americans, 0·45% for Asian Americans, and
`1·2% for native Americans.34 There is conflicting evidence
`on whether patients with VTE and factor V Leiden have
`an increased rate of recurrence after anticoagulation is
`discontinued compared with individuals who do not have
`this mutation.35,36
`A single point mutation (G→A at position 20210) has
`been identified in the prothrombin gene, which causes an
`increased risk of VTE.37 As with factor V Leiden,
`inheritance
`is autosomal dominant. However,
`the
`magnitude of the effect is slightly less than that of factor
`V Leiden.38
`Hyperhomocysteinaemia is associated with VTE and is
`most commonly caused by an acquired nutritional
`deficiency of folate exacerbated by inadequate intake of
`vitamin B12 or vitamin B6. Folate antagonists, such as
`methotrexate and phenytoin or vitamin B6 antagonists,
`such as oestrogens, tobacco, or theophylline, also raise
`homocysteine concentrations. Impaired renal function
`can cause hyperhomocysteinaemia because homocysteine
`is predominantly metabolised by the kidneys.39
`
`SEMINAR
`
`The antiphospholipid antibody syndrome, an acquired
`disorder, is the most ominous hypercoagulable state for
`PE. Anatomically large and recurrent VTE is the most
`common clinical manifestation of this syndrome, but
`increases in antibodies to cardiolipin are also associated
`with myocardial infarction, stroke, and first-trimester
`miscarriage.40
`laboratory diagnosis of
`in
`Despite
`advances
`hypercoagulability, predisposing thrombophilic states are
`identifiable in only a minority of patients with VTE.
`Therefore, the most important action is to obtain a careful
`family history. Patients and their families should be
`reassured
`that
`some
`asymptomatic
`carriers
`of
`prethrombotic genetic risk factors will never develop
`clinical evidence of PE or DVT. There is no published
`evidence to support screening of first-degree relatives of
`patients with thrombophilia.41
`
`Pathophysiology
`Venous stasis and endothelial damage predispose to
`VTE, especially among patients with underlying hyper-
`coagulable states. Those with previous PE or DVT are
`particularly susceptible to recurrences. Most cases of PE
`result from thrombi that originate in the pelvic region or
`deep veins of the leg. When venous thrombi become
`dislodged from their sites of formation, they move
`through the venous system to the pulmonary arterial
`circulation. Extremely large emboli can lodge at the
`bifurcation of the pulmonary artery, forming a “saddle
`embolus”. More commonly, however, a pulmonary vessel
`of second, third, or fourth order is affected. In rare cases,
`thrombi in the axillary, subclavian, or other arm veins
`embolise to the pulmonary arteries.42
`PE can have the following pathophysiological effects:
`increased pulmonary vascular resistance resulting from
`vascular
`obstruction,
`neurohumoral
`agents,
`or
`pulmonary-artery baroreceptors; impaired gas exchange
`caused by increased alveolar dead space from vascular
`obstruction and hypoxaemia from right-to-left shunting,
`as well as impaired transfer of carbon monoxide due to
`loss of gas exchange surface; alveolar hyperventilation
`owing to reflex stimulation of irritant receptors; increased
`airway resistance resulting from bronchoconstriction; and
`decreased pulmonary compliance caused by lung oedema,
`lung haemorrhage, and loss of surfactant.
`
`Right-ventricular dysfunction
`The haemodynamic response to PE depends on the size of
`the embolus, coexisting cardiopulmonary disease, and
`neurohumoral activation. Pulmonary-artery obstruction
`and circulating neurohumoral substances decrease the
`pulmonary vascular bed and cause an increase in right-
`ventricular afterload. As right-ventricular and pulmonary-
`artery pressures rise, the right ventricle dilates, becomes
`hypokinetic, and ultimately fails. Progressive right-heart
`failure leads to reduced forward cardiac output and is the
`cause of death from acute PE in most cases.
`Sudden increases in right-ventricular pressure adversely
`affect left-ventricular function because of the anatomical
`juxtaposition of the two ventricles and ventricular
`interdependence. Moderate right-ventricular hypertension
`can displace the interventricular septum towards the left
`ventricle, resulting in decreased left-ventricular diastolic
`filling and end-diastolic volume. The subsequent
`reduction in coronary-artery perfusion pressure to the
`overloaded right ventricle can cause progressive right-
`ventricular
`ischaemia and failure. Ultimately, right-
`ventricular infarction, circulatory arrest, and death can
`ensue.43
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`

`SEMINAR
`
`Diagnosis
`Clinical suspicion
`Diagnosis of PE poses a major challenge because classic
`symptoms and signs are not present in many cases. PE
`can present with subtle findings in young, previously
`healthy patients who have excellent cardiac reserve. With
`increasing age, PE tends to masquerade as other illnesses
`such as acute coronary syndrome or exacerbation of
`chronic obstructive pulmonary disease. Accurate
`diagnosis of PE is particularly difficult when patients
`present with two concurrent illnesses, such as obvious
`pneumonia plus occult PE or obvious congestive heart
`failure plus occult PE. Such patients may not improve
`clinically despite appropriate treatment for the apparent
`illness, until the PE is also recognised and treated.
