Summary box
Clinical context—Pulmonary embolism has been described as one of the most commonly
missed deadly diagnoses
Diagnostic change—The introduction and rapid uptake of multidetector computed tomographic
pulmonary angiography
Rationale for change—CT pulmonary angiography is much more sensitive than ventilation
perfusion scanning so fewer pulmonary emboli will be missed
Leap of faith—Finding “missed” pulmonary emboli saves lives
Increase in disease—US data show 80% rise in incidence of pulmonary embolism between
1998 and 2006 after CT pulmonary angiography was introduced (from 62.1/100 000 to
112.3/100 000)
Evidence of overdiagnosis—Combination of large increase in incidence, reduced case
fatality (in-hospital deaths among people with a diagnosis of pulmonary embolism),
and a minimal decrease in mortality (deaths from pulmonary embolism in the population)
suggests that many of the extra emboli being detected are not clinically important
Harms from overdiagnosis—Substantial increase in complications from anticoagulation.
Anxiety and inconvenience for patients following diagnosis and treatment
Limitations—Evidence for overdiagnosis is derived from administrative data or single
institution case series. Without prospectively observing untreated patients, it is
impossible to be certain which emboli are not clinically important
Conclusion— CT pulmonary angiography has reduced missed pulmonary embolism but seems
to result in overdiagnosis. We need to learn which small emboli need treatment
For decades clinicians have been taught that pulmonary embolism—defined by the National
Institutes of Health as a “sudden blockage in a lung artery”1—always matters and to
be vigilant because a missed embolism can be fatal.2 When a patient presents with
shortness of breath, pleuritic chest pain, tachycardia, or signs of right heart strain,
clinicians are trained to think “pulmonary embolism.” Because these symptoms and signs
are neither sensitive nor specific, scoring systems (such as the Wells criteria) have
been developed to help clinicians decide which patients to scan,3 although in practice,
many clinicians simply proceed with imaging4 to confirm or refute the diagnosis.
Explosion in use of CT imaging
Until recently, ventilation-perfusion (VQ) scanning, introduced in the mid-1960s,
was the first line test for pulmonary embolism (table) with clinicians maintaining
an appropriately high threshold for invasive pulmonary angiography.5 VQ scanning has
the advantage of being non-invasive, but the results are often inconclusive. A new
technology introduced in 1998—multidetector computed tomographic (CT) pulmonary angiography—offers
higher resolution and more definitive results.
Comparison of imaging tests to diagnose pulmonary embolism
Pulmonary angiography
Ventilation-perfusion scan
Computed tomography pulmonary angiography
Year introduced
1931
1964
1998
Accuracy relative to gold standard
Gold standard
Sensitivity 98%, specificity: 10%
Sensitivity 96-100%, specificity: 89-98%
Advantages
Gold standard diagnostic test
Non-invasive
High sensitivity and specificity
No contrast dye (safe for patients with renal impairment)
Visualises lung parenchyma as well as vasculature
Widely available
Widely available
Less radiation exposure
Disadvantages
Invasive test with potential complication of bleeding
Scans hard to interpret
Too much resolution
Often indeterminate
Finds many subsegmental emboli of unclear importance
Nephrotoxic contrast and moderate radiation exposure
Abnormal chest x ray appearance makes it even harder to interpret
Incidental findings like pulmonary nodules
More limited availability
Higher radiation exposure and nephrotoxic contrast
With the increasing availability of CT scanners, there has been an explosion in the
use of CT for various indications,6 including pulmonary embolism. A 2005 US survey
of emergency department physicians showed that most considered CT pulmonary angiography
to be the first line test for pulmonary embolism.7 This finding is consistent with
observations in health maintenance organisations8: use of CT pulmonary angiography
rose 14-fold (from 0.3 to 4.0 per 1000 beneficiaries) while VQ scanning decreased
by 52% (from 2.3 to 1.1 per 1000 beneficiaries) from 2001 to 2008.
