Real-World Analysis of the Safety and Effectiveness of Apixaban Therapy in Cancer Patients with Venous Thromboembolism in Saudi Arabia

: Purpose: This study was conducted to evaluate the effectiveness and safety of apixaban in patients with cancer for the treatment of venous thromboembolism (VTE) at a tertiary medical institution in Saudi Arabia. Methods: An observational retrospective cohort study was conducted on adult patients with cancer who were diagnosed with VTE and received apixaban therapy from August 2016 to October 2020. Results: A total of 478 patients were screened; 99 patients were included in the ﬁnal analysis. Of those included, 38 (38%) were female, 74 (77.1%) had a solid tumor, and 36 (36.4%) were receiving apixaban therapy due to developing proximal deep vein thrombosis (DVT), and the mean age was 58.59 ( ± 14.77). At six months, thrombotic events occurred in 11 patients (11.1%), and bleeding events occurred in 14 (14.1%) of the included individuals. Mortality occurred in 9 (9.09%) of the included individuals. Close to 32% individuals discontinued apixaban therapy at six months. Conclusion: The prevalence of recurrent VTE and bleeding events in patients with cancer using apixaban for treating VTE is in line with many other real-world studies but slightly higher compared to the patients enrolled in the Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer (CARAVAGGIO) trial.


Introduction
Venous thromboembolism (VTE) is a common complication in patients with cancer. Globally, it increases mortality by two to six-fold and is considered the most prevalent cause of mortality in cancer patients [1]. A single-center retrospective study conducted in Saudi Arabia between 2006 and 2017 showed that the incidence of VTE in cancer patients was four-fold higher compared to non-cancer patients. The most common types of cancer were lymphoma, followed by breast, colorectal, pancreatic, and hepatocellular cancers [2]. According to the National Comprehensive Cancer Network Guidelines on Cancer-Associated Venous Thromboembolic Disease, pancreatic, brain, stomach, kidney, uterus, lung, and genitourinary cancers were associated with the highest risk for increasing the rates of VTE [1]. Trials have shown that low-molecular-weight heparin (LMWH) was superior to warfarin in the secondary prevention of VTE among patients with cancer. Ever since then, LMWH has become the gold standard for treating cancer-associated thrombosis (CAT). Direct oral anticoagulants (DOACs) might represent an efficient alternative to LMWH. Several trials were conducted to evaluate the safety and efficacy of DOACs versus LMWH, such as Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism (HOKUSAI VTE Cancer), Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D), Apixaban and dalteparin in active malignancy-associated venous thromboembolism: The ADAM VTE trial (ADAM-VTE), and Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer (CARAVAGGIO) trials [3][4][5][6].
A meta-analysis of these trials showed that the risk of recurrent VTE was 32% lower in patients who received DOACs. In contrast, there was a 36% increase in the risk of major bleeding and a 63% increase in clinically relevant non-major bleeding (CRNMB) in patients who received DOACs. Mortality was comparable in both groups (RR, 0.96; 95% CI, 0.68-1.36) [7]. As a result of these trials, treatment guidelines now recommend DOACs as the first-line treatment option for patients without gastrointestinal or genitourinary CAT who also have a low bleeding risk. For patients with gastrointestinal or genitourinary CAT, LMWH is the most reasonable option since there is an increased risk of bleeding with DOACs [1,[8][9][10]. Although studies regarding the utilization of DOACs for the management of thrombosis in cancer patients are growing in number, there is a lack of real-world studies conducted in Saudi Arabia. Moreover, most of the landmark trials did not include patients from the Middle East. Therefore, this study aimed to evaluate the effectiveness and safety of apixaban therapy among patients with cancer and VTE in Saudi Arabia.

