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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 501-516

Cancer thrombosis: Narrative review


Department of Medical Oncology, Tata Memorial Hospital and Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission10-Jan-2020
Date of Decision31-Mar-2020
Date of Acceptance13-May-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Kumar Prabhash
Tata Memorial Hospital, Parel, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_18_20

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  Abstract 


Venous thromboembolism (VTE) is a common disease in patients with cancer and carries a poor prognosis. Although the exact incidence of VTE in patients with cancer lies between 10% and 40%, it is prevalent in a substantial number of patients, either before starting treatment or during the treatment. Vitamin K antagonists have been traditionally used as the preferred agents for the treatment of VTE. However, multiple studies have revealed that low-molecular-weight heparin (LMWH) is a better alternative for controlling and treating the thrombotic process. Direct oral anticoagulants (DOACs) have aroused considerable interest ever since their introduction. Despite the higher risk of bleeding associated with DOACs, patients prefer taking an oral tablet over parenteral therapy. The data from direct comparative studies are slowly emerging but are currently in favor of LMWH as compared to DOACs. However, in certain scenarios, such as renal failure and thrombocytopenia, other drugs should be considered before prescribing LMWH. Here, we have tried to analyze the current treatment strategy for cancer-associated thrombosis by reviewing articles, studies, and the guidelines based on them. We searched in MEDLINE for articles related to thrombosis and anticoagulation in patients with cancer, published between January 2000 and May 2020, with the full text available in the English language.

Keywords: Cancer-associated thrombosis, direct oral anticoagulants, low-molecular-weight heparin, Vitamin K antagonists


How to cite this article:
Munot PN, Noronha V, Patil V, Joshi A, Menon N, Prabhash K. Cancer thrombosis: Narrative review. Cancer Res Stat Treat 2020;3:501-16

How to cite this URL:
Munot PN, Noronha V, Patil V, Joshi A, Menon N, Prabhash K. Cancer thrombosis: Narrative review. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Oct 25];3:501-16. Available from: https://www.crstonline.com/text.asp?2020/3/3/501/295535




  Introduction Top


Thrombotic presentation is a common phenomenon that confers a poor prognosis with a high fatality rate, especially in patients with cancer. It is the third most common cause of death due to cardiovascular disease, following acute coronary syndromes and stroke.[1] Several risk factors such as obesity, the use of hormonal pills, and immobility have been associated with venous thromboembolism (VTE); cancer is a common and an important risk factor. Armand Trousseau, a famous pathologist, was the first to point out the correlation between thrombosis and cancer in the year 1865. Ironically, he was diagnosed with gastric cancer after developing similar symptoms later in his life.

Patients with cancer are generally in a state of high hemodynamic stress due to the rapid proliferation of the malignant clones of cancerous cells and their circulation in the blood, with many prothrombotic and hypercoagulable factors working simultaneously, thus providing a suitable niche for thrombosis. Cancer affects all the three components of the Virchow triad – hypercoagulability, stasis, and endothelial injury. Several studies have emphasized that thrombosis is very common in patients with cancer, making it the second most common cause of mortality in these patients after cancer itself.[2]

Low-molecular-weight heparin (LMWH) has become the main treatment strategy for thrombosis, largely based on the positive results of studies comparing LMWH with Vitamin K antagonists (VKAs).[3] However, bleeding along with the long duration of treatment with a non-oral route of administration has led to a low proportion of patients completing the 6-month-long treatment course. In the Indian setting, a large proportion of patients take VKAs for the treatment of cancer-associated thrombosis (CAT) because of the need of daily non-oral administration of the LMWH and the associated logistic issues. In this context, the direct oral anticoagulants (DOACs) have emerged as an interesting and simpler option due to the ease of administration and a reduced need for monitoring. In this article, we aim to review the current treatment strategy for cancer-associated thrombosis.


  Materials and Methods Top


We searched the MEDLINE database for randomized controlled trials, meta-analyses, clinical trials, practice guidelines, and systematic reviews on cancer, published between January 2000 and May 2020, with full text available in the English language. The following search terms were used and combined: Cancer thrombosis, anticoagulant treatment, anticoagulant therapy, low molecular weight heparin, enoxaparin, dalteparin, venous thromboembolism, venous thrombosis, deep venous thrombosis, vitamin K antagonists, warfarin, tinzaparin, direct oral anticoagulants, apixaban, rivaroxaban and edoxaban. We excluded articles from the review if they were (1) meeting abstracts not subsequently published in peer-reviewed journals; (2) editorials, commentaries, letters, news articles, case reports, or narrative reviews; (3) not published in the English language; and (4) not related to the topic of discussion. We screened a total of 410 articles, of which 4 were excluded for duplication and 49 were found to be relevant to the topic of discussion and were included in this review [Figure 1].
Figure 1: Flowchart of the study selection process for the review on cancer-associated thrombosis

