Low Molecular Weight Heparin Treatment Patterns and Outcomes in Cancer Patients with Acute Venous Thromboembolism: A Nationwide Cohort Study in France

Simple Summary Venous thromboembolism (VTE) is a common and often fatal complication in cancer patients. The initial treatment for VTE in cancer patients is typically low molecular weight heparins (LMWH), a type of anticoagulant that prevents VTE from recurring. However, information on outcomes of LMWH treatment in cancer patients with VTE have not typically been collected from large national databases, such as the one in France. The aim of this study was to assess VTE recurrence, bleeding (a common side effect of anticoagulant treatment), and all-cause mortality in cancer patients in France who were prescribed LMWH for VTE in 2013–2018. Our results indicate that cancer patients who experience VTE have unmet medical needs due to high rates of mortality, VTE recurrence, and bleeding after LMWH treatment initiation. Our study may help further research on outcomes in cancer patients with VTE who receive the next generation of therapy, direct oral anticoagulants. Abstract Patients with cancer have an increased risk of developing venous thromboembolism (VTE) and an increased risk of death from VTE. Until recently, the standard of care for treatment of VTE in cancer patients was low molecular weight heparins (LMWH). To determine treatment patterns and outcomes, we performed an observational study using a nationwide health database. Treatment patterns, rates of bleeding, and VTE recurrence at 6 and 12 months were assessed in cancer patients with VTE in France prescribed LMWH in 2013–2018. Of 31,771 patients administered LMWH (mean age 66.3 years), 51.0% were male, 58.7% had pulmonary embolism, and 70.9% had metastatic disease. At 6 months LMWH persistence was 81.6%, VTE recurrence had occurred in 1256 patients (4.0%) at a crude rate per 100 person-months (PM) of 0.90, and bleeding had occurred in 1124 patients (3.5%) at a crude rate per 100 PM of 0.81. At 12 months, VTE recurrence had occurred in 1546 patients (4.9%) at a crude rate per 100 PM of 0.71 and bleeding had occurred in 1438 patients (4.5%) at a crude rate per 100 PM of 0.66. Overall, VTE-related clinical event rates were high among patients administered LMWH, suggesting an unmet medical need.


Introduction
Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT), caused by a blood clot in a deep vein (usually in the leg), and pulmonary embolism (PE), caused by a blood clot that embolized to the lungs. VTE commonly occurs in patients with cancer and those undergoing cancer surgery and is a leading cause of death in these patients [1,2]. Patients with cancer have a four-to seven-fold higher risk of having a VTE event than patients without cancer [1]. VTE may even be underreported in cancer patients, as VTE rates based on autopsy are higher than those based on clinical diagnoses [3,4]. Moreover, VTE recurrence is three-to four-fold more frequent in patients with cancer than in people without cancer [1]. Furthermore, the risk of death from VTE is significantly higher in cancer patients with VTE than in non-cancer patients with VTE [3,5]. For cancer patients, the risk of experiencing a VTE event is influenced by patient age, type and stage of cancer, type of cancer treatment, and other comorbidities [6,7]. Typically, the risk of recurrent VTE is highest in the first few months after diagnosis of a malignancy but can persist for years after the initial VTE, especially if the cancer is still active [3,8]. Therefore, collecting data about VTE-related events in the long term is important.
To prevent recurrence, patients with VTE are prescribed anticoagulants such as low molecular weight heparins (LMWH), direct oral anticoagulants (DOACs) including apixaban and rivaroxaban, and vitamin K antagonists (VKAs) [9]. LMWH have been recommended as the standard of care for initial treatment of VTE in cancer patients for nearly 20 years [10,11]. DOACs are now recommended as an alternative treatment for cancer associated VTE [10,12,13]. However, there is limited real-world evidence in France on treatment patterns and outcomes for cancer patients who are administered LMWH for VTE events, making comparisons of VTE associated outcomes with patients administered DOACs difficult. Using data from a large nationwide healthcare database, we assessed long-term (up to 6 months) and extended (beyond 6 months) treatment patterns, as well as rates of VTE recurrence, bleeding, and mortality in cancer patients with VTE in France who were administered LMWH in 2013-2018. The aim was to collect real-world data on the treatment patterns and outcomes of patients with cancer who were treated with LMWH after a VTE.

