Rivaroxaban versus enoxaparin for the prevention of recurrent venous thromboembolism in patients with cancer

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Introduction
Venous thromboembolism (VTE) is a very common comorbidity in patients with cancer. It is known that VTE comprises pulmonary embolism (PE) and deep venous thrombosis (DVT), and approximately 10% to 20% patients with PE or VTE have either active cancer or a history of cancer. [1,2] In patients with active cancer and VTE, low-molecular-weight heparin (LMWH) is recommended as the first-line treatment. [3] However, LMWH injections are inconvenient and patients are more willing to choose oral anticoagulants. Warfarin, the most used oral vitamin K antagonists (VKAs), has its natural drawbacks, such as frequent serum monitoring of international normalized ratio, high risk of bleeding, [4] and less time in therapeutic range. [5] Thus, new anticoagulation strategies for patients with cancer and VTE are needed. The advent of newer factor Xa inhibitors such as rivaroxaban might bring a new option.
Rivaroxaban has been shown to be as effective as VKAs for the treatment and prevention of VTE in the general population. [6] The number of cancer patients involved in previous studies is relatively small, [7][8][9] and evidence comparing rivaroxaban with LMWH remains limited. In this study, we collected currently available data to evaluate the efficacy and safety of rivaroxaban compared with enoxaparin, a most used LMWH, in patients with cancer and VTE.

Methods
An ethical approval is not necessary as this is a meta-analysis. We performed this study in accordance with the PRISMA statement. [10] Systematic Review and Meta-Analysis Table 1 Baseline characteristics of included studies and subjects. Data are mean ± SD, median (25%-75% quartile) or n (%). BMI = body mass index, NA = not available. terms were used in the search process: cancer or carcinoma and rivaroxaban. We also scanned the references lists of searched papers for potential eligible articles. No language restriction was applied. According to the predefined criteria, we included articles comparing enoxaparin with rivaroxaban in patients with cancer and VTE. Conference abstracts were excluded.

Data extraction
Two independent researchers extracted baseline data, including the number of patients, ages, and body mass index. Outcomes of interest in each group, such as recurrences of VTE (including DVT and PE), major bleeding, and deaths were recorded. Disagreements were resolved by consulting a third party.
Quality assessment of included studies was conducted using the Newcastle-Ottawa Scale.

Statistics
Risk ratios (RRs) and 95% confidence intervals (95%CIs) were calculated in Review Manager Software (Version 5.2; The Cochrane Collaboration, Oxford, United Kingdom), using the method of Mantel-Haenszel. The value of I 2 was used to show the heterogeneity across studies, a random-effects model was applied if I 2 >50%. Funnel plot was used to indicate the publication bias. P < .05 was taken as statistically significant.

Baseline characteristics
According to our predefined criteria, a total of 4 articles and 667 patients were included in the final analysis [8,9,11,12] (Flow Diagram). The majority of included articles (3 out of 4) were published in 2017. There were 369 and 298 patients in rivaroxaban and enoxaparin group, respectively. As shown in Table 1, the mean age of included patients was around 60 years, and median treatment duration ranged from 110 to 204 days.

Mortality
The mortality was 15.5% and 18.9% in rivaroxaban and enoxaparin group, respectively. No significant difference was

Discussion
This study comprises a relatively large number of selected patients and demonstrates that rivaroxaban is as effective and safe as enoxaparin for the prevention of recurrent VTE in patients with cancer. VTE is an independent risk factor for mortality and an important cause of death in patients with malignancy. [13] The disadvantages of LMWH and warfarin make new oral anticoagulants such as rivaroxaban an attractive option for cancer patients with VTE. However, there is a lack of strong evidence in favor of rivaroxaban administration in patients with cancer. To our best knowledge, this is the first metaanalysis comparing rivaroxaban to LMWH in patients with malignancy.
Our analysis showed that there was a trend towards decreased recurrent VTE in cancer patients treated with rivaroxaban compared those with enoxaparin. Although the difference did not reach statistical significance due to the limitation of sample size, we found that all the endpoints, including recurrence of VTE, incidence of major bleeding, and mortality were non-significantly lower in rivaroxaban group than in enoxaparin group. It is plausible to believe that future data will provide stronger evidence. However, in this stage, we may conclude that rivaroxaban is at least not inferior to LWMH for treatment and prevention of VTE in cancer patients, which offers an additional choice for patients cannot adhere to injections.
Our paper comprises several limitations. First, it was a metaanalysis based on observational studies. In the absence of a randomized controlled trial in this topic, our work might represent the highest level of evidence to date, and call for future large, randomized, well-designed trials to provide new insight. Second, the sample size was relatively small, with only 4 articles being included in the final analysis. So the result should be interpreted with some caution. Third, age is an important factor to predict risk of VTE. However, previous studies included have not compared the mean age of patients with VTE and active cancer with that of patients only with VTE. Future studies should take consider of this issue. Last, different types and stages of cancers will affect the results and conclusion of this study. However, not all included studies have classified the types or stages of cancers, and the limited sample size precluded us to conduct further sub-group analysis. More large, well-designed studies are needed to explore this issue.

Conclusion
Rivaroxaban is as effective and safe as enoxaparin for the prevention of recurrent VTE in patients with malignancy.
Rivaroxaban is a potential option for patients with cancer and VTE.