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  Epidemiology Top


CAT accounts for about 20% of the newly diagnosed cases of VTE.[4] Even among patients with no known cause of thrombosis, many are diagnosed with some form of cancer within 12 months of the diagnosis of thrombosis.[2],[5] Patients with cancer who develop thrombosis have a high risk of mortality within the first 6 months of diagnosis of thrombosis.[6],[7] Even in patients treated with anticoagulants, there is an increased risk of VTE recurrence in the early months of discontinuation of therapy, as the inciting cause is often not eliminated from the body. This risk can be about 2–3 times higher in patients with cancer than in those who develop VTE without underlying cancer.[6],[8]


  Risk Factors Top


The following patient characteristics increase the risk of CAT: adulthood, female sex, medical comorbidities, high body mass index, immobility, and previous VTE history.[9] Chemotherapy in patients with cancer further increases the risk of thrombosis, over and above the risk conferred by the cancer itself.WW[2],[10],[11] According to the study by Blom, patients receiving chemotherapy have a 2.5 times higher risk of developing thrombosis.[12],[13] Other contributing factors for the development of CAT are prolonged immobilization due to the disease or its associated complications, prolonged central venous catheterization, and repeated and frequent intravenous access.[14] However, the exact incidence of CAT remains elusive because of the multiple factors acting simultaneously or sequentially, one after another, adding to the eventual risk of thrombosis. Different populations have a differing baseline thrombosis risk that depends on the race, color, sex, heredity, and other factors.

The anatomical location, stage, aggressiveness, histology, and the type of malignancy influence the occurrence of CAT.[15],[16] Pancreatic, gastric, and lung cancers have a greater association with CAT.[17],[18] Different forms of cancer treatments such as surgery, radiation, conventional chemotherapy, hormonal agents, and immunomodulatory agents have a different risk of thrombosis.[19],[20] The incidence of thrombosis is high early in the diagnosis of cancer not only because of the aggressive disease biology and the performance status of the patient, but also because of the multiple interventions performed initially for the diagnosis and staging of cancer.[21]

Considering these factors, it is necessary to stratify cancers according to their risk of CAT so that adequate and timely measures can be taken, keeping a close watch for complications. Khorana et al. developed a simple algorithm to predict the risk of thrombosis in patients with cancer, based on the cancer type, hematological parameters, and physiological characteristics of the patient [Table 1].[22] Over a period of time, the criteria for risk stratification have been modified to include the p-selectins or D-dimers,[23] leading to various updated algorithms, but none are as easy and reproducible.
Table 1: Khorana score: A risk assessment tool to calculate the risk of developing thrombosis in outpatients with cancer

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  Anticoagulants for Cancer-Associated Thrombosis Top


Low-molecular-weight heparin

Since the last couple of decades, warfarin has been the main treatment modality for CAT. The problem with the use of warfarin is the requirement for frequent monitoring of prothrombin time/international normalized ratio (PT/INR) because of the narrow therapeutic window and several drug–drug interactions (DDIs). Complications associated with the use of warfarin are a risk of major bleeding and altered drug levels of concomitant medications. A sizeable number of patients do not respond to warfarin because of either compliance issues or genetics or drug interactions with associated treatments. Hence, there was an utmost need to find an alternative, which was not only better in terms of disease control and treatment, but also in terms of side effects and tolerance.

The comparison of LMWH with oral anticoagulants was first reported in 2003 in the study comparison of LMWH vs. oral anticoagulant therapy (CLOT), a randomized controlled trial in 676 patients with cancer and acute symptomatic proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Patients were randomized to receive dalteparin 200 IU/kg subcutaneously once a day for 5–7 days along with warfarin (target INR of 2.5) for 6 months versus dalteparin alone (200 IU/kg subcutaneously once daily for a month, followed by 150 IU/kg subcutaneously once daily for 5 months). The CLOT study showed a 55% reduction in the risk of recurrent venous thrombosis in patients with cancer taking dalteparin compared to those taking warfarin (8% in the dalteparin arm vs. 15.8% in the warfarin arm; hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.3–0.77; P = 0.002). There was no statistically significant increase in the risk of major bleeding in the dalteparin arm compared to the warfarin arm (5.6% in dalteparin arm vs. 3.6% in warfarin arm; P = 0.27). This study paved the way for further studies to be conducted on CAT.[3]

In the Phase III randomized comparison of acute treatments in cancer hemostasis trial (CATCH) that compared tinzaparin with warfarin, patients treated with tinzaparin had a numerically reduced risk of VTE recurrence than those treated with warfarin (7.2% in the tinzaparin arm vs. 10.5% in the warfarin arm; HR, 0.65; 95% CI, 0.41–1.03, P = 0.07), which was not statistically significant. The risk of major bleeding was not statistically significantly higher in the patients treated with tinzaparin (2.7% in the tinzaparin arm vs. 2.4% in the warfarin arm; P = 0.77).[24]

Subsequent studies proved that LMWH is superior to warfarin for the treatment of CAT as well as in reducing the risk of further VTE recurrence.[25],[26] Hence, most of the guidelines recommend LMWH as the drug of first choice in patients with CAT. The downsides of using LMWH as a treatment modality are that it requires self-injection and has safety concerns in case of renal failure and thrombocytopenia among others. A meta-analysis of various randomized studies showed a 44% reduction in the risk of recurrent VTE in patients on LMWH compared to those on warfarin (relative risk [RR], 0.56; 95% CI, 0.43–0.74), without a statistically significant increment in the risk of major bleeding.[27]

Direct oral anticoagulants

DOACs are drugs that directly act on the coagulation cascade and inhibit specific clotting factors, such as factor Xa (apixaban, rivaroxaban, and edoxaban) and factor IIa, also known as thrombin (dabigatran).

