Comparative analysis of enoxaparin versus rivaroxaban in the treatment of cancer associated venous thromboembolism: experience from a tertiary care cancer centre

Venous Thromboembolism (VTE) which broadly consists of deep vein thrombosis (DVT) and pulmonary embolism (PE) is associated with a poor prognosis in patients with cancer and remains a leading cause of mortality and morbidity [1]. Cancer patients are at 6 to 7 fold increased risk of venous thromboembolism (VTE) compared with age-matched controls corresponding to an annual incidence of about one thrombotic event per 200 active cancer patients [2]. Therefore adequate management of VTE is of utmost importance for clinicians involved in the care of cancer patients.

There has been substantial advances in the management of cancer associated thrombosis (CAT) in the last few decades. Low molecular weight heparin (LMWH) which was once considered the gold standard is no more the only treatment option available [3‐5]. Direct oral anticoagulants (DOACs) i.e. rivaroxaban, apixaban, and edoxaban which are taken orally and do not require laboratory monitoring have become an appealing alternate choice as oppose to LMWH which require daily subcutaneous injections. The initial literature on use of DOACs was drawn from meta-analysis evaluating randomized controlled trials (RCTs) with cancer subgroups i.e. RECOVER, AMPLIFY, Hokusai-VTE, EINSTEIN-PE & DVT. They drew conclusion that DOACs were non-inferior to LMWH in preventing recurrent VTE and are associated with similar bleeding rates [6‐11]. On the contrary its key criticism stems from the fact that only less than 7% of the study population in these RCTs had cancer.

More recently two randomized control trials (SELECT D & Hokusai VTE- Cancer) have emerged involving the use of DOACs versus LMWH in preventing cancer associated thrombosis [12, 13].These studies showed that DOACs were noninferior to LMWH in preventing recurrent VTE; however this is with increased risk of bleeding. In the randomized SELECT D trial, 203 patients were compared with dalteparin versus rivaroxaban. The VTE recurrence rate for dalteparin versus rivaroxban was 11% versus 4% respectively [HR 0.43 (0.19–0.9)]. However major bleeding risk for dalterparin versus rivaroxaban was 4% versus 6% respectively [HR 1.83 (068–4.96)]. In the randomized Hokusai VTE trial, 1050 patients were compared with LMWH for 5 days followed by oral edoxaban versus dalteparin. The VTE recurrence rate for dalteparin versus edoxaban was 11.3% versus 7.9% respectively. However major bleeding risk for dalterparin versus edoxaban was 4% versus 6.9% respectively.

Following these recent trials, American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) have revised their recommendations and have added the use of rivaroxaban and edoxaban for cancer associated thrombosis treatment [14, 15]. Although the recommendations for the use of DOACs have recently become popular in guidelines, they are still few and inconsistent across the current literature. In the absence of multiple large randomized controlled trials and dearth of literature in cancer population we designed a retrospective single center study to investigate the efficacy and safety profile of rivaroxaban over enoxaparin in preventing recurrent cancer associated thrombosis.

One of the population based study from Walker European Journal has shown a steady increase in the absolute rate of venous thrombosis from 10 VTE (per 1000 person-years) to 20 VTE (per 1000 person-years) from 1997 to 2007 in cancer patients; where as it has remained steady i.e. 4 VTE (per 1000 person-years) in non-cancer group [1]. This rise in cancer associated thrombosis poses a serious problem that diminishes the patient’s life span and quality of life. Hence identifying adequate management of cancer associated thrombosis is imperative especially when use of anticoagulation is complicated by a delicate balance between risk of recurrent VTE and major bleeding.

