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Abstract
Introduction The post-thrombotic syndrome (PTS) is a form of chronic venous insufficiency due to a prior ipsilateral deep venous thrombosis (DVT). This is a frequent complication that develops in 20%–50% of patients after a proximal DVT and is associated with significant healthcare, economic and societal consequences. In the absence of effective and well-tolerated treatment options for established PTS, effective preventative measures are needed. Anticoagulation itself reduces the risk of PTS, and low-molecular-weight heparin may reduce this further through anti-inflammatory properties targeting the initial acute inflammatory phase of DVT.
Methods and analysis The Tinzaparin Lead-In to Prevent the Post-Thrombotic syndrome pilot trial is an investigator-initiated, multicentre, open-label assessor-blinded trial that will randomise patients with first acute symptomatic common femoral or iliac DVT to receive either a 3-week lead-in course of tinzaparin, followed by rivaroxaban (experimental arm) or rivaroxaban alone (control arm). Its primary objectives are to assess: (1) proportion of PTS at 6 months using the Villalta scale and (2) study feasibility, which consists of (a) the proportion of screened patients eligible for the study, (2) the proportion of eligible patients recruited and (c) the proportion of recruited patients adherent to treatment (defined as at least 80% of drug taken). This study will determine the feasibility of a subsequent larger definitive trial. Secondary outcomes include change of quality of life scores, PTS severity, global improvement, patient satisfaction, bleeding, recurrent venous thromboembolism, leg pain, death and lost to follow-up. Target recruitment will be a total of 60 participants, recruited at 5–6 centres.
Ethics and dissemination Primary ethics approval was received from the Sunnybrook Health Sciences Center Research Ethics Board (approval ID 3315). Results of the study will be disseminated via peer-reviewed presentation at scientific conferences and open access publication.
Trial registration number NCT04794569.
- HAEMATOLOGY
- Thromboembolism
- Anticoagulation
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STRENGTHS AND LIMITATIONS OF THIS STUDY
A strength of our study is that it is a multi-center, assessor blinded randomized trial.
A limitation of our study is that its open label design may bias assessment of outcomes.
Introduction
The post-thrombotic syndrome (PTS) is a form of chronic venous insufficiency due to a prior ipsilateral deep venous thrombosis (DVT).1 PTS is a frequent complication that develops in 20%–50% of patients after a DVT and is severe in 5%–10% of cases.2 3 PTS includes a broad spectrum of manifestations ranging from mild leg pain or heaviness up to venous claudication and cramping, with the most severe form of PTS presenting as disabling ulcers. While it is not a lethal condition, PTS is a public health concern as it strongly impacts patient’s quality of life (QoL) and is one of the main drivers of costs after a DVT.4 5 In the absence of effective therapies for established PTS, management relies mainly on prevention after a DVT.6 7 To date, the best preventative measure is timely administration of therapeutic anticoagulation.8–10 This is thought to lower the risk of PTS by around 80% by reducing thrombus extension, minimising residual venous obstruction (RVO) and reducing valvular damage.11–13 Current guidelines do not favour a specific class or type of anticoagulant for lowering the risk of PTS.13
However, the pathophysiological mechanisms of PTS as well as biological and clinical data suggest that there may be a difference in regards in the ability of various anticoagulants to prevent PTS.14 Indeed, both low-molecular-weight heparins (LMWHs) and direct oral anticoagulants (DOACs) have been reported to be superior to vitamin K antagonists for the prevention of PTS.14–17 This difference in efficacy could be driven by the differential ability of various anticoagulants to interact with inflammation, one of the main mechanisms of PTS.18–26 As LMWH may be more potent at inhibiting inflammatory response than DOACs, they may be more effective at preventing PTS.22 27 However, so far there have not been any direct comparisons regarding PTS outcomes between LMWHs and DOACs, the current standard of care for DVT.
A randomised trial is thus needed to assess whether the theoretical and laboratory evidence supporting the superiority of LMWHs over DOACs for the prevention of PTS translates to better clinical outcomes.