Overall Study Design and Data Source
The study design and data source have been reported in a previous publication [14]. Briefly, this was an observational study using data from the French national health data system (Système National des Données de Santé [SNDS]), which covers approximately 99% of the French population (EU PAS registration number: EUPAS35888).

Study Population
The analysis included adult (≥18 years) patients with active cancer who were hospitalized for a VTE between 1 January 2013 and 30 June 2018 [14] and who were reimbursed for LMWH (the index treatment) within 30 days after hospital discharge. The study included patients who were hospitalized for reasons other than VTE, but VTE had to be the primary discharge diagnosis. The International Classification of Diseases 10th Revision (ICD-10) codes used to identify patients with a VTE diagnosis were previously reported [14]. Active cancer was defined as a cancer diagnosis or cancer treatment within 6 months before or 30 days after the first VTE diagnosis during the study period (the index VTE diagnosis is the first recorded VTE event and the index VTE event date is the date of the first admission for VTE hospitalization) [14]. Patients who were anticoagulant naïve (AC-naïve) or who had previously received anticoagulant treatment (AC-experienced) were included. AC-naïve patients had no evidence of oral or parenteral anticoagulant use during the 24 months preceding the index VTE diagnosis, unless such therapy was administered prophylactically (only for hip or knee replacements). AC-experienced was defined as evidence of non-prophylactic oral or parenteral anticoagulant use during the 24 months preceding the index VTE diagnosis. Exclusion criteria are detailed in a previous publication [14].

Study Outcomes
The study outcomes chosen for analysis were included because of their clinical relevance. Rates of bleeding leading to hospitalization, recurrent VTE, all-cause mortality, and chronic thromboembolic pulmonary hypertension (CTEPH) were assessed at 6 and 12 months after the index date; the index date is defined as the date of the first recorded AC reimbursement occurring within 30 days after the index VTE event. CTEPH was included as an outcome in the study because it is a potentially life-threatening long-term complication of VTE, including in cancer patients [15], as a result of the risks of cardiotoxicity from cancer treatment [16].
Treatment persistence, discontinuation, and switching were analyzed. Persistence was defined as no discontinuation, interruption, or switching of LMWH treatment during the follow-up period. Discontinuation was defined as no evidence of LMWH reimbursement for at least 30 days from the estimated end of supply of LMWH treatment. Interruption was defined as a gap with no new treatment for less than 30 days after the estimated end of supply of LMWH, with subsequent restart of LMWH treatment after this period. Switching was defined as prescription of a class of anticoagulant other than LMWH at least 1 day after the last reimbursement date for LMWH and within 30 days after the estimated end of supply of LMWH.

Statistical Analysis
Descriptive statistics were calculated for patient demographics, clinical characteristics, and study outcomes. Data for AC-experienced and AC-naïve patients were compared by chi-square test (categorical variables) or ANOVA (continuous variables). The follow-up period ran from the day after the index date to the date of death, loss to follow-up, or end of study (whichever was earliest) and patient data were censored if LMWH treatment was switched, discontinued, or interrupted, or if the patient died. Treatment patterns were analyzed in the timeframes 0-3 months, >3-6 months, >6-12 months, and >12 months. Outcome rates were evaluated at 6 months and 12 months. To ensure anonymization and to comply with data privacy requirements, exact numbers and percentages were not reported when the number of patients was <10.
In a sensitivity analysis, outcomes were analyzed separately for AC-naïve and ACexperienced cohorts.
In an exploratory analysis, patients who remained on treatment were separated into subgroups based on the most common treatment scenarios after VTE in clinical practice. Subgroup 1 included patients who remained on LMWH throughout the study period. Subgroup 2 included patients who were prescribed LMWH as their index treatment and who later switched to an oral anticoagulant (OAC).

Clinical Outcomes at 12 Months
VTE recurrence occurred in 1546 patients (4.9%) in the overall cohort ( Table 5). The crude rate of VTE recurrence per 100 PM was 0.71 (95% CI 0.67-0.74) in the overall cohort. Bleeding leading to hospitalization occurred in 1438 patients (4.5%) in the overall cohort at a crude rate per 100 PM of 0.66 (95% CI 0.62-0.69). GI bleeding occurred in 550 patients (1.7%) at a crude rate per 100 PM of 0.25 (95% CI 0.23-0.27) and, as at 6 months, was the most common type of bleeding. CTEPH occurred in 74 patients (0.2%) overall. In the overall cohort, all-cause death occurred in 14,124 patients (44.5%) at a crude rate per 100 PM of 6.44 (95% CI 6.34-6.55). Again, outcomes were consistent between AC-naïve and AC-experienced patients.

