Venous Disease
Incidence and Risk Factors for Bilateral Deep Venous Thrombosis of the Lower Limbs
Angiology Volume 60 Number 1 February/March 2009 99-103 © 2009 SAGE Publications 10.1177/0003319708316897 http://ang.sagepub.com hosted at http://online.sagepub.com
Ivan B. Casella, MD, Maria A. Bosch, MD, and Cláudio RD. Sabbag, MD The incidence of bilateral deep venous thrombosis in patients with single limb or bilateral symptoms was determined using duplex scan examination. In a prospective study, 157 inpatients with clinical suspicion of deep venous thrombosis underwent duplex scan evaluation of the lower extremities. Demographic characteristics, physical examination data, and risk factor information were collected. In all, 57 (36.3%) patients evaluated presented echographic evidence of acute deep venous thrombosis. Forty-six individuals presented unilateral thrombosis, and 11 patients presented bilateral disease (19.3% of all thrombosis, 7.0% of all patients). Sensitivity and specificity of
clinical examination in identifying bilateral thrombosis was 27.2% and 93.3%, respectively. For the risk factors evaluated, active human immunodeficiency virus disease and iliofemoral thrombosis presented an increased risk for bilateral thrombosis (P = .045 and P = .049, respectively). The high incidence of bilateral deep venous thrombosis justifies bilateral duplex scan examination. Active human immunodeficiency virus disease and proximal thrombosis were risk factors for bilateral disease.
D
Doppler have also provided conditions to restart investigations concerning the incidence of bilateral DVT in patients with a single symptomatic limb. Yet doubt persists as to whether the cost-benefit relationship of bilateral scan for DVT is valid. Some authors consider that the actual incidence of bilateral manifestation justifies its adoption,3-5 whereas other investigators disagree, claiming that investigation of both limbs would increase costs without providing clear benefits or changes in therapy.6-10 Studies have tried to identify the clinical features that would point toward a higher risk for bilateral disease, suggesting that specific groups of individuals should perform bilateral scanning.11 The objectives of this study are to estimate the incidence of bilateral lower limb DVT in symptomatic patients and to identify possible clinical features that may represent increased risk for its occurrence.
eep venous thrombosis (DVT) of the lower limbs and its complications remain a finding of high incidence in hospitalized patients. Previous studies using phlebography that have investigated inpatients with unilateral signs and symptoms have generally encountered a significant incidence of bilateral DVT.1,2 Despite such results, phlebographic study of both limbs has rarely been performed in clinical practice, due to cost and logistical issues, and the risk of complications related to the procedure. The use of color-flow Doppler has achieved a higher accuracy in diagnosis of lower limb DVT than clinical examination alone. Also, duplex scanning techniques are faster, safer, and less expensive than phlebography, which has now experienced a decline in its applications. The advantages of color-flow
From the Division of Vascular surgery, Hospital Regional Sul, São Paulo, Brazil. Address correspondence to: Ivan B. Casella, MD, R. Gal Roberto Alves de Carvalho Filho, 270, CEP 04744-000 São Paulo, SP Brazil; e-mail:
[email protected]. The authors have no conflict of interests. No grants or other supports were received for this study. This article was presented orally at the 2007 Brazilian Congress of Vascular Surgery, September 4, 2007, Goiania, Goias, Brazil.
