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Withholding Anticoagulation after a Negative Result on Duplex Ultrasonography for Suspected Symptomatic Deep Venous Thrombosis

Scott M. Stevens, MD; C. Gregory Elliott, MD; Karen J. Chan, BS; Marlene J. Egger, PhD; and Kirmanj M. Ahmed, MD
[+] Article and Author Information

From LDS Hospital and University of Utah, Salt Lake City, Utah; and Franklin Square Hospital Center, Baltimore, Maryland.


Acknowledgments: The authors thank Charles Laggore, MD; Elizabeth Underwood, MD; and Troy Chatwin, PA-C, for their work in patient enrollment and follow-up. They also thank Greg Goodman, MD; Steven Merrell, MD; Joni Boone, RVT; the staff of the LDS Hospital Peripheral Vascular Laboratory; Willis Layton, RVT; and Lawrence Porter for their work on preparation of multimedia materials and especially acknowledge Graham F. Pineo, MD; James George, MD; and Gary E. Raskob, PhD, for their service as independent adjudicators.

Grant Support: By the Deseret Foundation, Salt Lake City, Utah (grant no. 371).

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Scott M. Stevens, MD, Department of Medicine, LDS Hospital, Eighth Avenue and C Street, Salt Lake City, UT 84143; e-mail, scott.stevens@ihc.com.

Current Author Addresses: Dr. Stevens: Department of Medicine, LDS Hospital, Eighth Avenue and C Street, Salt Lake City, UT 84143.

Dr. Elliott: Pulmonary/Critical Care Division, Department of Medicine, LDS Hospital, Eighth Avenue and C Street, Salt Lake City, UT 84143.

Ms. Chan: Statistical Data Center, LDS Hospital, Eighth Avenue and C Street, Salt Lake City, UT 84143.

Dr. Egger: Public Health Programs, Department of Family and Preventive Medicine, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132.

Dr. Ahmed: Franklin Square Hospital Center, 9105 Franklin Square Drive, Baltimore, MD 21237.

Author Contributions: Conception and design: S.M. Stevens, C.G. Elliott, K.J. Chan, M.J. Egger.

Analysis and interpretation of the data: S.M. Stevens, C.G. Elliott, K.J. Chan, M.J. Egger.

Drafting of the article: S.M. Stevens, C.G. Elliott, K.J. Chan, M.J. Egger.

Critical revision of the article for important intellectual content: S.M. Stevens, C.G. Elliott, K.J. Chan, M.J. Egger.

Final approval of the article: S.M. Stevens, C.G. Elliott, K.J. Chan, M.J. Egger, K.M. Ahmed.

Statistical expertise: K.J. Chan, M.J. Egger.

Obtaining of funding: S.M. Stevens, C.G. Elliott.

Administrative, technical, or logistic support: S.M. Stevens, K.M. Ahmed.

Collection and assembly of data: S.M. Stevens, K.M. Ahmed.


Ann Intern Med. 2004;140(12):985-991. doi:10.7326/0003-4819-140-12-200406150-00007
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Previous studies have shown that it is safe to withhold anticoagulants once 2 compression ultrasonography examinations limited to the common femoral vein in the groin and the popliteal vein are performed 5 to 7 days apart and yield negative results (910). One such examination is not sufficient because undetected calf vein thrombi can propagate proximally, with potentially serious complications (910, 15). Fatal pulmonary embolism has occurred before the common femoral vein and the popliteal vein could be examined again (9, 13). Although the technique of comprehensive duplex ultrasonography used in our study takes 15 to 30 minutes longer than simplified compression ultrasonography, the second study required for follow-up of the latter method consumes substantial resources and is not always practical (29). Previous investigators have considered the role of a single examination of the entire deep venous system with duplex ultrasonography (15, 3032), but this approach has been the subject of only limited study. Our trial was designed to address this issue directly, adding data that evaluate the safety of withholding anticoagulant therapy after only 1 examination of the symptomatic leg with comprehensive duplex ultrasonography.

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Figure.
Enrollment and analysis of patients.

*Of the 384 patients enrolled who showed no signs of deep venous thrombosis on comprehensive duplex ultrasonography the negative cohort), 9 were excluded from the analysis because of use of therapeutic anticoagulants (7 for diagnoses not related to venous thromboembolism and 2 in violation of protocol).

