Quality of life in cancer patients undergoing anticoagulant treatment with LMWH for venous thromboembolism: the QUAVITEC study on behalf of the Groupe Francophone Thrombose et Cancer (GFTC)

Background Clinical guidelines recommend at least 3-months low molecular weight heparin (LMWH) treatment for established venous thromboembolism (VTE) in cancer patients. However, no study has analyzed the impact of 3–6 months of LMWH therapy on quality-of-life (QoL) in cancer patients. Results Among 400 cancer patients included at M0, 88.8% received long-term LMWH. Using a random-effects linear regression model with time as covariate, QoL scores in the MOS SF-36 (Global HRQoL, 1.3-fold per month [95% confidence interval (CI) 0.81–1.79], p < 0.0001) and EORTC QLQ-C30 (global health status/qol, 2.25-fold per month [95% CI 1.63–2.88]; p < 0.0001) questionnaires significantly improved over the 6-month study period in patients treated with LMWH, while VEINES-QOL scores did not change. In the MOS SF-36 and EORTC QLQ-C30, the following factors were associated with change in QoL: symptomatic VTE, cancer dissemination and histological type. Factors pertaining to reduced mobility were also identified as significant predictors of QoL outcomes, including being bedridden in the MOS SF-36 and ECOG score ≥ 2 in the EORTC QLQ-C30. Presence of acute infection and not undergoing anti-angiogenic therapy were additional factors associated with QoL improvement in the EORTC QLQ-C30. Methods QUAVITEC, a prospective, longitudinal, multicenter study, recruited all consecutive eligible adult cancer patients with objectively confirmed VTE between February 2011 and 2012. Patients were asked to answer three QoL questionnaires at anticoagulant treatment initiation (M0) and at 3 (M3) and 6 (M6)-month follow-ups. Conclusion QUAVITEC is the first study to show that QoL was improved in cancer patients receiving long-term LMWH treatment for established VTE.


INTRODUCTION
Cancer is a major risk factor for venous thromboembolism (VTE) [1], and cancer patients who develop VTE tend to have a poorer prognosis and diminished life expectancy [1]. These patients are also at increased risk of experiencing VTE recurrence and major bleeding complications [1]. Overall, VTE is the second leading cause of death in cancer patients in both medical and surgical settings, after metastasi s [1]. Current national and international clinical practice guidelines for the management of VTE in patients with cancer recommend administering LMWH for at least 3 months [2][3][4]. After 3-6 months, the decision to continue or terminate anticoagulant treatment should be based on the benefit-torisk ratio, tolerability, drug availability, patient preference, and cancer activity. These recommendations are based on evidence that LMWH is the safest and most efficacious anticoagulant for the treatment and prophylaxis of VTE in this patient population, and that it is associated with a lower incidence of bleeds and recurrent VTE compared to unfractionated heparin (UFH) or vitamin K antagonists (VKAs) [5][6][7].
There is discrepancy, however, between evidencebased recommendations and clinical practice [8]. The French CARMEN study, which assessed 500 cancer patients treated for VTE two years after the release of French national guidelines, indicated that while physicians administered appropriate anticoagulation for established VTE during the initial phase of treatment (first 10 days) in 98% of cases, guideline adherence dropped to 62% during the treatment maintenance phase (10 days-3 months) [9]. Similarly, an analysis of data from the RIETE registry reported that only 66% of cancer patients were maintained on LMWH for the appropriate recommended treatment duration [10]. Results from a recent study of insurance claims records in the United states indicated that LMWH continues to be under-prescribed in cancer patients; VKA was the most commonly used anticoagulant (50%), with LMWH prescribed in 40% of cases [11]. Similar recent studies carried out on a global scale suggest that LMWH may be prescribed in as few as 25% of cases worldwide [12]. These continued failures in guideline adherence appear to stem in part from 1) concerns about whether cancer patients can tolerate long-term LMWH treatment and their potential side effects, despite their grade A evidence-based established benefit, [2] 2) beliefs about patients' lack of willingness to accept treatment regimens involving daily subcutaneous injections [13], and 3) preconceptions about the overall impact LMWH treatment will have on QoL. Potential complications of LMWH treatment include heparin-induced thrombocytopenia (HIT), allergic reactions, pain and ecchymosis at injection sites. A number of prospective studies examining longterm use of LMWH in cancer patients have not reported any cases of severe thrombocytopenia and, overall, the incidences of thrombocytopenia in patients on longterm LMWH or receiving VKA s are similar [5][6][7]. Risk of allergic reaction was not found to differ between LMWH and placebo arms in the MALT study [14]. Pain and development of indurations at injection sites can develop in 30-90% of patients [15], which could prove to be a barrier to treatment compliance . Health-related Quality of life (QoL) has never been assessed in this patient population, although it is an important variable in evaluating treatment effectiveness and compliance in oncology [16,17]. We therefore designed this prospective, longitudinal, multicenter, observational study to assess QoL in cancer patients initiated on long-term anticoagulant therapy for VTE in a real-world setting with treatment management determined by the local attending physicians.
In  Figure 3). Improvements in both the physical (1.32-fold [95% CI 0.80-1.84]; P < 0.0001) and mental (1.33-fold [95% CI 0.79-1.87]; P < 0.0001) health summary scores were observed, as well as across all specific dimensions examined ( Table 2). In the patients who answered the questionnaires at 3-month follow-up, there was a mean 2.9 (19) point increase in global HRQoL scores compared to their respective scores at baseline, with a 2.7 (20) point increase in the physical health status summary score, and a 3.1 (22) point increase in the mental health status summary score (Supplementary Table 2). At 6 month follow-up, patients on LMWH showed a mean 7.6 (22) point increase relative to their respective scores at M0, with increases in both the physical (7.7 (23)) and mental health status (7.6 (24)) summary scores (Supplementary Table 2 Figure 3). Underlying improvements across all functioning and symptom scales of the EORTC QLQ-C30 survey were observed ( Table 2). Compared to scores at M0, global Health status/QoL scores increased by a mean 6.6 (26) points at 3-month follow-up, and by 11 (29) points at 6-month follow-up (Supplementary Table 2).