The Tinzaparin Lead-In to Prevent the Post-Thrombotic syndrome pilot trial
The Tinzaparin Lead-In to Prevent the Post-Thrombotic syndrome (TILE) pilot study is an open-label, assessor-blinded, multicentre, randomised pilot trial comparing a 3 week lead-in period of tinzaparin, followed by rivaroxaban to treatment with rivaroxaban alone to in patients with a common femoral or iliac vein DVT who are at high risk of developing PTS. This is an investigator-initiated study funded by LEO Pharma.
Trial objectives
Primary objective
The primary objectives of the TILE pilot trial are to assess whether the conduct of a large, definitive multicentre RCT is feasible in terms of recruitment and compliance to study drug and to estimate the rates of PTS in each treatment group to inform the calculation of sample size for the larger TILE trial. This will help guide the principal research question of the TILE trial, which is to determine whether an initial 3-week lead-in course of an LMWH (tinzaparin) followed by a DOAC (rivaroxaban) is superior to rivaroxaban alone in resolving acute DVT symptoms and preventing PTS in high-risk patients (those with symptomatic iliac or common femoral DVT).
Secondary objective
The secondary objectives of the TILE pilot trial are to compare the change in QoL scores from baseline (at 3 weeks and 6 months), PTS severity (6 months), global symptomatic improvement (at 10 days and 3 weeks), patient satisfaction (at 3 weeks and 6 months), DVT-specific leg pain (at 10 days and 3 weeks), recurrent DVT or pulmonary embolism (PE), major bleeding, clinically relevant non-major bleeding, death, serious adverse events (SAEs) (baseline to 3 weeks and 3 weeks to 6 months) and rate of lost to follow-up between groups.
Description of trial procedures
This study will be conducted at 5–6 Canadian centres. The clinical trial coordinating centre is located in Toronto (Sunnybrook Research Institute). The co-principal investigators are JPG and SK. All investigators are members of the Canadian Institutes of Health Research-funded CanVECTOR research network. Patients with a symptomatic, acute, common femoral or iliac DVT (without prior ipsilateral DVT) diagnosed within the past 10 days will be eligible to participate, provided they do not meet any of the exclusion criteria. Full inclusion and exclusion criteria are listed in figure 1. Of note, patients with cancer associated venous thromboembolism (VTE) will be excluded, as some guidelines still recommend LMWH for upfront treatment.28 Eligible and consenting participants will be randomised to receive either 3 weeks of tinzaparin 175 IU/kg subcutaneous injections once daily followed by rivaroxaban 20 mg orally daily or rivaroxaban 15 mg orally two times per day for 3 weeks, followed by rivaroxaban 20 mg orally daily. The total treatment duration for all patients will be at least 12 weeks, with further treatment at the discretion of the physician. Patients will be permitted to undergo other treatments that the treating physician prescribes, such as elastic compression stockings (ECS), exercise training and lifestyle measures (eg, leg elevation, moisturising creams). Patients who received early mechanical and thrombolytic thrombus removal techniques to treat the acute DVT will not be eligible. Ancillary DVT treatment is expected to be similar at all study sites across Canada and balanced between groups. Any compressive structural factors identified on ultrasound imaging such as aneurysms and May-Thurner syndrome will be managed in consultation with the appropriate surgical and interventional specialists.
TILE pilot trial flow diagram. DVT, deep venous thrombosis; HIT, heparin induced thrombocytopaenia; LMWH, low-molecular-weight heparin; NSAID, non-steroidal anti-inflammatory drug; PTS, post-thrombotic syndrome; QOL, quality of life; SAE, serious adverse event; Sc, subcutaneous; TILE, Tinzaparin Lead-In to Prevent the Post-Thrombotic syndrome.
