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Original Research |

Safety and Feasibility of a Diagnostic Algorithm Combining Clinical Probability, d-Dimer Testing, and Ultrasonography for Suspected Upper Extremity Deep Venous Thrombosis: A Prospective Management StudyDiagnostic Algorithm for Suspected Upper Extremity Deep Venous Thrombosis

Ankie Kleinjan, MD, PhD*; Marcello Di Nisio, MD, PhD*; Jan Beyer-Westendorf, MD; Giuseppe Camporese, MD; Benilde Cosmi, MD, PhD; Angelo Ghirarduzzi, MD; Pieter W. Kamphuisen, MD, PhD; Hans-Martin Otten, MD, PhD; Ettore Porreca, MD; Anita Aggarwal, MD, PhD; Marianne Brodmann, MD; Maria Domenica Guglielmi, MD; Matteo Iotti, MD; Karin Kaasjager, MD; Virginia Kamvissi, MD; Teresa Lerede, MD; Peter Marschang, MD; Karina Meijer, MD, PhD; Gualtiero Palareti, MD; Frederick R. Rickles, MD; Marc Righini, MD, PhD; Anne W.S. Rutjes, MD, PhD; Chiara Tonello, MD; Peter Verhamme, MD, PhD; Sebastian Werth, MD; Sanne van Wissen, MD, PhD; and Harry R. Büller, MD, PhD
[+] Article and Author Information

* Drs. Kleinjan and Di Nisio contributed equally to this work.


From Academic Medical Center, Slotervaart Hospital, and Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands; Gabriele d'Annunzio University and Center of Excellence on Aging, Gabriele d'Annunzio University Foundation, Chieti, Italy; Center for Vascular Diseases and Medical Clinic III, Dresden University Hospital Carl Gustav Carus, Dresden, Germany; University Hospital of Padova, Padova, Italy; University Hospital of Bologna, Bologna, Italy; Instituto di Ricovero e Cura a Carattere Scientifico, Azienda Arcispedale Santa Maria Nova, Reggio Emilia, Italy; University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Veterans Affairs Medical Center, Washington, DC; Medical University, Abteilung für Angiologie, Graz, Austria; University Medical Utrecht, Utrecht, the Netherlands; Hospital Papa Giovanni XXIII, Bergamo, Italy; Innsbruck Medical University, Innsbruck, Austria; Geneva University Hospital, Geneva, Switzerland; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; and University Hospital Leuven, Centre for Molecular and Vascular Biology, Leuven, Belgium.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2056.

Reproducible Research Statement: Study protocol: Available from Dr. Kleinjan (e-mail, ankiekleinjan@gmail.com). Statistical code and data set: Not available.

Requests for Single Reprints: Ankie Kleinjan, MD, PhD, Department of Vascular Medicine, F4, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; e-mail, ankiekleinjan@gmail.com.

Current Author Addresses: Drs. Kleinjan and Büller: Department of Vascular Medicine, F4, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.

Dr. Di Nisio: Gabriele d'Annunzio University, Ambulatorio di Medicina Vascolare, Piano 12 Corpo C, Ospedale Santissima Annunziata, 66100 Chieti, Italy.

Drs. Beyer-Westendorf, Kamvissi, and Werth: Center for Vascular Diseases, Medical Clinic III, Dresden University Hospital Carl Gustav Carus, Fetscherstraße 74, 01307 Dresden, Germany.

Drs. Camporese and Tonello: University Hospital of Padova, Department of Angiology, Via Giustiniani 2, 35126 Padova, Italy.

Dr. Cosmi: University Hospital of Bologna, Divisione di Angiologia e Malattie della Coagulazione “Marino Golinelli,” Dipartimento Medicina Specialistica, Diagnostica e Sperimentale Ospedale S. Orsola-Malpighi, Via P. Albertoni 15, 40138 Bologna, Italy.

Drs. Ghirarduzzi and Iotti: Instituto di Ricovero e Cura a Carattere Scientifico, Azienda Arcispedale Santa Maria Nova, Viale Risorgimento 80, 42123 Reggio Emilia Reggio nell'Emilia, Italy.

Dr. Kamphuisen: University of Groningen, University Medical Center Groningen, Department of Vascular Medicine, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.

Dr. Otten: Department of Internal Medicine, Slotervaart Hospital, Louwesweg 6, 1066 AC Amsterdam, the Netherlands.

Drs. Porreca and Guglielmi: Center of Excellence on Aging, Gabriele d'Annunzio University, Ambulatorio di Medicina Vascolare, Piano 12 Corpo C, Ospedale Santissima Annunziata, 66100 Chieti, Italy.

Drs. Aggarwal and Rickles: Veterans Affairs Medical Center, Division of Hematology, Department of Medicine, 50 Irving Street NW, Washington, DC 20422.