Materials and Methods
This was a single-center, retrospective cohort study conducted using the databases of all the Ministry of National Guard Health Affairs (MNG-HA) hospitals in Saudi Arabia. Institutional review board (IRB) approval was obtained from the King Abdullah International Medical Research Center (KAIMRC) (reference number: IRBC/0131/21). All cancer patients on apixaban from August 2016 through October 2020 were screened. We included all adult patients aged 18 years and above who had a regular follow-up in an inpatient or outpatient setting and were known to have an active or history of cancer (other than basal or squamous cell skin cancer) using the World Health Organization (WHO) International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), Chapter II: Neoplasms (C00-C97, Malignant neoplasms, and D00-D09, In situ neoplasms). We used the electronic hospital record system to extract detailed information for each patient.
We collected the following patient information: patient demographic, past medical history, indication of apixaban, dose of apixaban, initiation date of apixaban, interacting medications, prior use of anticoagulation therapy, and diagnosis of recurrent VTE or bleeding events. The list of interacting medications with apixaban was collected from the United States Food and Drug Administration (U.S. FDA) and the European Medicines Agency (EMA) package inserts. We excluded patients who were known to have documented adherence problems, could not be confirmed to have started the drug (despite the prescription), or had missing information. Patients who had undergone a thrombectomy, vena cava filter insertion, or thrombolysis, and those who had an unclear history of malignancy, creatinine clearance less than 30 mL/min based on the Cockcroft Gault equation or were receiving hemodialysis were also excluded from this study.
We also collected any documentation related to the clinical outcomes of a recurrent VTE event or bleeding event and recorded the type of event, onset of the event, death and discontinuation rate of apixaban, and reason for death and discontinuation. Patients were followed from the first prescription date until their discontinuation of apixaban, death, or the end of the study period. Bleeding events were included if they met the criteria for clinically relevant non-major or major bleeding according to the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Active cancer was defined as a diagnosis of new or recurrent or metastatic cancer within six months before the study inclusion or receiving treatment for cancer at the time of inclusion. History of cancer was defined as cancer diagnosis within two years before study inclusion.
The first endpoint of this study was to describe the effectiveness of apixaban therapy in cancer patients with VTE by estimating the recurrence of VTE within six months. The second endpoint was to describe the safety of apixaban therapy in cancer patients with VTE by estimating the incidence of bleeding events within six months. We also assessed the rate of deaths and discontinuation rate of apixaban and the reason for death and discontinuation.
All data collected were combined in an electronic data collection sheet using Excel version 16.58, 2019 (Microsoft, Redmond, WA, USA). The data were entered into the SPSS version 21 for Windows (SPSS) for analysis (IBM, Chicago, IL, USA). Descriptive analysis was used, categorical variables being reported as numbers and percentages, with continuous variables reported as mean (± standard deviation (SD) and 95% confidence interval (CI).

Demographic and Clinical Characteristics
A total of 475 patients were screened for inclusion during the study period. A total of 99 individuals met the inclusion criteria and were included in the final analysis as shown in Figure 1. Of the 99 included patients, 38 (38.4%) were female, and the mean age was 58.59 (±14.77). For most of the included patients, 85 (85.9%) had a baseline creatinine clearance of more than 50 mL/min as shown in Table 1. Regarding the type of cancer, 74 (74.7%) of the included individuals had a solid tumor as shown in Table 2. Of those included, 36 (36.4%) were receiving apixaban therapy due to developing proximal DVT. The most prevalent comorbid conditions in our cohort were hypertension and diabetes mellitus.
agnosis within two years before study inclusion.
The first endpoint of this study was to describe the effectiveness of apixaban therapy in cancer patients with VTE by estimating the recurrence of VTE within six months. The second endpoint was to describe the safety of apixaban therapy in cancer patients with VTE by estimating the incidence of bleeding events within six months. We also assessed the rate of deaths and discontinuation rate of apixaban and the reason for death and discontinuation.
All data collected were combined in an electronic data collection sheet using Excel version 16.58, 2019 (Microsoft, Redmond, Washington, USA). The data were entered into the SPSS version 21 for Windows (SPSS) for analysis (IBM, Chicago, IL, USA). Descriptive analysis was used, categorical variables being reported as numbers and percentages, with continuous variables reported as mean (± standard deviation (SD) and 95% confidence interval (CI).

Demographic and Clinical Characteristics
A total of 475 patients were screened for inclusion during the study period. A total of 99 individuals met the inclusion criteria and were included in the final analysis as shown in Figure 1. Of the 99 included patients, 38 (38.4%) were female, and the mean age was 58.59 (±14.77). For most of the included patients, 85 (85.9%) had a baseline creatinine clearance of more than 50 mL/min as shown in Table 1. Regarding the type of cancer, 74 (74.7%) of the included individuals had a solid tumor as shown in Table 2. Of those included, 36 (36.4%) were receiving apixaban therapy due to developing proximal DVT. The most prevalent comorbid conditions in our cohort were hypertension and diabetes mellitus.

Thrombotic and Bleeding Events
As shown in Table 3 and Figure 2, thrombotic events occurred in 11 (11.1%) individuals. Of these, four (36.4%) patients developed recurrent DVT, four (36.4%) patients developed recurrent Pulmonary embolism (PE), and one (9.1%) patient developed cerebrovascular events. All patients who developed recurrent DVT presented with proximal DVT. Three of the four patients who developed recurrent PE presented with segmental PE. In terms of the onset of VTE since apixaban initiation, seven (63.6%) patients developed recurrent thrombotic events within 0-3 months of apixaban initiation.

