The evidence on the treatment of CAT with VKAs is based on RCTs conducted in patients without cancer [8]. LMWHs were assigned for 5–10 days followed by the VKA international normalized ratio (INR) target of 2.0 to 3.0 [9]. It is not easy for the VKAs to keep the INR in range due to interactions with chemotherapy drugs that affect VKA metabolism, inconsistent dietary intake due to anorexia, nausea or vomiting, low body mass, and low albumin [10]. Therefore, the therapy of choice with LMWH or DOAC (for 6 months) should be preferred over VKAs.

According ESMO guidelines, if rVTE occurs in patients on VKAs with an INR in the subtherapeutic range, then they should be treated with LMWH until the INR reaches its therapeutic values again [11]. If rVTE occurs on VKAs in the therapeutic range, a switch to LMWH is recommended by most guidelines [2, 3, 4, 5, 6, 7], without a subsequent return to the VKA. According to ESMO recommendations, if rVTE occurs in patients taking VKAs with an INR in the sub-therapeutic range, they should be treated with LMWH until the INR reaches therapeutic values.

LMWHs have remained the first-line treatment for VTE for more than two decades [12, 13, 14, 15, 16]. Among the five RCTs only the CLOT [13] trial reported statistically improved rates of rVTE with dalteparin compared with a VKA and the other four (CANTHANOX, ONCENOX, LITE, and CATCH [12, 13, 14, 15, 16]) demonstrated non-statistically significant reductions in rVTE with an LMWH compared with a VKA.

The current guidelines recommend DOAC (apixaban or rivaroxaban) or LMWH as the initial treatment (5 to 10 days) for patients with CAT [3, 4, 5, 6, 7].

For the short-term treatment of CAT (up to 6 months), the current guidelines indicate DOAC (apixaban, edoxaban, or rivaroxaban) over LMWH.

For the long-term treatment ($>$6 months) for patients with malignancy and VTE, guidelines suggest using DOACs or LMWHs [2, 3, 4, 5, 6].

Four recent RCTs have compared the efficacy and safety of DOACs vs. LMWH in cancer patients. The Hokusai cancer study compared edoxaban with subcutaneous dalteparin during a 12-month treatment in cancer patients with acute VTE. rVTE occurred in 7.9% in the edoxaban group and in 11.3% in the dalteparin group at the 6- and 12 month follow-up points [17].

Select-D was a pilot open-label trial in patients with VTE, comparing rivaroxaban and dalteparin [18]. The incidence of rVTE over 6 months was significantly lower in the rivaroxaban than in the dalteparin arm (4% vs. 11%).

In both studies [17, 18], DOACs showed non-inferiority in reducing rVTE compared with LMWH however they were associated with a higher risk for major bleeding complications in patients with gastrointestinal (GI) cancer.

In an open-label RCT - the ADAM VTE trial - apixaban and dalteparin were compared in patients with CAT [19]. rVTE occurred in 0.7% in the apixaban group in comparison to 6.3% in the dalteparin, group. rVTE was 0.7% in the apixaban group in comparison to 6.3% in the dalteparin group.

Major bleeding events up to 6 months occurred in 0% of patients assigned to apixaban in contrast to 1.4% of patients on dalteparin. The composite bleeding endpoint (major or clinically relevant non-major bleeding) was 6% for each arm.

In the largest RCT, Caravaggio study, rVTE at 6 months of follow-up occurred in 5.6% of patients randomized to apixaban compared with 7.9% of those assigned to dalteparin [20]. Major bleeding occurred in 0.6% of patients in the apixaban arm and in 1.8% in the conventional-therapy group.

In the ADAM VTE and CARAVAGGIO studies, there was no excess of GI bleeding in patients treated with apixaban, including those with GI cancer.

The CASTA DIVA study, which explored 3 months of treatment with rivaroxaban, found a rate of rVTE of 6.4%, compared to 10.1% in patients who received dalteparin. The study was stopped prematurely and was unable to confirm noninferiority against dalteparin for the prevention of rVTE [21].

