Risk of Clot When Imaging Says, “Not.”

Authors: Anne Flower, MD (@Flow_Pow, Emergency Medicine Resident) and Amy Zeidan, MD (@amyjwal), University of Kentucky Department of Emergency Medicine // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Background of VTE

Venous thromboembolism (VTE) has a high prevalence, varied presentation, and critical diagnostic importance to emergency physicians. Clinical decision tools have become fundamental in the workup of pulmonary embolism (PE) and deep vein thrombosis (DVT) with CT of the pulmonary arteries (CTPA) and lower extremity ultrasound being the diagnostic gold standards, respectively¹. How good are these tests? Should we feel comfortable sending patients home without anticoagulation when CT or US does not show a thrombus?

Case:

55-year-old female with history of obesity and tobacco use presents to the ED with shortness of breath. Described as pain below her ribs with inspiration and feeling like she is unable to “get enough air.” Her symptoms started yesterday morning and are getting worse. She also has a productive cough. Her left leg has been in a cast for the past 3 weeks after a nonoperative ankle fracture. She has had difficulty getting around her house and has mostly been sitting and sleeping in her recliner. She notes mild swelling of her left leg but attributes this to her cast. She denies fevers, recent travel, history of DVT/ PE, hemoptysis, and history of malignancy. Vital signs: BP 140/90, HR 85, T 101F, RR 20, O2 95% on RA.

Wells’ Score: 4.5 = 3 (PE #1 diagnosis or equally likely) + 1.5 (immobilization/ surgery) = moderate risk (16% chance of PE)

Laboratory work:

• Elevated white blood cell count (12k)
• Renal function within normal limits
• D dimer: 800ng/mL
• Troponin not elevated

EKG: Nonspecific, sinus rhythm, normal rate

CXR: Hazy opacity in the lower lobes, atelectasis vs infiltrate, worse on left

LLE 3 Point Compression Ultrasound: negative for DVT

CTPA: Negative for acute PE

Treatment: Antibiotics for community acquired pneumonia, no anticoagulation

Question 1: Could this patient still have a PE after negative CT?

Possibly. A number of studies have pursued this question, and the data are mixed.  A review by Hogg and colleagues highlighted the variability in studies evaluating the diagnostic accuracy of CTPA. The sensitivity of CTPA ranged from 53% to 100%, with a pooled sensitivity of 88.9%². The PIOPED-II trial concluded that CTPA had an overall sensitivity of only 83% and specificity of 96% of ruling out PE. This hallmark study illustrated that pretest probability, based on Wells’ score, was a critical factor in ruling out PE (in low risk patients) and in diagnosing PE (in high risk patients)³. A prospective study by Akhter and colleagues concluded that negative CTPA does not safely rule out PE in patients with a high pretest probability. Twelve percent of patients in this study with a high pretest probability were found to have a negative CTPA and ultimately diagnosed with a PE⁴. Similarly, a study by Hammer evaluated patients with a positive CTPA study after an initial negative CTPA study. The positive rate was found to be 7% if the CTPA was performed within one year of the initial negative CTPA, which was similar to the control group. They concluded that patients with a prior negative CTPA study are just as likely as the general patient population to have a PE in the future, suggesting that there is no risk free period after a negative CTPA⁵.

Conversely, a meta-analysis by Mos concluded that a normal CTPA can safely exclude PE in patients with a moderate probability, with a negative predictive value of 98.8%. Further, the incidence of VTE at 3 months was 1.2% in patients who had a normal CTPA test⁶. Similarly, The Christopher Study Investigators summarized that a diagnostic management strategy using a clinical decision rule, d-dimer, and CTPA can be used to rule out PE. In patients with a low clinical probability, negative d-dimer, and negative CTPA, there was a 0.5% incidence of VTE at three months⁷.

Who is at future risk of PE after negative CTPA?

Patients who have a negative CTPA but intermediate or high pretest risk based on the Wells’ score are still at considerable risk of PE.  This was demonstrated in a large 2018 meta-analysis of three month follow-up outcomes in high risk patients who had negative CTPA. Patients with high pretest prevalence (>40%) had risk of future PE as high at 8.1%. Patients with low pretest prevalence (<20%) had 3 month subsequent risk of 1.8%⁸.This brings into question whether the clot was missed on initial imaging or if it developed in the short time after. Recent guidelines from the American Society of Hematology (ASH) suggest that additional testing following a negative CTPA in low and intermediate prevalence populations is unnecessary. For patients with high clinical probability and negative CTPA, the ASH recommends considering additional testing based on clinical judgement⁹.