Keywords: deep venous thrombosis; Doppler; duplex; bilateral; risk factor; HIV
Method Between October 2004 and October 2005, 157 inpatients with clinical suspicion of DVT were evaluated in a prospective, transversal study. All patients presented signs and symptoms of single or bilateral disease, and a high probability of disease according to Wells criteria.12 99
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The possible DVT risk factors studied were age, sex, prolonged immobilization, chronic venous occlusive disease, disabling stroke, limb trauma, hormonal contraception or reposition therapy, recent post-operative state (up to 30 days), pregnancy, and clinical active human immunodeficiency virus (HIV) infection with ongoing antiretroviral therapy. Confirmed diagnosis of cancer and thrombophilia were also collected, but no effort was made to identify any unreported incidence of these diseases in the group as a whole. A single certified investigator performed all duplex scan examinations. The first patients were studied using an ATL HDI 1500 ultrasound scanner (Advanced Technology Laboratories, Bothell, Washington,), and a Logiq 5 ultrasound system (GE Healthcare, Milwaukee, Wisconsin) was used for the rest of the patients. Linear multifrequencial (7-12 MHz) transducers were used for limb scan and convex low-frequency (5 MHz) transducers were applied to iliocaval veins. Venous segments evaluated were external iliac vein, common femoral, deep femoral, femoral, popliteal, tibial posterior, fibular, and calf muscle veins. Inferior vena cava and common iliac vein were evaluated in cases of common femoral or external iliac vein thrombosis. Duplex scan examination of both extremities was performed and included gray scale, color Doppler, and spectral evaluation. The echographic criteria for acute DVT were absence of venous compressibility, direct hypoechoic thrombus B-mode identification, and absence of spontaneous or maneuver-induced venous flow. Presence of highly echoic thrombus, signs of recanalization, and wall-thickened veins with normal diameter and residual thrombi were considered evidence of chronic venous occlusion and were not considered subjects of this study. The accuracy of medical history and clinical examination results were compared with the standard of color-flow Doppler findings to confirm their sensitivity, specificity, and predictive values. Chi-square or Fisher’s test, Student’s t test, and multivariate logistic regression were used for data analysis. P values of less than .05 were considered significant.
Results According to the inclusion criteria described above, 157 patients were submitted to duplex scan evaluation. In all, 57 patients (36.3%) had acute DVT diagnosis, and 4 patients (2.5%) presented duplex scan signs of chronic venous occlusion. In all, 46 individuals had
Table 1. Accuracy of Clinical Examination on Identifying Bilateral Deep Venous Thrombosis Duplex Scan Duplex Scan Bilateral DVT Unilateral DVT Total Clinical bilateral DVT Clinical unilateral DVT Total
03 08 11
Sensitivity Specificity Predictive positive value Predictive negative value
27.2% 93.3% 50.0% 84.3%
03 43 46
06 51 57
NOTE: DVT = deep venous thrombosis.
unilateral DVT, being 31 on the left limb. In 11 cases, bilateral DVT was present (19.3% of DVT cases and 7.0% of the whole group). No isolated DVT contralateral to the symptomatic limb was observed. Of the 68 limbs presenting with DVT, thrombi was detected in the iliac veins in 30.3%, common femoral in 63.6%, femoral in 78.7%, popliteal in 78.7%, and infragenicular veins in 82.5%. Inferior vena cava vein thrombosis was identified in only 1 patient. Clinical examination was positive for bilateral disease in only 3 of 11 cases identified by echo-Doppler, which represents a sensitivity of 27.2% and specificity of 93.3% (Table 1). In 8 patients, clinical signs and symptoms were restricted to the left (5 cases) or the right limb. Positive and negative predictive values of clinical examination in identifying bilateral disease were 50.0 % and 84.3%, respectively. Significant association between active HIV disease and acute DVT of both limbs was observed, showing a relative risk of 3.9 (range of 1.5-10.17) for bilateral disease in comparison with non-HIV patients with DVT symptoms. The presence of iliac or femoral thrombosis in the symptomatic limb also showed significant association to acute bilateral disease. This feature was observed in all 11 cases. Also, 10 of 11 patients had proximal bilateral DVT. There were no cases of distal bilateral DVT. Detailed clinical features and risk factors presented by the patients and the P values for significant association between these and bilateral disease are presented in Table 2. Multivariate analysis did not determine clinical or anatomical risk factors for bilateral DVT. All 57 patients were treated with classic anticoagulant therapy, with the exception of 2 cases treated with catheter-directed thrombolytic therapy.
Incidence and Risk Factors for Bilateral Deep Venous Thrombosis / Casella et al
Table 2.