In the RE-COVER I and RE-COVER-II trials conducted in 2009 and 2014, respectively, dabigatran, a DOAC, was compared with warfarin after acute parenteral anticoagulation for 5 days. Among the 4886 patients cumulatively recruited in the two studies, there was no significant difference in the VTE recurrence risk (2.4% in the dabigatran arm vs. 2.1% in the warfarin arm; HR, 1.09; 95% CI, 0.76–1.57). The difference in the risk of major bleeding was also not significantly different between the two groups (1.6% in the dabigatran arm vs. 1.9% in the warfarin arm; HR, 0.73; 95% CI, 0.48–1.11).[28],[29]

Studies comparing rivaroxaban and warfarin in VTE (EINSTEIN-DVT) and rivaroxaban and warfarin in PE (EINSTEIN-PE), apixaban as first-line therapy in deep-vein thrombosis (DVT) and PE (AMPLIFY), and edoxaban versus warfarin in VTE (Hokusai VTE) also reported similar results, with DOACs being noninferior to warfarin in terms of safety, side effects, and efficacy [Table 2].[30],[31],[32],[33] A meta-analysis of the studies comparing DOACs with warfarin was conducted by Vedovati et al.[34] They observed that 3.9% of the patients using DOACs had VTE recurrence, whereas recurrence was observed in 6% of those using warfarin. Even though there was a reduction in the recurrence rates in the DOACs group, this was not statistically significant (odds ratio, 0.63; 95% CI, 0.37–1.10). Van Es et al. conducted another meta-analysis, and their results were consistent with those of the previous study.[35] Thus, DOACs are noninferior to VKA in terms of efficacy and side effects.
Table 2: Different randomized controlled trials for the treatment of cancer-associated thrombosis

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All of the above studies have some shortcomings. These studies compared DOACs to warfarin even though there is adequate proof to suggest that LMWH is better than warfarin for the treatment of VTE. Moreover, the definition of active cancer in all the studies was variable. Some studies included patients with recently diagnosed VTE, whereas others included patients with ongoing treatment for cancer or patients who had completed treatment. In addition, the patient cohorts in the DOAC studies were relatively healthy and had a better performance status than those of the patients in the CLOT and CATCH studies.[24],[36] As a result, clinical practice guidelines continue to recommend LMWH as the frontline therapy for the management of CAT.[3]


  Direct Oral Anticoagulant Versus Low-Molecular-Weight Heparin Top


Yhim et al.[37] performed a prospective study including patients with similar characteristics as those included in the CLOT and CATCH studies, to investigate the efficacy of rivaroxaban in patients with active cancer. Of the 124 patients during the 6-month study period, 7 patients experienced symptomatic recurrent VTE (5.9%). Major bleeding events occurred in 6 patients (5.3%) and Clinically relevant non-major (CRNM) bleeding events in 11 patients (10.2%). Twenty-eight patients (overall mortality, 24%) died.

New studies have compared LMWH with DOACs. The Hokusai VTE study was one of the earliest studies to compare LMWH with DOACs, and indicated that the usage of edoxaban or dalteparin was not significantly different in terms of outcomes and complications.[38] The study included 1406 patients with cancer, either diagnosed or treated within the last 24 months. They randomized patients with acute symptoms and breathlessness to receive LMWH for 5 days, which was followed by dalteparin or edoxaban. Edoxaban was initiated at 60 mg orally daily, with adequate renal corrections and administered for 6 months. Dalteparin was given at 200 U/kg subcutaneously for 1 month followed by 150 U/kg subcutaneously daily with a maximum dose of 1800 U/day for the next 5 months. Low platelet counts led to reductions in the dalteparin dose. The study showed noninferiority between DOACs and LMWH (HR, 1.01; 95% CI, 0.69–1.46; P = 0.02) in terms of a composite endpoint of recurrent VTE and major bleeding. Furthermore, the incidence of VTE recurrence did not differ between the two groups (12.8% in edoxaban vs. 13.5% in dalteparin; HR, 0.97; 95% CI, 0.70–1.36; P = 0.006), but major bleeding was more common in the DOAC group (HR, 1.77; 95% CI, 1.03–3.04; P = 0.04). As seen in other studies on DOACs, the most common sites of bleeding complications were the upper gastrointestinal (GI) and genitourinary tracts.