Special Considerations

Not all clots are clinically or hemodynamically significant, and there are risks associated withincidental findings, including need for anticoagulation.  The false positive rate for CTPE has been reported as high at 10-25%^10,11. Advances in imaging technology allow for diagnosis of clots that are as small at 2mm, but also may identify artifact as thrombi. In the PIOPED II study, 6% of patients diagnosed with PE had isolated subsegmental clots³. There is debate within the medical community as to whether or not subsegmental clots warrant anticoagulation, considering patient-specific risks and benefits¹².  The most recent CHEST guidelines recommend surveillance in patients with subsegmental PE who have no proximal DVT in the legs and who are at low risk for recurrent VTE. For patients who are high risk for recurrent VTE, they suggest anticoagulation¹³. ACEP Clinical Policy provides a Level C recommendation regarding treatment of subsegmental PE. They summarize that there is lack of evidence pertaining to this topic however treatment for “patients with subsegmental PE without associated DVT should be guided by individual patient risk profiles and preferences¹⁴.”

Question 1 Summary

This patient is at intermediate risk of having a PE based on Wells’ Score (16%), and after negative CT her likelihood is less than 10%, maybe significantly less. This patient is hemodynamically stable, and it would be safe to send her home today with follow up and without anticoagulation. However, her risk factors for VTE warrant consideration of and evaluation for DVT.

Question 2: Could this patient still have a DVT after a negative DVT study?

Possibly.Given this patient’s history of recent surgery, lower extremity ultrasound was performed to evaluate for a DVT. Typically, venous ultrasound is the test of choice for evaluation of DVT in conjunction with risk stratification using the Wells’ Score (read more at http://www.emdocs.net/em3am-dvt/).  D-dimer alone can be used in the setting of a low pretest probability with a Wells’ score of 0 but will not be covered here^12,15. D-dimer can also be used in combination with US in the evaluation for DVT. For moreinformation on this see: https://coreem.net/core/deep-venous-thrombosis-dvt/.

Type of Ultrasound

There are multiple ultrasound techniques that evaluate for DVT. It is important to understand and distinguish the type of study performed, as the diagnostic accuracy varies depending upon technique. Compression ultrasound is typically the simplest technique with a high specificity¹⁶. Whole leg compression evaluates both proximal and distal, veins whereas other techniques like the two or three point compression evaluate for proximal clots only. Two point compression typically evaluates for compression at the common femoral vein and popliteal vein, with the addition of the superior femoral vein in three point compression¹⁷. Doppler and color ultrasound techniques can also evaluate for DVT and have higher sensitivity. However, these techniques are more challenging, which can lead to greater variability in results and will not be covered in depth here¹⁶.

Diagnostic Accuracy of Ultrasound

Ultrasound evaluation of proximal DVTs in symptomatic patients has been shown to have sensitivities and specificities of 94% and 98%, respectively. This pooled data is summarized from studies that mostly utilize compression ultrasound performed by radiology departments¹⁶. However, proposed algorithms often suggest obtaining a repeat ultrasound in one week to evaluate for propagation of calf DVTs¹⁸. The rationale for this is that these studies evaluated for proximal DVTs only, not distal DVTs. The prevalence of isolated calf DVT propagation has been shown to be as high as 25%¹⁹. But there are many barriers that make follow up studies challenging.

One solution proposed is whole leg ultrasound, which evaluates for both proximal and distal clots. A number of studies have evaluated whether a single whole leg ultrasound could be performed to avoid follow up testing. Two studies in outpatient settings in France concluded that patients with a negative compression ultrasound of the whole leg did not require repeat testing. In one study, the incidence of DVT was 0.5% after an initial negative ultrasound, whereas the incidence of VTE in the other study was 0.6%^20,21. A meta-analysis by Johnson and colleagues demonstrated similar results. This review of both inpatient and outpatient studies summarized that whole leg compression ultrasound evaluating both proximal and distal veins can reliably exclude DVT without the need for follow up testing. The risk of developing VTE after the initial negative ultrasound was 0.57%¹⁹.

The challenge to this rule-out approach is that whole leg ultrasound is not always available²². A possible solution to this is the incorporation of clinical probability in decision making.

