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Original Article
Patients’ experience and compliance with extended low molecular weight heparin prophylaxis post-surgery for gynecological cancer: a prospective observational study
  1. Zibi Marchocki1,2,
  2. Lucy Norris2,
  3. Sharon O'Toole2,
  4. Noreen Gleeson1,2 and
  5. Feras Abu Saadeh1,2
  1. 1 Department of Gynaecological Oncology, St. James's Hospital, Dublin, Ireland
  2. 2 Trinity College Department of Obstetrics and Gynaecology, Trinity Centre for Health Sciences, St. James's Hospital, Dublin, Ireland
  1. Correspondence to Dr Zibi Marchocki, Department of Gynaecological Oncology, St. James's Hospital, Dublin D03 VX82, Ireland; zmarchocki{at}gmail.com

Abstract

Objective Gynaecological cancer patients have a high risk of developing venous thromboembolism (VTE). There is limited information on patient experience and compliance with an extended low molecular weight heparin prophylaxis in this setting. The aim of this study was to assess patient compliance, satisfaction and experience with the extended low molecular weight heparin prophylaxis after major surgery for gynaecological cancer.

Methods This was a prospective observational study conducted in a large tertiary center for gynaecological cancer between July 2017-March 2018. Consecutive patients undergoing surgery for gynaecological cancer who received low molecular weight heparin prophylaxis for four weeks following surgery were recruited. All participants received a log book to record all injections, side effects, and questionnaire to be completed at the end of the study.

Results A total of 106 patients completed and returned the VTE prophylaxis logbook and questionnaire. Sixty-six (62%) patients received low molecular weight heparin for 28 days, twenty-five (24%) for 26-27 days, and 15 (14%) for less than 26 days. The median number of days of therapy was 28 days (range; 12-28 days). Reasons for missed or stopped injections included: forgetfulness(n=12), medical procedures (n=6), pain (n=5), incorrect prescription (n=4), patient choice (n=3), cost (n=2), physician request (n=2), non-availability of person administering the injections (n=1) or unknown (n=5). Sixty-one (58%) patients self-administered the injections. Patients who had the injection performed by a third person were twice as likely to experience pain compared to patients who self-administered (OR 2.81, p=0.003). Eighty-nine (84%) patients self-reported side effects during low molecular weight heparin prophylaxis including: bruising (75%), pain after injections (49%), itchiness (9%), swelling (9%) or other (8%). Although 83 (78%) patients were satisfied with injections, 91 (86%) admitted they would much prefer a tablet form.

Conclusions Compliance with standard recommended regimen of 28-days prophylaxis was completed by 62% of patients. Majority of patients (86%) reported a preference for a tablet form, if one was available.

  • thrombosis
  • cancer
  • low molecular weight heparin

http://dx.doi.org/10.1136/ijgc-2019-000284

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    HIGHLIGHTS

    • Patient preference is for an oral anticoagulation prophylaxis.

    • 86% of patients were compliant with low molecular weight heparin for >26 days.

    • Pain score was significantly lower during low molecular weight heparin self-administration versus the administration by someone else.

    Introduction

    Patients with cancer have up to a 6.5-fold higher risk of developing venous thromboembolism compared with non-cancer patients.1 2 The risk of venous thromboembolism in patients with gynecological malignancies varies between 3–25% depending on tumor origin and histology.3–5 This risk is higher following major surgery.6–8 Early studies reported post-operative venous thromboembolism rates in patients with gynecological malignancy up to 38% compared with 14% in women with benign conditions.9 More recently, the incidence of venous thromboembolism within 30 days of laparotomy for gynecological cancer was decreased from 2.7% to 0.6% following implementation of extended low molecular weight heparin prophylaxis in a study by Schmeler et al.10

    Similarly, the Enoxaparin and Cancer II (ENOXACAN II) study showed a reduction in venous thromboembolism rates from 12% to 4.8% with extended low molecular weight heparin prophylaxis following abdominal, gynecological or urological surgery for cancer.11 This effect was still present at 3 months post-surgery. The benefit of extended low molecular weight heparin thromboprophylaxis post minimally invasive surgery for gynecological cancer is less certain. The 30-day rate of venous thromboembolism following minimally invasive surgery for endometrial, cervical, and ovarian cancer without thromboprophylaxis was 0.57%.12 However, in a study by Nick et al, the 6-week rate of venous thromboembolism following high-complexity minimally invasive surgery for gynecological cancer (radical hysterectomies, pelvic, para-aortic lymphadenectomy, splenectomy or bowel surgery) without extended low molecular weight heparin thromboprophylaxis was found to be 2.8%.13 Post-operative venous thromboembolism rates in endometrial cancer patients who received extended prophylaxis following minimally invasive surgery were reported to be 0.5–0.7%.14

