Gray areas in vein disease: In this series of articles, we discuss the uncertain and the unsure. Eight thoughtful, knowledgeable, and confident vein specialists contemplate four venous disease areas: superficial disease; deep disease, reflux; deep disease, post-thrombotic; and acute DVT.

THERAPEUTIC anticoagulation is the standard of care for acute deep vein thrombosis (DVT) in the femoropopliteal or iliocaval system. Treatment of isolated calf deep venous thrombosis (IDDVT), whether it be in the tibial veins or muscular veins of the calf, has been controversial since one of the earliest randomized trials of patients with IDDVT was published in The Lancet in 1985.¹ This trial randomized 51 patients to five days of heparin overlapping with warfarin for three months versus heparin alone. Of the warfarin patients, 22 out of 23 (96%) were free from recurrence at one year compared to only 19 out of 28 (68%) in the non-warfarin group. It seemed that treatment with three months of anticoagulation, even in patients with IDDVT, was beneficial. However, controversy continues, and clinical equipoise exists.

Multiple studies have demonstrated that IDDVT is prevalent in as many as 60–70% of all DVTs.^2,3 IDDVT is typically associated with transient risk factors and carries a lower mortality risk than proximal DVT.4 The risk of sequalae and complication is not negligible, however, and varies significantly in the literature. One review placed the risk of proximal extension between zero and 35%, with the risk of pulmonary embolism (PE) between zero and 8%.5 Galanaud, et al. have shown the three-year risk of recurrence after completion of anticoagulation to be 2.7% for IDDVT versus 5.2% for proximal DVT.⁶

Finally, the risk for post thrombotic syndrome has been shown to be as high as 30% at six years.⁷

It is not clear, however, that anticoagulation significantly changes outcomes for those with IDDVT. It is likely that most IDDVTs go undiagnosed, and therefore untreated, as most are asymptomatic. In addition, anticoagulation is associated with at least some risk of bleeding. Therefore, it is attractive to consider treating with observation rather than anticoagulation.

In recent years, there have been several randomized controlled trials (RCTs) evaluating various anticoagulation strategies in IDDVT. The ACT trial, a feasibility study published in 2014, randomized 70 patients to three months of warfarin versus no anticoagulation at all.8 All received a repeat ultrasound at seven and 21 days. The combined primary outcome included proximal extension, (PE), venous thromboembolism (VTE) death, and major bleeding. At 90 days, the primary outcome occurred in 11.4% of the untreated group as compared to 0% in the treated group. There was no major bleeding.

In 2010, Schwarz, et al. published a randomized, controlled trial of 107 patients with muscular DVT.9 They randomized patients to 10 days of low molecular weight heparin (LMWH) and compression versus compression alone and found an identical 3.7% propagation risk in both groups. There was no incidence of PE, death or bleeding, and there was no difference in rates of recanalization at three months.

The CACTUS trial, published in 2016, enrolled low-risk patients with no active cancer or history of previous VTE who were found to have IDDVT at 23 centers in Canada, France, and Switzerland.10 The trial enrolled 259 patients and randomized them to LMWH versus placebo for six weeks. All patients received compression. These patients were followed for 90 days, and the composite primary endpoint was proximal extension, contralateral DVT or PE. The trial found no difference in the primary endpoint between the treatment and control groups (3% versus 5%), but there was more bleeding in the treatment group as compared to controls (4% versus 0%; p < 0.05). This trial was stopped early due to slow enrollment and was therefore underpowered. The investigators did a post-hoc analysis, evaluating the effect of anticoagulation on pain and again found no difference in patient-rated pain in the treatment versus the control groups, nor in those with tibial versus muscular thrombus.11 They did demonstrate that those who wore their compression had less pain.