Study participants will be followed for 6 months after study enrolment. They will have scheduled clinical assessments at baseline (within 10 days of DVT diagnosis; day 0), 10 days, 3 weeks, 3 and 6 months. Unscheduled assessments will occur if patients have symptoms suggestive of an SAE or become pregnant. Women of childbearing age will need to use effective contraception and will be instructed that it is contraindicated to take DOACs while pregnant. If a patient is unable to attend any of the follow-up visits in person, a telephone follow-up visit will be scheduled to assess PTS using the patient-reported Villalta scale.29 However, in person visits will be strongly encouraged. In the event that a patient discontinues the study drug, she/he will be asked to attend all follow-up visits. The study flow is shown in figure 1 and a summary of all study visits is shown in online supplemental table 1.
Supplemental material
At their own discretion, participants may withdraw from the study at any time and for any reason. Study participants may also be withdrawn from the study at the discretion of an investigator for reasons such as, but not limited to, safety, participant compliance or behavioural concerns. No specific post-trial care will be provided beyond the 6-month trial period. All participating sites will receive protocol updates through email communication.
Barriers to early recruitment may include a delay between assessment in the emergency department and study entry. Depending on the institutional policy of each site, emergency physicians may be educated about the study, and posters may be placed in emergency departments regarding the trial. The radiology departments will be aware of the trial and may advise on-call physicians when a relevant patient with thrombosis is detected. Barriers to participation may include the injectable nature of LMWH. Potential participants will be educated about injections and will be provided ongoing assistance regarding technique and complications.
Assessment of outcomes
Primary outcomes
For the pilot trial, there will be two primary outcomes. The first is the proportion of patients with PTS at 6 months, which will be used to determine sample size for the larger definitive TILE trial. The second primary outcome will be feasibility outcomes. This includes (1) the proportion of eligible patients, among patients screened, (2) the proportion of recruited patients, among eligible patients and (3) the proportion of patients adherent to treatment, among recruited patients. These outcomes will be derived from screening logs maintained by each local study coordinator. PTS will be diagnosed using the Villalta scale, as recommended by the International Society on Thrombosis and Haemostasis (ISTH).30 Adherence to treatment will be monitored by counting remaining syringes or tablets in the box supplied to the participant. Greater than 80% use of the study drug will be considered as adequate adherence. Greater than 50% of eligible patients agreeing to participate in the study will be considered a positive result in terms of feasibility. This is based on patient volume and experience with DVT treatment at the participating sites, and assumes an average recruitment of 1 patient per centre per month during the 18-month recruitment phase. For the large definitive trial, the primary outcome will be the proportion of patients with PTS at 2 years.
Secondary outcomes
PTS severity will be assessed based on the Villalta scale: mild, score 5–9; moderate, score 10–14 and severe, score >14 or the presence of a venous ulcer.13 Treatment satisfaction and global improvement will be assessed using a 7-point Likert Visual Analogue Scale questionnaire (1=strongly agree to 7=strongly disagree). QoL will be measured using validated general and venous disease-specific measures. General QoL will be measured using the Short-Form Health Survey-36 instrument.31 Venous disease-specific QoL will be assessed with Venous Insufficiency Epidemiological and Economic Study Quality of Life Questionniare (VEINES-QoL).32 DVT-related leg pain will be assessed using an 11 point Likert rating scale.33 Suspected recurrent DVT or PE will be confirmed by objective testing using criteria recommended by the ISTH.34 Major bleeding and clinically relevant non-major bleeding will be defined using the ISTH criteria.35 Death will be classified as due to VTE, due to bleeding or not due to VTE or bleeding. SAEs will be defined as per the Health Canada definition and reported as required by local regulations.36 Recurrent VTE, bleeding and deaths will be blindly adjudicated by two external assessors not involved in the trial. Follow-up radiologic indices such as venous reflux and RVO were not included due to resource limitations of this pilot study. Compression stocking use will be captured at each visit but is not part of the secondary outcomes because this is a co-intervention as opposed to a study outcome. All of the visits are outlined in table 1.
