- Email: [email protected]
Risk of asymptomatic pulmonary embolism in patients with deep venous thrombosis
Risk of asymptomatic pulmonary embolism in patients with deep venous thrombosis Mariana Krutman, MD,a Nelson Wolosker, MD, PhD,b,e Sérgio Kuzniec, MD, PhD,b João Carlos de Campos Guerra, MD,c Adriano Tachibana, MD, PhD,d and Cynthia de Almeida Mendes, MD,b São Paulo, Brazil Objective: The aim of our study is to evaluate the incidence of asymptomatic pulmonary embolism (PE) in patients with deep venous thrombosis (DVT), submitted to routine angiography of pulmonary vessels, and analyze the relationship between the site of DVT and extent of PE. Methods: Between January 2006 and April 2012, 52 consecutive patients with acute inferior limb DVT were divided into two study groups composed of individuals with proximal and distal thrombotic involvement. All patients had no respiratory symptoms and were submitted to routine pulmonary computed tomography angiography for active investigation of PE. We assessed the incidence and extent of PE in both study groups.
Results: Thirty-eight patients (72%) had PE, detected by computed tomography angiography. The incidence of PE in patients with proximal and distal thrombosis, respectively, was 72.7% and 73.7%. Occurrence of segmental embolism was equally high in both groups, affecting 71.4% of the patients with distal thrombosis and 66.6% of the individuals with proximal DVT (P > .99). Conclusions: The incidence of asymptomatic PE observed in patients with DVT is higher than what is reported in the current literature. This supports the importance of screening and the need for high levels of suspicion regarding this complication. (J Vasc Surg: Venous and Lym Dis 2013;1:370-5.)
Symptomatic pulmonary embolism (PE) is the most severe complication of deep venous thrombosis (DVT) and is usually associated with significant morbidity and mortality. Because DVT and PE rely on anticoagulation therapy, and many cases of PE are asymptomatic,1 the need for routine screening of this condition is debatable,2 especially in cases of distal vein thrombosis. Studies have demonstrated that silent PE may occur in 32% to 60%3-5 of patients with DVT, but these numbers are probably underestimated for two main reasons: (1) most asymptomatic cases are never investigated, and PE may go by unnoticed; (2) improved quality of imaging studies has allowed a safer and more precise detection of this condition.6 Within the past decades, multidetector computed tomography (MDCT) has rapidly spread into practice, replacing other diagnostic methods such as ventilationperfusion scans and pulmonary angiography.7 The new computed tomography scanners available, with high acquisition speeds and thin collimations, have resulted in
increased resolution and peripheral pulmonary artery visualization,5 allowing a more precise diagnosis of PE. The aim of our study is to evaluate the incidence of asymptomatic PE in patients with DVT by means of routine MDCT angiography of pulmonary vessels and analyze the relationship between the site of DVT and extent of PE. This analysis will enable further assessment of the impact of PE in patients with DVT and provide additional insight on the potentially hidden risks of distal DVT.
From the Department of Vascular and Endovascular Surgery,a Department of Vascular Surgery,b Department of Clinical Pathology,c and Department of Radiology,d Hospital Israelita Albert Einstein; and the Division of Vascular Surgery, Hospital das Clínicas, University of São Paulo Medical School.e Author conflict of interest: none. Reprint requests: Mariana Krutman, MD, Avenida Albert Einstein, 627 Morumbi, São Paulo, Bloco A1, Sala 423, Brazil 05652-900 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 2213-333X/$36.00 Copyright Ó 2013 by the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvsv.2013.04.002
370
METHODS This study was carried out in accordance to the Ethics Committee of our institution (Albert Einstein Israelite Hospital). We retrospectively analyzed the records of 65 consecutive patients admitted to our vascular surgery group, with diagnosis of DVT, from January 2006 to April 2012. Since the beginning of our data collection in 2006, we have used a detailed evaluation protocol for all patients, which remained unchanged throughout the study. This protocol contains important information concerning patient epidemiologic data, risk factors, physical examination on admission, and radiologic findings. This has allowed us to carry out the present research adequately, with minimal data loss, despite its retrospective nature. The major risk factors analyzed in our protocol were age >75 years, presence of active cancer, history of recent surgery or trauma, and hematological disorders. Predisposing conditions other than the aforementioned were noted and categorized as “other.” All patients in our protocol were tested for prothrombin and factor V Leiden mutation, and an active screening for cancer was performed by means of abdominal ultrasound and basic blood tests.
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Table I. Age, gender, location, and laterality of DVT in the studied protocol groups
No. (%) Gender, No. (%) Female Male Age, years Median Range Laterality of DVT, No. (%) Left Right Bilateral Proximal site of DVT, No. (%) Muscular veins (gastrocnemius and soleus veins) Axial calf veins (tibial and peroneal veins) Popliteal Femoral Iliac
Proximal group
Distal group
33 (63.5)
19 (36.5)
18 (54.5) 15 (45.5)
8 (42.1) 11 (57.9)
.39a
58 25-86
45 21-64
.01b
16 (48.5) 14 (42.4) 3 (9.1)
9 (47.4) 10 (52.6) 0 (0.0)
e
6 (31.6)
e
13 (68.4)
10 (30.3) 10 (30.3) 13 (39.4)
e e e
P
DVT, Deep venous thrombosis. a Pearson c2 test. b Student t-test.