Drivers for the increased use of CT pulmonary angiography
Clinicians like CT pulmonary angiography because it allows them to find causes besides
pulmonary embolism to explain non-specific symptoms (such as pleural effusion or pneumonia).7
But the main reason why doctors have embraced the technique is to avoid missing “a
silent killer.”9 The widespread availability of CT pulmonary angiography has also
encouraged doctors to lower their threshold for looking for pulmonary embolism.10
With more testing, more pulmonary emboli are found. These extra diagnoses lead to
testing even more patients because of the pervasive belief that finding even a tiny,
subsegmental pulmonary embolism means you may have saved a life. Case finding has
also increased as a result of the widespread use of non-specific blood tests like
D-dimer and troponin, which raise suspicion of pulmonary embolism (and imaging to
look for it) in patients in whom it would not otherwise have been considered.11 Radiologists
like CT pulmonary angiography because they can make definitive diagnoses more readily
than with VQ scans.12 Concerns about accusations of malpractice may also increase
the use of CT pulmonary angiography.13
Commercial interests are also fuelling imaging rates
Purchasing the most advanced multidetector scanners can help a hospital establish
a reputation for being on the cutting edge. To recoup the cost of the scanner, though,
the machines must be used.6 In addition, deep vein thrombosis and pulmonary embolism
awareness campaigns led by drug companies have encouraged patients to ask about testing.
In the US, Sanofi-Aventis, which produces the anticoagulant enoxaparin, ran the direct
to consumer advertising campaign “killer legs,” sponsored conferences on “economy
class syndrome” (deep vein thrombosis and pulmonary embolism among air travellers);14
and created a website featuring scary anecdotes like, “My husband didn’t have to die,”
written by “people just like you” (Preventdvt.org). It also successfully lobbied the
US Congress to declare an annual deep vein thrombosis awareness month and a national
screening day.15
Evidence of overdiagnosis
The high resolution of CT pulmonary angiography makes it possible to detect filling
defects in subsegmental arteries as small as 2-3 mm in diameter.16 Only 1% of VQ scans
rated as “high probability” correspond to an isolated subsegmental pulmonary embolism,17
compared with 15% of positive CT pulmonary angiography scans.18
If all pulmonary emboli caused important harm or death if untreated, finding more
small clots would be an unqualified advance. However, there is evidence that some
small clots do not need treatment, and finding them represents overdiagnosis. It has
been argued that a normal function of the lungs is to act as a sieve to prevent small
emboli formed in leg veins from travelling to the systemic arterial circulation with
devastating effect, such as stroke.19 These emboli are believed to be resorbed by
the body without treatment and to have no clinical effect. This idea is supported
by the finding that a surprisingly high proportion of consecutive contrast CT scans
performed for other indications found incidental pulmonary emboli: in 16% of mechanically
ventilated patients,20 in 17% of inpatients over age 80,21 and in 20% of trauma patients.22
In addition, 50-60% of consecutive patients having autopsy were found to have an unsuspected
pulmonary embolism when the pulmonary arteries were carefully dissected.23
Natural course studies of subsegmental pulmonary embolism also provide evidence that
some emboli may not need to be found. Donato and colleagues summarised three month
outcomes of 192 patients with isolated subsegmental pulmonary embolism reported in
the literature.24 Among the 65 patients who did not receive anticoagulants (at the
clinician’s discretion), none had a recurrent pulmonary embolism or death. And only
one of the 127 patients who received anticoagulation had a recurrent (non-fatal) pulmonary
embolism, a substantially lower rate than the typical recurrence rate with larger
pulmonary embolism (6%).25
Evidence from population trends and one randomised trial also supports the view that
pulmonary embolism is overdiagnosed.26
27
28
29
30 Using national US administrative data, we showed that age adjusted incidence of
pulmonary embolism, which was stable in the five years before the introduction of
multidetector CT pulmonary angiography, increased by 80% in the eight years after
it was introduced: from 62.1 to 112.3 per 100 000 US adults (fig 1
).26 Despite this near doubling of diagnoses, age adjusted mortality from pulmonary
embolism (deaths in the US population) changed little: from 12.3 to 11.9 per 100 000.
Age adjusted case fatality of pulmonary embolism (in-hospital deaths), however, decreased
by one third, from 12.1% to 7.8%, P<0.001), suggesting that the extra pulmonary emboli
being detected are less lethal (given that treatment has not become more effective).
More non-fatal pulmonary emboli dilute case fatality but do not change mortality.
Similar patterns have been observed at the state level.27
28
Incidence, mortality, and case fatality of pulmonary embolism in United States, 1993-2006.26
The rising incidence of pulmonary embolism and stable mortality is particularly striking
given the simultaneous push for venous thromboembolism prophylaxis for hospital patients,
most notably through the adoption of a national quality measure (http://qualitymeasures.ahrq.gov).