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Differences in the Distribution of Clinical Features and Risk Factors in Patients With Single Limb or Bilateral Deep Venous Thrombosisa
Age, mean/SD Wells criteria score, mean/SD Male Left limb Symptomatic limb left/right/bilateral Immobilization Venous insufficiency Local trauma Stroke Hormonal therapyb Pregnancyb Postoperative state HIV active infection Proximal DVT Neoplasia Thrombophilia
Unilateral DVT, n = 46
Bilateral DVT, n = 11
Total, n = 57
P
42.6 (±16.2) 2.61 (±0.87) 18 (39.1) 28 (62.2) 29:14:3 16 (35.6) 01 (2.2) 03 (6.7) 04 (8.9) 05 (17.9) 03 (10.7) 06 (13.3) 02 (4.4) 31 (67.3) 01 (2.2) 00 (0.0)
44.0 (±20.4) 2.73 (±1.01) 05 (45.4) N/A 5:3:3 05 (45.5) 00 (0.0) 00 (0.0) 03 (27.3) 01 (16.7) 01 (16.7) 01 (9.1) 03 (27.3) 11 (100.0) 00 (0.0) 03 (6.7)
42.9 (±16.9) 2.64 (±0.89) 23 (40.4) N/A 34:17:6 21 (37.5) 01 (1.8) 03 (5.4) 07 (12.5) 06 (17.6) 04 (11.8) 07 (12.5) 05 (8.9) 42 (73.7) 01 (1.8) 03 (5.4)
NS NS NS NS NS NS NS NS NS NS NS NS .045 .049 NS NS
NOTES: DVT = deep venous thrombosis; SD = standard deviation; N/A = not applicable; NS = not significant; HIV = human immunodeficiency virus. a Percentages in parenthesis (except for age and Wells criteria). b Limited to females (n = 34).
Discussion The incidence of bilateral DVT in patients showing single limb symptoms has been previously investigated, first by phlebography and more recently with duplex scanning. The results reported are somewhat heterogeneous, with the incidence reaching up to 32%.9,13-16 Despite these results, the studies were not able to provide rationales to optimize and improve the investigation and accuracy of bilateral DVT diagnosis. Although some authors11 identified risk groups in their investigated samples, these data cannot be applied to all populations. Before the popularization of duplex scan, bilateral investigation was rarely performed, because phlebography represented additional risks and costs. Another alleged reason has been that the anatomic diagnosis of bilateral disease represented no change in therapy choice. Phlebography is still considered the gold-standard diagnostic tool for lower limb DVT, especially for scientific investigation. But this method has been almost abandoned in practical daily use.17 Duplex scan evaluation became the procedure of choice for DVT imaging, due to its low cost, availability, and virtual absence of complications. Actual described values of accuracy are higher than 95% and allow effective evaluation of even infragenicular veins.18-19
In this study, the clinical diagnosis of lower limb bilateral DVT showed poor accuracy, and especially low sensitivity. This finding was somewhat expected and matches with the previously published data. In a study by Strothman et al,9 72 patients had bilateral DVT, but only 28 patients had symptoms in both limbs, representing a sensitivity of 38.9%. The main importance of this finding is that it strengthens the perception that clinical examination is not a reliable diagnostic method for bilateral DVT. The present study identified an overall incidence of 7% of bilateral DVT in the studied group, representing almost 20% of the patients with DVT. The authors consider that this evidence, in itself, justifies indication of bilateral investigation for all patients with positive duplex scan findings in the symptomatic limb. The only risk factors identified for bilateral DVT on univariate analysis were active HIV infection and proximal DVT on the symptomatic side. Relationship between venous thromboembolism events, HIV infection, and active antiretroviral therapy has been previously documented.20-24 Nonetheless, there are no reports of augmented incidence of bilateral DVT in AIDS. Further studies with HIV-infected specific populations should be conducted for a better comprehension of the physiopathology of DVT in these patients. All individuals with bilateral DVT had femoral vein thrombosis in the symptomatic limb. Proximal
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thrombus was also found in 10 of 11 of the contralateral limbs. Inferior vena cava thrombus was noted in only 1 case, and this suggests that bilateral thrombosis is not a consequence of a caval disease that spreads to the limbs. Considering these findings, we strongly emphasize that patients with positive duplex findings of DVT extending to the common femoral veins in the symptomatic limb should include examination of both sides, as previously suggested by others.25 Despite the data above, multivariate analysis did not confirm active HIV infection or proximal DVT as risk factors for bilateral disease, and this was probably due to a combination of the small casuistic and the near-limit P values found in the univariate analysis. In the authors’ opinion, the concept that bilateral investigation for DVT is not important because it does not change the course of anticoagulant therapy is essentially incorrect. The anatomic evaluation of disease extension is as important as the syndromic diagnosis itself. The presence of contralateral disease has an influence on therapeutic options, such as changing the strategies for catheter-directed thrombolysis, for example. Complete duplex evaluation can guide thrombolytic therapy to the affected vessels, preventing unnecessary use of contrast agents in thrombusfree areas. Additionally, determination of the presence of bilateral DVT prior to inferior vena cava filter placement may decrease the contrast load administered to the patient, and avoids the risk of puncture and manipulation of guidewires and sheaths through a thrombosed vessel. The diagnosis of DVT in an asymptomatic contralateral limb allows the physician to apply early measures to avoid the development of symptomatic postthrombotic syndrome (PTS). The social and economical effect of PTS are well known,26,27 and the costs of extending duplex examinations in patients with confirmed unilateral DVT may be largely compensated by future savings. Also, an unidentified contralateral thrombosis may lead to misinterpretation of future clinical manifestations, eventually causing confusion between chronic venous obstructions and acute thrombosis. We believe that bilateral duplex examination can be cost-effective when DVT is confirmed in the symptomatic limb of inpatients. But differently from other authors,28 we have not attempted to express this concept in direct examination costs because these values vary greatly from one country to another, and from public to private healthcare models as well. We have opted to advocate this idea based on our arguments above.