Dr. Brodmann: Medical University, Abteilung für Angiologie, Universitätsplatz 4, 8010 Graz, Austria.

Dr. Kaasjager: Department of Internal Medicine, University Medical Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.

Dr. Lerede: Hospital Papa Giovanni XXIII, Division of Hematology, Piazza OMS, 1, 24127 Bergamo, Italy.

Dr. Marschang: Innsbruck Medical University, Department of Internal Medicine, Innrain 52, Christoph-Probst-Platz, 6020 Innsbruck, Austria.

Dr. Meijer: University of Groningen, University Medical Center Groningen, Department of Hematology, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.

Dr. Palareti: University Hospital of Bologna, Department of Angiology, University Hospital S. Orsola-Malpighi, Via Massarenti 9, 40138 Bologna, Italy.

Dr. Righini: Division of Angiology and Hemostasis, Geneva University Hospital, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland.

Dr. Rutjes: Institute of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, CH-3012 Bern, Switzerland.

Dr. Verhamme: University Hospital Leuven, Centre for Molecular and Vascular Biology, Herestraat 49, 3000 Leuven, Belgium.

Dr. van Wissen: Department of Internal Medicine, Onze Lieve Vrouwe Gasthuis, Oosterpark 9, 1091 AC Amsterdam, the Netherlands.

Author Contributions: Conception and design: A. Kleinjan, M. Di Nisio, J. Beyer-Westendorf, P.W. Kamphuisen, H.M. Otten, E. Porreca, M. Righini, H.R. Büller.

Analysis and interpretation of the data: A. Kleinjan, M. Di Nisio, J. Beyer-Westendorf, P.W. Kamphuisen, E. Porreca, A. Aggarwal, M. Righini, A.W.S. Rutjes, S. van Wissen, F.R. Rickles, H.R. Büller.

Drafting of the article: A. Kleinjan, M. Di Nisio, P.W. Kamphuisen, E. Porreca, S. van Wissen, H.R. Büller.

Critical revision of the article for important intellectual content: M. Di Nisio, J. Beyer-Westendorf, G. Camporese, B. Cosmi, P.W. Kamphuisen, H.M. Otten, E. Porreca, A. Aggarwal, M. Brodmann, K. Kaasjager, T. Lerede, P. Marschang, G. Palareti, M. Righini, A.W.S. Rutjes, C. Tonello, F.R. Rickles, H.R. Büller.

Final approval of the article: A. Kleinjan, M. Di Nisio, G. Camporese, B. Cosmi, A. Ghirarduzzi, P.W. Kamphuisen, H.M. Otten, E. Porreca, A. Aggarwal, M. Brodmann, M.D. Guglielmi, K. Kaasjager, T. Lerede, P. Marschang, K. Meijer, G. Palareti, M. Righini, A.W.S. Rutjes, S. van Wissen, F.R. Rickles, C. Tonello, H.R. Büller.

Provision of study materials or patients: G. Camporese, B. Cosmi, A. Ghirarduzzi, P.W. Kamphuisen, H.M. Otten, A. Aggarwal, M. Brodmann, M.D. Guglielmi, M. Iotti, K. Kaasjager, V. Kamvissi, T. Lerede, P. Marschang, K. Meijer, G. Palareti, M. Righini, C. Tonello, P. Verhamme, S. Werth, S. van Wissen, F.R. Rickles.

Statistical expertise: H.R. Büller.

Administrative, technical, or logistic support: A. Kleinjan, P.W. Kamphuisen, H.R. Büller.

Collection and assembly of data: A. Kleinjan, M. Di Nisio, J. Beyer-Westendorf, G. Camporese, A. Ghirarduzzi, P.W. Kamphuisen, A. Aggarwal, M. Brodmann, K. Meijer, M. Righini, P. Verhamme, H.R. Büller.


Ann Intern Med. 2014;160(7):451-457. doi:10.7326/M13-2056
Text Size: A A A

Background: Although well-established for suspected lower limb deep venous thrombosis, an algorithm combining a clinical decision score, d-dimer testing, and ultrasonography has not been evaluated for suspected upper extremity deep venous thrombosis (UEDVT).

Objective: To assess the safety and feasibility of a new diagnostic algorithm in patients with clinically suspected UEDVT.

Design: Diagnostic management study. (ClinicalTrials.gov: NCT01324037)

Setting: 16 hospitals in Europe and the United States.

Patients: 406 inpatients and outpatients with suspected UEDVT.

Measurements: The algorithm consisted of the sequential application of a clinical decision score, d-dimer testing, and ultrasonography. Patients were first categorized as likely or unlikely to have UEDVT; in those with an unlikely score and normal d-dimer levels, UEDVT was excluded. All other patients had (repeated) compression ultrasonography. The primary outcome was the 3-month incidence of symptomatic UEDVT and pulmonary embolism in patients with a normal diagnostic work-up.