Patient Subgroups
Two notable subgroups of patients were identified; 2710 patients were not included in either of these subgroups due to LMWH discontinuation, treatment interruption, or switching to a different anticoagulant administered intravenously. Subgroup 1 (n = 25,256) included patients with persistent use of LMWH and subgroup 2 (n = 3805) included patients who switched from LMWH to OACs (Table S3). Mean age (SD) and proportion of males were similar between subgroups: 66.1 (13.2) years and 51.5% males in subgroup 1 and 67.2 (12.9) years and 48.6% males in subgroup 2. Over half of patients in subgroup 1 (57.5%) had PE (with or without DVT) and most (74.9%) had metastatic disease, whereas in subgroup 2, just over two-thirds of patients (68.0%) had PE (with or without DVT) and about half (52.8%) had metastatic disease.

Discussion
A recent study indicated that about one in two patients seen in clinical practice for acute cancer-associated thrombosis would not be eligible for a DOAC randomized, controlled trial [18]. For some of these patients (e.g., those with severe renal failure), LMWH remains the main option, supporting the need for real-world data such as that provided in the current study. Most cancer patients diagnosed with VTE in France were treated with LMWH during the study period, in accordance with the treatment guidelines at the time of the study. VTE-related clinical event rates were high in cancer patients treated with LMWH, most of whom had metastatic disease and aggressive cancer types, suggesting a key unmet medical need. Additionally, mortality was very high at both 6 and 12 months. The high comorbidity burden in the patients included in our study may partially explain the high clinical event rates.
The high clinical event rates in our study are also highlighted when results are compared to the same outcomes in patients without cancer. In an observational real-world database study in France that used the same methodology and study time periods, patients without cancer who had a VTE event experienced lower incidence rates of bleeding, allcause death, and VTE recurrence after treatment with rivaroxaban, apixaban, and VKA than patients in the current study [14]. For instance, at 6 months after the initial VTE event, the incidence of bleeding that required hospitalization ranged from 0.15-0.43 per 100 PM (calculated from PY) in non-cancer patients whereas it was 0.81 per 100 PM in patients with cancer. All-cause death incidence in non-cancer patients ranged from 0.23-1.02 per 100 PM, whereas it was 7.47 per 100 PM in patients with cancer. VTE recurrence ranged from 0.28-0.42 per 100 PM in non-cancer patients vs. 0.90 per 100 PM in patients with cancer.
The crude VTE recurrence and overall bleeding rates at 6 and 12 months show some similarities to and differences from what was found in other studies. For example, in PREDICARE, a prospective observational study of patients with cancer and VTE prescribed tinzaparin in France, the incidence of VTE recurrence at 6 months was higher (7.3%) than in our study (4.0%) [19]. This difference in incidence rate may have been due to differences in study design and the smaller patient population in PREDICARE (409 patients). Additionally, because our study included patients who had a VTE event triggered by cancer surgery, the prognosis of those patients was likely better than the patients in the PREDICARE study. In the prospective single arm interventional TiCAT (Tinzaparin in Cancer-Associated Thrombosis) study, VTE recurrence at 1-6 months (4.5%) and 1-12 months (5.3%) was similar to VTE recurrence at 6 months and 12 months in our study [20]. Our results for VTE recurrence incidence rate per 100 person-years are also similar to a long-term observational cohort study in the UK in cancer patients who had VTE [21]. The mean crude recurrent VTE incident rate per 100 person-years over the course of that study was 9.6 (0.80 per 100 PM) [21]; our combined PE and DVT incident rate per 100 person-years was 10.8 (0.90 per 100 PM) at 6 months and 8.5 (0.71 per 100 PM) at 12 months. In the TiCAT study, the rate of clinically relevant bleeding (major and non-major) after an initial VTE event was similar at 1-12 months (0.8% per PM) as at 1-6 months (0.9% per PM) [20], which was different from our study, in which the crude rate of overall bleeding leading to hospitalization was lower at 12 months (0.66 per 100 PM) than at 6 months (0.81 per 100 PM). The differences between our findings and those of the TiCAT study could be due to TiCAT being an interventional study with a defined patient sample, whereas our study was a retrospective analysis of a national cohort that included a wider spectrum of patients with cancer. Additionally, the TiCAT study included clinically relevant non-major bleeding, which typically does not lead to hospitalization and may also explain why the bleeding rates in our study were lower. In a retrospective non-interventional study in France showed that patients with cancer treated with the LMWH drug tinzaparin and followed up for 6-12 months after an initial VTE event had similar rates of VTE recurrence (5.7%) and clinically relevant bleeding (5.1%) as in our study (4.0% at 6 months and 4.9% at 12 months for VTE recurrence, 3.5% at 6 months and 4.5% at 12 months for overall bleeding leading to hospitalization) [22].
CTEPH occurred in a small proportion of our study patients. Cancer has been shown to increase the risk of CTEPH [23]. However, limited data exists on the proportion of cancer patients with VTE who go on to develop CTEPH. Despite possible under-reporting, our results indicate that risk of CTEPH in cancer patients with VTE is low. Our results may serve as an epidemiologic reference for future studies. Additionally, the European Society of Cardiology Working Group on Pulmonary Circulation and Right Ventricular Function recommends regular screening for CTEPH in patients after an initial PE event [24], including in patients with cancer as its treatment can cause cardiotoxicity [16]. If regular screening for CTEPH is incorporated into clinical practice, more accurate numbers of patients with CTEPH will likely become available.
