Preventing recurrence from distal deep vein thrombosis: Still searching for answers

Deep vein thrombosis (DVT) afflicts 300,000–600,000 patients annually in the United States. ¹ Of those, nearly half are isolated to the distal veins of the leg (peroneal, posterior tibial, anterior tibial, and muscular calf veins). ² These seemingly small venous clots often lead to bothersome symptoms and can extend to the proximal veins or embolize to the pulmonary arteries. While mortality associated with isolated distal DVT is thought to be quite low, a pulmonary embolism portends significantly higher risk for many patients. Therefore, anticoagulant therapy to prevent extension and embolization is frequently considered for these patients. The choice of anticoagulant, intensity of therapy, and duration of treatment are issues commonly encountered by clinicians and patients.

Due to a relative paucity in data regarding long-term outcomes and management strategies for isolated distal DVT, guidelines have often offered low-grade recommendations. In 2012, the American College of Chest Physicians (ACCP) recommended treatment with 3 months of full-dose anticoagulation for patients with severely symptomatic, isolated distal DVT but serial imaging instead of anticoagulation for patients without severe symptoms. ³ In 2016, the ACCP updated their guidelines to recommend full-dose anticoagulation for 3 months in all patients with isolated, distal DVT. ⁴ The Anticoagulation Forum provided guidance in 2016 as well, recommending 3 months of anticoagulation unless a contraindication to anticoagulation exists. ⁵ Yet all three of these documents highlight that recommendations are made without robust clinical trial data and that additional data are needed to better understand the natural history and treatment options.

In that light, Donadini and colleagues developed an institutional practice pattern that includes 4–6 weeks of low molecular weight heparin for all patients with isolated distal DVT. ⁶ Specifically, they initiated treatment-dose therapy for 1 week, then reduced the dose to 50% (prophylactic dose) for the next 3–5 weeks. Between 2004 and 2011, all patients were followed clinically for 6 months and received follow-up phone calls 2 years after the initial treatment period. During that time, and as reported in this issue of Vascular Medicine, 15% of patients experienced recurrent venous thromboembolism (VTE), for a recurrence rate of 4.4/100-patient-years. ⁶ This was highest among patients with an initial unprovoked DVT (7.2/100-patient-years) and lowest among patients with a transient provoking factor (3.5/100-patient-years). In multivariable analysis, an unprovoked index DVT and a history of prior DVT were significant predictors of VTE recurrence during follow up.

The work of Donadini and colleagues provides new insights beyond other published cohorts. The RIETE registry published a large, multi-center experience of nearly 2000 isolated distal DVT patients with a lower 2% recurrence risk. ⁷ However, follow-up in that study was limited to 3 months and details about the intensity of anticoagulation are not available. With an annualized rate of VTE recurrence of 4.4/100-patient-years in the Donadini cohort, the 3-month recurrence rate is most likely similar to the RIETE experience. Additionally, the OPTIMEV multicenter cohort of nearly 500 distal DVT patients reported a VTE recurrence rate of 2.7/100-patient-years. Similar to the Donadini cohort, the OPTIMEV study had a longer follow-up period (3 years). However, unlike the Donadini cohort, patients within the OPTIMEV cohort mostly received therapeutic doses of anticoagulation for 3 months while those within the Donadini cohort received 4–6 weeks of anticoagulation, the majority of which was at prophylactic doses. Finally, the OPTIMEV study excluded patients with cancer or prior VTE, two of the higher-risk groups for VTE recurrence. The most recently published cohort from Germany demonstrated an annualized recurrence rate of 2.0% for isolated distal DVT (most of which were symptomatic). ⁷ This occurred over a median follow-up duration of about 7 years in 202 patients with isolated distal DVT. Intermediate or therapeutic dose anticoagulation was given for up to 3 months for the majority of these patients, perhaps explaining the lower rate of recurrence than reported in the Donadini cohort, despite the longer follow-up period.

In comparison to patients with proximal DVT or pulmonary embolism from the recent REVERSE-2 validation study, low-risk patients who did not receive extended anticoagulation experienced a VTE recurrence rate of 3.0/100-patient-years while high-risk patients who discontinued anticoagulation after a short course experienced a much higher recurrence rate of 8.1/100-patient years. ⁹ These values are similar to the recurrence rates reported by Donadini and colleagues in their provoked (3.5/100-patient-years) and unprovoked (7.2/100-patient-years) isolated distal DVT cohorts, respectively.

How should these results impact our care of patients with isolated distal DVT? They certainly provide additional data to guide our discussion with patients diagnosed with isolated distal DVT. In particular, they provide efficacy data on a short course of (primarily) prophylactic dose anticoagulation. Although this strategy may be sufficient for patients who present with isolated distal DVT in the setting of a transient provoking risk factor (e.g. recent surgery or immobilization), it likely is insufficient for patients with unprovoked or cancer-associated isolated distal DVT. Whether longer courses of full-dose anticoagulation would offer better results has not been fully examined.

The rates of VTE recurrence within the Donadini cohort rise above the threshold at which most clinicians recommend longer-term or indefinite anticoagulation. With newer treatment options, including direct oral anticoagulants (DOACs), offering lower rates of bleeding, future studies should explore if patients with isolated distal DVT portend benefit from longer courses of treatment with these easy-to-use anticoagulants. Studies exploring both the duration and dose of DOACs for isolated distal DVT patients would help to guide clinicians who frequently encounter this scenario. Similarly, ongoing studies exploring the link between inflammation and VTE may lead to treatments with very low bleeding risk and would offer additional therapeutic options. ¹⁰ Until those data are available, Donadini and colleagues have provided clinicians with important data about the natural history of isolated distal DVT.