Best Evidence Topics
  • Send this BET as an Email
  • Make a Comment on this BET

Do patients with a clinically suspected subsegmental pulmonary embolism need anticoagulation therapy?

Three Part Question

In [a symptomatic patient with an isolated subsegmental pulmonary embolism] does [anticoagulation therapy or no treatment] lead to [lower rates of mortality and recurrent venous thromboembolism?]

Clinical Scenario

A 62-year-old gentleman attends your Emergency Department with shortness of breath and chest pain. You suspect a pulmonary embolism (PE) and request a CT pulmonary angiogram. The radiologist reports an isolated subsegmental PE and you question whether this gentleman requires anticoagulation therapy given the size and location of his PE.

Search Strategy

(pulmonary embol$.mp. OR lung embol$.mp. OR pulmonary infarct$.mp. OR lung infarct$.mp. OR OR AND (anticoagula$.mp. OR exp heparin/OR OR low molecular weight OR exp low molecular weight heparin/OR OR exp enoxaparin/OR exp dalteparin/OR exp tinzaparin/OR exp nadroparin/OR exp bemiparin/OR exp certoparin/OR exp reviparin/OR exp parnaparin/OR exp ardeparin/OR OR OR OR OR OR OR OR OR OR OR OR exp warfarin/OR exp antivitamin K/OR vitamin k OR exp coumarin/or OR novel oral OR novel OR OR OR exp rivaroxaban/OR OR exp apixaban/OR OR exp edoxaban/OR exp dabigatran etexilate/OR exp dabigatran/OR AND ( OR

LIMIT to Human and English Language.

LIMIT to “therapy (maximises sensitivity)” or “therapy (maximises specificity)” or “therapy (best balance of sensitivity and specificity)”

Search Outcome

Embase (1974 to 2014 June 17): 877 papers.

Ovid Medline (1946 to June Week 2 2014): 355 papers.

Cochrane Central Register of Controlled Trials (May 2014) and Cochrane Database of Systematic Reviews (2005 to May 2014): 226 papers.

Six papers were relevant to the research question (Table 1). Prospective cohort studies were the best level of evidence available (A Cochrane Review showed that no relevant RCTs have been completed to date).

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Eyer et al
1435 (721 male, 714 female; average age 57 years) consecutive patients with a clinical suspicion of PE from a single trauma centre. Inclusion criteria: patients undergoing MDCT (multidetector CT) for suspected acute PE. Exclusion criteria: chronic PE; incidental radiological diagnosis of PE when performed for other indications. 121 patients had a central PE, 78 a segmental PE, 77 a subsegmental PE and 130 had an inconclusive report suggesting possible PE. Retrospective analysis of radiology database and clinical case notes (level 2b). Clinicians’ responses to radiological diagnosis of ISSPE (isolated subsegmental PE) or inconclusive CTPA in terms of treatment were recorded. PE recurrence within 3 monthsISSPE—25/67 patients were not given anticoagulants. Two of these patients (8%) returned with symptoms of PE but repeat CTPAs did not demonstrate PE.

ISSPE—31/67 patients were given anticoagulants as a result of CTPA showing an ISSPE. Two of 31 patients (6%) returned with symptoms of PE but repeat CTPAs did not demonstrate recurrent PE.

Inconclusive CT—108/125 patients were not given anticoagulants. Two patients (2%) returned with symptoms of PE but repeat CTPAs did not demonstrate recurrent PE.