`Detection of PE begins with consideration of VTE as a
`diagnostic possibility. The clinical scenario is crucial in
`assessing the likelihood of PE. Wells and colleagues44 have
`developed a rapid seven-feature bedside assessment that is
`useful because almost half of their study patients could be
`classified as “PE unlikely”. The researchers designated a
`score of 4·0 or less as PE unlikely. In this low-risk group,
`only about 5% of patients were subsequently found to
`have PE. The seven features are: clinical signs and
`symptoms of DVT (3·0 points); an alternative diagnosis is
`less likely than PE (3·0 points); heart rate above 100 bpm
`(1·5 points); immobilisation or surgery in the previous
`
`History
`Physical examination
`Clinical setting
`
`Assess clinical
`likelihood
`
`4
`
`Electrocardiogram
`Chest radiograph
`
`Patient
`already in
`hospital
`
`Patient in
`emergency
`department
`
`v
`D-dimer
`
`Normal
`
`High
`
`No PE
`
`Chest CT
`
`Lung scan if
`contrast allergy
`or renal insufficiency
`
`Normal
`
`Positive
`
`Equivocal
`
`Normal
`
`Ultrasonography
`of deep leg veins
`
`Positive
`
`Negative
`
`v
`No PE
`
`Treat for PE
`
`No PE
`
`Consider
`pulmonary
`angiography
`
`Figure 1: Diagnostic algorithm for suspected PE
`
`4 weeks (1·5 points); previous DVT or PE (1·5 points);
`haemoptysis (1·0 point); and cancer, being treated
`currently or within the previous 6 months or palliative
`(1·0 point).
`For optimum diagnostic accuracy, symptoms and signs
`should be integrated with appropriate laboratory tests,
`including electrocardiography, chest radiography, and,
`when available, D-dimer testing. In many cases, no
`further diagnostic
`investigation
`is warranted. When
`appropriate, though, imaging tests, such as a chest CT or
`lung scan, should be done (figure 1).
`
`Initial diagnostic studies
`The electrocardiogram (figure 2) is useful to help exclude
`a myocardial infarction with ST-segment elevation and
`acute pericarditis. In patients with large PE, pulmonary
`hypertension and right-ventricular strain cause incomplete
`or complete right bundle-branch block, T-wave inversion
`in leads V1 to V4, an S wave in lead I, and both a Q wave
`and an
`inverted T wave
`in
`lead III.45 A normal
`electrocardiogram is very unusual in patients with acute
`PE.
`The chest radiograph cannot be used to diagnose or
`exclude PE. It is useful in the differential diagnosis
`because it can detect pneumonia, pneumothorax, rib
`fracture, and congestive heart failure. Common abnor-
`malities
`in patients with
`large PE
`include cardiac
`enlargement,
`pulmonary-artery
`enlargement,
`and
`oligaemia of the embolised lung.46 In patients with small
`PE, a small wedge-shaped density at the periphery of the
`lungs
`indicates pulmonary
`infarction—“Hampton’s
`hump”.
`
`Laboratory studies
`Testing of the arterial blood for hypoxaemia and
`calculation of the alveolar–arterial oxygen gradient have
`been basic tools in the investigation of PE for a long time.
`However, comparison of blood gas results with pulmonary
`angiography has shown that hypoxaemia is not specific
`and does not serve as a useful triage tool in patients with
`suspected PE.47 Furthermore, the alveolar–arterial oxygen
`gradient is normal in about 20% of patients with
`angiographically proven PE.48
`The D-dimer blood test has practical usefulness in the
`diagnostic investigation of some patients with suspected
`PE. Plasma D-dimers are cross-linked fibrin derivatives
`produced when fibrin is degraded by plasmin.49 Among
`most patients with PE, endogenous fibrinolysis (which
`was clinically ineffective in preventing thromboembolism)
`results in a rise in the amount of D-dimer circulating in
`plasma. By contrast, a normal D-dimer concentration has
`a very high negative predictive value for excluding the
`diagnosis of PE. However, raised D-dimer concentrations
`are not specific for PE and are observed among patients
`with myocardial
`infarction, pneumonia, sepsis, and
`cancer, during the second and third trimesters of
`pregnancy, and after surgery. Therefore, this test is most
`useful in the setting of the emergency department,
`because most patients already in hospital have raised
`D-dimer concentrations.
