Isolated distal deep vein thrombosis (iDDVT) is an infra-popliteal DVT, without concomitant
proximal DVT and without pulmonary embolism (PE). Until recently, few large studies have
focused on iDDVT, and the clinical significance and therapeutic management of iDDVT was
mostly based on expert opinion and "gestalt" rather than on strong scientific data. iDDVT is
the most frequent presentation of venous thromboembolic disease (VTE). Indeed, in the large
French, multicentre, observational, OPTIMEV study, where all patients with suspected DVT
underwent systematic whole leg compression ultrasound (CUS) exploration, iDDVT represented
56% of all DVTs. A similar high proportion of distal DVT among DVT (52.1%) was reported in
Johnson's meta-analysis.
The risk of proximal extension of iDDVT to the proximal veins is substantial. In an extensive
review of the literature published 15 years ago, the investigators reported that the risk of
proximal extension of iDDVT, whether treated or left untreated, ranged from 0-44%,
underlining the heterogeneity of the available data. Data from the CALTHRO study and CACTUS
trial and extrapolation of data from management studies comparing the safety of serial
proximal CUS vs. whole leg CUS for DVT diagnosis suggest that the rate of extension of
untreated iDDVT to proximal deep veins was ~ 10% and up to 28% in high-risk populations, such
as patients with cancer (3, 7-9). This 10% average risk of proximal extension is far above
the usual 2% cut-off for an acceptable false-negative rate for negative findings in DVT
diagnostic strategies. Hence, from a strict natural history standpoint, clinical significance
of iDDVT is no longer in question. In summary, iDDVT is the most frequent clinical
presentation of VTE and patients with iDDVT are at significant risk of proximal extension and
of adverse outcomes both in the short and in the long-term.
Management of iDDVT is one of the most debated issue in the field of VTE. Thus, in all trials
that validated the use of DOAC, distal location of DVT was an exclusion criterion.
While the American society of Hematology (ASH) guidelines do not comment on iDDVT specific
treatment, the American college of chest physicians (ACCP) guidelines state that only 'high
risk' distal DVT should be systematically treated with anticoagulation. Non high risk iDDVT
could benefit from surveillance by repeated CUS. However, in the international CACTUS study,
the investigators observed that a primary reason for refusal of participation and failure to
fulfil recruitment was that patients and their treating physicians refused that iDDVT be left
untreated. In routine clinical practice, data from observational registries showed that the
majority iDDVT are treated with full dose of anticoagulants: 97% of iDDVT in the French
OPTIMEV study, 98% in the Italian MASTER registry and 99% in the international RIETE
registry. These therapeutic attitudes reflect physicians' beliefs (and patients' preference)
that anticoagulation is important in case of iDDVT.
For proximal DVT and PE, "therapeutic" doses of anticoagulants are prescribed as use of lower
doses was associated with an unacceptably high VTE risk. In contrast, for superficial vein
thrombosis (SVT), "prophylactic" doses (fondaparinux 2.5mg or rivaroxaban 10 mg daily) were
shown to be very effective and associated with a very low bleeding risk. Regarding iDDVT,
risk of VTE recurrence and effectiveness of different dose regimen of anticoagulation are
less clear and literature suggests that it could depend on patients' characteristics . Based
on literature review, main risk factors for VTE extension/recurrence include cancer, calf
trifurcation involvement, previous VTE, unprovoked character of DVT or presence of a
permanent risk factor, and multiple vein distal vein thromboses.
In the CACTUS study, at 3 months, the proportion of extension to proximal deep veins in the
therapeutic anticoagulation arm was lower than in the placebo arm (3.3% vs. 6.2% at 3 months;
p=NS), but the risk of significant bleeding was significantly higher (4.1% vs. 0.0%)(3).
Namely, in CACTUS, the benefit of therapeutic anticoagulation in terms of VTE risk reduction
was offset by the excess in risk of bleeding.
In summary, iDDVT is the most frequent clinical presentation of VTE and is associated with a
significant morbidity and risks of long-term complications. Data from clinical trials
highlighted that patients with iDDVT might require some level of AC treatment. However, the
optimal anticoagulant intensity is uncertain, and it is plausible that the best benefit/risk
ratio for AC might be achieved with lower intensity doses rather than therapeutic doses.
The principal research question of the Apixaban to treat calf vein thrombosis (API-CALF)
study is to determine whether, after a conventional course of 7 days of Apixaban 10mg BID,
Apixaban 2.5mg BID (experimental arm) is non inferior to Apixaban 5 mg BID (standard arm) in
preventing VTE recurrence and bleeding in patients with iDDVT. Patients will be treated with
Apixaban for a total of 3 months. In that perspective we will conduct an international
multicentre open-label assessor-blinded study