Predictors of QoL outcomes in cancer patients with established VTE receiving Long-term LMWH
Independent predictors of QoL outcomes in the MOS SF-36 and the EORTC QLQ-C30 questionnaires during the study period were identified (Supplementary  Tables 3-5). In the MOS SF-36 survey, decreased functional activity at inclusion (ie.: bedridden; = 0.016) and symptomatic as opposed to asymptomatic VTE (P < 0.001) were independent predictors of improvement in HRQoL scores (Supplementary Tables 3, 4). Cancer dissemination (local, regional, metastatic; p = 0.022) and cancer histological type (adenocarcinoma, squamous, neuroendocrine, sarcoma, other; p = 0.001) were also predictors of QoL outcomes (Supplementary Tables 3, 4).

DISCUSSION
QUAVITEC is the first study to assess HRQoL in cancer patients with acute VTE undergoing anticoagulant treatment over six months. In this independent prospective observational study, QoL was assessed in a real-world setting with anticoagulant therapy determined by expert treating clinicians who were members of the Groupe Francophone Thrombose et Cancer (GFTC), which aims to improve good clinical practices for the treatment of VTE in cancer patients. The majority of patients were treated with LMWH (88.8%), consistent with evidence- based clinical practice guidelines. In the MOS SF-36 questionnaire, significant improvements in HRQoL were observed over the 6-month study period in patients receiving LMWH, relative to their respective scores at inclusion. The EORTC QLQ-C30 survey similarly indicated a robust significant increase in cancer-related global health status/QoL over time in patients on LMWH. Studies estimating the minimal important differences  [17,24,25] and that statistically significant changes in scores that are less than 6 are unlikely to be of clinical significance for patients [26]. In the MOS SF-36, the physical and mental health summary scores we observed also exceeded reported estimated MID (3-5 points) [27]. Scores in the disease-specific VEINES-QOL survey, which assesses QoL and symptom burden in patients with DVT, did not change during the 6-month study observation period. The Kaplan-Meier survival analysis indicated that patients treated with LMWH had non-significant better survival outcomes than patients receiving other anticoagulant therapies. However, the number of patients receiving treatments other than LMWH were few (n = 41). Furthermore, these data are difficult to interpret because the patients on other treatments, were patients in whom LMWH was contra-indicated and therefore likely to be more medically ill, such as hospitalized patients on iv unfractionated heparin, or patients with severe renal insufficiency on warfarin.
ECOG scores indicate that at follow-up the surviving study population had shifted toward improved  health, with the percentage of patients with ECOG scores of 0 or 1 increasing from 62.5% at M0 to 70.6% at M6 ( Figure 2C). The observation that QoL improved with increasing ECOG scores over the six-month study period suggests that the LMWH treatment regimen did not have a negative impact on QoL. In our study, 18.9% of patients on LMWH reported at least one side effect of injection, and 7.3% reported experiencing pain associated with LMWH injection. There is the possibility that painful side effects associated with daily LMWH injections may have an impact on treatment compliance in certain patients. However, an international qualitative survey of anticoagulant healthcare providers and their patients reported that physicians underestimate patient willingness to follow long-term treatment regimens that require injection, when it is the optimal treatment choice [13]. A later study assessed which features of anticoagulant treatment are most important to patients in making anticoagulant treatment decisions. Patients reported that avoiding interference with their cancer treatment was the most important factor (39%). This was followed by anticoagulant safety and efficacy (ie.: low thrombosis rate (24%) and minimizing bleed risk (19%)), which were rated to be of greater importance over convenience of route of administration (oral over injection, 13%) [28]. In the TROPIQUE study, patients reported that longterm LMWH was very convenient (mean score, 79.7 (SD:17.1)), and treatment satisfaction was relatively high (62.9 (SD:16.7)), particularly on measures of reassurance about treatment efficacy and experience with side effects. However, 23.4% of patients did report being unsatisfied or very unsatisfied with daily LMWH injections, indicating that a subpopulation of patients may significantly benefit from oral anticoagulant treatment as appropriate options become available. Studies in non-cancer patients are confirming that DOACs are associated with improved QoL compared to LMWH and VKA [29]. Although DOACS may be effective and safe in cancer patients, dedicated studies are needed before DOACS can be used with certainty in the cancer patient population. At present, LMWH is the appropriate first-line choice for the majority of cancer patients with VTE [2]. Our results indicate that HRQoL, as assessed by the MOS SF-36, EORTC QLQ-C30, and VEINES-QOL surveys, is not negatively affected by the use of LMWH; HRQoL increased in surviving patients despite LMWH treatment.
Our study had a number of limitations. This independent prospective observational real-life study could not be randomized due to the fact that this patient population required anticoagulant treatment with LMWH, unless contra-indicated, according to evidence-based clinical practice guidelines. While the drop-out rate was relatively low (32 of 400), a significant proportion of patients died over the 6-month study period, mainly due to cancer progression (23.7%). Notably, the mortality rate observed in our study was similar to the rates reported in the CLOT and CATCH trials, which also had 6-month followups. ECOG scores improved in the group of surviving patients over the study period. Thus, QoL improved with ECOG scores, suggesting that LMWH did not hinder an increased QoL associated with a better global health.