In this study, all 3 patients with diagnosis of thrombophilia had bilateral thrombosis. But this finding could not be evaluated accurately because there was no attempt to exclude thrombophilia in cases of single limb disease. Further investigations with this specific category of individuals and its eventual association with bilateral DVT are awaited. The association between neoplasms and DVT has been exhaustively described,29 and specific data concerning bilateral venous thrombosis is available.30,31 In this study, there was only 1 case of DVT and neoplastic disease, and no conclusions could be made. The low incidence of cancer in this casuistic reflects the assistance profile of our institution, which is not focused in patients with cancer. In conclusion, the presence of bilateral DVT in inpatients with unilateral symptoms showed an incidence high enough to justify bilateral duplex scanning investigation in this group. Although this study identifies specific characteristics that appear to have enhanced risk of bilateral DVT, the authors believe that other institutions should perform their own similar investigations, according to their clinical assistance profile.
References 1. Lee AY, Gent M, Julian JA, et al. Bilateral vs. ipsilateral venography as the primary efficacy outcome measure in thromboprophylaxis clinical trials: a systematic review. J Thromb Haemost. 2004;2:1752-1759. 2. Borris LC, Christiansen HM, Lassen MR, Olsen AD, Schott P. Comparison of real-time b-mode ultrasonography and bilateral ascending phlebography for detection of postoperative deep vein thrombosis following elective hip surgery. The venous thrombosis group. Thromb Haemost. 1989;61:363-365. 3. Naidich JB, Torre JR, Pellerito JS, Smalberg IS, Kase DJ, Crystal KS. Suspected deep venous thrombosis: is us of both legs necessary? Radiology. 1996;200:429-431. 4. Lohr JM, Hasselfeld KA, Byrne MP, Deshmukh RM, Cranley JJ. Does the asymptomatic limb harbor deep venous thrombosis? Am J Surg. 1994;168:184-187. 5. Prandoni P, Lensing AW, Piccioli A, Bagatella P, Girolami A. Ultrasonography of contralateral veins in patients with unilateral deep vein thrombosis. Lancet. 1998;352:786. 6. Sheinman RG, McArdle CR. Bilateral lower extremity US in the patient with unilateral symptoms of deep venous thrombosis and assessment of need. Radiology. 1995;194:171-173. 7. Miller N, Obrand D, Tousignant L, Rossignol M. Venous duplex scanning for unilateral symptoms: when do we need a contralateral evaluation? Eur J Vasc Endovasc Surg. 1998; 15:18-23.