    The International Initiative on Thrombosis and Cancer (ITAC-CME) guidelines recommend 28 days of post-operative low molecular weight heparin for venous thromboembolism prophylaxis for patients undergoing major cancer surgery.15 Despite all available evidence, there has been a wide variation in clinicians’ adherence to these guidelines.16 17 Samama and colleagues have shown that 57.4% of patients received 4 to 6 weeks of venous thromboembolism prophylaxis following all major abdominal or pelvic surgeries for cancer.16 We have previously shown that among European gynecological-oncology society members, only 65% of cancer surgeons prescribed the extended prophylaxis for at least 4 weeks.17 Reluctance to prescribe post-operative venous thromboembolism prophylaxis could be due to concerns regarding bleeding risk, the cost involved or patient compliance. Studies examining patients who received low molecular weight heparin for cancer-associated thrombosis have shown that low molecular weight heparin remains an acceptable intervention, but only as an acceptable compromise against their strongly negative experiences of symptomatic venous thromboembolism.18 In studies of other patient groups, the lack of education and a negative opinion toward injection has negatively influenced compliance.19

    There is a paucity of data evaluating patients’ experience and compliance with low molecular weight heparin extended prophylaxis in the setting of gynecological cancer. The aim of this study was to investigate patient compliance and experience with extended low molecular weight heparin prophylaxis following major surgery for gynecological cancer.

    Methods

    This was a prospective observational study involving patients undergoing major surgery for confirmed or suspected gynecological cancer. The study was conducted at St James’s University Hospital, a tertiary referral cancer center in Dublin, Ireland, between July 2017 and March 2018. All consecutive patients who underwent major gynecological cancer surgery and who were given extended low molecular weight heparin prophylaxis were invited to participate. Patients receiving a long term therapeutic anticoagulation or those who had a recent diagnosis of venous thromboembolism were excluded from the study. The St James’s University Hospital Ethics Committee approved the study. All participants received weight adjusted low molecular weight heparin within 24 hours of surgery (4500 IU of tinzaparin once daily for body mass index <40 kg/m2; and 75 IU/kg for patients with body mass index >40 kg/m2).

    Before discharge from the hospital, nursing staff trained patients or their carers in the administration of low molecular weight heparin. Following informed and written consent, the participants received a logbook to record the injections and any side effects, a questionnaire to be completed at the end of the extended prophylaxis, and an information leaflet on signs and symptoms of venous thromboembolism. The following data were recorded in the patient logbook: date of administration, reason for missed injections, site of the administration, the person who administered the injection, pain score, and side effects (online appendix 1). Pain score relating to injection was assessed using a Visual Analog Scale. Following 28 days of prophylaxis (4 weeks), the patients were asked to complete the questionnaire, assessing the knowledge and experience with the extended venous thromboembolism prophylaxis (online appendix 2). All participants were followed up at 30 days post-surgery by a telephone interview and medical records were reviewed at 6 months.

    Supplemental material

    Supplemental material

    Descriptive statistics were used for patient demographics. Logbook and questionnaire data were recorded as frequencies with percentages. Logistic regression models were used to examine the association between patients’ reported pain, satisfaction, and compliance, and the following factors: injection site, patient age, hospital stay, surgical approach, pathology, and the person administering the injections. The type of cancer was removed from the model because of multicollinearity with pathology and surgical approach. A dataset was created with each injection representing a row in the dataset, considering that pain was assessed following each injection and compliance and satisfaction were based on the number of injections. We used the cluster option in the logistic regression in order to account for the dependent data as each patient was represented in up to 28 rows. A value of p<0.05 was considered significant. The statistical analysis was performed by using Stata Version 13.1 (StataCorp LLC, Texas, USA).