Summary of visits
Sample size and power calculations
The objective of this pilot trial is to assess feasibility of the study protocol and to obtain an estimate of the magnitude of difference in effectiveness between tinzaparin followed by rivaroxaban compared with upfront rivaroxaban. This will inform our estimation of the required sample size for a larger, definitive future trial. There are currently no available data to estimate the expected magnitude of this difference, as DOACs have not been directly compared with LMWHs for the prevention of PTS. Other PTS literature has shown effect sizes around 0.25 in terms of the effect of the intervention on the Villalta scale score at 6 months,37 suggesting that a sample size of around 25 patients per treatment arm would be sufficient.38 In an audit of sample sizes for pilot and feasibility trials undertaken in the UK, Billingham et al found that the median sample size per arm for pilot studies was 30 participants (range 8–114) and for feasibility studies was 36 (range 15–114).39 Another factor that may influence the required sample size is the temporal effect on frequency of PTS. While some authors have found that PTS frequency increases with time,40 others have not,41 suggesting that adjusting the sample size for this is premature. We plan to recruit 60 participants in total, which places our pilot trial within the recommended sample size range for pilot studies.
Statistical analyses
Descriptive statistics will be used to present the baseline characteristics of excluded participants and those in the two study arms. Categorical variables will be expressed as frequencies and percentages and continuous variables as means and SD or medians and IQRs.
For the outcomes PTS, PTS severity, DVT-related leg pain, global improvement, patient’s satisfaction with treatment, venous-disease specific and generic QOL, SAE and lost to follow-up, rates in the two intervention groups will be described, and between-group differences explored using a χ2 test stratified by centre. The analysis of feasibility indicators will be calculated as simple frequencies and proportions. We will also explore the impact of iliac versus common femoral vein location as well the number of days and doses of LMWH and DOAC administered prior to randomisation on clinical study outcomes. For differences in mean QOL scores between groups, analysis of covariance will adjust for baseline score. Score differences on the order of 3–4 points will be considered clinically significant.31 42 For binary and nominal data, the appropriate χ2 tests will be used to examine the respective crude associations, and for continuous variables, the unpaired two-tailed t-test. Tests will be two sided with α level set at 0.05. This pilot study does not incorporate any correction for multiplicity testing. The final TILE trial could include a correction for clinical outcomes beyond the Villalta scale score (eg, for DVT-related leg pain, global improvement, patient satisfaction, QoL scores). This study will be stopped prior to its completion if: (1) the intervention is associated with adverse events that call into question the safety of the intervention; (2) difficulty in study recruitment or retention will significantly impact the ability to evaluate the study endpoints; (3) any new information becomes available during the trial that necessitates stopping the trial or (4) other situations occur that might warrant stopping the trial.
Data management
Study coordinators at each site will screen and recruit patients, perform online randomisation via REDCap, a web-based system (Sunnybrook Research Institute, Toronto, ON), at a 1:1 allocation ratio (stratified by centre and DVT location (iliac vs common femoral)) using permuted blocks of variable size and complete case report forms. Data management will be overseen by the Centre for Clinical Trial Support (Sunnybrook Research Institute). Data will be reviewed and cleaned by the database coordinator on an ongoing basis. Assessors of PTS will be blinded to treatment allocation. Patients will also be instructed not to reveal their treatment group or the laterality of their DVT to the assessors. The final database will be provided to the biostatistician for analysis, which will be supervised by the study investigators. All study records will be kept for 15 years as per Health Canada regulations. No interim analyses are planned. The steering committee and a data safety management committee (DSMC) will oversee the study. The steering committee will be composed of the co-principal investigators, the qualified investigators, the collaborator, the patient partners, the statistician, the sponsor representative and the project manager. The DSMC will consist of an experienced thrombosis physician, a biostatistician and an experienced clinical trialist. The institutions and local REBs reserve the right to conduct independent audits as necessary. Once the trial is completed, relevant deidentified participant data (with a data dictionary) may be available to other researchers on reasonable request after publication, pending approval from both principal investigators and study sponsor, and after a data access agreement is signed.
