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Three Part Question

In [a patient with isolated distal deep vein thrombosis] does [therapeutic anticoagulation] reduce [adverse clinical outcomes].

Clinical Scenario

A 45-year-old woman attends the emergency department with a painful and swollen right calf. Her Wells score is low risk, but a d-dimer returns over the cut point for your local assay. Whole leg ultrasound examination later that day confirms a thrombosis of the posterior tibial and peroneal veins. She has no other medical history but you cannot identify a clear provoking factor for the thrombus. She is worried and symptomatic.
A colleague reports to you that he does not treat any below knee DVT’s, as the NICE guidance supports above leg scanning only and he believes that the sensitivity and specificity of whole leg ultrasound are too low to be of clinical value.
You are concerned about the idea of leaving an unprovoked isolated distal deep vein thrombosis (IDDVT) untreated in a patient who is symptomatic. However, you also worry about anticoagulation related bleeding. You decide to consult the literature to guide your decision-making.

Search Strategy

Medline 1946 to July week 3 2016 using the OVID interface.
[exp Venous Thrombosis/ OR deep vein thrombosis.mp. OR DVT$.mp.] AND [distal.mp. OR below knee.mp. OR calf.mp. OR popliteal.mp. OR exp Popliteal Vein/ OR fibular.mp. OR peroneal.mp. OR posterior tibial.mp.] AND [exp Therapeutics/ OR therapy.mp. OR treatment.mp. OR exp Heparin, Low-Molecular-Weight/ OR exp Heparin/ OR heparin.mp. OR exp Warfarin/ OR warfarin.mp. OR exp Coumarins/ or coumarin.mp. OR exp Anticoagulants/ OR NOACs.mp. OR apixaban.mp. OR exp Rivaroxaban/ OR rivaroxaban.mp. OR edoxaban.mp. OR exp Dabigatran/ OR dabigatran.mp. ] LIMIT to human AND English Language.

Search Outcome

A previous BET on this topic(1) published in 2003, concluded that all patients with calf thrombosis should receive oral anticoagulation. The evidence studied in this BET was limited in its generalizability; more recent research including several meta-analyses and a randomised controlled trial necessitates an update.

Altogether 1399 papers were found. The titles and abstracts of these were scrutinized for relevance and overall 11 studies published since the last meta-analysis(2) were found which directly addressed the question.

1. Hogg K. Antithrombotic treatment of below knee deep venous thrombosis. Emergency Medicine Journal. 2003;20(4):364-365.