Inclusion criteria consisted of acute inferior limb DVT, confirmed by color Doppler in patients with no respiratory symptoms, submitted to routine chest computed tomography angiography (CTA) for active investigation of PE. As part of the protocol, CTAs were performed within 24 hours of the DVT diagnosis in patients with related symptoms that included leg pain and/or edema. Thirteen patients were excluded from our study, 10 due to the presence of pulmonary symptoms (dyspnea or thoracic pain), five of whom had proximal DVT and five distal thrombosis, and three in consequence of renal insufficiency (creatinine levels over 1.5 mg/dL), all with distal DVT. Therefore, out of the 65 patients with DVT initially enrolled, 52 were included for analysis. To ensure the validity of our patient sample, we analyzed the epidemiology and risk factors of a control group consisting of patients with DVT that spontaneously presented to the emergency department of Albert Einstein Israelite Hospital within the same time period analyzed in our study and were conducted by other vascular surgery groups. We used the hospital’s official database and surveyed the cases of DVT using the International Classification of Diseases, Tenth Revision (ICD-10) coding system. The codes analyzed were I82.8 (embolism and thrombosis of other specified veins) and I82.9 (embolism and thrombosis of unspecified vein). Cases of thrombosis in sites other than inferior limbs, cases of isolated superficial thrombophlebitis, and cases of PE with no detected DVT were excluded from the control group analysis. Patients were treated according to well-accepted guidelines.9 Enoxaparin (1 mg/kg twice daily) and simultaneous warfarin were administered to a target international normalized ratio between 2.0 and 3.0. Enoxaparin was
Krutman et al 371
then suspended and the patient was discharged with an adjusted dose of warfarin. None of the patients required treatment in intensive care units and were followed in an ambulatory setting after discharge. All CTAs were performed in 16- or 64-row multislice scanners (Toshiba Medical Systems, Tokyo, Japan) with reconstructed axial images with 1 mm of thickness in either of the scanners. Intravenous iodinated contrast media was used in all subjects in doses ranging from 90 to 120 mL (iobitridol 350 mg/mL), administered by a power injector with a rate of at least 3.5 mL/s (usually 4.0 mL/s). CTAs were oriented for acute PE research, and the interpretation was based on the initial radiologist’s reading. The extent of PE was classified according to an anatomic classification, extensively used by radiologists, that divides the pulmonary arterial tree into 10 segmental arteries and their subsegmental branches.8 The location of the filling defects defines the embolization as segmental or subsegmental, being the more proximal involvement associated with greater potential for unfavorable clinical outcomes.6 Patients were divided into two groups according to the location of the most proximal thrombus involvement, since this factor is usually predictive of PE risk. The proximal group consisted of patients with proximal vein thrombosis, characterized by popliteal and suprapopliteal involvement (including or not more distal below-knee sites). The distal group included patients with isolated calf thrombosis affecting muscular, tibial, or peroneal veins. We assessed the incidence and extent of PE in patients with proximal and distal DVT. Statistical analysis. We compared groups with c2 or Fisher exact test for categorical variables. Fisher exact test was used when expected values less than 5 were observed. For numerical variables, we used the Student t-test. Homogeneity of variances was evaluated using the Levene test, and correction was applied when the P value for this test was less than .05. All analyses were performed using SPSS (SPSS Statistics for Windows, Version 17.0; SPSS Inc, Chicago, Ill), and P values less than .05 were considered statistically significant. RESULTS As outlined in Table I, our sample consisted of 26 women and 26 men, with acute onset of inferior limb DVT and without associated respiratory symptoms. Median ages were similar in both proximal and distal study groups (range, 21-86 years). Sites of DVT included right lower limb (44%), left lower limb (50%), and bilateral lower limb involvement (6%). We observed no bilateral involvement in the distal DVT group. In the distal group, over one-third of the patients presented with muscular vein thrombosis, that is, involvement of veins draining solear or gastrocnemius muscles. The remaining cases consisted of axial calf vein thrombosis, affecting tibial and/or peroneal veins. In the proximal group, the proximal vein most commonly involved was the iliac vein, followed equally by femoral and popliteal involvement.
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Fig 1. Extent of pulmonary embolism (PE) in the proximal and distal groups.
As demonstrated in Fig 1, 38 patients (72%) had PE, detected by CTA. Sixty-eight percent of these emboli involved major segmental pulmonary arteries, whereas the remaining 32% affected only subsegmental smaller arteries. The incidence of PE in patients with proximal and distal thrombosis, respectively, was 72.7% and 73.7%. Occurrence of segmental embolism was equally high in both groups, affecting 71.4% of the patients with distal thrombosis and 66.6% of the individuals with proximal DVT (P > .99). A stratified analysis of the distal group, as shown in Fig 2, reveals that out of the 14 cases of PE in patients with distal DVT, 11 were in patients with axial vein thrombosis and three were in patients with intramuscular DVT. Analyzing the distribution of PE within the distal group, we notice that segmental PE occurred twice as frequently in the axial vein thrombosis group when compared with intramuscular DVT (P ¼ .02). The main associated risk factors identified in our study group are presented in Table II. Our sample consisted almost entirely of outpatients that spontaneously presented to the hospital with complaints of moderate leg pain and/ or edema 3 to 5 days before admission. No cases of more severe symptoms such as phlegmasia were observed. There were only two cases of DVT observed in hospitalized patients, all of them with a previous cancer history,
admitted for oncological purposes. Both cases were associated with PE, and in one patient, thromboembolic complications occurred despite prophylactic treatment with a 40-mg daily dose of enoxaparin. In 25 patients (48.1%), a predisposing factor was not identified. Our screening for malignancies revealed only one case of previously unknown renal cancer, detected on abdominal ultrasound. The proximal group portrays a sample of patients with an apparently higher degree of comorbidities (21.2% incidence of malignancy; P ¼ .04), possibly associated with the observed higher average age. On the other hand, the distal group presents younger patients with thrombotic complications significantly associated with a recent history of trauma (P ¼ .04). Our control group investigation revealed that a total of 207 patients were admitted to the emergency department of Albert Einstein Hospital from January 2006 to April 2012 with the ICD-10 codes I82.8 and I82.9. After an individual review of the medical records and application of exclusion criteria, 80 cases were included in our analysis. Table III discloses a comparative evaluation between our protocol sample population and the control group. Our protocol population was similar to the control group with respect to age (P ¼ .20), gender (P > .10), proximal site of DVT involvement (P ¼ .07), and all studied risk factors. The only parameter that differed in
Fig 2. Extent of pulmonary embolism (PE) in the distal muscular and axial vein groups.
