Washington University Emergency Medicine Journal Club- February 2024
Vignette
Mr. M is a 53-year-old patient with a history of high blood pressure and high cholesterol who flew back to St. Louis from Shanghai five days ago. Two days after getting back he noted pain and swelling in his left calf, which he thought was due to a muscle strain while getting off of the airplane. Since then, the swelling has remained constant while the pain has worsened slightly. He reports a dull ache that is worse with ambulation and improves with rest. He denies shortness of breath or chest pain.
On physical exam his vitals are normal, his lungs are clear, and he has a normal S1 and S2 without a cardiac murmur or gallop. He has mild swelling noted to the left calf with focal calf tenderness. There is no erythema, warmth, or induration, and his pulses are symmetric bilaterally.
Concerned for a possible DVT given his recent long flight, you obtain lower extremity dopplers which reveal echogenic material in the peroneal and soleal veins consistent with acute DVT, but no signs of DVT proximal to the calf.
You call the patients PMD to discuss management, and she recommends sending the patient home with no therapy because, “It’s just a calf DVT. You don’t treat those.” While you understand that has been the classic teaching, you also remember seeing a journal on this topic from a few years ago (https://emergencymedicine.wustl.edu/items/management-of-isolated-calf-dvts-with-anticoagulation/) that spoke about the controversy surrounding this dogma, but wonder if there is any new evidence. You send Mr. P home and recommend repeat dopplers in 5-7 days, but later decide to search the literature to make your own evidence-based decision…
PICO Question
Population: Adult patients with isolated calf DVT distal to the popliteal veins
Intervention: Therapeutic anticoagulation (heparin, low molecular weight heparin, factor Xa inhibitor, direct thrombin inhibitor, or vitamin K antagonist)
Comparison: No anticoagulation
Outcome: Propagation of clot to the popliteal veins or beyond, PE, bleeding, death,
cost, patient satisfaction, quality of life, post-thrombotic syndrome
Search Strategy
PubMed was searched using the terms “calf AND (thrombosis OR DVT) AND
anticoagulation” which resulted in 636 citations (http://tinyurl.com/nu7ztxwh).
Three primary articles were identified. The Cochraine Database of Systematic
Reviews was also searched, resulting in one systematic review and meta-analysis
which was included.
Article 1: Righini M, Galanaud JP, Guenneguez H, Brisot D, Diard A, Faisse P, Barrellier MT, Hamel-Desnos C, Jurus C, Pichot O, Martin M, Mazzolai L, Choquenet C, Accassat S, Robert-Ebadi H, Carrier M, Le Gal G, Mermilllod B, Laroche JP, Bounameaux H, Perrier A, Kahn SR, Quere I. Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled trial. Lancet Haematol. 2016 Dec;3(12):e556-e562. doi: 10.1016/S2352-3026(16)30131-4. Epub 2016 Nov 8. PMID: 27836513. Answer Key.
Article 2: Kirkilesis G, Kakkos SK, Bicknell C, Salim S, Kakavia K. Treatment of distal deep vein thrombosis. Cochrane Database Syst Rev. 2020 Apr 9;4(4):CD013422. doi: 10.1002/14651858.CD013422.pub2. PMID: 32271939; PMCID: PMC7144816. Answer key.
Article 3: Utter GH, Dhillon TS, Salcedo ES, Shouldice DJ, Reynolds CL, Humphries MD, White RH. Therapeutic Anticoagulation for Isolated Calf Deep Vein Thrombosis. JAMA Surg. 2016 Sep 21;151(9):e161770. doi: 10.1001/jamasurg.2016.1770. Epub 2016 Sep 21. PMID: 27437827. Answer Key.
Article 4: Horner D, Hogg K, Body R, Nash MJ, Baglin T, Mackway-Jones K. The anticoagulation of calf thrombosis (ACT) project: results from the randomized controlled external pilot trial. Chest. 2014 Dec;146(6):1468-1477. doi: 10.1378/chest.14-0235. PMID: 25010443. Answer key.