The SELECT-D trial compared 406 patients with CAT treated with either dalteparin or rivaroxaban. During the 6-month treatment period, patients received either rivaroxaban 15 mg orally twice daily for 3 weeks and then 20 mg orally daily, or dalteparin 200 IU/kg subcutaneously daily for 1 month and then 150 IU/kg subcutaneously daily. Doses of both the drugs were changed or discontinued for a low platelet count or various levels of renal impairment. The recurrence rate of VTE in the dalteparin group was higher than that in the rivaroxaban group (11% in dalteparin group; 95% CI, 7%–16% vs. 4% in rivaroxaban group; 95% CI, 2%–9%). The risk of major bleeding was not significantly different between the two groups, but rivaroxaban was associated with a higher risk of CRNM bleeding, mostly GI or urologic.[39]

The Caravaggio study was a randomized study that compared apixaban with dalteparin in patients with symptomatic or incidental DVT or PE and found oral apixaban to be noninferior to subcutaneous dalteparin (HR, 0.63; 95% CI, 0.37–1.07; P < 0.001 for noninferiority). Major bleeding was seen in 3.8% of the patients in the apixaban group and 4% in the dalteparin group; the difference was not statistically significant.[40]

A meta-analysis of studies comparing the DOACs with LMWH has recently been published, which showed a reduced incidence of recurrent VTE at 6 months (odds ratio, 0.65; 95% CI, 42–1.01) but with an increased risk of major bleeding at 6 months (odds ratio, 1.74; 95% CI, 1.05–2.88).

Thus, DOACs appear to be an alternative to LMWH for CAT, with an increased risk of major bleeding.[41]


  Parenteral Anti-Factor Xa (Fondaparinux) Top


Fondaparinux is a synthetic pentasaccharide that acts by binding to antithrombin and increasing its inhibitory effect against factor Xa by a factor of approximately 300. Exclusive studies of the use of fondaparinux in patients with cancer are not available. A subgroup analysis of 237 patients with cancer in the Matisse-DVT trial, which compared fondaparinux to enoxaparin for the initial treatment of symptomatic DVT (at least 5 days or until therapeutic INR of 2 or higher on VKA), showed that the 3-month recurrent VTE rates were 12.7% in the fondaparinux-treated patients versus 5.4% in the patients treated with enoxaparin, for an absolute difference of 7.3% (95% CI, 0.1%–14.5%, P = 0.046). Major bleeding rates in patients with cancer during the entire study period were 7.1% in the fondaparinux group versus 7.2% in the enoxaparin group, for an absolute difference of −0.1% (95% CI, −6.7%–6.5%, P = 0.99).[42]

Another subgroup analysis of 240 patients with cancer in the Matisse-PE study (which compared intravenous unfractionated heparin [UFH] to subcutaneous fondaparinux for initial treatment of PE, i.e., for at least 5 days or until INR was over 2 on VKA) reported that recurrent VTE rates were 8.9% for patients who received fondaparinux versus 17.4% in the UFH group, for an absolute difference of −8.3% (95% CI, −16.7%–0.1%, P = 0.054). Major bleeding rates in patients with cancer during the entire period were 3.6% in the fondaparinux group versus 6.3% in the UFH group, for an absolute difference of −2.7% (95% CI, −8.1%–2.7%, P = 0.33).[42] Thus, fondaparinux is noninferior to LMWH or UFH in terms of anticoagulation and is an alternative to it.


  Upper Extremity and Catheter-Related Venous Thromboembolism Top


The previous Canadian consensus recommendations suggested that catheter-related cancer-associated DVT required treatment if the thrombus involved the deep veins (such as the axillary and subclavian) or more proximal veins.[36] No head-to-head trials have compared the various types of anticoagulation in such patients. In a study on 74 patients with cancer with upper limb DVT that aimed to look at catheter survival, treatment with dalteparin and warfarin was shown to be safe and effective, with a recurrence rate of 0% and a major bleeding event rate of 4% at 3 months.[43] A study on 89 patients treated with a complete dose of LMWH followed by smaller doses showed no evidence of new-onset recurrent VTE.[36] A prospective cohort study evaluating rivaroxaban monotherapy on 70 patients with cancer demonstrated a VTE recurrence rate of 1.43%, including one fatal PE and a total bleeding event rate of 12.9% at 12 weeks.[44]

Thus, treatment alternatives for patients with cancer who have catheter-related upper-extremity DVT include warfarin, LMWH monotherapy, and DOACs. Based on the evidence available, the consensus favors therapeutic-dose LMWH monotherapy over DOACs and warfarin.

There are no specific guidelines for the duration of anticoagulation in this group of patients, although previous guidance has suggested continuation of anticoagulation for at least three months, and in patients with ongoing risk factors, for the entire duration that the catheter remains in place.[45]


  Incidental DVT Top


It is very common to detect incidental DVT during the evaluation for cancer.[46],[47] As many as 40% of the VTE cases can be an incidental finding.[48],[49] There is no difference in outcomes between patients with symptomatic and incidental VTE, which has been noted in retrospective and prospective studies.[50] As a result, most major guidelines currently recommend treatment of incidental VTE with anticoagulation.