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Table II. Risk factors in the study groups Proximal group Distal group (n ¼ 33), (n ¼ 19), No. (%) No. (%) Pa
Risk factors Age >75 years Recent surgery Orthopedic (ipsilateral to thrombotic involvement) Plastic surgery Cancer Hematological disorder Policitemia vera Factor V Leiden mutation Prothrombin gene mutation Recent traumab Other Crohn’s disease Recent travel history Use of oral contraceptives History of foam injection Unidentified risk factors
6 (18) 3 (9.1) 2
1 (5.2) 5 (26.3) 5
1 7 (21.2) 4 (12.1) 1 3 0 0 (0.0) 2 (6.1) 0 0 2 0 15 (45.5)
0 0 1 (5.2) 0 0 1 3 (15.8) 8 (4.2) 1 2 4 1 10 (52.6)
.24 .12
.04 .64
.04 <.01
.62
c or Fisher exact test.
a 2 b
One patient was run over by a car, one suffered a fracture of the fifth metatarsus (not requiring surgery) and the other, a sprained ankle.
our comparative analysis was laterality of DVT, where we observed a significantly greater involvement of the left limb in the control group (P ¼ .04). DISCUSSION Distal leg thrombosis is still regarded as a condition with an underestimated impact, especially because the Table III. Comparative analysis between the protocol population and the control group Protocol group (n ¼ 52) Age, years Median 47 Range 21-86 Gender, No. (%) Female 26 (50.0) Male 26 (50.0) Laterality of DVT, No. (%) Left 25 (48.1) Right 24 (46.2) Bilateral 3 (5.8) Proximal site of DVT, No. (%) Muscular veins 6 (11.5) Axial calf veins 13 (25.0) Popliteal 10 (19.2) Femoral 10 (19.2) Iliac 13 (25.0) Risk factors, No. (%) Age >75 years 7 (13.5) Recent surgery 8 (15.4) Cancer 7 (13.5) Recent trauma 3 (5.8) Other 10 (19.2) Unidentified risk factor 25 (48.1) DVT, Deep venous thrombosis. a 2 c or Fisher exact test.
Control group (n ¼ 80) 56 21-92
Pa .20
40 (50.0) 40 (50.0)
>.10
54 (67.5) 20 (25.0) 6 (7.5)
.04
14 9 15 29 13
(17.5) (11.2) (18.8) (36.2) (16.2)
.07
18 8 11 8 7 44
(22.5) (10.0) (13.8) (10.0) (8.8) (55.0)
.20 .35 .96 .53 .08 .44
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evidence supporting anticoagulation treatment is inconclusive, not based on direct comparison between treated and nontreated patients.9 The ability to predict distal DVT extension is therefore limited, and objective guidelines are difficult to establish. A growing interest in defining safe and effective treatment strategies can be observed as the Ninth American College of Chest Physicians Guidelines9 have attempted, for the first time, to establish specific management criteria for patients with distal DVT. However, the notion that these patients can be treated conservatively persists. Recent recommendations support less aggressive measures such as no anticoagulation and follow-up ultrasounds to evaluate eventual thrombosis progression and outpatient treatment in cases of distal limb thrombosis, where the potential for associated PE is considered low. However, our study outcomes, with an astonishingly high incidence of silent PE in patients with DVT (72%), demonstrate that previous reports disclosing 60%2 incidence rates underestimate the real impact of this condition. Furthermore, the knowledge that PE is present in 73.7% of the cases of distal DVT may lead to the adoption of more rigorous management strategies in these patients, such as initial inpatient treatment and eventually more prolonged anticoagulation therapy. A recent publication analyzing progression of isolated calf thrombosis discloses a 6% incidence of PE in a 3month follow-up of these patients.10 These numbers again convey the false impression of a low risk for PE but do not reflect the real prevalence of this complication in calf thrombosis since asymptomatic patients were not investigated. The detected leg thrombus may be only the residual portion of a larger clot that has migrated to the lungs. All the cases of PE diagnosed in our study patients were considered acute events, with this evaluation based on suggestive radiologic findings indicative of recent embolic episodes. Findings such as acute pulmonary infarction, wedge-shaped pleural consolidation, linear bands, and enlargement of central or segmental pulmonary arteries are signs significantly associated with acute PE11 and allow for a reliable diagnosis of this condition, especially when in association with acute inferior limb DVT. Although the clinical importance of small, asymptomatic PE may be uncertain,12 there is evidence indicating that the presence of asymptomatic peripheral lung emboli is a predictor of recurrent DVT with the potential for development of more severe and even fatal embolic events.12 Studies have shown that the estimated venous thromboembolism recurrence rate at 1 year after the diagnosis of DVT was 11% for patients with symptomatic DVT and silent PE, compared with 0% in patients with isolated symptomatic DVT.13 As a result, the choice of not indicating anticoagulation therapy for patients with distal DVT may leave untreated, in over 72% of cases, undiagnosed patients with PE. It has been shown that 6% to 30%14 of patients with documented PE have emboli only in subsegmental and smaller arteries. These numbers are coincident with our findings that indicate a 34% incidence
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of subsegmental thrombus among patients with diagnosed PE. The clinical importance of such peripheral emboli is controversial; however, there seems to be agreement that the presence of small thrombus is predictive of more severe embolic events.15,16 Furthermore, in patients with limited cardiopulmonary reserve, small and recurrent asymptomatic peripheral emboli may lead to pulmonary hypertension and overall clinical status deterioration.9 The early diagnosis of asymptomatic PE may alert physicians to the development of a potentially correctable cause of pulmonary hypertension known as chronic thromboembolic pulmonary hypertension, a condition that may otherwise remain silent until a late stage of the disease.17 The improved technology in the fabrication of vena cava filters and increased availability of this device has led to a rise in implantation, supported by a broadening range of indications for insertion.18,19 It is widely accepted that symptomatic PE during anticoagulant therapy is a formal indication for filter insertion. The availability of a baseline exam performed in the early stages of treatment may prevent unnecessary filter placement in patients incorrectly diagnosed with a new embolic event in follow-up tests. Two patients in our study group (one with proximal and the other with distal DVT) sought the emergency department 1 month after the acute episode of thrombosis, with pulmonary complaints (thoracic pain and dyspnea). Both were receiving warfarin within target international normalized ratio levels, and initial X rays were normal. Control CTAs were performed to rule out PE. In one case, pneumonia was diagnosed, with no signs of the previous PE; and in the other case, no pulmonary abnormalities were found except for the segmental thrombus previously observed in the initial CTA. Without the previous knowledge of PE, the second patient would most likely be considered for an unnecessary vena cava filter implantation. The control group analysis outlines a similar demographic profile when compared with our protocol population, therefore minimizing the chances of bias concerning our sample. This demonstrates that our study population is no different from DVT patients attended by other vascular surgery groups in our hospital, and also similar with respect to age and gender to patients assisted in North American services, as demonstrated by Wiener and colleagues.2 Risk factor analysis suggests that patients in the proximal group are clinically worse than those observed in the distal group, mainly due to more advanced age and important comorbidities such as cancer. It is interesting to observe that, despite this difference in the original clinical status, which would lead us to expect inferior outcomes in patients with proximal DVT, rates of PE are equivalent in both study groups. Previous reports have proven superior accuracy of MDCT angiography over single-slice CT for the detection of PE (sensitivity and specificity of MDCT ranges from 83% to 100% and 89% to 97%, respectively, compared with single-slice 53% to 91% and 78% to 97%, respectively).