2. De Martino R, Wallaert J, Rossi A, Zbehlik A, Suckow B, Walsh D. A meta-analysis of anticoagulation for calf deep venous thrombosis. Journal of Vascular Surgery. 2012;56(1):228-237.e1.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Gillet JL et al 2007 France	128 patients with symptomatic calf vein thrombosis confirmed by ultrasound scan.	Prospective cohort study	Complications of anticoagulation	2 non-fatal haemorrhagic events occurred	Not all cases followed up. No information recorded regarding length of anticoagulation and outcomes. Treatment preference dictated by clinical interaction.
			Extension of initial thrombus or recurrence of VTE confirmed by ultrasound/radiology.	18.75% of patients had VTE recurrence after 3 months. No anticoagulated patients had VTE recurrence.
			Assess recanalization.	Recanalization was complete at 1, 3, and 9 months in 54.8%, 84.7%, and 96% of cases, respectively
Parisi R et al 2009 Italy	171 patients with isolated distal deep vein thrombosis confirmed by colour coded Doppler ultrasonography. All patients given full dose LMW heparin for 1 week then half dose LMW heparin for 3 weeks.	Prospective cohort study.	Progression to proximal deep veins	In the first 4w, 10/171 (5.8%) had complications. Statistically significant association between IDDVT and complications in first month (odds ratio 8.15, CI 1.67-39.15)	Small number of patients No long-term anticoagulation tested. No control group. Small bleeds included in complications – could have been influenced by LMW heparin treatment.
			Pulmonary embolism or death due to VTE	No patients had a PE or died.
Schwarz T et al 2010 Germany	107 patients with symptomatic isolated calf muscle thrombosis confirmed by sonogrophy. 54 received low molecular weight heparin for 10 days then 3 months compression therapy. 53 received compression therapy alone.	Randomised control trial	Extension into the deep veins and clinical PE confirmed by objective testing.	No PE occurred. No significant difference in extension into the deep veins between groups	Low risk patient group (only 10.72% had a high risk for VTE). Subclinical pulmonary emboli not imaged. Long-term anticoagulation not tested.
Palareti G et al 2010 Italy	431 symptomatic patients without proximal DVT and with high pre-test clinical probability or altered D-Dimer.	Prospective cohort study with patients and clinicians initially blinded to below knee ultrasound results	Rate of VTE at 3 months	Isolated calf DVT diagnosed in 65 patients, 59 remained uneventful. Difference in outcomes between patients with ICDVT and those without was 4.7% ; 95% CI:1–13; p=0.049	Relatively small number of patients studied. Patients were non-consecutive – selection bias cannot be excluded. No exploration of anterior tibial veins. Small numbers of VTE events thus large confidence intervals.
Alhalbouni S et al 2011 United States	4035 consecutive patients receiving lower extremity venous duplex scans.	Retrospective cohort study.	Distribution of DVT and relation to PE occurrence.	Of 304 isolated infra-popliteal DVTs, 68.1% were calf muscle vein DVTs with PE evidenced in 12 (5.8%). No significant difference in the risk of PE between isolated femoral-popliteal and isolated infra-popliteal DVTs.	Retrospective. No identification of patient pathology, reason for admission, co-morbidities, length of stay or treatment given. Subclinical PE’s may have been missed.
De Martino R et al 2012 United States	2 Randomised control trials and 6 prospective cohorts studying patients with calf deep vein thrombosis confirmed by ultrasound scanning (126 patients treated with anticoagulation and 328 controls).	Meta-analysis	Outcomes of the studies were pooled. Main outcomes studied were rate of pulmonary embolism and thrombus propagation in anticoagulated patients vs. controls.	Pulmonary embolism (odds ratio 0.12; 95% CI 0.02-0.77; p= 0.03) and thrombus propagation odds ratio 0.29; 95% CI 0.14-0.62; p=0.04) both significantly less frequent in those who received anticoagulation.	Small number of studies included. Overall methodological quality of included studies was low. No standardized criteria for control status of patients with a range of ‘control’ therapies across different studies.
Singh et al 2012 United States	156 patients with isolated calf vein thrombosis confirmed by sonography. All were started on prophylactic LMW heparin or unfractionated heparin unless already anticoagulated.	Prospective cohort study	Propagation to proximal vein or pulmonary emboli	At 1-3 months follow up 7% had propagation to proximal vein and 6% had developed a PE. All affected patients were observed to be in a high-risk group for DVT. No further complications between 6-8 months.	No controls over length of time each patient received prophylactic heparin. Small numbers of patients in high-risk group – no appropriate risk analysis calculation.
Guarnera G 2014 Italy	110 patients with distal DVT confirmed by ultrasound, treated with nadroparin once daily and compression therapy.	Prospective cohort study	Recanalization of veins	Complete recanalization in 56.4% of patients	Small number of patients. No control group. Different anticoagulation treatments not tested. Pain scores subjective. Pulmonary embolism rate not studied.
			Calf circumference	Average calf circumference significantly decreased from the baseline 38.1cm to 35.7cm at week four
			Pain Scores	Pain score significantly decreased from the baseline ( 58.4 to 12.7 at week four).
			Side effects from treatment	No side effects reported
Sartori M 2014 Italy	90 patients with isolated distal DVT confirmed by ultrasound. Patients with provoked DVTs received low-molecular-weight heparin for 30 days. Patients with unprovoked DVTs received vitamin k antagonists for three months.	Prospective cohort study	Composite outcome including: 1) Pulmonary embolism 2) proximal DVT 3) IDDVT recurrence or progression in 24month follow up.	17 events recorded at 24month follow up (3 PE, 4 proximal DVT, 10 IDDVT). Male sex (HR 4.73, 95% CI: 1.55-14.5; p = 0.006) and cancer (HR 5.47 CI95%: 1.76-17.6; p = 0.003) were associated with a higher risk of complications.	Small number of patients, therefore small number of composite outcome events, thus wide confidence intervals. No control group. Different therapies given for provoked and unprovoked DVT masks effects of natural history of DVT and different therapy regimes.
Olson et al 2014 United States	251 trauma inpatients with DVT ±PE on surveillance lower extremity duplex ultrasound.	Retrospective cohort study	Time of DVT onset and progression or regression.	BKDVT progressed to AKDVT and/or PE in 12.9% of patients. PE rates were 6.1% in BKDVT compared to 1.1% in AKDVT (p= 0.1)	Retrospective Only trauma patients evaluated. Small numbers of VTE events. Conservative use of pharmacologic prophylaxis during time of study.
			Use of anticoagulation between below knee DVT and above knee DVT groups.	86% of AKDVT received anticoagulation compared to 24% of BKDVT (p=<0.0001).
Horner D et al 2014 UK	70 consecutive patients with symptomatic isolated distal DVT. Equal allocation to receive either conservative management or therapeutic anticoagulation.	Randomised control trial.	Composite clinical outcome including 1) Proximal propagation of thrombus 2) Pulmonary embolism 3) Death related to VTE 4) Major bleeding	Composite clinical outcome in 4/35 patients treated conservatively (11.4%) and 0/35 patients anticoagulated. Absolute risk reduction 11.4%, 95% CI -1.5 to 26.7	Small number of patients studied Not powered for detection of clinical outcomes (feasibility trial) High rate of allocation crossover as open label methodology. Low median time in therapeutic range for those anticoagulated compared to other international standards Composite outcome used potentially overestimates clinical benefit.
Utter G et al 2016 United States	384 patients with IDDVT confirmed by ultrasound. Therapeutic coagulation given in 243 patients, 141 control patients (of whom >50% received prophylactic dose LMWH).	Retrospective cohort study.	Proximal DVT or PE within 180 days of diagnosis	Proximal DVT in 5% of controls and 1.6% of anticoagulation recipients. PE in 4.3% of controls and 1.6% of anticoagulation recipients. Anticoagulation associated with decreased risk for VTE related complication at 180 days (OR, 0.34; 95% CI, 0.14-0.83) but increased bleeding risk (OR, 4.35; 95% CI, 1.27-14.9).	Retrospective. Single centered. Testing for proximal DVT and PE not standardized and not performed in all patients. 57.4% of controls received prophylactic anticoagulation, therefore not true controls. Unable to differentiate anticoagulation for calf DVT from concomitant conditions in some patients. Bleeding episodes far higher than other reported studies (8.6%) likely as not standardized and recorded as ‘clinically relevant’ in subjective manner.