Results: The algorithm was feasible and completed in 390 of the 406 patients (96%). In 87 patients (21%), an unlikely score combined with normal d-dimer levels excluded UEDVT. Superficial venous thrombosis and UEDVT were diagnosed in 54 (13%) and 103 (25%) patients, respectively. All 249 patients with a normal diagnostic work-up, including those with protocol violations (n = 16), were followed for 3 months. One patient developed UEDVT during follow-up, for an overall failure rate of 0.4% (95% CI, 0.0% to 2.2%).

Limitations: This study was not powered to show the safety of the substrategies. d-Dimer testing was done locally.

Conclusion: The combination of a clinical decision score, d-dimer testing, and ultrasonography can safely and effectively exclude UEDVT. If confirmed by other studies, this algorithm has potential as a standard approach to suspected UEDVT.

Primary Funding Source: None.

Figures

Grahic Jump Location
Figure 1.

Study flow diagram.

DVT = deep venous thrombosis; SVT = superficial venous thrombosis; UEDVT = upper extremity deep venous thrombosis.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Results of the diagnostic work-up.

Of the 203 patients in the unlikely group evaluated at 3-mo follow-up, 2 died of causes not associated with venous thromboembolism, and there was no strategy failure or loss to follow-up. Of the 203 patients in the likely group evaluated at 3-mo follow-up, 1 experienced strategy failure, 5 died of causes not associated with venous thromboembolism, and there was no loss to follow-up. The Results section shows outcomes. DVT = deep venous thrombosis; ND = not done; SVT = superficial venous thrombosis; UEDVT = upper extremity deep venous thrombosis.

* One patient had 2 indeterminate ultrasonograms and needed venography, which excluded DVT and SVT.

Grahic Jump Location

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Comments

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Upper Extremity Deep Venous Thrombosis And Upper Extremity Superficial Venous Thrombosis
Posted on May 12, 2014
Michelangelo Sartori
Department of Angiology and Blood Coagulation, S. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
Conflict of Interest: None Declared
To the Editor:
Kleinjan et al. have recently evaluated the utility of a new diagnostic algorithm in patients with clinically suspected upper extremity deep venous thrombosis UEDVT in the article published in your journal [1]. This covers an important topic since I deal with patients with a suspicion of UEDVT everyday. In the result section, the authors considered both superficial vein thrombosis (SVT) and deep vein thrombosis (DVT) as UEDVT [1]. In my opinion pooling together SVT and DVT raises some concerns.
The aim of the study was to validate a new diagnostic algorithm in patients with clinically suspected arm DVT, but, at the initial work-up, the authors found 54 SVTs (more than one to 10 patients had a SVT). SVT diagnosis is based on the clinical signs and symptoms that include all components of inflammation (pain, reddening of the skin and swollen surrounding tissue, leading to a warm, tender and swollen area or cord along a superficial vein) [2] and these are not included in the Constans Clinical Decision Score used in the algorithm. Since several SVTs were found in the group at low pre-test probability, it seems to me that patients with clinically suspected SVT were included in the study. Moreover, the algorithm included D-dimer, but D-dimer levels are not reliable in patients with suspected SVT [3]. In my opinion, in case of clinical suspected SVT, an ultrasound examination is important to confirm SVT diagnosis and extension (excluding extension into the deep vein system), even in patients with normal D-dimer and “unlikely” pre-test probability for UEDVT.
It would be interesting to see the accuracy of the new algorithm in patients with clinically suspected true UEDVT (deep vein thrombosis), excluding patients with clinically suspected and/or confirmed superficial vein thrombosis.
In my opinion, Kleinjan et al. are somewhat optimistic in concluding that a management strategy using only the Constans clinical score and D-dimer testing can safely and effectively exclude DVT and SVT in patients with low pre-test probability and normal D-dimer levels


REFERENCES

1. Kleinjan A, Di Nisio M, Beyer-Westendorf J, Camporese G, Cosmi B, Ghirarduzzi A, Kamphuisen PW, Otten HM, Porreca E, Aggarwal A, Brodmann M, Guglielmi MD, Iotti M, Kaasjager K, Kamvissi V, Lerede T, Marschang P, Meijer K, Palareti G, Rickles FR, Righini M, Rutjes AW, Tonello C, Verhamme P, Werth S, van Wissen S, Büller HR. Safety and Feasibility of a Diagnostic Algorithm Combining Clinical Probability, d-Dimer Testing, and Ultrasonography for Suspected Upper Extremity Deep Venous Thrombosis: A Prospective Management Study. Ann Intern Med. 2014;160:451-7
2. Bauersachs RM. Diagnosis and treatment of superficial vein thrombosis. Hamostaseologie. 2013;33:232-40.
3. Aguilar C, del Villar V. D-dimer is not useful for the diagnosis of isolated superficial venous thrombosis. Am J Med. 2005;118:1417.
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