A meta-analysis of four studies (Hokusai cancer, Select-D, ADAM VTE, and CARAVAGGIO) evaluating the efficacy and safety of DOACs compared with LMWH for CAT demonstrated that DOACs significantly decrease recurrent thrombosis compared with dalteparin without significantly increasing major bleeding. Edoxaban significantly increased major bleeding events compared with dalteparin, while rivaroxaban increased clinically relevant non-major bleeding compared with dalteparin and other DOACs [22].

The non-inferior risk of rVTE among patients with active cancer was confirmed in the CANVAS study, where the use of a DOAC compared with an LMWH was without differences in rates of bleeding or death [23].

It should be noted that DOACs increase the risk of bleeding, so in patients with GI cancer and upper or unresected lower GI cancer, LMWH may be preferred.

An inferior vena cava (IVC) filter should be considered in cancer patients with absolute contraindications for anticoagulation therapy such as active bleeding or a high risk of bleeding with recently diagnosed deep vein thrombosis (DVT). Anticoagulation should be started immediately after the resolution of any contraindications. Retrievable filters in comparison to permanent filters are preferable in the cancer setting.

According to American Society of Clinical Oncology (ASCO), an IVC filter may be suggested to patients with absolute contraindications to anticoagulation in the acute setting if the thrombus propagation is considered life-threatening [9].

An IVC filter may be offered in addition to anticoagulation in patients with thrombosis progression despite optimal treatment. As indicated by ITAC, an IVC filter may be considered for initial treatment when anticoagulation is contraindicated or when pulmonary embolism (PE) occurs despite optimal anticoagulation [5].

It is recommended that contraindications to anticoagulation should be periodically reviewed and anticoagulation can be considered.

Patients with CAT have a high risk of rVTE despite receiving anticoagulation. Risk factors for recurrence are identified in the RIETE registry [27]. Rates of rVTE in cancer patients differ between tumor sites and depend on the type of anticoagulation agents. In patients treated with VKA, recurrence rates were 10 to 17% during the first 6 months after VTE [12, 16]. Rates of recurrence with the LMWH, based on the CLOT trial, were 7–9% [12, 16], and with DOACs varied between RCTs from 3.9 to 7.9% [17, 18, 19, 20].

Other reasons for rVTE may include non-compliance, temporary interruption of treatment due to bleeding or surgery, inappropriate dosing, disease progression, or drug-drug interactions that may reduce the anticoagulant effect.

Based on the data from modern guidelines, in the case of rVTE, the next options should be used: (i) switching to LMWH if a DOAC or VKA is used, (ii) LMWH dose escalation, (iii) or insertion of IVC filter in the setting of rVTE despite optimal anticoagulation or in case of contraindication to anticoagulation due to bleeding.

Non-compliance is a key reason of “obvious treatment failure”. Compliance with VKAs is easy to monitor with an INR at the time of the rVTE. Controlling noncompliance with the DOAC regimen is even more challenging without available and validated tools. Available literature data supports that non-compliance with DOACs is common [28].

If the patient is not compliant, they should be managed with the same anticoagulant therapeutic strategies and doses as a patient with a first VTE to prevent a subsequent recurrence. In the case of non-compliant VTE events, there is no clear answer as to whether to remain on the current treatment option or switch to another anticoagulant.

No RCT has explored different treatment options in patients with therapeutic failure of anticoagulation, and there are no clear data to guide the management strategy for these patients.

Additionally, there is no published research covering treatment options after DOAC failure—DOAC dose escalation or switching DOAC to another agent?

In cases of rVTE on DOAC, the same approach as with patients who experienced VKA failure can be proposed by switching to a therapeutic dose of LMWH.

Although underdosing may potentially increase the risk of thromboembolic complications, overdosing may result in bleeding.

Therefore, an appropriate initial dose of anticoagulant is crucial for patients with active malignancies.

Reduced doses of the anticoagulant should be considered only in patients with a high bleeding risk, with thrombocytopenia, and renal failure. Current guidelines recommend treatment with a therapeutic dose of LMWH for platelets (PLT) $\ge$ 50 100 $\times$ 10⁹/L, a reduced dose to 50% of LMWH for PLT $\ge$ 30 50 $\times$ 10⁹/L, and discontinuation of therapy for PLT 30 $\times$ 10⁹/L [7].