This is especially true for thin-slice acquisition of 1 mm,7 the same as used in our study. Arguments against systematic CT angiography screening for PE involve potential risks of radiation-associated malignancy, contrast-induced nephropathy, and increased costs. The reported dose of radiation required to perform an MDCT varies between 1.6 and 8.3 mSv, which is roughly twice the amount of background radiation that an average person is exposed to per year.20 Due to these limitations, certain clinical conditions restrict indiscriminate use of this method. Our group routinely performs CTA for active investigation of PE in patients with DVT since we believe it is a safe method, requiring increasingly lower doses of contrast and radiation.7,11,15 In cases of distal calf thrombosis, for example, where no anticoagulation is still considered an option and 3-month treatment regarded as optimal, we prefer to lengthen anticoagulation therapy for 6 months in the presence of PE. Further studies are required to analyze late clinical outcomes in patients with asymptomatic PE and evaluate the impact this may have on long-term lung function. In summary, some clinical considerations should be taken into account when analyzing the importance of actively investigating patients with DVT for PE: (1) there is an unexpectedly high incidence of silent PE in patients with distal DVT (including calf thrombosis); (2) patients with DVT and silent PE have a greater chance of developing future recurrent PE and consequent pulmonary hypertension; (3) silent PE may occur in the central pulmonary arteries; and (4) early diagnosed PE may prevent implantation of unnecessary inferior vena cava filters in suspected cases of anticoagulation failure.3,4,21-23 The arguments listed above supporting routine screening should be weighed against the potential risks of contrast-induced nephropathy and radiation exposure. CONCLUSIONS The incidence of asymptomatic PE observed in patients with DVT is higher than what is reported in the current literature. This should alert physicians to the importance of this complication, especially in patients with distal DVT who are generally regarded as having a lower risk for embolic events. Further studies are required to analyze late clinical outcomes in patients with asymptomatic PE and evaluate the impact this may have on long-term lung function. AUTHOR CONTRIBUTIONS Conception and design: MK, NW, SK Analysis and interpretation: MK, NW, SK, AT Data collection: MK, CM Writing the article: MK, AT Critical revision of the article: SK, NW, JC Final approval of the article: NW, SK, MK, JC, CA, AT Statistical analysis: MK Obtained funding: Not applicable Overall responsibility: MK, NW
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REFERENCES 1. Stein PD. Pulmonary embolism. Pulmonary embolism and deep venous thrombosis at autopsy. 2nd ed. Oxford, UK: Blackwell Publishing Co; 2007. p. 3-15. 2. Wiener R, Schwartz L, Woloshin S. Time trends in pulmonary embolism in the United States. Arch Intern Med 2011;171:831-7. 3. Huisman MV, Büller HR, ten Cate JW, van Royen EA, Vreeken J, Kersten MJ, et al. Unexpected high prevalence of silent PE in patients with deep venous thrombosis. Chest 1985;95:498-502. 4. Stein P, Matta F, Musani MH, Diaczok B. Silent pulmonary embolism in patients with deep venous thrombosis: a systematic review. Am J Med 2010;123:426-31. 5. Meignan M, Rosso J, Gauthier H, Brunengo F, Claudel S, Sagnard L, et al. Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis. Arch Intern Med 2000;160:159-64. 6. Storto M, Di Credico A, Guido F, Larici AR, Bonomo L. Incidental detection of pulmonary emboli on routine MDCT of the chest. AJR Am J Roentgenol 2005;184:264-7. 7. Schoepf UJ, Holzknecht N, Helmberger TK, Crispin A, Hong C, Becker CR, et al. Subsegmental pulmonary emboli: improved detection with thin-collimation multi-detector row spiral CT. Radiology 2002;222:483-90. 8. Wu AS, Pezzullo JA, Cronan JJ, Hou DD, Mayo-Smith WW. CT pulmonary angiography: quantification of pulmonary embolus as a predictor of patient outcome-initial experience. Radiology 2004;230:831-5. 9. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ. Antithrombotic therapy for VTE disease. Chest 2012;141(2 Suppl):e419S-94S. 10. Singh K, Yakoub D, Giangola P, DeCicca M, Patel CA, Marzouk F, et al. Early follow-up and treatment recommendations for isolated deep vein thrombosis. J Vasc Surg 2012;55:136-40. 11. Coche EE, Müller NL, Kim K, Wiggs BR, Mayo JR. Acute pulmonary embolism: ancillary findings at spiral CT. Radiology 1998;201:753-8. 12. Remy-Jardin M, Pistolesi M, Goodman LR, Gefter WB, Gottschalk A, Mayo JR, et al. Management of suspected acute pulmonary embolism in the era of CT angiography: a statement from the Fleischner Society. Radiology 2007;245:315-29.