We found that recurrent VTE, bleeding, and mortality were frequent in patients with cancer prescribed LMWH. Although LMWH as a monotherapy in cancer patients has long been supported by the American Society of Clinical Oncology, the National Cancer Comprehensive Network, the American Society of Hematology, and the American College of Chest Physicians, more recent guidelines also recommend DOACs as an alternative to LMWH in the first 6 months of treatment [10,12,13,25]. A recent meta-analysis reported increased efficacy (a significantly reduced frequency of VTE recurrence) with DOACs vs. LMWH in cancer patients with VTE [26], indicating that DOACs may be preferred over LMWH in cancer patients to reduce the risk of VTE recurrence.
Data on the bleeding risk with DOACs vs. LMWH is conflicting. In the meta-analysis mentioned above, the risk of major bleeding was not different between DOACs and LMWH, but the risk of clinically relevant bleeding (major and non-major) was significantly higher with DOACs than with LMWH [26]. Considering individual DOACs, apixaban was not associated with an increased risk of major bleeding (mainly GI bleeding) in ADAM VTE [27] or CARAVAGGIO [28], a finding confirmed by a real-world evidence study [29]. However, other DOACS were reported to result in more bleeding than with LMWH, including in the GI tract [30,31]. Clinical trials have also confirmed that GI cancers are more likely to bleed than other types of cancer [32]. To support the clinical trial findings, updated guidelines for DOAC treatments in patients with GI cancers have been published [12,33,34]. It is also important to note that GI bleeding was also the most common type of bleeding in the patients in our study. In the clinic, it is important to be able to identify patients who are at risk for GI bleeding so that the safest AC medications can be prescribed to them. Because of the increased risk of GI bleeding after AC therapy, a predictive score for identifying GI bleeding risk was recently published [35] and may help clinicians determine which AC therapy to prescribe.
We found that the rates of VTE recurrence (4.0-4.9%) and bleeding leading to hospitalization (3.5-4.5%) were similar at 6 and 12 months. These results highlight the challenge of managing VTE in patients with cancer, especially beyond 6 months of treatment as previously described in the literature [36]. Individualized and tailored treatment plans may be beneficial for extended treatment periods after initial VTE. Here, the results of ongoing clinical trials may help clinicians in selecting optimal doses for patients. For instance, the EVE and API-CAT trials are exploring which dose of apixaban is the most appropriate or has the most favorable benefit to risk ratio for extended treatment in patients with cancer-associated VTE [37,38].
A strength of our study is that the SNDS is a large nationwide observational database, which allowed us to identify a cohort of thousands of cancer patients prescribed anticoagulants for VTE. The SNDS covers about 99% of the French population and therefore includes patients with a wide sociodemographic range. Additionally, with such a large population included in the database, we were able to estimate event rates more accurately, especially for rare outcomes such as CTEPH. Another strength of our study is that we collected follow-up data until 12 months after the index VTE diagnosis. Because patients with cancer and VTE have poor survival rates, there is limited published data beyond 6 or 9 months, with only a few studies reporting outcomes and treatment patterns at 12 months [20,22,30]. A limitation is that anticoagulant use was assessed only by reimbursement after hospital discharge. Moreover, patient adherence to prescribed treatment is unknown. Another limitation is that a competing risk analysis for cancer-specific mortality vs. other causes for mortality was not conducted; however, we acknowledged the competing risk by stratifying the presentation of data according to different time points and included a carefully selected choice of denominators (among alive patients, etc.). A further limitation of the study is that some data were missing, including for patients who did not return home after being discharged from hospital but were instead transferred to rehabilitation centers where drugs are dispensed outside of the reimbursement system.
Cancer management (chemotherapy, surgery, radiotherapy) may affect the risks of events such as recurrent VTE and bleeding. Unfortunately, our data, based on a national medico-administrative database, did not allow us to fully describe individual events, as would have been possible with a prospective cohort with an independent adjudication committee. Additionally, our study focused on data from patients hospitalized with VTE because diagnosis codes are not available for non-hospitalized patients, which may have led to underestimated VTE-related events. However, most patients undergoing anticoagulant therapy to prevent VTE recurrence are typically managed in the hospital and not in other healthcare settings. Moreover, it is possible some of the patients in our study were receiving palliative care at the end of life, leading to possible underreporting of VTE related events [39]. However, we expect the number of missing events due to palliative care to be very low because in France, most palliative care facilities are part of the hospital system and the events that occurred in palliative care would have been included in the database used in our study. Lastly, our study included a relatively large percentage of patients who were already AC-experienced (55.6%); this may have been due to previous AC treatment after surgical procedures related to cancer treatment (thromboprophylaxis).
Most patients who switched to an OAC were prescribed rivaroxaban or apixaban, neither of which were recommended by guidelines in France at the time this study was conducted. We hypothesized that patients who switched from LMWH to an OAC (subgroup 2) would have less severe disease than those who continued on LMWH (subgroup 1). Our reasoning was that if clinicians would risk switching patients to a non-recommended anticoagulant, this was likely because these patients had less severe disease than patients who continued on LMWH. Our findings support this reasoning: patients in subgroup 2 had lower percentages of very high-or high-risk cancers and metastatic disease and fewer co-morbidities than those in subgroup 1. Additional work is planned to identify determinants of treatment switching and treatment choices after VTE recurrence or bleeding.