In the case of LMWH underdosing, a weight-adjustment dose of LMWH should be prescribed according to guidelines.

In the case of DOAC underdosing, switching DOAC to the therapeutic dose of LMWH can be the best strategy. In case of successful therapy with LMWH, it is possible to switch LWMH back to oral treatment, typically to another DOAC.

Patients with rVTE, despite therapeutic doses of anticoagulant therapy, should be assessed for several factors, such as treatment compliance, heparin-induced thrombocytopenia (HIT), antiphospholipid syndrome, thrombophilia (protein C, protein S, Factor V Leiden mutation, and antithrombin deficiency), malignancy compression or invasion resulting in tumor-thrombosis [29]. Management options for recurrent VTE on optimal anticoagulation include an alternative anticoagulant regimen or an increase in LMWH dose.

In a small retrospective study, 47 patients with cancer and rVTE who were already receiving a therapeutic dose of LMWH had a dose escalation of 20 to 25% for 4 weeks [30]. The recurrence rate on super therapeutic dose was 8.6% during 3 months, and the author suggests that escalating the dose of LMWH can be effective for treating patients that are resistant to standard, weight-adjusted doses of LMWH [31]. The international ISTH registry demonstrated no significant difference in the risk of further recurrences over 3 months between patients who had a dose escalation of $\ge$20–25% and those with a standard dose of LMWH [32]. The ACCP guidelines recommend a dose escalation of LMWH by 25–33% [31], and ASCO recommends a 20 to 25% increase [6].

Data of rVTE on DOACs is limited. A meta-analysis of VTE trials (26,872 patients) demonstrated a 2% risk of rVTE during the acute treatment phase [33].

The one-year cumulative rate of rVTE in cancer patients is estimated to be at about 21%, compared to only 7% in patients without cancer [34]. A meta-analysis of 29 studies (8000 patients with CAT), demonstrated the overall risk of rVTE 23.7 events per 100-patient years [35]. In the SELECT-D study, the 6-month risk of rVTE in patients treated with rivaroxaban was 4% vs 11% with LMWH [18], in the Hokusai VTE Cancer trial, risk of rVTE at 6- and 12-months in edoxaban arm was 4.4% and 7.9%, vs 6.7% and 11.3% in LMWH arm, respectively [17], and in the Caravaggio trial, patients assigned to the apixaban arm had a risk of rVTE at 6 months of 5.6% vs 7.9% with LMWH [19]. So, the risk of rVTE in cancer patients varied from study to study from 4 to 5.6%.

The systematic review of four RCTs (Caravaggio, ADAM VTE, SELECT-D, and Hokusai VTE) that analyzed 2894 patients with CAT, demonstrated that treatment with a DOAC significantly decreased rVTE in comparison to dalteparin (5.6% and 9.1%, respectively) without any significant increase in major bleeding event rates (4.8% vs 3.6%) [22].

Three DOACs—apixaban, edoxaban, and rivaroxaban are not only more treatment-effective but also more cost-effective than LMWH [36].

A 58-year-old man was diagnosed with sigmoid colon adenocarcinoma and received surgery followed by three courses of chemotherapy (CapeOx). He was referred to the Cardio-Oncology Center and noticed the sudden onset of right calf pain without any previous trauma one week before his visit. His initial physical exam revealed a tender and swollen right calf. Compression ultrasound (CUS) demonstrated DVT of the right popliteal vein (Fig. 1A). He was prescribed rivaroxaban 15 mg twice a day for the first 21 days, then 20 mg once daily; he adhered to this regimen. After four weeks, CUS showed partial recanalization of the right popliteal vein and normal blood flow in the deep veins of the left leg (Fig. 1B). Two weeks later, the patient returned to the Cardio-Oncology Center with progressive swelling in his right leg and right thigh, accompanied by pain. Physical examination revealed a swollen, tender right lower extremity. CUS revealed an extension of the right popliteal DVT with a new DVT in his right thigh (Fig. 1C). Computed tomographic pulmonary angiography (CTPA) did not show PE. Recurrent VTE was diagnosed and DOAC was switched to enoxaparin in a therapeutic dose based on body weight twice a day on the recommendation of a cardio-oncologist. At the 2-month Follow-up (FU), subtotal recanalization in both lower limbs was confirmed by CUS.