Ethics and dissemination
The study investigators will ensure that this study is conducted in accordance with the principles set forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Participants of Research, and codified in the Tri-Council Policy Statement and/or the ICH E6.43 Approval has been obtained at the participating sites’ REBs. Primary ethics approval was obtained through Sunnybrook Health Sciences Center (approval ID 3315). Written informed consent will be obtained from all participating patients. Results of the study will be disseminated via presentations at scientific conferences and publication in open access, peer-reviewed journals. Authorship will be determined according to the statement from the International Committee of Medical Journal Editors.44 Open access to individual patient data is not planned, but all requests for the trials data will be considered on an individual basis by the trial steering committee. All investigators will be given access to the cleaned data sets.
Patient and public involvement statement
Two patient-partners, who are members of the Patient Partner platform of the CanVECTOR research network, are involved in the design and conduct of the trial and will be a member of the study steering committee.
Discussion
PTS is a frequent, costly and burdensome complication of DVT, especially in patients with large iliac or common femoral DVTs. There are currently few simple and effective treatment options for established PTS, increasing the importance of preventing PTS. Anticoagulant therapy is effective for preventing PTS, and a lead-in period of LMWH treatment followed by DOAC may reduce the risk of PTS further compared with DOAC use alone, based on laboratory data suggesting a more potent anti-inflammatory effect with LMWH. The objective of the future larger definitive TILE trial will be to determine whether a lead-in period of LMWH reduces the risk of PTS through faster symptomatic resolution during the initial acute phase of DVT treatment.
However, we chose to begin first with a pilot trial. Indeed, no trial to date has compared PTS outcomes between a lead-in period of LMWH followed by DOAC compared with DOAC treatment alone. We, thus, need an estimate of the effect size to inform the sample size calculation for a definitive trial. Also, a pilot trial is needed to demonstrate the feasibility of recruitment and drug adherence. The pilot trial will need to confirm that a sufficient proportion of screened patients will agree to a 50:50 chance of being randomised to receive an injectable anticoagulant for 3 weeks for PTS prevention purposes.
We will focus on a very specific population of proximal DVT: common femoral and iliac vein DVT. Indeed, they are the ones at highest risk of PTS and severe PTS for which tinzaparin is the most likely to be beneficial. In the ATTRACT RCT, the rates of PTS and moderate-severe PTS in the anticoagulant only treatment arm at 6 months were 46% and 19%, respectively in patients with iliofemoral DVT,41 compared with 33% and 10%, respectively, in patients with femoral and popliteal involvement.45
The choice of tinzaparin as the LMWH to be used in the TILE pilot trial is justified by several considerations. First, most of the studies with PTS focused outcomes that evaluated an LMWH used tinzaparin.14 Among all the trials that reported PTS outcomes, 248 patients received tinzaparin, 84 received enoxaparin, 53 received nadroparin and 44 received dalteparin.14 Second, there is laboratory evidence supporting more potent anti-inflammatory properties of tinzaparin compared with other LMWHs,27 46 suggesting that tinzaparin may be more likely to show a benefit. Third, from a pragmatic perspective, tinzaparin offers once daily administration with a 29 gauge needle (for some prefilled syringes) which is thinner than the 27 gauge needle used by other LMWHs.47 How long should tinzaparin be administered to be beneficial? In our BioSOX study, the inflammatory response was highest at DVT diagnosis, and declined rapidly over the first month.48 Over the following 5 months, there was only a small further decline in inflammation.48 Additionally, baseline inflammation predicted subsequent development of PTS.48 This suggests that the anti-inflammatory benefit of a study drug may yield the most effect over the first month after DVT diagnosis and treatment initiation. From a pragmatic perspective, the 3-week mark is when rivaroxaban dosing changes from twice daily tablets to daily tablets. Choosing a 3-week LMWH treatment duration allows for the transition of both intervention groups to the 20 mg orally daily dosing of rivaroxaban at the same time. Lastly, we believe that a longer treatment duration for the injectable formulation would reduce study recruitment and adherence to treatment, and we have thus attempted to minimise this while maintaining the theoretical benefit of LMWH treatment. Rivaroxaban was chosen as the DOAC to be used in this trial because the majority of current PTS-related studies have used it.16 17 49–55 While there have been no head-to-head trials of different DOACs, indirect data suggests that all DOACs are similar in terms of bleeding risk and effectiveness of VTE treatment. Once daily dosing (after the initial 3-week period) as well as the absence of a lead-in period of 5–7 days of LMWH also make rivaroxaban a pragmatic choice.56