Comment(s)

Whether patients with IDDVT should receive anticoagulation remains a controversial question, with variability of international practice (14). The current best evidence, summarized above, consists mainly of small prospective cohort studies with an additional limited number of randomised studies, each with methodological limitations. It is clear that some patients with untreated IDDVT will develop VTE related complications, such as proximal propagation or embolization. The composite risk of this is roughly 7-10% within 90 days. Certain clinical features suggesting high VTE risk appear to increase the rate of complications. Therapeutic anticoagulation markedly reduces this risk, down to <2% in most studies. Prophylactic dose anticoagulation appears to have less effect, with the most recent cohort studies reporting propagation and PE rates of 5%. However, the benefits of anticoagulation must be balanced against the risks. Whilst the results above present minimal risk associated with anticoagulation, extensive research has been done in this field(14). A meta-analysis published in 2003(15) found a major bleeding rate of 2.06% (95% CI 2.04%-2.08%) during the first three months of therapeutic anticoagulation, with a fatal bleeding rate of 0.37% (95% CI 3.6%-3.8%). A lower risk may be associated with the new oral anticoagulants(16). As yet, no large randomized controlled trial has been conducted which compares therapeutic anticoagulation in patients with IDDVT directly against conservative management. As such, risks and benefits of treatment must therefore be considered in shared decision-making. The 9th edition American College of Chest Physicians guidelines regarding antithrombotic therapy for VTE disease(17) recommends treatment dose anticoagulation in IDDVT patients only with severe symptoms or those with a high risk for thrombus extension. These groups are defined below: “(1) D-dimer is positive (particularly when markedly so without an alternative reason); (2) thrombosis is extensive (eg, >5 cm in length, involves multiple veins, >7 mm in maximum diameter); (3) thrombosis is close to the proximal veins; (4) there is no reversible provoking factor for DVT; (5) active cancer; (6) history of VTE; and (7) inpatient status.” This, accompanied by discussion with the patient surrounding the risks and benefits of treatment, seems to be the most reasonable current solution to the clinical question. A larger scale, rigorous randomised control trial, as shown feasible by Horner et al, is needed to provide more robust evidence to guide decision-making. 14 Horner D, Hogg K, Body R. Should we be looking for and treating isolated calf vein thrombosis?. Emergency Medicine Journal. 2015;33(6):431-437. 15 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003;139:893–900. 16 Adam S, Mcduffie JR, Ortel TL. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med 2012;157:796–807 17. Kearon C, Akl E, Ornelas J, Blaivas A, Jimenez D, Bounameaux H et al. Antithrombotic Therapy for VTE Disease. Chest. 2016;149(2):315-352.