A 49-year-old woman with breast cancer (ductile, stage IIIA, hormone-dependent, Luminal type B) received radical mastectomy, four cycles of chemotherapy (AC), followed by 12 T (paclitaxel), local radiotherapy, and hormonal therapy with Tamoxifen. The patient was referred to the outpatient Cardio-Oncology department for cardiac function monitoring. During the physical examination the cardio-oncologist paid attention to a slight enlargement of the left leg that otherwise had no other symptoms. A CUS demonstrated DVT of the left popliteal and femoral vein (Fig. 2A). The patient denied any risk factors that could have provoked VTE, since she had neither a history of previous cardiovascular or respiratory disease nor a history of PE or DVT. Therefore, treatment with rivaroxaban 15 mg twice a day was started. Two weeks later patient suddenly developed dyspnea and tachycardia. A CTPA showed segmental and sub-segmental thrombi in the right PA (Fig. 2B). Also, CUS found only a slight thrombi recanalization in the left popliteal and femoral veins. LMWH—enoxaparin in a dose of 1 mg/kg subcutaneously every 12 hours was prescribed. In a 2-month FU, CUS detected subtotal recanalization with normalization of blood flow in the deep veins of the left leg (Fig. 2C). The patient was switched to DOAC therapy with 5 mg of apixaban, twice daily. The patient remained stable up to the 6-month FU.

A 71-year-old female, with non-Hodgkin mantle cell lymphoma, stage IVB, with involvement of thoracic, mediastinal, retroperitoneal lymphatic nodes and pleura was referred to Cardio-Oncology Center. Prior to cancer treatment, the risk of VTE was 1 point per Khorana’s score. After the third RB (rituximab+bendamustine) course she demonstrated grade 4 neutropenia, a high temperature of 39 °C, sudden dyspnoea, and weakness. Pneumonia signs and right pleural effusion were detected on X-ray. She received antibacterial therapy and steroids and underwent thoracentesis. However, the patient’s condition continued to deteriorate: she suffered from dyspnea, tachycardia, chest pain, edema of the legs, and heart failure (HF) signs (New York Heart Association, NYHA III). Electrocardiogram showed sinus tachycardia with a heart rate (HR) of 105 bpm. Transthoracic echocardiogram demonstrated a slightly dilated right ventricular with mildly reduced systolic function and left ventricle ejection fraction (EF) was 53%. Troponin I level was normal (0.015 ng/mL), while D-dimer elevated at 11,000 ng/mL. PE was suspected. CTPA showed a large saddle embolus in the bifurcation of the pulmonary trunk, which extends to both lung arteries with embolization up to 60% (Fig. 3A), right-sided pleural effusion, and pneumonia signs. Lower-limbs CUS revealed occlusive thrombotic masses in the deep veins of both legs. PE of intermediate-low risk and DVT were diagnosed.

Anticoagulation with rivaroxaban 15 mg twice a day, antibacterial, and heart failure therapy were prescribed.

After a 1-month patient was referred to the Cardio-Oncology Center for decision-making for restart of cancer treatment. She was asymptomatic, HR 72 bpm, blood pressure (BP) 130/78 mm Hg, EF 57%, D-dimer—1500 ng/mL.

However, CTPA scan demonstrated non-resolved saddle embolus in PA with obstruction of 50%. Lower-limb CUS showed only 10% recanalization and floating thrombus (Fig. 3B).

DOAC-resistant VTE was diagnosed and LMWH (enoxaparin 1 mg/kg subcutaneously every 12 hours) was prescribed. Additionally, we performed laboratory analysis for thrombophilia (protein C, protein S, antithrombin deficiency, and Factor V Leiden mutation), and no abnormalities were found.

She was scheduled for a follow-up examination in one month of the treatment period with enoxaparin. The patient demonstrated no PE signs on computed tomography (CT), and partial (60%) recanalization of DVT by lower-limb CUS. By the Cardio-oncology team’s decision, the patient was switched to another DOAC - apixaban. At the 3-month follow-up subtotal recanalization in both lower limbs was confirmed by CUS (Fig. 3C). The patient remained stable throughout the 6-month FU.