Nevertheless, some uncertainty remains in the treatment of clinically insignificant thrombosis. Studies have indicated that subsegmental PE without DVT, if not treated with anticoagulation, does not have an increased risk of recurrent or fatal PE.[51] Therefore, when using anticoagulants in such patients, one should consider an increased risk of bleeding.


  Duration of Anticoagulation Top


Anticoagulation can be started with LMWH, UFH, fondaparinux, or rivaroxaban. LMWH is preferred over UFH for the initial 5–10 days for newly diagnosed VTE without severe renal impairment (creatinine clearance [CrCl] <30 ml/min).[52] The minimum duration of anticoagulation required for acute DVT and PE is for 6 months. For anticoagulation, LMWH or DOACs are preferred over VKAs, as they are superior. However, VKAs can be considered in cases where LMWH or DOAC is inaccessible or unavailable. For patients with active cancer and those receiving chemotherapy, anticoagulation can be extended beyond 6 months, and it has to be intermittently reviewed to assess the risk–benefit profile. The decision regarding further use of anticoagulation is based on the type of cancer, the recurrence risk, plan for further treatment, and condition of the patient.[53],[54] Cancer-related VTE has a higher recurrence rate as well as higher chances of bleeding. Hence, the duration of anticoagulation must be chosen carefully.[53]

Stopping the therapy increases the chances of recurrence, whereas continuing it increases the chances of bleeding complications. There was a 6%–7% cumulative risk of recurrence of thrombosis in the CLOT and CATCH trials. The DOAC trials reported a 2.6%–5.8% cumulative incidence of thrombosis recurrence during treatment. The risk of bleeding in the CLOT study was about 6% and that in the CATCH study was about 2.5%. DOACs trials have shown a 2%–4% risk of major bleeding. Thus, it appears that the risk of bleeding while on the drug may be similar to the risk of recurrence of thrombosis on stopping the drug.

The DALTECAN study was done to determine the safety of dalteparin between 6 months and 12 months of treatment of patients with active cancers with acute DVT. The study evaluated patients at 1 month, 2–6 months, and 7–12 months for the risk of major bleeding and recurrent VTE.[55] The risk of recurrent VTE was highest in the 1st month of treatment with dalteparin (5.7%); it stabilized at about 3.4% between the 2nd and 6th months and increased to 4% thereafter. Similarly, the risk of major bleeding in the 1st month of treatment was 3.6%, which increased to 4.6% between the 2nd and 6th months and then decreased to 4.2% by the end of treatment. The Cancer-duration of anticoagulation based on compression ultrasonography study (DACUS), that examined the rate of VTE recurrence, classified the patients according to the presence of uncleared remnant VTE after 6 months of treatment with LMWH. The patients were randomized into 2 groups – patients in one group were given extended therapy for additional 6 months and the patients in the other group were not. The recurrence rates of VTE were 18.48% and 21.95%, respectively, in the two groups. Prolonging the duration of therapy did not decrease the risk of recurrent VTE (HR, 1.37; 95% CI, 0.7–2.5; P = 0.311).[56]

The Tinzaparin in Cancer-Associated Thrombosis beyond Six months (TiCAT) study, that was conducted in Spain, evaluated VTE recurrence rates and the related major bleeding complications during extended tinzaparin treatment.[57] The incidence of VTE recurrence with tinzaparin treatment was 4.5% (95% CI, 2.2–7.8) from 1 to 6 months and 1.1% (95% CI, 0.1–3.9) from 7 to 12 months. The rate of clinically relevant bleeding during months 1–6 and 7–12, was 0.9% (95% CI, 0.5%–1.6%) and 0.6% (95% CI, 0.2%–1.4%) (P = 0.5), respectively; the difference was not statistically significant. This study demonstrated the safety of the extended use of anticoagulation in patients, similar to the other studies. Therefore, patients can be given LMWH for an extended period, if required. However, additional studies are required to establish appropriate guidelines to determine the exact duration of anticoagulation in CAT.


  Recurrent Venous Thromboembolism in Patients on Anticoagulation Top


The most common cause for recurrent VTE is the lack of compliance; other causes include temporarily stopping anticoagulation for surgery, heparin-induced thrombocytopenia, and malignancy causing mechanical compression of the vessels. If recurrence occurs in patients on warfarin with INRs in the sub-therapeutic range, they should be treated with LMWH until the INR reaches the therapeutic range again; the possible reasons for subtherapeutic INR, including drug interactions, noncompliance, or increased Vitamin K intake, should be investigated.[58] If recurrence occurs on therapeutic-range INR, shifting to LMWH is recommended.[83] If recurrence occurs while the patient is on LMWH, options for treatment include increasing the dose of LMWH or changing the type of LMWH. Using an inferior vena cava (IVC) filter should be the last choice, as there is no proven survival benefit for using it.[59] For patients who can tolerate a high dose of LMWH and those with good renal function, increasing the dose of LMWH should be tried first.[60],[61] However, there are very few studies to validate this approach.


