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Editorials |
1 From the Department of Radiology, Medical College of Wisconsin, 9200 W Wisconsin Ave, Rm 2803, Milwaukee, WI 53226-3596. Received July 29, 2004; accepted July 30. Address correspondence to the author (e-mail: lgoodman@mcw.edu).
When helical computed tomography (CT) was first introduced for the diagnosis of pulmonary emboli (PE) in 1992, many were concerned that it could not reliably exclude small PE (1–5). Multi–detector row CT and high-quality workstations now make it possible to diagnose small PE more frequently, with greater confidence, and perhaps with the same sensitivity and specificity as one achieves by using conventional angiography. As multi–detector row CT replaces scintigraphy as the imaging modality of choice for the detection of PE in many institutions (6–8), some are beginning to question whether every small embolus discovered at multi–detector row CT is clinically important and requires anticoagulation therapy (9,10).
Egermayer and Town (11) emphasized that the clinical importance of small PE is uncertain and "is of more than an academic interest, since the clinical response to such a discovery may be the diagnosis of PE, followed by anticoagulation therapy and its associated problems." Gurney (12) correctly emphasized that healthy people often pass small clots from the lower extremities to the lungs, and the lung capillary bed traps the emboli, protecting the systemic circulation. At autopsies of apparently healthy accident victims who died immediately, macroscopic PE were found in 20% of the cases (13). The intrinsic fibrinolytic system is responsible for lysing these clots (11,14).
The literature on PE is extensive and often inconsistent. In this editorial, I will try to summarize some of the major historic studies that have led to our current understanding of the diagnosis and treatment of PE and some of the recent articles addressing small PE. Much of our basic understanding of the natural history of PE and the role of anticoagulation date back to the 1960s when definitive diagnoses were much more difficult to make and only moderate to severe disease was likely to be diagnosed. Because the systematic use of anticoagulation therapy preceded the advent of reliable methods of diagnosis, knowledge of the unmodified history of thromboembolic disease is very limited (15).
Early studies, which often were based on clinical assessments alone, showed that untreated PE were fatal in 18%–38% of cases (10,16,17). In the 1960s, the introduction of anticoagulation was so rapidly accepted into clinical practice that there were few controlled studies in which anticoagulation was compared with no treatment for PE (15,17,18). During that era, study results indicated that deep venous thrombosis (DVT) was also a frequent precursor to PE, and, thus, all patients with venous thromboembolism (VTE) received anticoagulation therapy.
With better imaging tools, the diagnosis of VTE has become more certain and our understanding of the pathophysiologic features of this disease has improved. In the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) (19) performed in the late 1980s, a broad cross section of patients suspected of having VTE was studied. The results of this study definitively established the roles of ventilation-perfusion (V/Q) scanning and pulmonary angiography for diagnosis. Carson et al (20) found that the majority of deaths related to PE occurred within 2 weeks after the diagnosis of the initial PE. Approximately 25% of patients treated with anticoagulation died within a year, mostly because of comorbid conditions such as chronic obstructive pulmonary disease, congestive heart failure, or cancer. Only 8.0% of treated patients had recurrent emboli, and only 2.5% died of PE within a year. Patients with a life expectancy of over 3 months who are treated for VTE have a 4.0% recurrence rate and a 1.7% fatality rate associated with PE (17,18).
The next major advance in imaging came in 1992, when Remy-Jardin et al (1) used newly developed helical CT to prospectively diagnose PE. Early investigators used 5- or 10-mm images and 20- to 30-second breath holds. It was generally agreed that helical CT had high sensitivity and specificity (80%–100%) for central PE detection but often "missed" segmental and subsegmental PE (1,2,21).
In more recent years, the use of multi–detector row CT has led to decreased section thicknesses, decreased scanning times, and markedly improved visualization of segmental and subsegmental vessels. Schoepf et al (22) compared 1- and 3-mm reconstructions in 17 patients known to have PE. Three independent readers detected 40% more subsegmental PE on the 1-mm sections than on the 3-mm sections. The number of indeterminate readings decreased by 70% with use of the 1-mm sections, while interobserver agreement increased. In a recent report of 94 emergency room patients examined by using four-section multi–detector row CT, Coche et al (23) achieved a sensitivity of 96% and a specificity of 86% in evaluating all vessels through the subsegmental level.
Although the use of multi–detector row CT appears to enable improved visualization of the subsegmental vessels, its accuracy in small clot detection is difficult to assess. Pulmonary angiograms, the reference standard, also are difficult to interpret at the subsegmental level. Diffin et al (24) had three experienced angiographers retrospectively review 120 consecutive pulmonary angiograms. For the patients with subsegmental emboli only, the consensus reading altered the initial per-patient clinical interpretation in 30% of the cases. The per-embolus interpretation was altered in 37% of the cases. Similarly, in the PIOPED, two readers disagreed on the diagnosis of subsegmental emboli 34% of the time (25). In studies of artificial small emboli in pigs, CT and pulmonary angiography have had equivalent sensitivity and specificity (26). However, if one assumed that pulmonary angiography—the reference standard—always yielded accurate results, both the sensitivity and the specificity of CT would decrease to about 80%.