Ultrasound and Clinical Probability

A study by Wells and colleagues concluded that patients with suspected DVT could be managed appropriately using clinical probability and ultrasound of the proximal veins of the legs. The algorithm suggests that patients with low pretest probability based on Wells’ Criteria and a negative DVT study do not need to undergo repeat testing. In the low pretest probability group, the negative predictive value was 99.7%, with only one patient developing a DVT at three month follow up. This essentially rules out a DVT in patients with low pretest probability. Of the patients with a moderate pretest probability and initially negative ultrasound, 17% developed a DVT on follow up testing. They conclude that patients with moderate pretest probability and initially negative DVT study should undergo repeat ultrasound in 1 week. Patients with a high pretest probability had an incidence of DVT of 75% on initial ultrasound. Thus, they suggest patients with a high pretest probability and negative initial DVT study should undergo venography¹⁸. The ACP and AFP guidelines suggest similar recommendations and incorporate pretest probability into their recommendations²³. Finally, other studies have evaluated the incorporation of d-dimer with clinical probability and ultrasound. A study by Tick and colleagues recommends obtaining a D-dimer when patients with moderate to high pretest probability for DVT have normal proximal ultrasound.  If the d-dimer is abnormal, they suggest repeat ultrasound in one week. None of the patients with a normal d-dimer developed a DVT at follow up testing. However, 15% of the patients with an abnormal d-dimer and normal US had an abnormal ultrasound one week after the initial²⁴. Recent guidelines from the ASH suggest for patients with low pretest probability and a negative lower extremity proximal US or whole leg ultrasound, no additional testing is needed⁹. For patients with intermediate pretest probability, no additional testing is needed if whole leg ultrasound is negative. However if proximal ultrasound is negative, serial proximal ultrasound should be performed if no alternate diagnosis is identified. For patients with high pretest probability, they recommend serial ultrasound if initial ultrasound is negative and no alternate diagnosis is identified⁹.

Special considerations

While not a comprehensive review of this topic, it is important to specifically mention ED performed DVT studies. DVT studies can be performed by emergency department physicians, but protocols may vary by individual and institution. Some studies have evaluated two or three point compression techniques performed by ED physicians and show mixed results. One study evaluating two point compression by ED physicians compared to radiology studies demonstrated a sensitivity of 100% and specificity of 99%. Of note, all participating physicians in this study received a 10-minute bedside training session and were either ED attending physicians or emergency medicine, internal medicine, or family medicine residents. This study did not incorporate follow up studies, pretest probability or d-dimer²⁵. A similar study evaluated a three point compression technique performed by ED attending physicians, fellows, and residents and found a sensitivity of 86% and specificity of 93%²⁶. Physician participants received a one hour didactic lecture and hands on session prior to performing DVT studies. The utilization of ED performed DVT studies can vary depending on the training of the operator, machine, and protocol used. Further studies are needed to risk stratify ED physician performed ultrasound that incorporate follow up testing and clinical probability.

Question 2 Summary

This patient is at moderate risk of having a DVT based on Wells’ Score. The ultrasound performed in the ED was a radiology performed three point compression ultrasound, not a whole leg ultrasound. Thus, it is reasonable to recommend follow up ultrasound in one week and to forgo anticoagulation at this time. Notably, in most ED settings, the gold standard for DVT ultrasound is still ultrasound performed by the radiology department, but recent studies highlight the diagnostic accuracy of ED physician performed DVT studies.

Takeaways

• Negative CT PE studies may miss some PE’s. Patients who are high risk likely warrant follow up, although the exact type and timing of follow up is unclear.
• It may be ideal to perform whole leg ultrasound if possible to evaluate for both proximal and distal clots. If two or three point compression ultrasound performed is negative, it is reasonable to recommend repeat ultrasound in one week for patients who have a moderate or high pretest probability.

References/Further Reading:

1. Task A, Members F, Konstantinides S V, et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism – web addenda. European heart journal 2014;3033–80.
2. Hogg K, Brown G, Dunning J, et al. Diagnosis of pulmonary embolism with CT pulmonary angiography: A systematic review. Emergency Medicine Journal 2006;23(3):172–8.
3. Maitland K, FEAST TRIAL GROUP. New England Journal. The New England Journal of Medicine 2011;364(26):2483–95.
4. Akhter M, Kline J, Bhattarai B, Courtney M, Kabrhel C. Ruling out Pulmonary Embolism in Patients with High Pretest Probability. Western Journal of Emergency Medicine [Internet] 2018;19(3):487–93. Available from: https://escholarship.org/uc/item/74h4h8qb
5. Hammer MM, Litt HI. Risk of pulmonary embolism after a prior negative CT pulmonary angiogram. American Journal of Emergency Medicine [Internet] 2016;34(10):1968–72. Available from: http://dx.doi.org/10.1016/j.ajem.2016.07.002
6. Mos ICM, Klok FA, Kroft LJM, De Roos A, Dekkers OM, Huisman M V. Safety of ruling out acute pulmonary embolism by normal computed tomography pulmonary angiography in patients with an indication for computed tomography: Systematic review and meta-analysis. Journal of Thrombosis and Haemostasis 2009;7(9):1491–8.
7. Writing Group for the Christopher Study Investigators. Effectiveness of Managing Suspected Pulmonary Embolism Using an Algorithm. Jama 2006;295(2):172–9.
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21. Elias A, Mallard L, Elias M, et al. A single complete ultrasound investigation of the venous network for the diagnostic management of patients with a clinically suspected first episode of deep venous thrombosis of the lower limbs. Thrombosis and Haemostasis 2003;89(2):221–7.
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23. Barry P, Hornbake ER, Rodnick JE, Tobolic T. Amir Qaseem. Annals Of Family Medicine 2007;57–62.
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