    Results

    A total of 117 patients who were deemed eligible for the extended 28 days venous thromboembolism prophylaxis were recruited for the study over the 9 month period (Figure 1). One patient was excluded because she developed pulmonary embolism 2 days after interval cytoreductive surgery for stage IV ovarian cancer, despite the appropriate venous thromboembolism prophylaxis. A further 10 patients were excluded from the final analysis because they did not return the packs (logbook and questionnaire). A total of 106 (91%) patients returned the completed logbook and questionnaire. The patients’ characteristics are detailed in Table 1. The median age of the patients was 57 years (range 29–84) and length of the hospital stay was 6.5 days (range 2–53). Seven patients spent more than 28 days in the hospital following primary surgery. Apart from a patient who developed pulmonary embolism 2 days after surgery, two more patients developed venous thromboembolism. In the first patient it developed 3 months post laparoscopic radical hysterectomy for cervical cancer, while receiving chemotherapy; it is unclear whether she completed an extended thromboprophylaxis course, as she did not return her logbook or questionnaire. The second patient developed pulmonary embolism and deep vein thrombosis 6 weeks following laparotomy for a small bowel obstruction, having completed a course of extended thromboprophylaxis.

    Figure 1
    Figure 1

    Flow diagram of patients recruited into the study (n=117). LMWH, low molecular weight heparin; PE, pulmonary embolism.

    View this table:
    Table 1

    Study population characteristics (n=106)

    Eighty-five (80%) patients understood the reason for extended prophylaxis while 21 (20%) did not. The majority of patients heard about the importance of prophylaxis for the first time after their surgery (n=74, 70%). The remaining patients were informed about the need for prophylaxis before surgery, either in the outpatient clinic (n=21, 20%) or after admission to the ward (n=8, 7%). Three patients (3%) knew about extended prophylaxis from their previous experience. The median number of days of injections was 28 (range 12–28). There were 2823 injections in total received by 106 patients. Sixty-six (62%) patients received prophylaxis for 28 days (Figure 2). Twenty-five (24%) patients completed 26 to 27 days and 15 (14%) completed 12 to 25 days. Reasons for missed injections in this group included: forgetfulness (n=12), medical procedures (n=6), inadequate prescription (n=4), pain (n=2), patient’s choice not to take the injection on the particular day (n=2), non-availability of the person administering the injections (n=1), unknown (n=5). Eight (8%) patients stopped low molecular weight heparin within 23 days of surgery due to: pain (n=3), cost (n=2), physician’s request or because they believed it was not necessary (n=1). Injection site, age, hospital stay, surgical approach or person administering the injections did not significantly influence compliance. Patients with borderline mucinous and serous tumors were less likely to complete 28 days of injections compared with patients with cancer (OR 5.33, 95% CI 1.23 to 23.07; p<0.025) (Table 2). At 30-day telephone follow-up, many patients provided feedback that tracking the progress and number of remaining injections in a study logbook played an important role in maintaining their compliance.

    Figure 2
    Figure 2

    Compliance with extended low molecular weight heparin prophylaxis (n=106).

    View this table:
    Table 2

    Variables affecting patients’ reported compliance*

    All patients or caregivers were educated on how to perform injections by nursing staff, either before (n=2, 2%) or following surgery (n=104, 98%). Sixty-one (58%) patients were able to administer the injections themselves, the remainder were helped by a family member (n=28, 26%) or a community nurse (n=17, 16%). Despite the prior experience with self-administration of an injection in 26 (25%) patients, only 16 of these patients self-administered the injection on this occasion. Within the group of patients who self-administered injections, 15 (14%) declared it was “very easy”, 30 (28%) “easy”, 14 (13%) “slightly difficult”, 1 (1%) “very difficult”, and 1 (1%) “impossible”. Patients who did not self-administer the injections were either not confident enough to proceed, were too afraid, found it too difficult to inject themselves (n=31, 29%), or had a severe fear of needles (n=5, 5%). The sites of the injections included: thighs (n=64, 60%), arms (n=26, 25%), abdomen (n=13, 12%), and buttocks (n=3, 3%). Following completion of the extended prophylaxis, 44 (42%) patients returned syringes to their local pharmacy, in 27 (25%) cases a community nurse collected them, 25 (24%) returned them to the hospital, and six (6%) discarded them in domestic waste.