Inconclusive CT—17/125 given anticoagulants. Three patients (18%) returned with symptoms of PE but repeat CTPAs did not demonstrate recurrent PE.
Retrospective analysis. Mild symptoms of PE may not have been recognised during follow-up. Follow-up was limited to the single centre. Loss to follow-up was 15 (7%), of which 12 were not given anticoagulants. Only two autopsies done out of 15 deaths. The true incidence of PE and causes of death in these patients hence unknown. Baseline clinical characteristics of patients not described in detail. Such information would have been useful for estimating the pretest probability of PE, which probably influenced the decision to treat (selection-bias). Did patients with ISSPE and inconclusive CT who were given anticoagulants have worse comorbidities? All nine patients that returned with symptoms suggestive of recurrent disease had negative CTPA results—does this represent poor sensitivity or was there indeed no recurrence of PEs within this patient cohort? N.B. In the Key results column the patients who were already receiving anticoagulants prior to their PE presentation were omitted since this is likely to influence outcome.
Mortality at 3 months13 deaths from other causes in untreated groups. 2 deaths from other causes in anticoagulant groups.
Kruit et al,
The Netherlands
169 consecutive patients (mean age 60 (20–89) years) with suspected PE who were admitted to Department of Internal Medicine. Exclusion criteria—life-threatening PE requiring fibrinolysis, pelvic pathology (eg, recent surgery to pelvis/lower extremities). All referred patients underwent ventilation-perfusion (V/Q) scanning within 48 h. Group A (44/169, 26%)—normal lung scan and no treatment given. V/Q scan repeated at 3 months. Mean age=44 years. Group B (63/169, 37%)—abnormal lung scan with deep vein thrombosis (DVT) confirmed by bilateral venograms of legs—treated with anticoagulants for 3 months. V/Q scans repeated at 3 months and 12 months, and impedance plethysmography performed at 3 months, 6 months and 12 months. Mean age=70 years. Group C (62/169, 37%)—abnormal lung scan with no DVT—treatment withheld. V/Q scans repeated at 3 months and 12 months, and impedance plethysmography performed at 3 months, 6 months and 12 months. Mean age=61 years. Prospective cohort study (level 2b).Recurrent VTE and mortality among the three separate patient groupsGroup A—1/44 (2.3%) developed DVT and PE. One death due to congestive cardiac failure (CCF) and renal insufficiency with no evidence of VTE.

Group B—4/63 (6.3%) developed VTE. Six deaths—two disseminated cancer, one CCF, one septicaemia, two sudden deaths, but none attributable to PE.