Since the deep veins of the pelvis and lower extremities are the most frequent source of PE, many now perform CT for the detection of DVT after performing CT of the pulmonary arteries (27). A CT result negative for DVT makes it less likely that a small embolus has been overlooked. A positive result indicates that anticoagulation is indicated, regardless of the presence or absence of PE.
In daily practice, the clinical importance of small PE is also called into question when small emboli are detected in asymptomatic patients who have undergone CT scanning for other reasons. Incidental PE have been detected in 1.0%–1.5% of all patients scanned by using single–detector row helical CT and intravenous contrast material (28,29). Rates among inpatients vary between 2% and 5%. Gosselin et al (29) found that the use of workstation rather than film image display improved PE detection by 25%. In current multi–detector row CT environments, routine CT examinations involve the use of thinner sections (2.5 or 5.0 mm) and are faster. Scans are regularly displayed on and read from high-quality workstations. Clearly, the detection of incidental emboli must have increased in recent years.
Since anticoagulation was rapidly accepted into clinical practice, at a time when diagnoses were crude and isolated small emboli were rarely diagnosed, there have been very few controlled studies of anticoagulation in the modern diagnostic era. Most of the evidence is indirect, and a true global understanding of the consequences of small PE is difficult because the majority of patients with small PE are never suspected clinically and are never evaluated (15,30,31). Autopsy studies show evidence of old or recent PE in 51%–90% of patients when there is careful examination of the pulmonary vessels (15,30). The majority of PE that are thought to be fatal are not suspected clinically and are not treated (30,32). Establishing the role of PE in a patient’s death is also extremely difficult because a comorbid condition, such as congestive heart failure, chronic obstructive pulmonary disease, or pulmonary artery hypertension, is often present (15,30–34).
It is not always clear whether small PE, in the absence of demonstrable DVT, justify the expense, mortality, and serious morbidity associated with anticoagulation. In well-controlled studies (international normalized ratio, 2.0–3.0), the rate of major bleeding caused by warfarin therapy has been less than 3.0% and the mortality rate has been less than 0.5% at 3 months (8). Under less stringent control, mortality and morbidity at 1 year are 1% and 7%, respectively (35). A summary of what we know—and do not know—about small PE and the need to anticoagulate follows.
Small PE: Recent Direct Evidence
How frequently do isolated subsegmental PE occur? Given the limitations just discussed, precise numbers are difficult to ascertain. Angiographic study results indicate that somewhere between 4% and 6% of patients who are examined for possible PE have isolated subsegmental PE (24,25,35). In a retrospective review of the reports on 1435 consecutive patients who were examined with eight- to 16-section multi–detector row CT at our hospital, we diagnosed isolated subsegmental PE in 77 (5.4%) cases (36). Coche et al (23), in a prospective study involving 94 outpatients examined with four-section multi–detector row CT, found isolated subsegmental PE in four (4.2%) cases.
The frequency of isolated subsegmental PE detected with scintigraphy and confirmed by using pulmonary angiography varies inversely with the probability reported for PE detection with V/Q scanning. In the PIOPED study, patients with high-probability V/Q scans had a 1% prevalence of isolated subsegmental PE, whereas those with low-probability V/Q scans had a 17% prevalence of isolated subsegmental PE. In patients with low-probability V/Q scans and no history of cardiopulmonary disease, the prevalence rose to 30% (37). In summary, in nonselected patient populations, approximately 5% of patients who are examined for possible PE have isolated subsegmental PE. In patients with proved PE, approximately 15% of the emboli are confined to the subsegmental arteries alone.
To my knowledge, there has been only one clinically controlled study in the modern era in which the recurrence and mortality rates among anticoagulation-treated patients with proved VTE were compared with those among nontreated patients with proved VTE. In 1994, Nielsen et al (14) examined 87 ambulatory patients with venography proved DVT and no symptoms of PE. Forty-nine percent of these patients had proved occult PE. One-half of them were treated with anticoagulation, and one-half were given phenylbutazone, an antiinflammatory agent. At 3 months, 19 patients in each group had developed progressive VTE, which was diagnosed by using venography, V/Q scanning, or clinical evaluation. Thus, anticoagulation did not appear to alter disease progression. One patient who was undergoing anticoagulation therapy died. There were no deaths among the 43 control patients, despite progressive VTE in 19 of them. Thus, the 18%–38% mortality rate quoted earlier for nontreated PE is not true for all subgroups.