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Single complete compression ultrasound for suspected DVT: ideal in clinical practice ?
Posted on July 1, 2004
Marc Righini
Division d'Angiologie et d'Hémostase, Hôpital Universitaire de Genève
Conflict of Interest: None Declared

SINGLE COMPLETE COMPRESSION ULTRASOUND FOR SUSPECTED DVT: IDEAL IN ROUTINE CLINICAL PRACTICE?

Marc Righini, MD, Grégoire Le Gal, MD, Henri Bounameaux, MD.

Division of Angiology and Hemostasis (HB, MR), Department of Internal Medicine, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland and Equipe d'accueil GETBO (GLG), Department of Internal Medicine and Chest Diseases, Brest University Hospital, Brest, France.

Address for correspondence: Marc Righini, MD, Division of Angiology and Hemostasis, Geneva University Hospital, 24, rue Micheli-du-Crest, 1211 Geneva 14 - Switzerland. Tel. +41.22.372.92.94 E-Mail : Marc.Righini@hcuge.ch

Wordcount: 347 References: 5

Dear Sir,

We read with great interest the article by Stevens et al. showing that a single complete (i.e. including the calf veins) lower limbs compression ultrasonography is safe for excluding DVT, as shown by a very low 0.8% (95% CI:0.1-2.3) three-month thromboembolic risk in the patients in whom the diagnosis had been ruled out on this basis. This article deserves some comments. First, it is interesting to note that previous studies using proximal (e.g. not studying the calf veins) serial (1, 2) or single proximal compression ultrasonography associated with clinical probability and D-dimer test (3) showed similar three-month thromboembolic risks. Using a single ultrasound examination without clinical probability assessment or D-dimer dosage may be very practical in an outpatient setting. However, even if this kind of strategy has the great advantage of avoiding repeated compression ultrasonography, an ultrasound exam has to be performed in every patient. This may not be particularly cost- effective, as D-dimer measurement may rule out the diagnosis without further testing at a lesser expense in a substantial proportion of outpatients (30 %), which turned out to be highly cost-effective (4).

Second, we are very concerned by the potential problem of overdiagnosis and over treatment of distal DVT, as stated in the excellent editorial of El Kheir et al. Previous studies limited to proximal vein compression ultrasonography showed a very low three-month thromboembolic risk (1, 2), suggesting that at least the great majority of distal DVT do not need anticoagulant treatment. In the study by Stevens et al., distal DVT accounts for 31% of all DVT and this proportion has been even higher, reaching 50% or more in previous studies (5). This is a crucial issue as many patients may be unduly anticoagulated. Therefore, there is an absolute need of properly designed studies to assess if anticoagulant treatment is warranted in distal DVT.

Admittedly, realizing a complete leg ultrasound may be useful in everyday clinical practice by diagnosing other conditions such as calf haematoma, partial muscle rupture, and popliteal cyst but its advantage in the diagnostic approach of venous thromboembolism as such appears at least debatable.

References

1. Cogo A, Lensing AW, Koopman MM, Piovella F, Siragusa S, Wells PS, et al. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. Bmj 1998;316(7124):17-20.

2. Kraaijenhagen RA, Piovella F, Bernardi E, Verlato F, Beckers EA, Koopman MM, et al. Simplification of the diagnostic management of suspected deep vein thrombosis. Arch Intern Med 2002;162(8):907-11.

3. Perrier A, Desmarais S, Miron MJ, de Moerloose P, Lepage R, Slosman D, et al. Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet 1999;353(9148):190-5.

4. Perone N, Bounameaux H, Perrier A. Comparison of four strategies for diagnosing deep vein thrombosis: a cost-effectiveness analysis. Am J Med 2001;110(1):33-40.

5. Schellong SM, Schwarz T, Halbritter K, Beyer J, Siegert G, Oettler W, et al. Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis. Thromb Haemost 2003;89(2):228-34.

Conflict of Interest:

None declared

Response to Negative Duplex Ultrasound Still Requires Pre-Test Probability
Posted on July 30, 2004
Kaveh Shojania
University of Ottawa and the Ottawa Health Research Institute
Conflict of Interest: None Declared

Stevens and colleagues (1) have conducted a very well-designed study, but their blanket conclusion about safety of withholding anticoagulation seems at odds with what we know about the value of assessing pre-test probability in the evaluation of patients with suspected venous thromboembolism (2-4).