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13. Jiménez D, Díaz G, Marín E, Vidal R, Sueiro A, Yusen RD. The risk of recurrent venous thromboembolsim in patients with unprovoked symptomatic deep venous thrombosis and asymptomatic pulmonary embolism. Thromb Haemost 2006;95:562-6. 14. Oser RF, Zuckerman DA, Gutierrez FR, Brink JA. Anatomic distribution of pulmonary emboli at pulmonary angiography: implications for cross-sectional imaging. Radiology 1996;199:31-5. 15. Patriquin L, Khorasani R, Polak JF. Correlation of diagnostic imaging and consequent autopsy findings in patients with pulmonary embolism. AJR Am J Roentgenol 1998;171:347-9. 16. Hull R, Raskob GE, Ginsberg JS, Panju AA, Brill-Edwards P, Coates G, et al. A non-invasive strategy for the treatment of patients with suspected pulmonary embolism. Arch Intern Med 1994;154: 289-97. 17. Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Eng J Med 2001;345:1465-72. 18. Stein P, Matta F, Hull R. Increasing use of vena cava filters for prevention of pulmonary embolism. Am J Med 2011;124:655-61. 19. Zerati AE, Wolosker N, Yazbek G, Langer M, Nishinari K. Vena cava filters in cancer patients: experience with 50 patients. Clinics 2005;60: 361-6. 20. Stein P, Woodard P, Weg J, Wakefield T, Tapson V, Sostman HD, et al. Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II investigators. Radiology 2007;242:15-21. 21. Horii Y, Yoshimura N, Hori Y, Takaki S, Takano T, Inagawa S, et al. Correlation between the site of pulmonary embolism and the extent of deep vein thrombosis: evaluation by computed tomography pulmonary angiography and computed tomography venography. Jpn J Radiol 2011;29:171-6. 22. Ghaye B, Willems V, Nchimi A, Kouokam L, Noukoua C, De Maertelaer V, et al. Relationship between the extent of deep venous thrombosis and the extent of acute pulmonary embolism as assessed by CT angiography. Br J Radiol 2009;82:198-203. 23. Girard P, Musset D, Parent F, Maitre S, Phlippoteau C, Simonneau G. High prevalence of detectable deep venous thrombosis in patients with acute pulmonary embolism. Chest 1999;116:903-8.
Submitted Jan 7, 2013; accepted Apr 14, 2013.
Results: Thirty-eight patients (72%) had PE, detected by computed tomography angiography. The incidence of PE in patients with proximal and distal thrombosis, respectively, was 72.7% and 73.7%. Occurrence of segmental embolism was equally high in both groups, affecting 71.4% of the patients with distal thrombosis and 66.6% of the individuals with proximal DVT (P > .99). Conclusions: The incidence of asymptomatic PE observed in patients with DVT is higher than what is reported in the current literature. This supports the importance of screening and the need for high levels of suspicion regarding this complication. (J Vasc Surg: Venous and Lym Dis 2013;1:370-5.)
Symptomatic pulmonary embolism (PE) is the most severe complication of deep venous thrombosis (DVT) and is usually associated with significant morbidity and mortality. Because DVT and PE rely on anticoagulation therapy, and many cases of PE are asymptomatic,1 the need for routine screening of this condition is debatable,2 especially in cases of distal vein thrombosis. Studies have demonstrated that silent PE may occur in 32% to 60%3-5 of patients with DVT, but these numbers are probably underestimated for two main reasons: (1) most asymptomatic cases are never investigated, and PE may go by unnoticed; (2) improved quality of imaging studies has allowed a safer and more precise detection of this condition.6 Within the past decades, multidetector computed tomography (MDCT) has rapidly spread into practice, replacing other diagnostic methods such as ventilationperfusion scans and pulmonary angiography.7 The new computed tomography scanners available, with high acquisition speeds and thin collimations, have resulted in
increased resolution and peripheral pulmonary artery visualization,5 allowing a more precise diagnosis of PE. The aim of our study is to evaluate the incidence of asymptomatic PE in patients with DVT by means of routine MDCT angiography of pulmonary vessels and analyze the relationship between the site of DVT and extent of PE. This analysis will enable further assessment of the impact of PE in patients with DVT and provide additional insight on the potentially hidden risks of distal DVT.
From the Department of Vascular and Endovascular Surgery,a Department of Vascular Surgery,b Department of Clinical Pathology,c and Department of Radiology,d Hospital Israelita Albert Einstein; and the Division of Vascular Surgery, Hospital das Clínicas, University of São Paulo Medical School.e Author conflict of interest: none. Reprint requests: Mariana Krutman, MD, Avenida Albert Einstein, 627 Morumbi, São Paulo, Bloco A1, Sala 423, Brazil 05652-900 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 2213-333X/$36.00 Copyright Ó 2013 by the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvsv.2013.04.002
370
METHODS This study was carried out in accordance to the Ethics Committee of our institution (Albert Einstein Israelite Hospital). We retrospectively analyzed the records of 65 consecutive patients admitted to our vascular surgery group, with diagnosis of DVT, from January 2006 to April 2012. Since the beginning of our data collection in 2006, we have used a detailed evaluation protocol for all patients, which remained unchanged throughout the study. This protocol contains important information concerning patient epidemiologic data, risk factors, physical examination on admission, and radiologic findings. This has allowed us to carry out the present research adequately, with minimal data loss, despite its retrospective nature. The major risk factors analyzed in our protocol were age >75 years, presence of active cancer, history of recent surgery or trauma, and hematological disorders. Predisposing conditions other than the aforementioned were noted and categorized as “other.” All patients in our protocol were tested for prothrombin and factor V Leiden mutation, and an active screening for cancer was performed by means of abdominal ultrasound and basic blood tests.