`At the Emergency Department of Brigham and
`Women’s Hospital, we introduced a requirement that the
`D-dimer ELISA was done for all patients with suspected
`acute PE.50 After a year, we found that 559 of 1106
`D-dimer assays had raised results and 547 were normal.
`Only two patients with normal D-dimer concentrations
`had PE. Thus, the sensitivity of the D-dimer ELISA for
`acute PE was 96·4%, and the negative predictive value
`was 99·6%. Therefore, chest CT and lung scanning are
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`SEMINAR
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`utn 12
`
`aVR
`
`i
`
`1
`
`V I
`
`V4
`
`II
`
`aVL
`
`vi
`
`7-7
`
`V6
`
`Figure 2: Electrocardiogram of a haemodynamically stable 63-year-old woman
`The patient presented with acute PE and moderately severe right-ventricular dilatation and dysfunction on echocardiography. The electrocardiogram shows
`an S wave in lead I, Q wave in lead III, and T-wave inversion in leads III, AVF, and V1–V4 (the McGinn-White pattern), which is typical of right-ventricular
`strain due to massive PE.
`not indicated for most patients with normal D-dimer
`results. This strategy may improve diagnostic efficiency
`and reduce costs. However, there is not yet enough
`evidence to stop the investigation for PE in patients with
`high
`clinical
`probability
`and normal D-dimer
`concentrations.51,52 Such evidence may soon emerge.
`
`lung
`alternative diagnoses can be established on
`parenchymal images that are not evident on chest
`radiography.
`Chest CT takes less than 30 s with a single breath-hold
`to minimise respiratory motion. Although excellent
`vascular opacification of the pulmonary arteries with
`contrast agent can be achieved in most cases, the major
`limitation of conventional chest CT has been failure to
`detect PE beyond
`third-order pulmonary arterial
`branches.58 In a prospective study with first-generation
`CT, the sensitivity of CT compared with angiography was
`70%.58 Other management studies are needed to show the
`safety of withholding anticoagulant therapy in patients
`with normal chest CT. With the newer multi-row detector
`CT scans, four slices can be acquired simultaneously
`during each rotation of the X-ray source. The total
`examination time
`is eight times
`faster than with
`conventional single-row detector systems. Fewer motion
`artifacts occur; resolution increases from 5·00 mm to
`1·25 mm; and subsegmental vessels can generally be well
`visualised. Compared with conventional CT,
`the
`
`Cardiac biomarkers
`Cardiac biomarkers are being used with increasing
`frequency to assess prognosis in patients with newly
`diagnosed PE. In the Management Strategies and
`Prognosis of Pulmonary Embolism 2 study,53
`raised
`troponin concentrations were related to overall mortality
`and a complicated in-hospital course, presumably because
`troponin
`serves as a marker of
`right-ventricular
`microinfarction.
`Low concentrations of pro-brain natriuretic peptide
`predict a benign clinical outcome in patients with acute
`PE.54 Conversely, high concentrations of brain natriuretic
`peptide predict an adverse outcome.55,56
`
`Imaging studies
`for
`test
`imaging
`The
`traditional
`suspected PE has been the ventilation/
`perfusion lung scan. High-probability
`lung scans and normal lung scans are
`well validated with paired contrast
`pulmonary angiograms for diagnosis
`and exclusion of PE, respectively.57
`The main difficulty with lung scanning
`is that most scans are of intermediate
`or indeterminate probability. These
`non-diagnostic
`scans
`can
`cause
`consternation among clinicians who
`have either to undertake additional
`imaging tests or to decide empirically
`to diagnose or exclude acute PE.
`Because of frustration with lung
`scanning and the clinical need for
`definitive diagnosis or exclusion of PE,
`chest CT is rapidly replacing lung
`scanning as the main imaging test for
`suspected acute PE. Lung scanning is
`becoming a second-line test reserved
`for patients with a history of allergy to
`contrast agent or renal insufficiency.
`Chest CT has two other advantages
`over lung scanning: thrombus can be
`directly visualised (figure 3); and
`
`Figure 3: Chest CT of the patient whose electrocardiogram is shown in figure 2
`The scan shows bilateral central PE, with larger thrombus burden in the left than in the right
`pulmonary artery.
