The epidemiology of pulmonary embolism has changed since CTPA was introduced. Compared to the pre-CTPA era, pulmonary embolism incidence rose, mortality changed little, and case-fatality decreased.
What explains these findings ()? At first glance, the rapid increase in incidence seems alarming – an apparent epidemic of pulmonary embolism. But the epidemic is unusual because it has only occurred among non-fatal emboli: despite increased incidence, population mortality from pulmonary embolism has not shown a parallel increase. Moreover, an epidemic (or true increase in disease incidence) is unlikely without a corresponding increase in risk factors. Risk of pulmonary embolism may actually be decreasing: in the past several years, quality improvement efforts have focused on increasing prophylaxis against venous thromboembolism in hospitalized patients. Despite the fact that most surgical patients now receive prophylaxis, pulmonary embolism incidence nonetheless has risen substantially in the surgical population. Incidence has risen even more dramatically among obstetric patients, nearly tripling in the eight years after CTPA was introduced. Although the major underlying risk factor (pregnancy) has remained constant, use of CT in the obstetric population has risen by 25% per year.24
The widespread adoption of CTPA points to an alternative explanation. Rather than an epidemic of disease, we think the increased incidence of pulmonary embolism reflects an epidemic of diagnostic testing that has created overdiagnosis. In this scenario, much of the increased incidence in pulmonary embolism consists of cases that are clinically unimportant, cases that would not have been fatal even if left undiagnosed and untreated.
Overdiagnosis explains the increased incidence, decreased case-fatality, and minimal change in mortality we observed (). If the extra emboli diagnosed were clinically important and benefited from treatment, mortality (i.e., number of fatal pulmonary emboli / population at risk) would show a parallel decrease. This is exactly what happened in the 20 years prior to the introduction of CTPA: with improved prevention and treatment, pulmonary embolism mortality in the US fell 50%, decreasing by 970 deaths per 100,000.20
By contrast, in the eight years since CTPA was introduced, despite the large increase in new cases, mortality decreased by only another 0.4 deaths per 100,000. Mortality changed little, because many of the extra emboli may not have needed treatment at all.
The concomitant improvement in case-fatality is also explained by overdiagnosis. Case-fatality (i.e., number of deaths / people diagnosed) decreases because the denominator has been inflated with clinically insignificant cases that are only identifiable by highly sensitive tests (corresponding mortality statistic is not distorted since the denominator includes all people at risk, not just those diagnosed). A recent time trend analysis of Pennsylvania residents hospitalized with pulmonary embolism confirms that patients admitted in recent years have a lower disease severity than patients admitted in the past.13
The discussion of overdiagnosis has been largely restricted to the cancer screening literature.11, 12
But the concept is relevant whenever there is a large reservoir of undiagnosed cases and a new, sensitive test to detect them. In the case of pulmonary embolism, both conditions exist. First, there appears to be a large reservoir of unsuspected emboli. Signs of recent or prior pulmonary embolism can be identified in more than half of autopsies if the pulmonary arteries are meticulously examined.9
Moreover, among consecutive patients undergoing contrast chest CT for unrelated reasons (e.g., cancer staging), unsuspected emboli are found in 4% overall,25
in 17% of patients over age 80,26
and in 24% of asymptomatic trauma patients.27
Second, evidence of overdiagnosis of pulmonary embolism initially arose in the randomized trial comparing CTPA to ventilation-perfusion scan: while the CTPA arm detected more patients with pulmonary embolism, there was no apparent improvement in outcomes.8
A recent meta-analysis confirms that many of the additional emboli identified by multidetector row CTPA are subsegmental emboli that do not lead to adverse outcomes even if left untreated.28
In this paper we demonstrate that it was not until after the introduction and rapid adoption of a highly sensitive test (CTPA) that the dramatic rise in pulmonary embolism incidence occurred.
Like any study relying on administrative databases, our study has limitations. While some factors inherent to administrative data may overestimate incidence, others cause an underestimate. Trends may be confounded by “upcoding,” an artifact whereby discharge records in later years contain more thorough ICD-9 coding in an effort to maximize reimbursement.29
While such upcoding could lead to an overestimate of the increase in incidence over time, it is unlikely to explain the magnitude of change we noted (i.e., near doubling in incidence). Because the NIS does not have identifiers to track individuals after hospital discharge, patients who are re-admitted may be erroneously counted as two unique individuals with pulmonary embolism. There are reasons, however, to suspect that incidence is actually underestimated. Pulmonary embolism is considered to be one of the most common missed diagnoses; thus, our estimate of pulmonary embolism incidence is likely to be falsely low. Furthermore, the NIS did not allow us to capture emboli diagnosed and treated solely as an outpatient. However, over 90% of pulmonary embolism patients seen in US emergency departments in 2006 were admitted to the hospital.30
This proportion was likely even higher early in the study period, when outpatient management of pulmonary embolism with low molecular weight heparin was unusual.31
Hence, the overall rise in pulmonary embolism incidence may be even greater than what we captured among inpatients.