JOURNAL OF VASCULAR SURGERY: VENOUS AND LYMPHATIC DISORDERS Volume 1, Number 4
Table I. Age, gender, location, and laterality of DVT in the studied protocol groups
No. (%) Gender, No. (%) Female Male Age, years Median Range Laterality of DVT, No. (%) Left Right Bilateral Proximal site of DVT, No. (%) Muscular veins (gastrocnemius and soleus veins) Axial calf veins (tibial and peroneal veins) Popliteal Femoral Iliac
Proximal group
Distal group
33 (63.5)
19 (36.5)
18 (54.5) 15 (45.5)
8 (42.1) 11 (57.9)
.39a
58 25-86
45 21-64
.01b
16 (48.5) 14 (42.4) 3 (9.1)
9 (47.4) 10 (52.6) 0 (0.0)
e
6 (31.6)
e
13 (68.4)
10 (30.3) 10 (30.3) 13 (39.4)
e e e
P
DVT, Deep venous thrombosis. a Pearson c2 test. b Student t-test.
Inclusion criteria consisted of acute inferior limb DVT, confirmed by color Doppler in patients with no respiratory symptoms, submitted to routine chest computed tomography angiography (CTA) for active investigation of PE. As part of the protocol, CTAs were performed within 24 hours of the DVT diagnosis in patients with related symptoms that included leg pain and/or edema. Thirteen patients were excluded from our study, 10 due to the presence of pulmonary symptoms (dyspnea or thoracic pain), five of whom had proximal DVT and five distal thrombosis, and three in consequence of renal insufficiency (creatinine levels over 1.5 mg/dL), all with distal DVT. Therefore, out of the 65 patients with DVT initially enrolled, 52 were included for analysis. To ensure the validity of our patient sample, we analyzed the epidemiology and risk factors of a control group consisting of patients with DVT that spontaneously presented to the emergency department of Albert Einstein Israelite Hospital within the same time period analyzed in our study and were conducted by other vascular surgery groups. We used the hospital’s official database and surveyed the cases of DVT using the International Classification of Diseases, Tenth Revision (ICD-10) coding system. The codes analyzed were I82.8 (embolism and thrombosis of other specified veins) and I82.9 (embolism and thrombosis of unspecified vein). Cases of thrombosis in sites other than inferior limbs, cases of isolated superficial thrombophlebitis, and cases of PE with no detected DVT were excluded from the control group analysis. Patients were treated according to well-accepted guidelines.9 Enoxaparin (1 mg/kg twice daily) and simultaneous warfarin were administered to a target international normalized ratio between 2.0 and 3.0. Enoxaparin was
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then suspended and the patient was discharged with an adjusted dose of warfarin. None of the patients required treatment in intensive care units and were followed in an ambulatory setting after discharge. All CTAs were performed in 16- or 64-row multislice scanners (Toshiba Medical Systems, Tokyo, Japan) with reconstructed axial images with 1 mm of thickness in either of the scanners. Intravenous iodinated contrast media was used in all subjects in doses ranging from 90 to 120 mL (iobitridol 350 mg/mL), administered by a power injector with a rate of at least 3.5 mL/s (usually 4.0 mL/s). CTAs were oriented for acute PE research, and the interpretation was based on the initial radiologist’s reading. The extent of PE was classified according to an anatomic classification, extensively used by radiologists, that divides the pulmonary arterial tree into 10 segmental arteries and their subsegmental branches.8 The location of the filling defects defines the embolization as segmental or subsegmental, being the more proximal involvement associated with greater potential for unfavorable clinical outcomes.6 Patients were divided into two groups according to the location of the most proximal thrombus involvement, since this factor is usually predictive of PE risk. The proximal group consisted of patients with proximal vein thrombosis, characterized by popliteal and suprapopliteal involvement (including or not more distal below-knee sites). The distal group included patients with isolated calf thrombosis affecting muscular, tibial, or peroneal veins. We assessed the incidence and extent of PE in patients with proximal and distal DVT. Statistical analysis. We compared groups with c2 or Fisher exact test for categorical variables. Fisher exact test was used when expected values less than 5 were observed. For numerical variables, we used the Student t-test. Homogeneity of variances was evaluated using the Levene test, and correction was applied when the P value for this test was less than .05. All analyses were performed using SPSS (SPSS Statistics for Windows, Version 17.0; SPSS Inc, Chicago, Ill), and P values less than .05 were considered statistically significant. RESULTS As outlined in Table I, our sample consisted of 26 women and 26 men, with acute onset of inferior limb DVT and without associated respiratory symptoms. Median ages were similar in both proximal and distal study groups (range, 21-86 years). Sites of DVT included right lower limb (44%), left lower limb (50%), and bilateral lower limb involvement (6%). We observed no bilateral involvement in the distal DVT group. In the distal group, over one-third of the patients presented with muscular vein thrombosis, that is, involvement of veins draining solear or gastrocnemius muscles. The remaining cases consisted of axial calf vein thrombosis, affecting tibial and/or peroneal veins. In the proximal group, the proximal vein most commonly involved was the iliac vein, followed equally by femoral and popliteal involvement.
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Fig 1. Extent of pulmonary embolism (PE) in the proximal and distal groups.