Conclusions
This study may be a steppingstone for future comparisons of LMWH to DOACs in cancer patients with VTE using real-world data. LMWH has been the standard of care for patients with cancer-associated VTE, yet rates of recurrent VTE, bleeding, and mortality remain high in this patient population. DOACs offer a potentially safer and more effective alternative to LMWH in cancer patients with VTE. More real-world data is needed to determine the relative effectiveness and safety of DOACs and LMWH which will help clinicians to offer a more tailored treatment approach for each patient.
Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/cancers15113011/s1, Figure S1: Clinical outcomes in patients treated with LMWH at 6 months follow-up. Data are event rates (95% CI) per 100 person-months. Abbreviations: CI, confidence interval; DVT, deep vein thrombosis; GI, gastrointestinal; ICH, intracerebral hemorrhage; LMWH, low molecular weight heparin; PE, pulmonary embolism; VTE, venous thromboembolism; Table S1: Cancer-related treatments and procedures in LMWH-treated patients with VTE; Table S2: Patient disposition according to follow-up time; Table S3: Clinical characteristics of patients in subgroups 1 and 2; Table S4: Clinical outcomes at 6 months for patients in subgroups 1 and 2; Table S5: Clinical outcomes at 12 months for patients in subgroups 1 and 2.  Informed Consent Statement: Informed consent was waived because this study used anonymized structured data, which, according to local legal requirements, is not subject to data privacy laws.

Data Availability Statement:
The patient-level data used for this study are not publicly available due to privacy restrictions per French law and the General Data Protection Regulation (GDPR).