A second limitation is that death certificates undercount pulmonary embolism mortality. Since there is no national autopsy database, the Multiple Cause-of-Death database contains the most comprehensive data available on deaths in the US population. Studies have found that death certificates have a sensitivity less than 40% compared to autopsy results for identifying deaths related to pulmonary embolism.32
To minimize this problem, we counted any diagnosis of pulmonary embolism listed on the death certificate (whether listed as the immediate or a contributing cause of death) as a pulmonary embolism death – a standard strategy in this area of research.20
Although death certificate data may underestimate pulmonary embolism mortality, it can accurately estimate time trends and is routinely used for this purpose.20, 33, 34
While our findings suggest there may be substantial overdiagnosis of pulmonary embolism, we cannot conclude that overdiagnosis explains the entire increase. Some of these “emboli” may represent false positive results; the PIOPED II trial found the positive predictive value of CTPA to be <60% in cases of low clinical suspicion for pulmonary embolism.35
Increasing indiscriminate use of both CTPA itself and d-dimer testing prompting follow-up CTPA4, 36
may have led over time to more false positive CTPA results in patients with low clinical pre-test probability of pulmonary embolism. Patients treated for a false positive pulmonary embolism – just like those treated for a clinically unimportant one – can only be harmed. Among true positive emboli detected by CTPA, there may be both clinically relevant and irrelevant emboli. The small decrease in population mortality may indicate there has been some increase in the detection and successful treatment of clinically meaningful embolism. In the “best case scenario” (i.e., assuming decreased deaths are from increased detection alone), there appear to be 128 extra patients diagnosed with a pulmonary embolism for every death avoided. CTPA, however, may have nothing to do with better outcomes – efforts at improved prevention and treatment of pulmonary embolism may be the explanation. Even if the increased diagnosis and treatment of the “new” pulmonary emboli detected by CTPA did not reduce death, it might reduce morbidity (e.g., hemodynamic compromise at presentation or subsequent complications like recurrent embolism or chronic thromboembolic pulmonary hypertension). However, we believe that the increased incidence following introduction of CTPA is unlikely to be attributable to increased detection of massive pulmonary emboli with hemodynamic compromise; these massive emboli could easily be detected in the pre-CTPA era by less sensitive tests like ventilation-perfusion scanning. While it is possible that recognition and treatment of some pulmonary emboli may have prevented subsequent non-fatal complications (e.g., pulmonary hypertension), which we could not detect using our databases, many patients will have received unnecessary treatment without any obvious benefit.
Overdiagnosis of these extra patients matters because treatment of pulmonary embolism can cause real harm. Anticoagulation, the current standard of care for all pulmonary emboli, is not benign. Even in the short-term context of the hospital stay we found significant increases in presumed complications of anticoagulation for pulmonary embolism. The true danger of anticoagulation, however, lies in its longer term use: 12% of patients anticoagulated for 3–6 months experience clinically significant bleeding.31
A recent study suggested that patients with subsegmental emboli detected by multidetector row CTPA are far more likely to experience complications of anticoagulation than adverse outcomes from the embolism itself.37
While newer treatments for pulmonary embolism, such as dabigatran, may be as effective but somewhat safer than warfarin,38
these agents are not yet standard of care. In addition to the harms of anticoagulation, IVC filters, which are increasingly used in the management of pulmonary embolism,39
can cause substantial morbidity, both during insertion (e.g., bleeding) and while in place (e.g., clotting of filter, fracture and migration of filter, increased incidence of subsequent deep vein thrombosis).40, 41
As use of CT scans continues to rise,5
the problem of overdiagnosis and overtreatment of pulmonary embolism will likely continue to grow. Since the harms of treatment can be substantial, including in the worst case death, it is imperative that we do not turn the problem of underdiagnosis into one of overdiagnosis. It is time to strengthen the evidence base: a trial randomizing stable patients with small emboli to observation versus anticoagulation would help determine whether all patients with pulmonary embolism require treatment.