As demonstrated in Fig 1, 38 patients (72%) had PE, detected by CTA. Sixty-eight percent of these emboli involved major segmental pulmonary arteries, whereas the remaining 32% affected only subsegmental smaller arteries. The incidence of PE in patients with proximal and distal thrombosis, respectively, was 72.7% and 73.7%. Occurrence of segmental embolism was equally high in both groups, affecting 71.4% of the patients with distal thrombosis and 66.6% of the individuals with proximal DVT (P > .99). A stratified analysis of the distal group, as shown in Fig 2, reveals that out of the 14 cases of PE in patients with distal DVT, 11 were in patients with axial vein thrombosis and three were in patients with intramuscular DVT. Analyzing the distribution of PE within the distal group, we notice that segmental PE occurred twice as frequently in the axial vein thrombosis group when compared with intramuscular DVT (P ¼ .02). The main associated risk factors identified in our study group are presented in Table II. Our sample consisted almost entirely of outpatients that spontaneously presented to the hospital with complaints of moderate leg pain and/ or edema 3 to 5 days before admission. No cases of more severe symptoms such as phlegmasia were observed. There were only two cases of DVT observed in hospitalized patients, all of them with a previous cancer history,
admitted for oncological purposes. Both cases were associated with PE, and in one patient, thromboembolic complications occurred despite prophylactic treatment with a 40-mg daily dose of enoxaparin. In 25 patients (48.1%), a predisposing factor was not identified. Our screening for malignancies revealed only one case of previously unknown renal cancer, detected on abdominal ultrasound. The proximal group portrays a sample of patients with an apparently higher degree of comorbidities (21.2% incidence of malignancy; P ¼ .04), possibly associated with the observed higher average age. On the other hand, the distal group presents younger patients with thrombotic complications significantly associated with a recent history of trauma (P ¼ .04). Our control group investigation revealed that a total of 207 patients were admitted to the emergency department of Albert Einstein Hospital from January 2006 to April 2012 with the ICD-10 codes I82.8 and I82.9. After an individual review of the medical records and application of exclusion criteria, 80 cases were included in our analysis. Table III discloses a comparative evaluation between our protocol sample population and the control group. Our protocol population was similar to the control group with respect to age (P ¼ .20), gender (P > .10), proximal site of DVT involvement (P ¼ .07), and all studied risk factors. The only parameter that differed in
Fig 2. Extent of pulmonary embolism (PE) in the distal muscular and axial vein groups.
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Table II. Risk factors in the study groups Proximal group Distal group (n ¼ 33), (n ¼ 19), No. (%) No. (%) Pa
Risk factors Age >75 years Recent surgery Orthopedic (ipsilateral to thrombotic involvement) Plastic surgery Cancer Hematological disorder Policitemia vera Factor V Leiden mutation Prothrombin gene mutation Recent traumab Other Crohn’s disease Recent travel history Use of oral contraceptives History of foam injection Unidentified risk factors
6 (18) 3 (9.1) 2
1 (5.2) 5 (26.3) 5
1 7 (21.2) 4 (12.1) 1 3 0 0 (0.0) 2 (6.1) 0 0 2 0 15 (45.5)
0 0 1 (5.2) 0 0 1 3 (15.8) 8 (4.2) 1 2 4 1 10 (52.6)
.24 .12
.04 .64
.04 <.01
.62
c or Fisher exact test.
a 2 b
One patient was run over by a car, one suffered a fracture of the fifth metatarsus (not requiring surgery) and the other, a sprained ankle.
our comparative analysis was laterality of DVT, where we observed a significantly greater involvement of the left limb in the control group (P ¼ .04). DISCUSSION Distal leg thrombosis is still regarded as a condition with an underestimated impact, especially because the Table III. Comparative analysis between the protocol population and the control group Protocol group (n ¼ 52) Age, years Median 47 Range 21-86 Gender, No. (%) Female 26 (50.0) Male 26 (50.0) Laterality of DVT, No. (%) Left 25 (48.1) Right 24 (46.2) Bilateral 3 (5.8) Proximal site of DVT, No. (%) Muscular veins 6 (11.5) Axial calf veins 13 (25.0) Popliteal 10 (19.2) Femoral 10 (19.2) Iliac 13 (25.0) Risk factors, No. (%) Age >75 years 7 (13.5) Recent surgery 8 (15.4) Cancer 7 (13.5) Recent trauma 3 (5.8) Other 10 (19.2) Unidentified risk factor 25 (48.1) DVT, Deep venous thrombosis. a 2 c or Fisher exact test.
Control group (n ¼ 80) 56 21-92
Pa .20
40 (50.0) 40 (50.0)
>.10
54 (67.5) 20 (25.0) 6 (7.5)
.04
14 9 15 29 13
(17.5) (11.2) (18.8) (36.2) (16.2)
.07
18 8 11 8 7 44
(22.5) (10.0) (13.8) (10.0) (8.8) (55.0)
.20 .35 .96 .53 .08 .44
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evidence supporting anticoagulation treatment is inconclusive, not based on direct comparison between treated and nontreated patients.9 The ability to predict distal DVT extension is therefore limited, and objective guidelines are difficult to establish. A growing interest in defining safe and effective treatment strategies can be observed as the Ninth American College of Chest Physicians Guidelines9 have attempted, for the first time, to establish specific management criteria for patients with distal DVT. However, the notion that these patients can be treated conservatively persists. Recent recommendations support less aggressive measures such as no anticoagulation and follow-up ultrasounds to evaluate eventual thrombosis progression and outpatient treatment in cases of distal limb thrombosis, where the potential for associated PE is considered low. However, our study outcomes, with an astonishingly high incidence of silent PE in patients with DVT (72%), demonstrate that previous reports disclosing 60%2 incidence rates underestimate the real impact of this condition. Furthermore, the knowledge that PE is present in 73.7% of the cases of distal DVT may lead to the adoption of more rigorous management strategies in these patients, such as initial inpatient treatment and eventually more prolonged anticoagulation therapy. A recent publication analyzing progression of isolated calf thrombosis discloses a 6% incidence of PE in a 3month follow-up of these patients.10 These numbers again convey the false impression of a low risk for PE but do not reflect the real prevalence of this complication in calf thrombosis since asymptomatic patients were not investigated. The detected leg thrombus may be only the residual portion of a larger clot that has migrated to the lungs. All the cases of PE diagnosed in our study patients were considered acute events, with this evaluation based on suggestive radiologic findings indicative of recent embolic episodes. Findings such as acute pulmonary infarction, wedge-shaped pleural consolidation, linear bands, and enlargement of central or segmental pulmonary arteries are signs significantly associated with acute PE11 and allow for a reliable diagnosis of this condition, especially when in association with acute inferior limb DVT. Although the clinical importance of small, asymptomatic PE may be uncertain,12 there is evidence indicating that the presence of asymptomatic peripheral lung emboli is a predictor of recurrent DVT with the potential for development of more severe and even fatal embolic events.12 Studies have shown that the estimated venous thromboembolism recurrence rate at 1 year after the diagnosis of DVT was 11% for patients with symptomatic DVT and silent PE, compared with 0% in patients with isolated symptomatic DVT.13 As a result, the choice of not indicating anticoagulation therapy for patients with distal DVT may leave untreated, in over 72% of cases, undiagnosed patients with PE. It has been shown that 6% to 30%14 of patients with documented PE have emboli only in subsegmental and smaller arteries. These numbers are coincident with our findings that indicate a 34% incidence