Given that clinical predictions rules can reliably distinguish patients at low, moderate, and high-risk for deep venous thrombosis, it is misleading to use the overall results for the cohort to apply to all three of these groups. In the study used to derive the clinical scoring system adopted by Stevens and colleagues (1), 75% of patients with scores in the high pre-test probability category proved to have DVT (2).

Test characteristics of Doppler ultrasound depend on the presence of symptoms or signs and the location of the veins showing abnormalities (5), but most patients with the combination of high pre-test probability and normal ultrasonography would have post-test probabilities in the range of 10-25%.

The question, then, is whether or not this range of post-test probabilities, which is clearly too high to permit withholding of anticoagulation or further investigation, is substantially lowered by present results. Stevens and colleagues (1) found only 3 DVTs among the 375 patients who remained in the negative cohort for analysis. Based on Table 1 (1), only 38 patients in this cohort had a high pre-test probability. Even if none of the 3 DVTs occurred in this group, the event rate in this group could still be as high as 11% (based on a continuity corrected 95% confidence interval for the proportion 0/38).

Even for the group with negative ultrasound and moderate pre-test probability, in which there were 180 patients, the event rate could exceed the threshold for safely withholding anticoagulation and pursuing no further evaluation for DVT. For instance, if all three of the DVTs observed in follow-up occurred in this group, then the true event could be as high as 5%.

It seems, therefore, that the decision on the safety of withholding anticoagulation and the decision not to pursue repeat ultrasound or other testing, such as D-dimer (3), still depends on the pre-test clinical assessment of the likelihood of DVT.

1. Stevens SM, Elliott CG, Chan KJ, Egger MJ, Ahmed KM. Withholding anticoagulation after a negative result on duplex ultrasonography for suspected symptomatic deep venous thrombosis. Ann Intern Med. 2004;140(12):985-91.

2. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet. 1997;350(9094):1795-8.

3. Kearon C, Ginsberg JS, Douketis J, et al. Management of suspected deep venous thrombosis in outpatients by using clinical assessment and D- dimer testing. Ann Intern Med. 2001;135(2):108-11.

4. Tick LW, Ton E, van Voorthuizen T, et al. Practical diagnostic management of patients with clinically suspected deep vein thrombosis by clinical probability test, compression ultrasonography, and D-dimer test. Am J Med. 2002;113(8):630-5.

5. Kearon C, Julian JA, Math M, Newman TE, Ginsberg JS. Noninvasive Diagnosis of Deep Venous Thrombosis. Ann Intern Med. 1998;128(8):663-677.

Conflict of Interest:

None declared

In Response
Posted on August 10, 2004
Scott M Stevens
Department of Medicine, LDS Hospital, Department of Medicine, University of Utah
Conflict of Interest: None Declared

IN RESPONSE We appreciate the insights of Dr. Righini et al into the ramifications of use of single comprehensive duplex ultrasonound for suspected, symptomatic deep vein thrombosis of the legs. We studied single comprehensive duplex ultrasound because it is efficient and convenient compared to routine repeated simplified compression ultrasound. We recognize the presence of validated strategies which utilize a sensitive d-dimer assay and clinical score as a means of reducing the number of simplified compression ultrasound studies used for suspected DVT (1), and do not believe that our findings reduce the attraction of such strategies. We agree with the recommendation in the editorial of El Kheir et al (2) that comprehensive duplex ultrasound should be studied in conjunction with clinical scoring and sensitive d-dimer.

The identification of isolated calf-vein DVT does indeed provide an extra challenge for the treating clinician. While outcome data on this diagnosis are limited, it is worth noting that clinicians may opt for serial duplex ultrasounds in lieu of therapeutic anticoagulation in this clinical situation, anticoagulating only those patients in whom thrombus propagates to involve the popliteal or more proximal deep veins (3). This raises the obvious criticism that serial duplex ultrasounds would then be performed, undermining the value of our results. However, isolated calf vein DVT was found in only a small proportion of the total patients in our study (4.3%), with more than 20 negative initial comprehensive ultrasound studies for every instance of isolated calf vein thrombosis detected. Even if a repeat testing strategy is chosen for isolated calf vein DVT, there would still be a significant reduction in the total number of ultrasound tests compared to the strategy of routine serial simplified compression. We very much agree that the natural history, risks and optimal management of isolated calf vein DVT should be the subject of further clinical study.