    Eighty-nine (84%) patients experienced some form of side effect during the extended prophylaxis, with pain and bruising being the most common (Figure 3). Fifty-eight per cent of injections (n=1635) were associated with pain at the time of injection, which in 49% of patients persisted afterwards. Injections into thighs were more likely to cause pain than those administered into arms (OR 2.49, 95% CI 1.21 to 5.11; p<0.013) (Table 3). Increasing age was associated with increased perception of pain (p<0.0001). Patients who had the injections administered by somebody else were more likely to experience pain compared with those who self-administered (OR 2.81, 95% CI 1.42 to 5.56; p=0.003). Interestingly, patients commented that as they gained experience in the injection technique the amount of pain was reduced. Although in five cases pain was responsible for premature cessation of prophylaxis, most of the patients who experienced pain or other side effects admitted they still continued with the injections, as they believed it was important to do so. Six patients experienced mild and self-limited bleeding from the injection site. There were no serious complications arising from the injections.

    Figure 3
    Figure 3

    Side effects and complications experienced by patients receiving extended low molecular weight heparin prophylaxis.

    View this table:
    Table 3

    Variables affecting patients’ reported pain*

    Most patients (n=83, 78%) were either satisfied or highly satisfied with injections (Figure 4). However, 91 (86%) patients admitted that they would prefer a tablet form if available and as effective as the injections. Patient satisfaction was not affected by the site of injection, age, hospital stay, surgical approach or whether injections were self-administered or not (Table 4). Patients with borderline mucinous and serous tumors were more likely to be partially satisfied, not satisfied or not at all satisfied compared with patients with cancer (p=0.027). When patients were asked what was most difficult about the experience, 37 (35%) answered that it was the injection itself, 25 (24%) thought it was the side effects (pain and bruising), nine (8%) listed compliance difficulty, and five (5%) stated dependence on somebody else. Thirty (28%) patients did not report any problems.

    Figure 4
    Figure 4

    Satisfaction with low molecular weight heparin injections.

    View this table:
    Table 4

    Variables affecting patients’ reported satisfaction*

    Discussion

    This study assessed patients’ experience and compliance with extended thromboprophylaxis in gynecological cancer settings. Sixty-six (62%) patients received a full 28-day course of low molecular weight heparin rendering full compliance adequate. More than half of the patients (58%) were able to self-administer the injections, which was associated with less pain. Although satisfaction was high (78%), most patients (86%) admitted they would much prefer a tablet version. The introduction of extended prophylaxis is an additional burden on the cancer patient who is responsible for purchasing, and in many cases, self-injecting the medication. Furthermore the educational and support services are also lacking in the community and many patients experience side effects.18 20

    The results of our study show that the overall patient-reported compliance with extended prophylaxis was good, with 86% of patients receiving injections for >26 days. This compares favorably with a similar study where 81% of patients reported perfect adherence to the extended prophylaxis following pancreas and liver resection.21 Our results alleviate concerns regarding patient compliance and correspond with previous studies, demonstrating that the problem with adherence to the guidelines is mainly due to the resistance of the prescribing clinician rather than patient compliance.19 One of the main factors influencing the decision to prescribe the extended prophylaxis is the concern regarding bleeding risks. In a study of advanced cancer patients undergoing treatment for cancer-associated thrombosis, patients reported that a low major bleeding rate was an important feature in their anticoagulant preference.22 Previous studies have demonstrated that there was no significant increase in hemorrhagic complications with the extended low molecular weight heparin prophylaxis.11 23 In agreement with these findings, none of our patients experienced any major bleeding. It is important to emphasize that only 12% of patients in our cohort injected into the abdomen, which has been known to be associated with increased risk of rectus sheath hematoma.24

    More than half of the patients in our study were able to self-administer the injections, which was associated with less pain, although this statistically significant difference in pain perception might not be necessarily clinically significant. Previous studies suggest that the slower administration of subcutaneous heparin is associated with less pain and bruising.25 26 This could be true in patients who self-administer the injection, as they can adjust the speed of injection according to the pain intensity. However, self-administration had no impact on the bruising reported by patients. Previous studies reported that using a specific injection technique, needle oriented bevel-down parallel to the skin, helps to achieve a painless injection.27 Self-administration minimizes dependency on family members and healthcare staff, and potentially increases compliance with extended prophylaxis. A study of German hematologists/oncologists has suggested that practical issues like the need for injections and the availability of a partner to perform injections are important in their choice of anticoagulant.28 However, studies have shown that injections are not a barrier to good compliance and should not therefore influence the choice of an anticoagulant.22 29 This suggests that the capability of cancer patients to accept injectable anticoagulant treatment is probably underestimated.