Patients
In this prospective, longitudinal, observational multicenter study, all consecutive cancer patients (>18 years), objectively diagnosed with symptomatic or asymptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), or superficial vein thrombosis, were recruited at 22 participating centers from the Groupe Francophone Thrombose and Cancer (www.thrombose-cancer.com) between February 2011 and 2012. Patients with less than 3 months lifeexpectancy or with unfeasible follow-up, those incapable of answering the questionnaires or who did not provide written informed consent were excluded from the study. The protocol was approved by the ethics committees of each participating center, according to local laws.

Procedures
The study primary objective was to evaluate QoL in cancer patients at the time of VTE diagnosis and start of anticoagulant therapy (M0), after 3 (M3) and 6 (M6) months of anticoagulant treatment for objectively confirmed VTE. Secondary objectives were survival after 3 and 6 months of anticoagulant therapy. Anticoagulant treatment was determined by the attending physicians, based on patient characteristics and comorbidities, and consistent with evidence-based clinical practice guidelines, most patients were under long-term LMWH, unless contraindicated.
In the Medical Outcome Study 36-item Short-Form Health Survey (MOS SF-36), [18], for generic Health-Related Quality of Life (HRQoL), generates 8 subscales (from scores of 0 to 100) and two summary scores that measure physical health (physical component score (PCS)) and mental health (mental component score (MCS)) status. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) [20] is used to assess QoL in cancer patients, through 9 multi-item scales that span three dimensions: functional, symptoms and a global health status and quality-of-life scale (HRQoL). The Venous Insufficiency Epidemiological and Economic Study (VEINES)-QOL questionnaire, for venous disease-specific QO L, is a 26-item questionnaire measuring the global impact of chronic venous disease [21] or recent DVT [22] on QoL with questions on the intensity and severity (VEINES-Sym subscale) and the impacts of venous symptoms [21,23].

Statistical analysis
Categorical variables were reported as frequencies with percentages and continuous variables as means with standard deviations (SD). To assess the impact of time on QoL scores, random-effects linear regression models with time as covariate were used. Patients' random effects were considered on the intercept and on the time coefficients to take in account the intra-patient correlations. Impact of patient characteristics on change in QoL were assessed using a random-effects linear regression model including a cross-level interaction term for each characteristic and time. Interaction terms for binary characteristics were tested using Wald tests, while interaction terms for nonbinary qualitative characteristics were globally tested using likelihood ratio tests. All analyses were performed in the group of patients treated by LWMH only. The Kaplan Meier estimator was used to estimate the probability of survival and the log-rank test to compare survival between LMWH and other treatments. All statistical tests were two-sided and a significance level of α = 0.05 was applied. Analyses were run using R 2.15.2 [30].

CONCLUSIONS
VTE in patients with cancer has a negative impact on morbidity and survival, and appropriate anticoagulant therapy is crucial for improving health outcomes in these patients. Despite this, studies continue to consistently show that LMWH is under-utilized in cancer patients. One barrier to conforming to evidence-based clinical practice guidelines has been physician concern about the burden of LMWH injections on QoL. Our study findings show that LMWH did not hinder QoL improvements in cancer patients who survived to 6-month follow-up and exhibited increased health overall. Given how crucial anticoagulant treatment is to decreasing morbidity and mortality, these data contribute to dispelling concerns about the negative impact of LMWH treatment regimens on overall patient well-being and QoL.

Author contributions
DF designed the study and wrote the manuscript; NF, TB, FC, OB, LV, HC, IB, DPP, MC, VL, and FC did clinical follow-up of patients and provided data for the study; MRR performed statistical analysis; IB collected data and helped with data management; HR and JC reviewed and edited the manuscript, and helped with submission. All authors read and approved the manuscript.