One of the major limitations of our study could be its open-label rather than double-blind design. PTS includes symptoms that are subjective and prone to the placebo effect. Thus, the strong efficacy of ECS to prevent PTS demonstrated in open-label RCTs was not seen in double-blinded studies. However, we opted for an open-label design due to the cost, complexity and potential for patient refusal of a double-blinded study including a placebo injectable. In fact, no prior study of extended LMWH treatment compared with oral anticoagulation has been double-blinded, likely for similar reasons.57 To limit the impact of such a bias, assessors will be unaware of patients’ allocated treatment .
The results of this pilot trial will be highly relevant for informing the design of the definitive TILE study. Once completed and if positive, the definitive TILE study could provide a simple, non-invasive, effective and time limited treatment for decreasing the risk of PTS. This would be highly desirable, as PTS confers a high economic and healthcare burden and lacks clearly effective and well tolerated treatments. The finding of LMWH superiority would change practice for acute management of patients with DVT at high risk of PTS. Alternatively, if the DOAC alone arm is found to be equivalent to LMWH followed by DOAC, this would reinforce its status as the standard of care for acute VTE treatment.
Confidentiality
Patients will be identified only by a study number denoting study site and chronological enrolment at that site. Identifiers will be deleted from all study records. Study data will be stored in a secure, locked area and the on-line data management platform will be password protected. Information about study participants will be kept confidential and managed according to the requirements of the Personal Health Information Protection Act of 2004 (PHIPA) and the Research Ethics Board. PHIPA outlines the rules for the collection, use and disclosure of personal health information (PHI). The Act requires each participant to consent to the collection, use and access of PHI, unless consent is waived by the REB. Where consent is required, each participant must be informed of the following:
What PHI will be collected during this study?
Who will have access to that information and why?
Who will use or disclose that information?
The rights of a research participant to revoke their authorisation for use of their PHI. In the event that a participant revokes authorisation to collect or use PHI, the investigator may use all information collected prior to the revocation of participant authorisation. For participants who have revoked authorisation to collect or use PHI, attempts should be made to obtain permission to collect at least vital status (ie, that the participant is alive) at the end of their scheduled study period.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors Writing of original protocol, JPG and SK; writing of original manuscript, IM; review and editing of manuscript draft, IM, JA, SS, AD, PLG, SK and JPG; supervision, JPG; funding procurement, JPG and SK; all authors have read and agreed to the published version of this manuscript.
Funding The TILE study is an investigator-initiated study supported by LEO Pharma (grant number N/A). LEO Pharma provided funding for the TILE pilot study, including provision of tinzaparin and provided input for our consideration on certain aspects of the study design, but did not have a role in the planned analysis or writing the manuscript. LEO Pharma reviewed the final manuscript before submission. IM was funded through a CanVECTOR research award (grant number N/A). SK holds a Tier 1 Canada Research Chair in venous thromboembolism. SK, AD, SS, PLG and JPG are investigators of the CanVECTOR Network; the Network received grant funding from the Canadian Institutes of Health Research (CDT-142654).
Competing interests IM and SK have no competing interests to declare. JPG received consultant fees from Sanofi SA and Servier Laboratories; research grants from Leo Pharma, Bayer AG and Bristol-Myers Squibb-Pfizer; and a travel grant from Innothéra.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.