    The majority of patients (84%) reported at least one side effect during the extended prophylaxis, with bruising and pain being the most frequent. Increased perception of pain related to injection in older patients in our study could be explained by findings from previous reports.30 31 It has been suggested that advancing age results in degeneration of endogenous inhibitory systems and increasing cell death that may increase susceptibility to pain. We found that injections into thighs were more likely to be associated with pain compared with arms. Previous studies found arms to be more favorable injection sites, with fewer blood vessels, painful sensations and less discomfort for the patients.32 Thighs on the other hand have been associated with more pain and bleeding by the patients.33 Despite the high rate of minor side effects, the overall satisfaction with injections was high. In our study, patients who experienced pain or other side effects admitted they still continued with injections, as they believed it was important to do so. This is in agreement with the studies of patients receiving low molecular weight heparin following cancer-associated thrombosis where patients were willing to persevere with the treatment in order to avoid a further thrombosis.18

    Ninety-one (86%) patients acknowledged they would much prefer a tablet form if available and as effective as low molecular weight heparin. Thromboprophylaxis with apixaban in ambulatory cancer patients starting chemotherapy (Khorana score ≥2) resulted in a significantly lower rate of venous thromboembolism (4.2%) than did placebo (10.2%) in a study by Carrier et al.34 However the rate of major bleeding episodes was higher with apixaban than with placebo. The efficiency of direct oral anticoagulants in the context of a post-surgical prophylaxis in the cancer setting is still absent, and the bleeding risk associated with direct oral anticoagulants in these patients is still a cause for concern.35 It has been shown that patient preference for oral administration over injection was only of moderate importance and patients favored efficacy and safety over convenience of route of administration.22

    There are a few limitations of our study. The self reported method we used to assess patient compliance could be considered a weakness of our data. Although there is no gold standard method for assessing adherence to medications in clinical practice, self-reported methods are one of the most common indirect methods used in the outpatient setting.36 37 Indirect methods including self-report are considered less reliable compared to direct methods. Direct observation of the patient taking the injection or measuring anti-factor Xa levels38 in our case would certainly be more reliable; however, they would also be invasive, expensive and more impractical in the outpatient setting than self-reported measures. There is a possibility that the patient adherence rate in our study is overestimated. Patients could document the injections in the logbook even if not taken, in order to appear to be following the regimen. Ten patients who did not return the pack could have done so because they did not take the injections at all. There is also the possibility that the patient experience was not fully captured since we only used quantitative methods of assessment (questionnaire) as opposed to mixed methods (combining both qualitative and quantitative methods). Although there is no standard method or ideal instrument for measuring the experiences of patients, in our study we tried to increase the chances of doing so by using prospective records of daily injections and a questionnaire with a mix of open and closed questions. The questionnaire we used had not been previously validated in patients with gynecological cancer, which could be regarded as another limitation.

    To our knowledge, this is the first study to examine patient perspectives on extended prophylaxis in a gynecological cancer setting. The logbook and questionnaire return rate was high (91%), which is a major strength of this study. Patient compliance and experience with extended prophylaxis were good. These findings would be applicable to other countries and settings in which extended thromboprophylaxis is recommended, and might encourage physicians to prescribe it more often. Future strategies should focus on education of healthcare providers on the importance of extended post-surgical venous thromboembolism prophylaxis in cancer settings, as this seems to be the major obstacle rather than patient compliance. Current management of extended prophylaxis following gynecological oncology surgery yielded good patient compliance and high satisfaction rating. The majority of patients would prefer oral prophylaxis if available, safe, and effective.

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    Footnotes

    • Contributors ZM: study concept and design, scientific conduct, data acquisition, data analysis and interpretation, drafting of the work and revising it critically for important intellectual content, final approval of the version to be published. LN: data interpretation, revising the work critically for important intellectual content, final approval of the version to be published. SO’T: revising the work critically for important intellectual content, final approval of the version to be published. NG: study concept and design, overlooking the study conduct, data interpretation, revising the work critically for important intellectual content, final approval of the version to be published. FAS: study concept and design, overlooking the study conduct, data interpretation, revising the work critically for important intellectual content, final approval of the version to be published.

    • Funding The study was partially funded by LEO Pharma Research Foundation. Grant Number: FASLN2916b.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.