Editor Comment

DH

Clinical Bottom Line

Patients diagnosed with isolated distal deep vein thrombosis should be individually risk assessed and treated according to their clinical risk of thrombotic complication, haemorrhage and personal preference. Treatment if commenced should consist of therapeutic dose anticoagulation for at least 6 weeks. Further evidence is needed to accurately identify patient factors associated with higher risk of complications and provide randomised trial evidence of event rates with and without treatment

References

1. Gillet J, Perrin M, Allaert F Short-term and mid-term outcome of isolated symptomatic muscular calf vein thrombosis Journal of Vascular Surgery 2007;46(3):513-519
2. Parisi R, Visona A, Camporese G, Verlato F, Lessiani G, Antignani P et al Isolated distal deep vein thrombosis: efficacy and safety of a protocol of treatment. Treatment of Isolated Calf Thrombosis (TICT) Study International Angiology 2009;28(1):68-72.
3. Schwarz T, Buschmann L, Beyer J, Halbritter K, Rastan A, Schellong S. Therapy of isolated calf muscle vein thrombosis: A randomized, controlled study Journal of Vascular Surgery 2010;52(5):1246-1250
4. Palareti G, Cosmi B, Lessiani G, Rodorigo G, Guazzaloca G, Brusi C et al. Evolution of untreated calf deep-vein thrombosis in high risk symptomatic outpatients: The blind, prospective CALTHRO study Thromb Haemost 2010;104(5):1063-1070
5. Alhalbouni S, Hingorani A, Shiferson A, Marks N, Ascher E. Infra-popliteal deep venous thrombi and the risk of symptomatic pulmonary embolism in hospitalized patients Vascular 2011;19(1):29-33
6. De Martino R, Wallaert J, Rossi A, Zbehlik A, Suckow B, Walsh D A meta-analysis of anticoagulation for calf deep venous thrombosis. Journal of Vascular Surgery 2012;56(1):228-237.e1
7. Singh K, Yakoub D, Giangola P, DeCicca M, Patel C, Marzouk F et al Early follow-up and treatment recommendations for isolated calf deep venous thrombosis Journal of Vascular Surgery 2012;55(1):136-140
8. Guarnera G, Abeni D, Antignani P, Apollonio A, Conti F, Mollo P et al Update on distal deep venous thrombosis. Reports of a multicenter study. Int Angiol. 2014;33(6):560-564.
9. Sartori M, Migliaccio L, Favaretto E, Palareti G, Cosmi B. Two years outcome of isolated distal deep vein thrombosis Thrombosis Research 2014;134(1):36-40.
10. Olson E, Zander A, Van Gent J, Shackford S, Badiee J, Sise C et al Below-knee deep vein thrombosis Journal of Trauma and Acute Care Surgery. 2014;77(3):459-463
11. Horner D, Hogg K, Body R, Nash M, Baglin T, Mackway-Jones K The Anticoagulation of Calf Thrombosis (ACT) Project Chest 2014;146(6):1468-1477.
12. Utter G, Dhillon T, Salcedo E, Shouldice D, Reynolds C, Humphries M et al Therapeutic Anticoagulation for Isolated Calf Deep Vein Thrombosis JAMA Surgery 2016;:e161770