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`SEMINAR
`
`sensitivity of multi-row detector scanners for acute PE
`increases
`from about 70%
`to more
`than 90%.59
`Nevertheless, few studies using multi-detector helical CT
`pulmonary angiography have been published. In future,
`contrast-enhanced magnetic resonance angiography may
`supersede chest CT because the contrast agents are safer
`and no ionising radiation is used.60
`In the unusual circumstance that high clinical suspicion
`persists despite a normal or non-diagnostic chest CT,
`invasive pulmonary angiography or venous ultrasono-
`graphy should be done. However, this latter strategy is of
`limited use; at the time of confirmed PE, the clot might
`have embolised completely from the leg veins and the
`diagnostic study of the legs will be normal.61
`Echocardiography is also a disappointing diagnostic test
`for suspected PE. In a prospective study, echocardio-
`graphy was normal and failed to identify 50% of patients
`with angiographically proven PE.62
`the
`Contrast pulmonary angiography has been
`traditional gold standard for the diagnosis of PE, though
`this invasive test is now rarely done for diagnostic
`purposes. The complication rate is low when experts carry
`out this procedure.63 Contrast pulmonary angiography can
`be used as the final diagnostic test whenever a diagnostic
`dilemma persists.64
`The second trial by the Prospective Investigation of
`Pulmonary Embolism Diagnosis investigators, now under
`way, will assess suspected PE prospectively with lung
`scanning, venous ultrasonography of the legs, digital
`subtraction pulmonary angiography, contrast venography,
`and chest CT. The study will provide a thorough analysis
`of the efficacy of chest CT.65
`The synthesis of history, physical examination, clinical
`setting, electrocardiography, chest radiography, D-dimer
`testing, and chest CT will in most cases lead to a
`definitive diagnosis or exclusion of PE. When clinical
`suspicion of PE is high and the necessary diagnostic tests
`are not immediately available, empirical treatment for PE
`should begin with anticoagulation in the absence of major
`contraindications, such as recent neurosurgery, while
`arrangements are made for further investigation.
`
`Treatment
`Risk stratification
`Clinically, PE ranges from massive thromboembolism
`with cardiogenic shock to asymptomatic, anatomically
`small emboli without haemodynamic, respiratory, or other
`adverse physiological consequences. The key
`to
`appropriate therapy is risk stratification. Low-risk patients
`have an excellent prognosis with anticoagulation alone.
`High-risk patients might benefit from thrombolysis or
`embolectomy in addition to intensive anticoagulation.
`The Geneva prognostic index identified six factors that
`predict adverse outcome: cancer, heart failure, previous
`DVT, hypotension, hypoxaemia,
`and DVT on
`ultrasonography.66 High troponin concentrations at the
`time of initial hospital admission signify right-ventricular
`microinfarction and also identify patients at high risk of a
`complicated hospital course.53
`Echocardiography, although a poor diagnostic tool for
`PE, is excellent for rapid and accurate risk assessment.67
`Right-ventricular dysfunction
`identifies patients who
`despite initial haemodynamic stability develop cardiogenic
`shock and are at increased risk of death while in hospital.68
`In a prospective study of 209 consecutive patients with
`acute PE, 31% presented with echocardiographic
`evidence of right-ventricular dysfunction. Of those with
`abnormal echocardiograms, 10% developed PE-related
`shock, and 5% died while in hospital. Conversely,
`
`right-ventricular
`without
`patients
`normotensive
`dysfunction had an excellent short-term prognosis.68
`Persistent pulmonary hypertension and right-ventricular
`dysfunction on echocardiography done 6 weeks after the
`diagnosis of PE identify high-risk patients with an
`increased likelihood of developing overt right-ventricular
`failure over the next 5 years.69
`
`Anticoagulation
`Heparin anticoagulation is the foundation of therapy for
`acute PE. The traditional approach uses unfractionated
`heparin in an initial bolus of 5000–10 000 units followed
`by a continuous intravenous infusion, commonly started
`at 1250 U/h, to maintain a partial thromboplastin time in
`the target range of 60–80 s. A potential drawback of this
`strategy is failure to achieve adequate anticoagulation
`rapidly.70 Use of nomograms, mostly weight based, can
`assist in reaching a therapeutic degree of anticoagulation
`more quickly than empirical dose adjustments.71
`More recently, clinicians have used weight-based
`dosing of subcutaneously administered low-molecular-
`weight heparins, without dose adjustment, to achieve an
`immediate anticoagulant effect. The scientific basis of this
`strategy is that low-molecular-weight heparins provide
`high and sustained plasma antithrombin activity.72 In
`clinical trials of acute PE, reviparin once daily73 and
`tinzaparin once daily74 have proven as effective and safe as
`unfractionated heparin as a bridge to oral anticoagulation.
`In a trial of acute DVT in which 32% of patients had
`confirmed PE, enoxaparin at 1·0 mg/kg twice daily or
`1·5 mg/kg once daily was as safe and effective as
`unfractionated heparin.75 In another DVT study, reviparin
`was more effective than unfractionated heparin
`in
`reducing the size of the thrombus and in preventing
`recurrent thromboembolism.76
`The obvious potential major adverse effect of heparin is
`haemorrhage. Less apparent, but potentially more serious,
`is heparin-induced thrombocytopenia with thrombosis,
`which is more likely w