Small PE: Recent Indirect and Clinical Evidence
In the PIOPED study, 20 patients had negative pulmonary angiography results at their local hospital and did not undergo anticoagulation therapy (38). Subsequently, an expert panel of angiographers ruled that PE were depicted on the original pulmonary angiograms. Of these 20 nontreated patients, one (5%) had a fatal embolus and one (5%) had a nonfatal embolus. These results are comparable to those for the patients in PIOPED who received anticoagulation therapy: In this group, the PE-associated fatality rate was 2.5% and the recurrence rate was 3.5%. The 20 nontreated patients had a limited clot burden. All of them, versus 60% of all the patients with PE, had fewer than three mismatched subsegmental equivalent perfusion defects. The angiographic results were positive only at the segmental or subsegmental level in 84% of these patients versus in 36% of all the patients with PE. Stein et al (38) concluded that "mild, untreated PE carries a lower immediate mortality from recurrent PE than PE described in prior decades."
In 1994, Hull et al (39) proposed that in patients with adequate cardiopulmonary reserve and nondiagnostic V/Q scans, anticoagulation was not required if serial impedance plethysmograms of the lower extremities showed normal findings. Hull et al (33,39) defined adequate cardiopulmonary reserve as the absence of any of the following conditions during the first 10 days after presentation: pulmonary edema, right ventricular failure, hypotension (systolic blood pressure less than 90 mm Hg), syncope, acute tachyarrhythmia, or respiratory failure as indicated by severely abnormal spirometric results (forced expiratory volume in 1 second less than 1.0 or vital capacity less than 1.5 L) or blood gas measurements (partial pressure of oxygen less than 50 mm Hg or partial pressure of carbon dioxide greater than 45 mm Hg while breathing room air). Four years later, Wells et al (40) proposed a similar strategy involving the use of serial lower extremity ultrasonography (US).
With use of the strategies above, the prevalence of subsequently detected PE among untreated patients ranged from 0.5% to 1.9% (39,40). Stein et al (41) reviewed the Wells et al (40) and Hull et al (39) studies and used the VTE frequencies established in the PIOPED (41). For 627 nontreated patients examined with impedance plethysmography, it was determined that 101 (16%) had undetected PE, four (0.6%) would have been predicted to have recurrent PE, and one (0.1%) would have been predicted to have fatal emboli. Of 702 patients examined with US, 133 (19%) were judged to have undetected PE; three of 96 (3%) of them, to have nonfatal PE; and none, to have fatal PE. Stein et al (41,42) concluded that withholding anticoagulation treatment of nonmassive PE is an acceptable strategy for patients who have indeterminate scintigraphic results, negative serial lower extremity venous examination results, adequate cardiopulmonary reserve, and relative or absolute contraindications to anticoagulation treatment.
Hull et al (33) also emphasized that comorbid conditions greatly influence the outcome of PE. They compared 117 patients who had inadequate cardiopulmonary reserve with 627 patients who had adequate cardiopulmonary reserve. All patients had low- or moderate-probability V/Q scans and negative results of serial plethysmography of the legs. Recurrent VTE was found in 12 (10%) of the patients with inadequate cardiopulmonary reserve and in 12 (2%) of those with adequate reserve. Kroegel and Reissig (31) stressed that patients with preexisting cardiopulmonary disease are four to seven times more likely to die of PE than are otherwise healthy patients.
Two clinical outcome studies at our institution addressed the problem of isolated subsegmental PE more directly. Schultz et al (43) prospectively performed multi–detector row CT for assessment of possible PE or DVT 3–7 days after admission in moderately to severely injured inpatients who had no signs or symptoms of VTE. Of these 90 patients, 22 (24%) had PE. Four patients with major occult PE and one patient with isolated subsegmental PE and DVT were treated with anticoagulation therapy. The remaining 17 patients, who had subsegmental emboli only, were not treated with anticoagulation therapy. No patients had clinical evidence of PE during their hospitalization. The 10 patients who were available for 3-month follow-up were symptom free.
As previously stated, we retrospectively reviewed the data on 1435 consecutive patients who were examined with multi–detector row CT for possible VTE to determine how frequently isolated subsegmental PE were reported and how clinicians responded to that diagnosis (36). We also studied the clinician response to a report of a suboptimal multi–detector row CT examination, which revealed no definite PE and no DVT. Presumably, some patients had nondetected small PE without DVT. Three-month follow-up data (including chart review, evidence of repeat imaging for possible VTE, autopsy reports, and death certificates) were available for 192 (92.8%) of 207 patients in these two groups (subsegmental PE only or inconclusive chest CT results and no DVT). For 25 (37%) of 67 patients with isolated subsegmental PE and for 106 (85%) of 125 patients with inconclusive multi–detector row CT results, the primary physician chose not to administer anticoagulation treatment. Two patients in each subgroup returned with signs and/or symptoms of PE, but all of the patients had negative repeat imaging results. Sixty-one (32%) of 192 patients were treated with anticoagulation, and five had recurrent signs and symptoms, but no VTE was found in any patient. In another study, performed prior to the CT era, involving patients who were not treated with anticoagulation therapy, one (2%) of 51 patients with an uncertain diagnosis of PE was subsequently found to have PE, whereas two (0.8%) of 247 patients with a diagnosis of "PE excluded" were subsequently found to have PE (44).