  Inferior Vena Cava Filters Top


Data on the efficacy and safety of IVC filters in patients with cancer thrombosis are limited. Rates of recurrent VTE up to 32% have been reported in patients with cancer treated with IVC filters.[62] In the PREPIC trial, 400 patients were randomized to receive IVC filters versus no filter, along with standard anticoagulation. The use of permanent IVC filters in conjunction with anticoagulation resulted in a decreased incidence of PE (6.2% vs. 15.1%; P = 0.008) with an increased risk of DVT (35.7% vs. 27.5%; P = 0.042) and no reduction in mortality at 8 years of follow-up (51.5% vs. 49%).[63],[42] Complications with the use of filters such as thrombosis of the IVC, device failure due to filter migration, fracture with embolization, and caval perforation raise further concerns about their use. Given the complications and lack of studies to support their efficacy, their use should be restricted to patients with acute VTE and contraindication to anticoagulation.


  Thromboprophylaxis Top


There are no direct trials evaluating thromboprophylaxis for inpatients in the cancer-only population. However, reduced mobility and additional risk factors, such as age, infections, cancer itself, and the site of cancer, confer an increased risk of thrombosis in patients with cancer. The recent American Society of Clinical Oncology (ASCO) guidelines recommend using prophylaxis in oncology inpatients with a Khorana score of 2 and above and those with additional risk factors. Those patients admitted only for minor procedures or chemotherapy infusion should not be offered thromboprophylaxis.

In terms of outpatient thromboprophylaxis, a 2016 Cochrane review done by Di Nisio et al. showed that LMWH reduced the risk of VTE by half (RR, 0.54; 95% CI, 0.38–0.75) compared to no thromboprophylaxis (2.81% in those with LMWH thromboprophylaxis vs. 5.99% in those without prophylaxis).[64] A meta-analysis by Hernandez et al. found that LMWH reduced the risk of VTE by almost half, but there was no difference in the overall survival.[65] The apixaban for the prevention of venous thromboembolism in high-risk ambulatory cancer patients (AVERT) study assessed the role of apixaban (2.5 mg orally twice a day) in 574 ambulatory patients with cancer starting chemotherapy, who had a Khorana score of 2 or greater. They observed that symptomatic VTE occurred in 4.2% of the 288 patients in the apixaban arm and 10.2% of the 275 patients in the placebo arm (HR, 0.41; 95% CI, 0.26–0.65; P < 0.001). Major bleeding occurred in 3.5% and 1.8% in the apixaban and the placebo arms, respectively (HR, 2.00; 95% CI, 1.01–3.95; P = 0.046).[66] The CASSINI trial assessed rivaroxaban (10 mg orally daily) in ambulatory patients with cancer started on chemotherapy, with a Khorana score of 2 or higher. They observed that VTE occurred in 6.2% of 420 patients in the rivaroxaban arm and 8.8% of 421 patients in the placebo arm (HR, 0.66; 95% CI, 0.40–1.09; P = 0.10). Major bleeding was seen in 2% and 1% of the patients in the rivaroxaban and placebo arms, respectively (HR, 1.96; 95% CI, 0.59–6.49).[67] The current ASCO guidelines recommend cancer thromboprophylaxis on an outpatient basis in high-risk patients (Khorana score of 2 or higher prior to starting a new systemic chemotherapy regimen) after adequate discussion with the patient about the risks and benefits and uncertainty of the duration of thromboprophylaxis.

Vedovatiet al. evaluated a subset of patients with cancer (n = 954), who underwent major abdominal surgery and demonstrated that the rate of VTE in patients who received fondaparinux for 5–9 days (2.5 mg per day) was 4.6%, whereas the rate of VTE in patients who received dalteparin (5000 units per day) was 6.1%; the RR reduction was 24.6% (95% CI, −9%–47.9%), and the incidence rate of major bleeding was 3.4% versus 2.4% (P = 0.355).[63]

All patients undergoing major surgical interventions should be offered thromboprophylaxis, either with UFH or with LMWH. For patients undergoing major surgery, the prophylaxis should be continued for at least 7–10 days, whereas an extended prophylaxis for 4 weeks postoperatively is advised after a major open or laparoscopic abdominal or pelvic surgery with high-risk features such as obesity or a previous history of VTE.[68],[69]

Mechanical thromboprophylaxis, like intermittent pneumatic compression, is indicated only when oral or parenteral forms cannot be given or as an add-on to LMWH/DOAC therapy, when these are inadequate.[59],[70] However, major studies regarding the use of mechanical thromboprophylaxis are missing. Moreover, these agents should never be used as monotherapy. Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should be offered pharmacologic thromboprophylaxis with either aspirin or LMWH for low-risk patients and LMWH for high-risk patients.[71],[72]