Group C—1/62 (1.6%) DVT (no PE seen in this group). Eight deaths—two myocardial infarctions, two CCFs, one cancer, one cardiac tamponade, two sudden deaths, but none attributable to PE.
Gold standard diagnostic test (pulmonary angiogram) not used on initial selection of patients. Also no mention of who interpreted imaging and whether they were blinded to treatment methods. All patients received intravenous heparin and a coumarin derivative prior to V/Q scan—this could be up to 48 h before treatment was stopped in some patients. Patients with negative V/Q scans were deemed not to have a clinically important PE—is this a reliable diagnostic test to rule out? Group B patients had concomitant DVT as well as PE—this group would be treated with AC therapy regardless as to whether imaging showed PE. Significantly more high probability scans in B (38/63; 60%) than in C (3/62; 5%). They're really comparing those with DVT and high clinical suspicion of PE to those without DVT and a low probability of PE.
Stein et al,
396 patients with PE from PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis) data. 376 treated with either full dose anticoagulation, thrombolysis, embolectomy, IVC interruption, antiplatelet agents or low dose anticoagulation. 297/376 treated with full dose anticoagulation only. 20 patients were not treated. Pulmonary angiogram obtained in 19 untreated and 362 treated patients. Age of untreated 60±18 years versus treated at 58±17 years. Retrospective subgroup analysis from PIOPED data to assess the 3-month outcome in 20 patients who did not receive anticoagulants compared with those that did (level 2b). Recurrent PE during first 3 months2/20 (10%) of untreated patients vs 22/376 (5.9%) treated patients by any means vs 21/297 (7.1%) patients treated with full dose anticoagulants only. Retrospective study design with small sample size. 19 angiograms initially interpreted as showing no PE were deemed positive after re-evaluation by a central panel. More V/Q scans were high probability in treated patients (160/376; 43%) compared with untreated patients (0/20; 0%) (p<0.001); the reverse is also true. Similarly, pulmonary angiography demonstrated a difference between the two groups with regards to the order of vessel involved. No blinding between reference standard tests and clinical details during follow-up.
Mortality during first 3 months8/20 (40%) deaths in untreated patient group. Only 1 (5%) due to PE vs 9/376 deaths (2.4%) within the treated patient group (causes of death not stated).
Donato et al,
1,463/10,453 CT scans from a single centre reported as having a PE. 93 patients (average age 63.5 years) were identified as having an isolated subsegmental pulmonary embolism (ISSPE) without other VTE disease or higher-order PE. 71 patients received anticoagulation (58 received warfarin, 10 had warfarin and an IVC filter, 1 a low molecular weight heparin and 2 were given an IVC filter only); 22 patients received no treatment.Retrospective analysis of 10,453 CT scans (with contrast)—these were reviewed manually to include those reporting PE and those with subsegmental level embolisms were selected for this study. Recurrent VTEOne recurrent subsegmental PE occurred in the treated arm (1/71; 1.4%). This patient was treated with warfarin and an IVC filter. There was no recurrent disease in patients without anticoagulation. Used coding to identify the recurrent VTE and bleeding; thus these outcomes may be underestimated. There is no hospital protocol for the management of VTE so treatment was based on the clinician's decision at the time; selection bias apparent between groups. Patients received a variety of treatment methods with no gold standard used. For 68/93 patients (73%) only inpatient notes were accessed while for the remaining 24/93 patients (25%) (1 lost to follow-up), the outpatient cardiologist/primary care physician was contacted. Thus further episodes of VTE may have been missed.
MortalityTwo deaths occurred in patients on anticoagulant therapy but neither was attributable to PE (one metastatic breast cancer, one pneumonia) No deaths in the untreated group.
Major and minor bleedingEight bleeding events occurring in patients on anticoagulants (11%) (three minor and five major bleeds). No bleeds if not on anticoagulation
den Exeter et al,
The Netherlands
3306+463=3769 patients of which 789 had a confirmed PE, although 41 were excluded due to unknown location of PE leaving 748 patients. 116 of these had an ISSPE while 632 had a PE in a more proximal pulmonary artery. All patients with PE were anticoagulated with subcutaneous low molecular weight heparin for a minimum of 5 days or intravenous unfractionated heparin (activated partial thromboplastin time (APTT) 1.5–2 times baseline value) followed by a vitamin K antagonist with an international normalised ratio (INR) of 2.0–3.0 for 6 months. Exclusion criteria: anticoagulation >24 h; life expectancy <3 months; pregnancy; geographical inaccessibility; age <18 years; allergy to intravenous contrast; or haemodynamic instability. Similar exclusion criteria and treatment protocols were followed in each study. Combination of two prospective cohorts—their aims were to compare risk profiles and 3-month clinical outcomes of (1) patients with isolated SSPE to (2) patients with a more proximally located PE and also to (3) patients without PE. The mean age of patients was 56 years, 57 years and 52 years, respectively. Risk profile/baseline characteristicsNo difference between patients with ISSPE and more proximal PE. The percentage of patients with malignancy (p=0.04), immobility (p=0.004), recent surgery (p<0.001) and recent oestrogen use (p<0.001) was higher in patients with ISSPE than in those without PE. An ‘unlikely’ Wells’ score was seen in 50% patients with ISSPE vs 38.6% (p=0.02) of patients with more proximal PE and compared with 73.1% (p<0.001) of patients without PE. The patient numbers in the ISSPE group were significantly lower than in the group without PE (n=116 vs 2980, respectively). The recurrent VTE outcome was assessed objectively but with varying investigative methods used for different patients. This was also the case with mortality where subjects would be classified as having a PE-attributable death if this could not be confidently ruled out. Radiologists were blinded to clinical information for primary PE diagnosis but no mention of blinding of clinicians who were assessing outcome data from patient imaging/notes, etc. All patients were treated not allowing for a comparative group for non-anticoagulant analysis.
Symptomatic recurrent VTEFour (3.6%) patients with ISSPE vs 10 (2.5%) patients with more proximal PE (p=0.42). Not influenced when adjusted for. 25 patients without PE developed VTE; this provided a significant (adjusted) HR of 3.8 (CI=1.3 to 11.1).
Incidence of major bleeding complicationsTwo (1.7%) patients with ISSPE vs 10 (1.6%) patients with more proximal PE—2 of the latter were classified as fatal.
All-cause mortality Twelve (10.3%) patients with ISSPE vs 40 (6.3%) patients with more proximal PE died (adjusted HR=1.5; CI 0.8 to 2.8; p=0.17). 156 (5.2%) patients without PE died. Significantly lower than patients with ISSPE (p=0.01) until adjustment for covariates (HR=1.4; CI 0.8 to 2.6).
Le Gal et al,
Fourteen prospective studies looking at spiral CT versus pulmonary angiography and four prospective pragmatic studies were included. Two of these studies had data on patients with ISSPEs (30/493 patients; 6.0%). Systematic review to determine the accuracy of spiral CT for detecting ISSPE and the characteristics and clinical outcomes can be found in this patient cohort 3 month outcomes (recurrent VTE, bleeding, mortality) in patients with an ISSPE detected via spiral CT (other outcomes involve assessment of spiral CT as a diagnostic tool) 16.7% with ISSPE vs 52% with more proximal PE had a high clinical probability of PE. 3.3% of patients with an ISSPE vs 43.8% of patients with more proximal PEs had an associated proximal DVT (p<0.0001). 8 of the 30 patients with an ISSPE were untreated with no recurrent VTE reported (0%; CI 0.0% to 32.4%); these patients were also less symptomatic. Selecting patients with ISSPE from a collection of studies is not ideal since they are from different patient cohorts and appear to have undergone a variety of diagnostic investigations, often without the use of a reference standard. Patients with an ISSPE that were left untreated underwent secondary investigation (V/Q scan or pulmonary angiogram) with seven out of eight having a negative result; potential for false positives.