More systematic use of prophylaxis would be expected to decrease both pulmonary embolism
incidence and mortality. Nevertheless, incidence has risen. This rise is unlikely
to represent a true change in the underlying rate of pulmonary embolism, as the major
risk factors for pulmonary embolism have not shown a parallel increase.27 The more
likely explanation is increased use of CT in general6 resulting in incidental detection
of pulmonary embolism on contrast CT scans performed for other reasons20
21
22) and CT pulmonary angiography specifically.
Limitations of the evidence
Inferring overdiagnosis by observing epidemiological trends has limitations because
the evidence is derived from administrative data (coding on discharge records and
death certificates) with imperfect accuracy, insufficient clinical detail, and lack
of standardisation across institutions. But its strength lies in its representativeness
of the population and reflection of actual clinical practice, in contrast with randomised
trials that study a highly selected population under highly controlled conditions.
Case series that identified patients with pulmonary embolism by review of imaging
for suspected embolism rather than relying on discharge coding have been able to link
outcomes to individual patients. These single institution series show that the rise
in incidence is largely due to the increased detection of subsegmental pulmonary embolism.31
32
33
The best evidence of overdiagnosis comes from a trial that randomised 1417 patients
with an intermediate to high probability of pulmonary embolism to receive VQ scanning
or CT pulmonary angiography.30 Although CT pulmonary angiography detected more emboli
than VQ scans (19.2% v 14.2%, P=0.01), there was no difference in death from pulmonary
embolism or other unknown causes (0.3% v 0.3%) over three months.
Definitive evidence of overdiagnosis would, of course, be the finding that untreated
patients never experienced harm from the pulmonary embolism during the rest of their
lives and died from another cause, but no such studies exist.
Harms to patients and cost to health systems from overdiagnosis
The main harm from overdiagnosis is unnecessary treatment, which in the case of pulmonary
embolism means anticoagulation—a leading cause of medication related death.34 Because
of ongoing controversy about duration of therapy, exposure to unnecessary and dangerous
anticoagulation may be lifelong. In some studies, complications of anticoagulation
are more common than the problem treatment is meant to prevent: recurrent venous thromboembolism.
Notably, in the largest case series of patients given anticoagulants for isolated
subsegmental pulmonary embolism (n=93), the risk of major bleeding was 5.3% but the
risk of recurrent venous thromboembolism was only 0.7%.24 In our study, in parallel
with the increased incidence of pulmonary embolism, we found presumed anticoagulation
complications for US patients admitted to hospital with pulmonary embolism to have
increased from 3.1 to 5.3 per 100 000 (P<0.001) between 1998 and 2006.26
Overdiagnosis also causes patients harm from inconvenience and anxiety. The current
standard of care (warfarin) requires frequent blood tests, dietary changes, and constant
fear of bleeding or clotting if the international normalised ratio is not in the target
range. Patients may also be harmed by the fear and anxiety from being unnecessarily
told that they have a potentially life threatening disease.23 In addition, health
insurers may charge them higher premiums because they have a “pre-existing condition.”
Overdiagnosis and overtreatment are also costly to health systems. The mean charge
associated with admission for pulmonary embolism in the US increased from roughly
$25 000 (£17 000; €19 000) to $44 000 between 1998 and 2006.35 The mean cost of subsequent
warfarin anticoagulation, associated laboratory tests, and clinic visits was $2694.36
The recent introduction of newer anticoagulants (dabigatran, rivaroxaban) will decrease
the need for testing, but the drugs are substantially more expensive than warfarin
($3000 v $48 a year37).
How to do better
Pulmonary embolism is underdiagnosed as well as overdiagnosed,38 and ideally, improved
tests would make it possible to find all clinically important emboli before patients
experience an adverse outcome. Unfortunately, although highly sensitive tests find
more emboli, they do so at the cost of overdiagnosis.
Computed tomography pulmonary angiogram showing a small pulmonary embolism
Addressing the problem of overdiagnosis is challenging (box). The answer is not simply
to do less testing—clinicians should continue to have a low threshold for considering
pulmonary embolism—but to test (and subsequently treat) more selectively and to consider
alternative tests such as VQ scanning and ultrasonography when appropriate.39
Challenging assumptions in pulmonary embolism
Whenever you think pulmonary embolism, test for it
This remains good advice, but doctors should first use the Wells score (www.mdcalc.com/wells-criteria-for-pulmonary-embolism-pe/)
and D-dimer testing to determine the likelihood of pulmonary embolism
Patients with a Wells score <4 do not need any imaging as long as their D-dimer blood
concentration is normal
CT pulmonary angiography is always the best test
CT pulmonary angiography is sensitive and easy to get, but for clinically stable patients,
alternative tests reduce exposure radiation, cost less, and are less likely to lead
to overdiagnosis
VQ scans may make more sense for younger patients (less radiation), patients with
normal lungs (a definitive result is more likely), and patients with renal dysfunction
(no nephrotoxic contrast)
Detection of deep vein thrombosis by ultrasonography of the legs when pulmonary embolism
is suspected makes subsequent lung imaging unnecessary because patients need anticoagulation
anyway
All patients need anticoagulants
For patients with an isolated subsegmental pulmonary embolism harms may outweigh benefits.