Bottom Line
The management of DVTs isolated to the calf veins has remained a controversial topic for
many years. The 2021 updated guidelines produced by the American College of Chest
Physicians (ACCP) recommend serial imaging for isolated distal DVT (without severe
symptoms or risk of proximal extension), rather than anticoagulation. It should be noted,
however, that this is a weak recommendation based on moderate-certainty evidence. In
contrast, the 2021 guidelines from the European Society for Vascular Surgery
recommends three months of anticoagulation for distal DVT, unless there is a clear
contraindication, again based on a low level of evidence. Given this lack of clear
consensus, we decided to review the current evidence.
A retrospective observational study conducted at UC Davis (Utter 2016) assessed
outcomes for isolated calf DVT based on whether or not there was an intention to treat
with any form of anticoagulation. The composite outcome of proximal DVT or PE was
less likely in those treated with anticoagulation (RR 0.36, 95% CI 0.15 to 0.84). This
benefit persisted after adjustment was made for several confounders. Unfortunately,
observational studies are never able to control for the unknown confounders, and hence
provide a lower level of evidence. Additionally, less than half of the patients in this study
underwent repeat testing to assess for propagation of DVT, and such testing was more
likely to occur in the control group, biasing the results in favor of the treatment group.
The study also included primarily inpatients, and less than 4% were from the ED
(external validity).
A pilot randomized, controlled trial conducted in the UK in 2014 (Horner 2014)
randomized patients with any isolated calf DVT to either warfarin or anti-inflammatory
medication. Seventy patients were analyzed, and for the composite outcome of proximal
propagation, symptomatic PE, VTE-related sudden death, or major bleeding, they found a
statistically nonsignificant trend towards benefit with anticoagulation (absolute risk
reduction 11.4%, 95% CI -1.5% to 26.7%). Unfortunately, no follow-up to this pilot study
was ever published to provide more definitive evidence.
3
A larger randomized controlled conducted at 23 centers in Canada, France, and
Switzerland compared nadroparin (a low molecular weight heparin) with placebo for the
treatment of isolated distal DVT (Righini 2016). With 252 total patients in the final
analysis, the authors found that the primary composite outcome (extension of the calf
DVT into the proximal veins, a contralateral proximal DVT, or symptomatic PE)
occurred by day 42 with similar frequency in the nadroparin (3%) and placebo (5%)
groups: risk difference -2.1%, 95% CI -7.8% to 3.5%. While proximal extension was less
common the nadroparin group, development of PE was seen more frequently in this
group. Major or clinically relevant non-major bleeding occurred more frequently in the
nadroparin group than the placebo group: risk difference 4.1%, 95% CI 0.4 to 9.2%. Of
note, this study was stopped early due to low enrollment rates and subsequent expiration
of the study drug, and remained underpowered to detect a potentially clinically significant
difference in the primary composite outcome.
In order to synthesize the evidence on this topic, a Cochrane systematic review and metaanalysis of randomized controlled trials was published in 2020 (Kirkilesis 2020). Eight
studies were included, comprising 1239 participants. Three studies compared vitamin K
antagonist (VKA) treatment for 6 weeks versus 12 weeks or more; 3 studies compared
anticoagulants versus no treatment or placebo for 3 months and 2 made the same
comparison for 6 weeks. The overall pooled risk of VTE recurrence was lower with
anticoagulation compared with no intervention or placebo: RR 0.34, 95% CI 0.15 to 0.77;
I2 = 3%. There was no significant difference in major bleeding events between groups,
while clinically relevant non-major bleeding rates were increased in the anticoagulation
group compared with the placebo or no intervention group: RR 3.34, 95% CI 1.07 to
10.46; I2 = 0%. The incidence of recurrent venous thromboembolism was lower for the
three months or more treatment period compared with the six weeks’ treatment period.
The evidence reviewed here is notably lacking in large, randomized controlled trials of
good methodology, underscoring the difficulty in making firm recommendations.
Additionally, all of the current evidence predates the use of direct oral anticoagulants
(e.g. apixaban, dabigatran, edoxaban, or rivaroxaban) which are currently recommended
for the treatment of acute deep venous thrombosis. Use of these agents would likely
affect compliance and rates of bleeding in these studies. Given the low level of evidence,
the decision to treat or not treat isolated calf DVTs should be based on several factors,
including location (muscle vs. deep veins), need for ongoing immobilization, bleeding
risk, and access to follow-up for repeat imaging. Emergency physicians will have to work
closely with patients, primary care physicians, and admitting teams when making such
decisions, given the controversy surrounding this topic.