  Dosing of Anticoagulants Top


The recommended doses and regimens for management of CAT are detailed in [Table 3].[73]
Table 3: Recommended anticoagulant regimens for venous thromboembolism prophylaxis and treatment in patients with cancer

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  Summary of Management of Cancer-Associated Thrombosis Top


The management recommendations for patients with CAT and their doses are detailed in [Table 4].[74]
Table 4: Therapeutic recommendations for venous thromboembolism in cancer

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  Special Conditions Top


Renal failure

About 40%–50% of patients with cancer develop some degree of renal dysfunction[75],[76] at some point in their life, either as a complication of the disease itself or because of the use of drugs and comorbidities such as hypertension and diabetes. The chances of developing renal dysfunction are higher in patients with cancer than in those with other chronic diseases or in normal individuals. Managing patients with renal failure and CAT requires active vigilance and close monitoring of the disease. The first-line anticoagulant in this setting has not yet been decided based on the studies. LMWH is excreted via the kidneys, while the liver excretes UFH.[77] Renal impairment can lead to the accumulation of LMWH in the body, thereby increasing the chances of complications due to LMWH. The CATCH trial included some patients with renal dysfunction (CrCl <60 ml/min) and noted that the risk of major bleeding was higher in patients with renal dysfunction than those with normal renal function (6.1% vs. 2%; RR, 2.98; 95% CI, 1.29–6.90). However, the difference in the risk of major bleeding was not statistically significant between patients given LMWH and those given VKA (4.3% vs. 8.1%).[78] The DALTECAN study also concluded that renal impairment did not affect the rate of major bleeding. As an implication of these results, LMWH can be considered an appropriate anticoagulant for patients with cancer who have renal dysfunction.[79] However, in severe renal dysfunction, the risk of major bleeding is twice that for patients with normal renal function.[80] In contrast, all DOACs are excreted mainly via the kidneys; therefore, the use of DOACs in patients with renal impairment requires more clinical attention toward complications. Direct factor Xa inhibitors are dependent on renal elimination for 20%–40% of their clearance.[81] In the AMPLIFY, EINSTEIN-DVT, and EINSTEIN-PE trials investigating apixaban and rivaroxaban, there was no increase in the risk of bleeding in patients with renal impairment.[30],[31],[32] Similarly, in the Hokusai VTE trial, edoxaban did not increase the risk of bleeding in patients with renal impairment.[33] Therefore, direct factor Xa inhibitors can also be considered as a treatment option in patients with mild-to-moderate (CrCl <90 ml/min to >30 ml/min) renal impairment, as shown in these major clinical trials.

On the other hand, dabigatran is excreted by the kidneys.[56] The RE-COVER study of dabigatran in patients with VTE indicated that renal impairment was associated with an increased risk of major bleeding complications (2.45% vs. 0.49%). Based on these results, dabigatran should be avoided in patients with severe renal impairment.[28]


  Thrombocytopenia Top


Thrombocytopenia is another very common issue in patients with cancer. It can last for a brief duration or may be refractory. A low platelet count due to cancer treatment with chemotherapeutic agents is one of the most common reasons for thrombocytopenia in such patients. The incidence of chemotherapy-induced thrombocytopenia varies according to the type of cancer and the chemotherapy used.[82],[83] In patients with CAT, it is observed that thrombocytopenia increases the risk of bleeding, but does not reduce the risk of VTE recurrence.[84]

Currently, it is recommended that if the platelet count is over 50 × 109/L, full-dose anticoagulants can be given. There is a certain amount of uncertainty with regard to the platelet count that is acceptable for the use of anticoagulation, but for practical purposes, in patients with cancer, levels over 50 × 109/L are considered acceptable as per the major guidelines.[85] Low platelet counts due to chemotherapeutic agents should be supplemented to maintain the platelet count above the recommended level for the continued use of anticoagulation. The anticoagulant usage should not be interrupted, especially in the 1st month of diagnosis of cancer-induced thrombocytopenia, as the risk of thrombosis is highest during this period.[3] If repeated platelet transfusions are not feasible, it is advised to reduce the dose of LMWH to 50% and maintain the platelet count above 25 × 109/L.[53] Although it is not clear whether IVC filters are helpful, they can be considered in patients with severe thrombocytopenia and a high risk of recurrence of thrombosis and embolic phenomenon. The survival benefit of using an IVC filter is not clearly defined.

For patients with platelet counts between 25 × 109/L and 50 × 109/L, there are no clear answers as to what dose of LMWH should be used. DOACs in the face of thrombocytopenia is yet another aspect that needs additional studies and proper guidelines.