Thrombotic and Bleeding Events
As shown in Table 3 and Figure 2, thrombotic events occurred in 11 (11.1%) individuals. Of these, four (36.4%) patients developed recurrent DVT, four (36.4%) patients developed recurrent Pulmonary embolism (PE), and one (9.1%) patient developed cerebrovascular events. All patients who developed recurrent DVT presented with proximal DVT. Three of the four patients who developed recurrent PE presented with segmental PE. In terms of the onset of VTE since apixaban initiation, seven (63.6%) patients developed recurrent thrombotic events within 0-3 months of apixaban initiation.

Outcome
Number % Primary efficacy outcome   As shown in Table 3 and Figure 2, bleeding events occurred in 14 (14.1%) individuals. Of these, three (21.4%) patients developed major bleeding events, eight (57.1%) developed clinically relevant non-major bleeding events, and three (21.4%) developed clinically nonrelevant non-major bleeding events. Hematuria followed by upper gastrointestinal were the most commonly reported sites of bleeding.

Mortality and Apixaban Discontinuation
As shown in Table 3 and Figure 2, mortality occurred in 9 (9.09%) patients. Cancerrelated mortality was the most common etiology of mortality. Of the included individuals, 32 (32.32%) discontinued apixaban therapy. The most prevalent reason for discontinuation was developing thrombosis or bleeding events.

Discussion
To the best of our knowledge, this is the first study to be conducted in Saudi Arabia to evaluate the real-world rates of recurrent VTE and bleeding events within six months while on apixaban in patients with cancer and VTE. Overall, we observed higher rates of recurrent VTE and major bleeding events in our cohort compared to the patients enrolled in the CARAVAGGIO trial-11.1% versus 5.6%, respectively, and 21.4% vs. 3.8%, respectively [6]. This might be due to the fact that we included patients with higher Eastern Cooperative Oncology Group (ECOG) performance status.
The current study showed that 11.1% of our cancer patients had recurrent VTE, which is consistent with previous retrospective studies that showed the prevalence range between 0 to 15.8% during a follow-up period of 6 months. Also, our study showed that 14.1% of our cancer patients had a bleeding event, which is consistent with previous retrospective studies that showed a prevalence that ranges between 11.1% to 13.91% during a follow-up period of six months [11,12]. One study reported that 2.5% of patients have major bleed, and 11.4% have CRNM bleed. However, the percentages were higher in our study (21.4% and 57.1%, respectively) [12]. The major and CRNM bleed events in this study were also more frequent than those reported in the CARAVAGGIO trial (21.4% vs. 3.8%, respectively, and 57.1% vs. 9%, respectively). On the other hand, the sites of bleeding events in this study were consistent with the CARAVAGGIO trial, which predominantly originated from the gastrointestinal and genitourinary systems. Death from any cause in this study was 9%, which is lower than that reported in the CARAVAGGIO trial, 23.4% [6]. The apixaban discontinuation rate in the current study was 32.3%, which is lower compared to 53.3% in another retrospective study [13].
Most of our patients were receiving alkylating agents (51%). Sixty-three percent of recurrent VTE events onset since apixaban initiation within 0-3 months, which is consistent with the recurrent VTE risk rate in non-cancer patients. This study is one of the few studies that evaluated the safety and efficacy of apixaban in patients with cancer in Saudi Arabia. Our results emphasize the importance of close monitoring for recurrent VTE within the first six months, especially after VTE diagnosis, and to use apixaban with caution in patients with gastrointestinal and genitourinary cancer due to the high risk of bleeding events observed in the CARAVAGGIO trial. This could provide further guidance for clinicians whenever they prescribe this agent. However, our study has several limitations, including retrospective study design, single-center, and the possibility of documentation bias. We also only assessed the potential safety and efficacy of apixaban, and the results of this study should not be extrapolated to the other DOACs. Moreover, this study was designed to evaluate the safety and effectiveness of apixaban use in cancer patients with VTE and not to report the use of apixaban in cancer patients with atrial fibrillation or any other indication. In a future study, we plan to evaluate the safety and efficacy of apixaban use in cancer patients with atrial fibrillation and versus other anticoagulants.

Conclusions
The prevalence of recurrent VTE and bleeding events in patients with cancer using apixaban for treating VTE is in line with many other real-world studies but slightly higher compared to the patients enrolled in the CARAVAGGIO trial. The results of our study emphasize the importance of closely monitoring apixaban prescribed for patients with gastrointestinal and genitourinary cancer due to the higher incidence of bleeding events observed in the CARAVAGGIO trial.