There is much debate about whether patients with isolated subsegmental pulmonary embolisms (ISSPEs) should be treated as aggressively as those with higher order PEs; this is mainly due to the associated risks of anticoagulation. The lack of randomised controlled trials in this area, as demonstrated by Yoo et al,7 is hardly surprising since not treating patients presenting symptomatically with a PE, however mild, may be seen as unethical. The concept of false negatives and false positives may play a significant role in several of these studies. First, there is a poor correlation between recurrent symptoms of VTE and positive CT pulmonary angiogram results; these results are therefore hard to analyse, especially without the use of a reference standard such as a pulmonary angiogram. Second, Stein et al report 19 consecutive negative angiograms, the results of which were ultimately amended to ‘PE present’ after re-evaluation. This possibly demonstrates human error but certainly brings about questions over the true diagnosis. A similar scenario was seen in the paper by Le Gal et al6 with untreated patients with ISSPE undergoing secondary investigation and all of these results being negative for PE. Consequently we should question whether our diagnostic techniques are sufficiently sensitive to confidently pick up cases of ISSPE should we reach the conclusion that such patients do in fact need to receive adequate anticoagulation. Finally without randomisation of (and blinding to) treatment in the studies evaluated, selection bias is a concern. Some studies attempt to address this by adjusting for patient characteristics and, as reported by den Exter et al,5 this can make a noticeable difference to the outcomes and their statistical value. It is more likely that those patients who received anticoagulant therapy did so because of their more serious clinical presentation, potentially skewing results in comparative analyses. The degree of influence this has is difficult to determine but must come into consideration when analysing such studies. Ultimately, we have identified six observational studies that present data relevant to the three-part question. Of those, only two studies included patients with ISSPE who did not receive either anticoagulation or an inferior vena cava filter. A total of 47 patients met those criteria, of whom none died and none developed recurrent venous thromboembolism within 3 months. Clearly, the number of patients is small meaning that CIs will be wide. The observational nature of the studies also precludes the drawing of definitive conclusions from these data.

Editor Comment

CTPA, CT pulmonary angiogram; ISSPE, isolated subsegmental pulmonary embolism; IVC, inferior vena cava; PE, pulmonary embolism.

Clinical Bottom Line

Ultimately there appears to be a low rate of recurrent venous thromboembolism and mortality in this subgroup of patients. There is insufficient evidence to recommend that we should universally stop treating patients with an isolated subsegmental pulmonary embolism. However, observational studies suggest that clinical outcomes are comparable between patients not receiving anticoagulation and patients receiving treatment. In some cases, the reported outcomes are similar to patients who do not have pulmonary embolism.


  1. Eyer BA, Goodman LR, Washington L . Clinicians’ response to radiologists’ reports of isolated subsegmental pulmonary embolism or inconclusive interpretation of pulmonary embolism using MDCT. AJR Am J Roentgenol 2005;184:623–8.
  2. Kruit WHJ, De Boer AC, Sing AK, et al . The significance of venography in the management of patients with clinically suspected pulmonary embolism. J Intern Med 1991;230:333–9.
  3. Stein PD, Henry JW, Relyea B . Untreated patients with pulmonary embolism. Outcome, clinical and laboratory assessment. Chest 1995;107:931–5.
  4. Donato AA, Khoche S, Santora J, et al . Clinical outcomes in patients with isolated subsegmental pulmonary emboli diagnosed by multidetector CT pulmonary angiography. Thromb Res 2010;126:e266–70.
  5. den Exter PL, van Es J, Klok FA, et al . Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism. Blood 2013;122:1144–9.
  6. Le Gal G, Righini M, Parent F, et al . Diagnosis and management of subsegmental pulmonary embolism. J Thromb Haemost 2006;4:724–31.
  7. Yoo HH, Queluz TH, El Dib R . Anticoagulant treatment for subsegmental pulmonary embolism. Cochrane Database Syst Rev 2014;4:CD010222.