Our study showed the cumulative VTE recurrence risk in enoxaparin and rivaroxaban at 6 months is consistent with the current literature. However there was a non-significant increase in VTE recurrence in rivaroxaban as compared to enoxaparin. It was noted that while recurrent VTE estimate in enoxaparin arm was comparable with previous RCTs (HOKUSAI-VTE, HOKUSAI-VTE CANCER and SELECT D); there was higher recurrent VTE estimate in rivaroxaban arm when compared to current data. On analyzing our data we found out that 50.6% of our population indication for anticoagulation was PE while it was only 29.7% in Chaudhury et al. and 39% in Young et al.; explaining that our patient population was more at risk at baseline [16]. We also noted that our study had larger percentage of gastric (7.3% Vs 3%) and cervical cancer (6.6% Vs 3%); which studies have shown to also cause a higher rate of VTE recurrence [17]. We also separately analyzed the demographic details of each one of the 6 recurrent DVT patients in rivaroxaban arm and found that 4 of 6 had gastric or pancreatic cancer, low albumin, BMI less than 22 and shared co-morbid (Diabetes, Hypertension and Coronary Artery Disease). All of which explains low nutritional reserve resulting in poor gut absorption for oral anticoagulant and inconversely higher adverse outcomes. We also analyzed historically significant risk factors for VTE in cancer patients such as high platelet count, high leukocyte count, low hemoglobin level, high risk gastrointestinal, genitourinary and lung cancers. They were not found to be independently significantly associated with the risk of VTE recurrence [18].

Another important objective of our study was to evaluate the safety outcome i.e. to access rates of major bleeding and clinically relevant non-major bleeding (CRNMB). Our study showed comparable major bleeding and CRNMB rates in rivaroxaban and enoxaparin arm as shown in RECOVER/RECOVER-2. It is worth mentioning that the trends in bleeding rate are not consistent across trials [6, 19]. The bleeding rates in our study were strikingly higher (11% Vs 4–7%) when compared with previously observed rates and were mainly related to GI bleed. Although bleeding rates as high as 16% in enoxaparin plus warfarin arm in CANTHANOX 2002 study and 9% in enoxaparin in ONCENOX 2006 study were seen in prior studies; however, no study has shown bleeding rates higher than 7% (HOKUSAI-VTE Cancer) with DOACs.

Rivaroxaban is a factor Xa inhibitor which directly and reversibly binds to factor Xa and competitively inhibits factor Xa. It is 10,000 fold more selective for factor Xa and it does not require co-factors to exert its anticoagulant effect [20, 21]. It is plausible that the enhanced antithrombotic effects of rivaroxaban as opposed to LMWH which acts on factor X indirectly, is associated with a greater perturbation of coagulation and predisposing to more bleeding. We take this as a learning opportunity to consider modifying DOAC doses to best suit your patient’s needs depending on their demographic and disease specific details. When we individually analyzed 8 episodes of major bleeding with rivaroxaban in our study population we found out they were mainly in older population i.e. aged 65 years or higher with poor nutritional reserve i.e. low albumin, BMI less than 22 and had an advanced metastatic breast or prostate cancer.

Our study despite being a retrospective study and having limited number of participants provides solutions for real world situations. It is felt that despite availability of results from SELECT D & Hokusai VTE-Cancer trial our study still manages to highlight that “one size fits all” cannot be applied to all patients and physicians will need to use their best clinical judgement. We believe NOACs have a promising future in cancer associated VTE due to its ease in utilization and comparable results with LMWH in preventing recurrent VTE. However we are still concerned about its safety profile. Especially as our study showed higher rates of major bleeding with Rivaroxaban when compared to SELECT D & Hokusai VTE-Cancer trial. This is particularly true for complex cancer patients due to rivaroxaban’s unpredictable higher risk of GI bleeding, inability to measure anticoagulant activity by using standard essays, potential interaction with medicines and altered metabolism in renal dysfunction, hepatic metastasis and lack of antidote. In addition patients with gastric and pancreatic cancer who have undergone surgical resection will have altered gut absorption hence making rivaroxaban pharmacodynamics even more unpredictable.

We conclude that there was no significant difference seen between the efficacy and safety profile of enoxaparin and rivaroxaban in our cancer patient population. While rivaroxaban has recently become popular in cancer associated VTE due to its ease in utilization and comparable results with LMWH in preventing recurrent VTE. Attention also needs to be paid on patient’s disease specific details and demographics before favoring DOACs over LMWH.