A feasibility study to inform the design of a randomised controlled trial to identify the most clinically effective and cost-effective length of Anticoagulation with Low-molecular-weight heparin In the treatment of Cancer-Associated Thrombosis (ALICAT)

Abstract

BackgroundVenous thromboembolism is common in cancer patients and requires anticoagulation with low-molecular-weight heparin (LMWH). Current data recommend LMWH for anticoagulation as far as 6 months, yet guidelines recommend LMWH beyond 6 months in patients who have ongoing or active cancer. This recommendation, based on expert consensus, has not been evaluated in a clinical study.Objectives(1) To identify the most clinically and cost-effective length of anticoagulation with LMWH in the treatment of cancer-associated thrombosis (CAT); (2) to identify practicalities of conducting a full randomised controlled trial (RCT) with regard to recruitment, retention and outcome measurement; and (3) to explore the barriers for progressing to a full RCT.DesignThe Anticoagulation with Low-molecular-weight heparin In the treatment of Cancer-Associated Thrombosis (ALICAT) trial is a randomised, multicentre, feasibility mixed-methods study with three components: (1) a RCT comparing ongoing LMWH treatment for CAT with cessation of LMWH at 6 months’ treatment (current licensed practice) in patients with locally advanced or metastatic cancer, consulted in three clinical settings (haematology outpatients, oncology outpatients and primary care); (2) a nested qualitative study, including focus groups with clinicians to investigate attitudes for recruiting to the study and identify the challenges of progressing to a full RCT, and semistructured interviews with patients and relatives to explore their attitudes towards participating in the study, and potential barriers and concerns to participation; and (3) a UK-wide survey exercise to develop a classification and enumeration system for the CAT models and pathways of care.SettingA haematology outpatients department, an oncology outpatients department and primary care.ParticipantsPatients with ongoing active or metastatic cancer who have received 6 months of LMWH for CAT.InterventionsOngoing LMWH treatment for CAT versus cessation of LMWH at 6 months’ treatment in patients with locally advanced or metastatic cancer.Main outcome measures(i) The number of eligible patients over 12 months; (ii) the number of recruited patients over 12 months (target recruitment rate of 30% of eligible patients); and (iii) the proportion of randomised participants with recurrent venous thromboembolisms (VTEs) during follow-up.ResultsFollowing several delays in setting up the RCT component of the study, 5 out of 32 eligible patients consented to be randomised to the RCT suggesting progression to a full RCT was not feasible. Reasons for non-consenting were primarily based on a fixed preference for continuing or discontinuing treatment after 6 months of anticoagulation, and a fear of randomisation to their non-preferred option. Views were largely influenced by patients’ initial experience of CAT. Focus groups with clinicians revealed that they would be reticent to recruit to such a study as they had fixed views of best management despite the lack of evidence. Patient pathway modelling suggested that there is a broad heterogeneity of practice with respect to CAT management and co-ordination, with no consensus on which specialty should best manage such cases.ConclusionsThe results of the RCT reflect recruitment from the oncology site only and provide no recruitment data from haematology centres. However, it is unlikely that these other sites would have access to more eligible patients. The management of cancer-associated thrombosis beyond 6 months will remain a clinical challenge. As it is unlikely that a prospective study will successfully recruit, other strategies to accrue relevant data are necessary. Currently the LONGHEVA (Long-term treatment for cancer patients with deep-venous thrombosis or pulmonary embolism) registry is in development to prospectively evaluate this important and common clinical scenario.Study registrationThis study is registered as clinical trials.gov number NCT01817257 and International Standard Randomised Controlled Trial Number (ISRCTN) 37913976.Funding detailsFunding for the ALICAT trial was provided by the Health Technology Assessment programme (10/145/01) in response to a themed funding call. The study was designed in accordance with the initial funding brief and feedback from the review process.

Treatment of cancer‐associated venous thromboembolism: 12‐month outcomes of the placebo versus rivaroxaban randomization of the SELECT‐D Trial (SELECT‐D: 12m)

“…Twenty‐five percent of patients had died and 9% had withdrawn from the trial before the 6‐month time point. Clinicians alongside the patients were choosing whether to enter the second randomization, most likely on the basis of clinical factors, reasons similar to a UK anticoagulation duration study in cancer patients that failed to recruit . However, the type of VTE at trial entry and the clinical outcomes for the 44 eligible patients who did not participate in the second randomization were similar to the 92 who did participate.…”

Cancer‐associated venous thromboembolism: Treatment and prevention with rivaroxaban

“…The shortcoming of this expert consensus is a paucity of clinical trial data on benefit–risk profile beyond the acute treatment period (3‐6 months) . Such data gathering is complicated by the recruitment and retention of patients in extended treatment trials (ie, because of high mortality and a general reluctance to continue treatment beyond 6 months) …”

Using the ‘Social Marketing Mix Framework’ to explore recruitment barriers and facilitators in palliative care randomised controlled trials? A narrative synthesis review

“…Barriers: Participants not interested/clinical equipose A number of papers highlighted high refusal rates as an issue 27,31,33,36,55,62,71 with the lack of clinical equipoise being cited as a possible reason for this, with concerns about being randomised to their non-preferred arm having an influence on whether or not patients agreed to take part. 62,71 A lack of belief in the intervention, 31,33 the lack of an acceptable control, 31 the feeling the intervention was not needed at that particular time 27,33,62 and competing priorities 55 were also cited as reasons for refusal. These concerns about the intervention, the control and randomisation also apply to health care professionals and may be one of the reasons for their gatekeeping.…”

“…Buss et al 33 Page of Palliative Medicine 4 http://mc.http://mc.manuscriptcentral.com/palliative-medicine al, 31 Noble et al, 62 Buss et al, 33 Anmari et al 27 Clinical equipose Noble et al, 62 Bausewein et al, 31 Westcombe et el 71 Buss and Arnold, 32 Goodwin et al, 44 Westcombe et al, 71 Hardy et al, 47 Jones et al, 52 Daniels and Exley 38…”