A recent Cochrane review evaluated eight RCTs looking at anticoagulation versus observation for IDDVT. This review found a reduction in the risk of recurrent VTE or DVT with anticoagulation, but no difference in risk of PE.12 There was no difference in the rate of major bleeding, but there was an increase in clinically relevant, non- major bleeding with anticoagulation. With regards to duration of anticoagulation, anticoagulation for three months or more decreased the incidence of recurrent VTE to 5.8% compared to 13.9% in those treated for six weeks. The risk for DVT recurrence was also lower with longer anticoagulation duration, but there was little or no difference in PE and no clear difference in major bleeding or clinically relevant, non-major bleeding with the longer duration of anticoagulation. The authors concluded that there was a benefit for people with IDDVT to be treated with anticoagulation; however, the small number of trial participants limited the strength of the analysis.

Because there is no clear consensus, it seems reasonable to follow the most recent CHEST guidelines, which were published in 2016. These guidelines advocate for two treatment options: therapeutic anticoagulation, or observation with serial duplex ultrasound exams at one and two weeks, with anticoagulation only if extension of the thrombus occurs. Clearly, no anticoagulation and no repeat duplex exam is unacceptable. The guidelines further suggest that serial exams should be employed for patients without severe symptoms or risk factors for extension, which include positive D-dimer, extensive thrombus (>5cm in length, multiple veins, or >7mm in diameter), thrombus close to proximal veins, unprovoked thrombosis, active cancer, history of VTE, and inpatient status. If the patient is placed on anticoagulation, the guidelines recommend a three month duration.

Another issue without clear evidence is which anticoagulation regimen is best. Options include a direct oral anticoagulant (DOAC), LMWH, or warfarin, just as with acute proximal DVT. There is no definitive answer to this, and the patient’s comorbidities, VTE risk factors, bleeding risk, insurance status, and other factors may influence the best anticoagulant choice.

I tend to treat these patients with serial duplex exams, unless they have an active cancer or previous history of VTE. However, if the thrombus is close to the popliteal vein, or if close follow-up will be difficult, I treat with therapeutic anticoagulation. In recent years, I have used DOACs, as long as the patient’s out-of-pocket cost is reasonable.

References:

1. Lagerstedt C, Fagher B, Olsson C, et The Lancet 1985; 326(8454):515-18.
2. Schellong “Distal DVT: worth diagnosing? Yes.” J Thomb Haemost 2007;5(Suppl 1):51-4.
3. Oger E. “Incidence of venous thromboembolism: a community based study in Western France.” EPI-GETBP Study Group. Groupe d’Etude de la Thrombose de Bretagne Occidentale. Thromb Haemost 2000;83(5):657-60.
4. Galanaud JP, Sevestre-Pietri MA, Bosson JL, et al. “Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis>results from the OPTIMEV study.” J Thromb Haemost 2009;102(3):493-500.
5. Garry J, Duke A, Labropaulos N. “Systematic review of the complications following isolated calf deep venous ” Br J Surg 2016; 103:789-796.
6. Galanaud JP, Sevestre MA, Genty C, et “Incidence and predictors of venous thromboembolism recurrence after a first isolated distal deep venous thrombosis.” J Thromb Haemost 2014;12:436-43.
7. Galanaud JP, Righini M, LeCollen L, et al. “Long-term risk of post thrombotic syndrome after symptomatic distal deep venous DVT: The CACTUS-PTS ” J Thromb Haemost 2020;18:857-864.
8. Horner D, Hog K, Body R, et “The anticoagulation of calf thrombosis (ACT) Project.” Chest 2014;146:1468.
9. Schwartz T, Buschmann L, Beyer J, et al. “Therapy of isolated calf muscle vein thrombosis: A randomized, controlled ” J Vasc Surg 2010;52:1246-50.
10. Righini M, Galanaud JP, Guenneguez H, et “Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomized, double-blind, placebo-controlled trial.” Lancet Haematol 2016; 3(12):e556-62.
11. Righini M, Robert-Ebadi H, Glauser F, et al. “Effect of anticoagulant treatment on pain in distal deep vein thrombosis: an ancillary analysis from the cactus ” J Thromb Haemost 2019;17:507-10.
12. Kirkilesis G, Kakkos SK, Bicknell C, et “Treatment of distal deep vein thrombosis.” Cochran Database Syst Rev 2020; Issue 4. Art. No: CD013422.DOI:10.1002/14651858.CD013422.pub2.