1. Bates SM, Kearon C, Crowther M, Linkins L, O'Donnell M, Douketis J, et al. A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis. Ann Intern Med. 2003 May 20;138(10):787-94. 2. El Kheir D, Büller H. One-Time Comprehensive Ultrasonography To Diagnose Deep Venous Thrombosis: Is That the Solution? Ann Intern Med. 2004;140:1052-3. 3. Hyers TM, Agnelli G, Hull R, Morris TA, Samama M, Tapson V, et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001;119:176S-193S.

Sincerely, Scott M. Stevens, MD C. Gregory Elliott, MD

Conflict of Interest:

None declared

In Response
Posted on August 17, 2004
C. Gregory Elliott
Division of Pulmonary/Critical Care, LDS Hospital and University of Utah
Conflict of Interest: None Declared

We appreciate Dr Shojania's compliment regarding the strength of our study design, as well as the point regarding the importance of the pre- test clinical assessment of the likelihood of deep vein thrombosis.

As summarized by Hulley et al (1) our study is useful to the extent that it yields valid inferences, first about events that happened in the study sample ("internal validity"), and then about generalizing our results to patients outside the study ("external validity"). We believe that our report possesses internal validity; and our conclusion that it is safe to withhold anticoagulation after negative results on comprehensive duplex ultrasonography describes correctly the inference to be drawn for the patient population that we studied. Clinicians can always ask whether the patient whom they are evaluating was represented in the population that we studied, and hence whether or not our results provide information applicable to the evaluation of their patient ("external validity").

Dr Shajania's point regarding pre-test suspicion addresses the external validity of our report, in particular the validity of applying our results to patients with a high pre-test probability score for deep vein thrombosis. It should be noted that the prevalence of deep vein thrombosis in populations with a high pre-test probability score for deep vein thrombosis varies. Wells et al (2) (cited by Dr Shajania) reported a prevalence of 75%. Anderson et al (3) reported a prevalence of 47%. In our study (4) 25 of 63 (40%) of patients with high pre-test probability scores had deep vein thrombosis confirmed, with an additional event occurring during follow-up.

Our study was not designed nor powered for subgroup analysis. Post hoc, our data shows that, as mentioned, 1 of the recurrent thrombi occurred in the 38 patients with negative comprehensive duplex ultrasonography and high pre-test clinical scores. The other 2 recurrent thrombi occurred in the 180 patients with negative comprehensive ultrasonography and moderate pre-test clinical scores. The importance of these observations varies depending upon the prevalence of deep vein thrombosis when the pre-test clinical probability score is high or moderate. Hence Dr Shajania's point is well taken. When the pre-test clinical score is high it may be incorrect to infer from our study that it is safe to withhold anticoagulants after one comprehensive duplex ultrasonography examination of the leg is negative. Additional study of this subgroup is necessary to establish or refute the safety of withholding anticoagulants for such patients on the basis of comprehensive duplex ultrasonography.

References

(1) Hulley SB, Newman TB, and Cummings SR. Getting started: the anatomy and physiology of research. In: Hulley SB, Cummings SR, editors. Designing clinical research. Baltimore: Williams and Wilkens 1988 pages 1- 11.

(2) Wells PS, Anderson DR, Bormanis J, et al Value of assessment of pretest probability of deep-vein thrombosis in clinical management Lancet 1997; 350(9094): 1795-1798.

(3) Anderson DR, Kovacs MJ, Kovacs G, et al Combined use of clinical assessment and d-dimer to improve the management of patients presenting to the emergency department with suspected deep vein thrombosis (the EDITED Study) Thromb Haemost 2003; 645-651

(4) Stevens SM, Elliott CG, Chan KJ, et al. Withholding anticoagulation after a negative result on duplex ultrasonography for suspected symptomatic deep vein thrombosis Ann intern Med 2004; 140: 985- 991

Conflict of Interest:

None declared

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Summary for Patients

Reliability and Safety of Managing Patients with Suspected Blood Clots in the Legs Using Comprehensive Duplex Ultrasonography

The summary below is from the full report titled “Withholding Anticoagulation after a Negative Result on Duplex Ultrasonography for Suspected Symptomatic Deep Venous Thrombosis.” It is in the 15 June 2004 issue of Annals of Internal Medicine (volume 140, pages 985-991). The authors are S.M. Stevens, C.G. Elliott, K.J. Chan, M.J. Egger, and K.M. Ahmed.

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