Patients with subsegmental emboli who take anticoagulants have a low chance of having
another clot (0.7%) but a 5.3% chance of major bleeding24
Patients need to understand these trade-offs and be offered the opportunity to choose
whether to take anticoagulants
Take steps to image less
Clinical practice guidelines11
40
41 and the Choosing Wisely Campaign42 suggest clinicians should reserve CT pulmonary
angiography for patients at intermediate to high risk of pulmonary embolism based
on algorithms that combine clinical probability and D-dimer test results.43 Large,
prospective studies have shown the safety of this approach.43
44 Use of algorithms could be increased by inserting them into the ordering process
for CT pulmonary angiography45 or empowering radiologists to challenge use of CT pulmonary
angiography in patients with a low likelihood of pulmonary embolism.12
Avoiding CT pulmonary angiography in patients with a low likelihood of pulmonary embolism
would reduce exposure to nephrotoxic contrast and carcinogenic radiation. The average
effective radiation dose from a CT pulmonary angiography is 10-15 millisieverts (compared
with 2-2.5 mSV for a VQ scan and 5 mSV for invasive pulmonary angiography).10
46 The radiation exposure is particularly worrisome for young women; for every 1000
20 year old women who have CT pulmonary angiography, about three will develop cancer.10
Less CT pulmonary angiography would also mean fewer false positive results and “incidentalomas.”
Roughly a quarter of CT pulmonary angiographs detect an unexpected abnormality such
as a pulmonary nodule, thyroid nodule, or adenopathy, resulting in further scans or
invasive testing to rule out cancer.47 Most are false alarms.
Consider less sensitive imaging
An alternative for clinically stable patients is to use other tests for venous thromboembolism,
such as VQ scan or Doppler ultrasonography of the legs. Implementing policies to use
VQ scans as the first line test for pulmonary embolism in stable patients with a normal
x ray appearance can reduce use of CT pulmonary angiography and decrease detection
of subsegmental pulmonary embolism without increasing deaths from pulmonary embolism.29
48
Consider not treating some subsegmental pulmonary emboli
Although some guidelines recommend anticoagulation for all pulmonary emboli,41
49 others acknowledge that anticoagulation may not be warranted in all cases because
of uncertainty about the balance of benefits and harms for treating isolated subsegmental
pulmonary embolism.11
40 Some authors suggest withholding anticoagulation for stable patients with isolated
subsegmental pulmonary embolism and adequate cardiopulmonary reserve.50 If a subsegmental
pulmonary embolism is not treated, patients should be monitored for new respiratory
symptoms and for deep vein thrombosis with serial ultrasonography for three to six
months to decide whether anticoagulation can be safely withheld.
Unresolved questions
Many unresolved questions remain which require further research. What is the natural
course and prognosis of untreated subsegmental pulmonary embolism? Does asymptomatic,
incidentally detected pulmonary embolism have the same outcomes and prognosis as symptomatic
pulmonary embolism? What are the benefits and harms of treating subsegmental pulmonary
embolism with anticoagulation?
Conclusion
Pulmonary embolism is unquestionably an important cause of death, and rapid diagnosis
and treatment can be life saving. But the diagnostic zeal and technological advances
meant to improve outcomes of patients with pulmonary embolism are double edged swords:
some patients are helped, but many are harmed through overdiagnosis and overtreatment.
The idea that pulmonary embolism can be overdiagnosed will be new and counterintuitive
for some clinicians, but the harms are just as real as those of underdiagnosis. To
improve outcomes for all patients, we need to learn more about which small emboli
need treatment. Importantly, an ongoing prospective cohort study is assessing the
safety of withholding treatment for stable patients with isolated subsegmental pulmonary
embolism (ClinicalTrials.gov Identifier: NCT01455818).