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of subsegmental thrombus among patients with diagnosed PE. The clinical importance of such peripheral emboli is controversial; however, there seems to be agreement that the presence of small thrombus is predictive of more severe embolic events.15,16 Furthermore, in patients with limited cardiopulmonary reserve, small and recurrent asymptomatic peripheral emboli may lead to pulmonary hypertension and overall clinical status deterioration.9 The early diagnosis of asymptomatic PE may alert physicians to the development of a potentially correctable cause of pulmonary hypertension known as chronic thromboembolic pulmonary hypertension, a condition that may otherwise remain silent until a late stage of the disease.17 The improved technology in the fabrication of vena cava filters and increased availability of this device has led to a rise in implantation, supported by a broadening range of indications for insertion.18,19 It is widely accepted that symptomatic PE during anticoagulant therapy is a formal indication for filter insertion. The availability of a baseline exam performed in the early stages of treatment may prevent unnecessary filter placement in patients incorrectly diagnosed with a new embolic event in follow-up tests. Two patients in our study group (one with proximal and the other with distal DVT) sought the emergency department 1 month after the acute episode of thrombosis, with pulmonary complaints (thoracic pain and dyspnea). Both were receiving warfarin within target international normalized ratio levels, and initial X rays were normal. Control CTAs were performed to rule out PE. In one case, pneumonia was diagnosed, with no signs of the previous PE; and in the other case, no pulmonary abnormalities were found except for the segmental thrombus previously observed in the initial CTA. Without the previous knowledge of PE, the second patient would most likely be considered for an unnecessary vena cava filter implantation. The control group analysis outlines a similar demographic profile when compared with our protocol population, therefore minimizing the chances of bias concerning our sample. This demonstrates that our study population is no different from DVT patients attended by other vascular surgery groups in our hospital, and also similar with respect to age and gender to patients assisted in North American services, as demonstrated by Wiener and colleagues.2 Risk factor analysis suggests that patients in the proximal group are clinically worse than those observed in the distal group, mainly due to more advanced age and important comorbidities such as cancer. It is interesting to observe that, despite this difference in the original clinical status, which would lead us to expect inferior outcomes in patients with proximal DVT, rates of PE are equivalent in both study groups. Previous reports have proven superior accuracy of MDCT angiography over single-slice CT for the detection of PE (sensitivity and specificity of MDCT ranges from 83% to 100% and 89% to 97%, respectively, compared with single-slice 53% to 91% and 78% to 97%, respectively).
This is especially true for thin-slice acquisition of 1 mm,7 the same as used in our study. Arguments against systematic CT angiography screening for PE involve potential risks of radiation-associated malignancy, contrast-induced nephropathy, and increased costs. The reported dose of radiation required to perform an MDCT varies between 1.6 and 8.3 mSv, which is roughly twice the amount of background radiation that an average person is exposed to per year.20 Due to these limitations, certain clinical conditions restrict indiscriminate use of this method. Our group routinely performs CTA for active investigation of PE in patients with DVT since we believe it is a safe method, requiring increasingly lower doses of contrast and radiation.7,11,15 In cases of distal calf thrombosis, for example, where no anticoagulation is still considered an option and 3-month treatment regarded as optimal, we prefer to lengthen anticoagulation therapy for 6 months in the presence of PE. Further studies are required to analyze late clinical outcomes in patients with asymptomatic PE and evaluate the impact this may have on long-term lung function. In summary, some clinical considerations should be taken into account when analyzing the importance of actively investigating patients with DVT for PE: (1) there is an unexpectedly high incidence of silent PE in patients with distal DVT (including calf thrombosis); (2) patients with DVT and silent PE have a greater chance of developing future recurrent PE and consequent pulmonary hypertension; (3) silent PE may occur in the central pulmonary arteries; and (4) early diagnosed PE may prevent implantation of unnecessary inferior vena cava filters in suspected cases of anticoagulation failure.3,4,21-23 The arguments listed above supporting routine screening should be weighed against the potential risks of contrast-induced nephropathy and radiation exposure. CONCLUSIONS The incidence of asymptomatic PE observed in patients with DVT is higher than what is reported in the current literature. This should alert physicians to the importance of this complication, especially in patients with distal DVT who are generally regarded as having a lower risk for embolic events. Further studies are required to analyze late clinical outcomes in patients with asymptomatic PE and evaluate the impact this may have on long-term lung function. AUTHOR CONTRIBUTIONS Conception and design: MK, NW, SK Analysis and interpretation: MK, NW, SK, AT Data collection: MK, CM Writing the article: MK, AT Critical revision of the article: SK, NW, JC Final approval of the article: NW, SK, MK, JC, CA, AT Statistical analysis: MK Obtained funding: Not applicable Overall responsibility: MK, NW
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Submitted Jan 7, 2013; accepted Apr 14, 2013.