Incidence and Risk Factors for Bilateral Deep Venous Thrombosis / Casella et al
8. Nix ML, Troillet RD, Nelson CL, Ferris EJ, Lavender R, Barnes RW. Is bilateral duplex examination necessary for unilateral symptoms of deep vein thrombosis. J Vasc Technol. 1991;15:296-298. 9. Strothman G, Blebea J, Fowl RJ, Rosenthal G. Contralateral duplex scanning for deep venous thrombosis is unnecessary in patients with symptoms. J Vasc Surg. 1995;22: 543-547. 10. Love M, Blebea J, Strothman G, Bodenham R. Bilateral duplex scanning for deep venous thrombosis is unnecessary in symptomatic patients. J Vasc Technol. 1996;20:217-220. 11. Garcia ND, Morasch MD, Ebaugh JL, et al. Is bilateral ultrasound scanning of the legs necessary for patients with unilateral symptoms of deep vein thrombosis? J Vasc Surg. 2001;34:792-797. 12. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet. 1997;350:1795-1798. 13. Patterson RB, Fowl RJ, Keller JD, Schomaker W, Kempczinski RF. The limitations of impedance plethysmography in the diagnosis of acute deep venous thrombosis. J Vasc Surg. 1989;9:725-730. 14. Markel A, Manzo RA, Bergelin RO, Strandness DE Jr. Pattern and distribution of thrombi in acute venous thrombosis. Arch Surg. 1992;127:305-309. 15. Winkler JL, Lohr JM, Lutter KS. Lower extremity venous duplex imaging of symptomatic patients: our one-year experience. J Vasc Technol. 1992;16:167-171. 16. Blebea J, Kihara TK, Neumyer MM, Blebea JS, Anderson KM, Atnip RG. A national survey of practice patterns in the noninvasive diagnosis of deep venous thrombosis. J Vasc Surg. 1999;29(5):799-804. 17. de Valois JC, van Schaik CC, Verzijlbergen F, van Ramshorst B, Eikelboom BC, Meuwissen OJ. Contrast venography: from gold standard to ‘golden backup’ in clinically suspected deep vein thrombosis. Eur J Radiol. 1990;11:131-137. 18. White RH, McGahan JP, Daschbach MM, Hartling RP. Diagnosis of deep vein thrombosis using duplex ultrasound. Ann Intern Med. 1989;111:297-304. 19. Theodorou SJ, Theodorou DJ, Kakitsubata Y. Sonography and venography of the lower extremities for diagnosing deep
20.
21.
22.
23. 24.
25. 26.
27.
28.
29.
30.
31.
103
vein thrombosis in symptomatic patients. Clin Imaging. 2003;27:180-183. Copur AS, Smith PR, Gomez V, Bergman M, Homel P. HIV infection is a risk factor for venous thromboembolism. AIDS Patient Care STDS. 2002;16:205-209. Saber AA, Aboolian A, LaRaja RD, Baron H, Hanna K. HIV/AIDS and the risk of deep vein thrombosis: a study of 45 patients with lower extremity involvement. Am Surg. 2001;67:645-647. Wilkes MS, Fortwin AH, Felix JC, Godwin TA, Thompson WG. Value of necropsy in acquired immunodeficiency syndrome. Lancet. 1988;2:85-88. Afessa B, Green W, Chiao J, Frederick W. Pulmonary complications of HIV infection. Chest. 1998;113:1225-1229. Saif MW, Bona R, Greenberg B. AIDS and thrombosis: retrospective study of 131 HIV-infected patients. AIDS Patient Care STDS. 2001;15:311-320. Cronan JJ. Deep venous thrombosis: one leg or both legs? Radiology. 1996;200:323-324. MacDougall DA, Feliu AL, Boccuzzi SJ, Lin J. Economic burden of deep-vein thrombosis, pulmonary embolism, and post-thrombotic syndrome. Am J Health Syst Pharm. 2006;63(suppl 6):S5-S15. Ramacciotti E, Gomes M, de Aguiar ET, et al. CLE-PTS investigators. A cost analysis of the treatment of patients with post-thrombotic syndrome in Brazil. Thromb Res. 2006;118:699-704. Bendayan P, Boccalon H. Cost effectiveness of noninvasive tests including duplex scanning for diagnosis of deep venous thrombosis. A prospective study carried out on 511 patients. Vasa. 1991;20:348-353. Prandoni P, Lensing AW, Buller HR, et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med. 1992;327:1128-1133. Bura A, Cailleux N, Bienvenu B, et al. Incidence and prognosis of cancer associated with bilateral venous thrombosis: a prospective study of 103 patients. J Thromb Haemost. 2004;2:441-444. Giess CS, Bach AM, Hann LE. Lower extremity venous sonography in the high-risk cancer population: one leg or two? AJR. 2001;176:1049-1052.