  Intracranial Malignancy Top


Limited data suggest that therapeutic anticoagulation does not increase the risk of intracranial hemorrhage (ICH) in patients with brain metastases, but may increase the risk among patients with primary brain cancer.[86] Preliminary data from retrospective cohort analysis suggest that DOACs may be associated with a lower risk of ICH than LMWH in patients with CNS malignancies.[87]


  Obesity Top


Studies using LMWH have indicated that dosing should be based on the patient's actual body weight.[88],[89] Bleeding risk does not appear to increase in obese patients. The data for DOAC usage in obese patients are not yet mature, but the use of standard dosing of DOACs is safe and efficacious in patients weighing up to 120 kg.[90] If DOACs have to be used in patients weighing more than 120 kg, the use of drug-specific peak and trough levels is suggested. If the levels are within the expected range, the use of DOACs is continued, else it is advised to change the anticoagulant.[90]


  Older Patients With Cancer Top


Although the prevalence of medical conditions carrying a thromboembolic risk is higher in older than in younger patients, the actual indications for anticoagulation are primarily the same in all age groups, and there are no data specifically focused on older patients with cancer. Advanced age (>75 years) itself is a risk factor for increased VTE. All older inpatients except those with low risk of VTE, like those admitted for minor surgical procedures and medical patients who are fully mobile, should be offered anticoagulant prophylaxis.[91] Unless there is an absolute contraindication, anticoagulation should be initiated at regular doses keeping in mind the weight and renal status. Anticoagulation should be continued for 6 months. Patients with active cancers should receive anticoagulation until their cancer is resolved.

[TAG:2]Drug–drug Interaction With Direct Oral Anticoagulants[92][/TAG:2]

Patients with cancer are generally treated with multiple anticancer therapies and many supportive medications, and an evaluation of the potential for DDIs is therefore important when selecting the appropriate anticoagulant therapy for CAT. It includes consideration of the potential direct toxicity and any potential pharmacokinetic interactions that might occur with the concomitant use of anticoagulant regimens or other drugs.[93]

All DOACs are metabolized by P-glycoprotein-related mechanisms. Apixaban and rivaroxaban are metabolized by cytochrome P450 3A4 (CYP3A4), whereas edoxaban and dabigatran are not. [Table 5] provides a list of common DDIs associated with P-glycoprotein and CYP450 metabolism. However, the exact assessment of the drugs and their effects become complex when multiple drugs are used concomitantly, as one drug may have an opposing effect on the metabolism of another.
Table 5: Common drug-drug interactions with direct oral anticoagulants

Click here to view



  Monitoring of Therapy Top


Regular monitoring of PT/INR is required in cases where warfarin is used. An increased frequency of testing may be required following a change in dose, change in diet, intercurrent illness, and use of concomitant medications. The PT/INR is kept between 2 and 3 in cases where adequate anticoagulation is achieved with warfarin. For UFH, monitoring is done with activated partial thromboplastin time levels. The levels should be 1.5–2.5 times the control.[94] For LMWH, monitoring is generally not recommended. However, in patients with renal failure, extremes of weight, or in conditions with increased risk of bleeding, monitoring with anti-factor Xa levels may be done.[95] ASCO, in its recent guidelines, recommends using anti-factor Xa in patients with cancer with moderate-to-severe renal dysfunction (CrCl <60 ml/min), with appropriate dose modifications. However, monitoring is not required to achieve clinical efficacy or to predict the risk of bleeding, which is minimal with routine doses and normal renal function.[96] DOACs do not require regular monitoring except in cases where clinically significant bleeding occurs when specific drug levels may be monitored.


  Cost Implications Top


Discussion about the cost of treatment is an important part of counseling the patients. The impact of treatment and the benefits and risks of not treating VTE have to be clearly explained to the patients. Whenever possible and feasible, the less expensive option must be chosen, especially in a country like ours where finances are a privilege not available to many. A monthly estimate of treating VTE in our setup with VKA is approximately ₹100–150; for LMWH (enoxaparin), the cost is about ₹3000–3500, and that for rivaroxaban is around ₹4500. Hence, considering the differences and after proper discussion with the patient, an appropriate choice needs to be made.


  Conclusion Top


CAT is one of the very neglected and undertreated complications of cancer, which if addressed on time can lead to better survival and reduced mortality. Although LMWH is the preferred drug for treating CAT, the momentum is gradually shifting in favor of DOACs. Although more studies that directly compare LMWH with oral anticoagulants are still required, it is safe to say that an oral and equipotent regimen will always be preferred over a parenteral regimen. Until such a time though, LMWH should be the go-to regimen if there are no direct absolute contraindications.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Materials and Me...
Epidemiology
Risk Factors
Anticoagulants f...
Direct Oral Anti...
Parenteral Anti-...
Upper Extremity ...
Incidental DVT
Duration of Anti...
Recurrent Venous...
Inferior Vena Ca...
Thromboprophylaxis
Dosing of Antico...
Summary of Manag...
Special Conditions
Thrombocytopenia
Intracranial Mal...
Obesity
Older Patients W...
Drug–drug ...
Monitoring of Th...
Cost Implications
Conclusion
References
Article Figures
Article Tables

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