Gulsun and Goodman (45) recently reviewed the findings in seven clinical outcome studies involving patients with negative CT results who were not treated for PE. Helical scanners were used in four studies; four-section multi–detector row CT scanners, in two studies; and electron-beam CT scanners, in one study. A total of 7128 patients were included, and the follow-up period varied between 3 and 12 months. The concurrent use of other imaging modalities for assessment of possible VTE, such as US and V/Q scanning, varied between 100% and a nonstated percentage. Recurrence rates varied between 0.5% and 1.8% (average, 0.7%), and fatal PE rates varied between 0% and 1.6% (average, 0.2%). In three studies, the authors calculated the recurrence and fatality rates for a worst-case scenario, in which every patient who died during the follow-up period was considered to have a pulmonary embolus. Recurrence rates varied between 0.8% and 4.6% (average, 1.1%), and fatality rates varied between 0.2% and 1.0% (average, 0.6%) (45).
In two studies published since that review, which together included 324 additional patients, the investigators reached the same conclusions (46,47). In an older study (48), we prospectively compared, among patients who were not treated with anticoagulation therapy, the 3-month follow-up data of patients who had negative helical CT results with those of patients who had negative scintigraphy results. PE were subsequently found in two (1%) of 198 patients with negative CT results, in none of 188 patients with negative V/Q scanning results, and in five (3%) of 162 patients with low-probability V/Q scans, none of whom received anticoagulation treatment (48). If one assumes that CT has a sensitivity of 85%–90%, it could be concluded that many small PE must have been overlooked and gone untreated in these patients. Yet, overall, the clinical outcome after negative CT results were obtained was almost identical to that in eight clinical studies after negative conventional angiography results were obtained. van Beek et al (49), summarizing the results for 1050 patients, reported a 1.7% PE recurrence rate and a 0.3% associated fatality rate.
Do All Patients with PE Need to Receive Anticoagulation Therapy?
During the past 4 decades, there has been definite improvement in the diagnosis of VTE, and almost all patients with diagnosed VTE have been treated with anticoagulation. Despite the methodologic difficulties discussed earlier, an overview of the data indicates that anticoagulation is an effective treatment for VTE. Until further large studies are performed, it seems prudent to continue to treat the majority of patients who have VTE with anticoagulation (8,16–18,31).
There are three scenarios in which most would agree that even small PE require treatment: (a) in patients with small PE and inadequate cardiopulmonary reserve, (b) in patients who have a small embolus and coexisting acute DVT, and (c) in patients who have recurrent small PE possibly due to thrombophilia, to prevent chronic PE and pulmonary artery hypertension.
There appear to be subsets of patients with small or questionable PE in whom the risks associated with anticoagulation may outweigh the benefits: (a) in symptomatic patients who have clots limited to the subsegmental vessels, no DVT, and adequate cardiopulmonary reserve; (b) in patients with indeterminate multi–detector row CT or V/Q scanning results, no DVT, and adequate cardiopulmonary reserve (36,39,40) (patients with a high preexamination probability of PE require additional testing); (c) in asymptomatic patients with incidentally discovered small emboli, no DVT, and adequate cardiopulmonary reserve; and (d) in patients with contraindications to anticoagulation (eg, intracranial hemorrhage, recent surgery, or trauma), isolated subsegmental PE or indeterminate multi–detector row CT results, and no DVT (41,50). In these four patient groups, a follow-up examination of the lower extremities to exclude DVT performed at 1 week seems prudent (39,40). Because of the intrinsic fibrinolytic activity of the lung, small PE usually resolve spontaneously; DVT does not (11).
There are several secondary factors that might strengthen the decision to withhold anticoagulation: (a) no or few risk factors for VTE (51), (b) transient (eg, recent surgery or recent injury) rather than persistent (eg, coagulopathy, cancer) risk factors for VTE (8,52), (c) other cardiopulmonary disease that might explain the patient’s signs and symptoms, and (d) negative D-dimer test results (53).
Multi–detector row CT provides a relatively noninvasive, reliable tool for diagnosing VTE in a broad range of patients. With this information, radiologists and clinicians have the opportunity to reevaluate the natural history of VTE and more precisely tailor therapy to the individual patient.
ACKNOWLEDGMENTS
I thank Sylvia Bartz for her help in preparing this manuscript.
FOOTNOTES
Author stated no financial relationship to disclose.
REFERENCES
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