https://orcid.org/0000-0003-1011-7440
Introduction
Deep-vein thrombosis (DVT) occurs in 1 in 1000 persons in the UK annually1. Half of those with lower limb, proximal DVT (involving the popliteal, femoral, or iliac vein, or a combination of these veins) go on to develop chronic pain, swelling, skin changes, and/or skin breakdown secondary to post-thrombotic syndrome (PTS)2. PTS is a lifelong disability affecting men and women of working age3. Patients with PTS may have difficulty walking, standing for prolonged intervals, and maintaining employment4. The severity of PTS increases with age and BMI2. With an older, heavier UK population, the burden of PTS is set to rise.
There is controversy over the role of graduated compression stockings (GCS) in preventing PTS. A meta-analysis of RCTs revealed that two early trials showed a large reduction in PTS after GCS use; however, the most recent SOX trial showed no benefit5. The SOX trial randomized 806 patients to receive ‘active’ GCS or placebo GCS, but was criticized for poor patient adherence to GCS, which tended to diminish over follow-up and may have affected efficacy. In the UK, the National Institute for Health and Care Excellence (NICE) recommends against GCS use after DVT6, as does the American College of Chest Physicians7. However, the European Society for Vascular Surgery and the Australia and New Zealand Working Party on the Management and Prevention of Venous Thromboembolism recommend the opposite8,9. The aim of the Compression Hosiery to Avoid Post-thrombotic Syndrome (CHAPS) RCT was to establish whether the use of GCS prevents PTS in patients with proximal DVT.
Methods
Between March 2020 and May 2022, participants were enrolled into this RCT at 19 hospitals across the UK. The National Research Ethics Service (NRES) granted ethical approval (reference 19/LO/1585). Further details are provided in the protocol10. The study was registered in an international trial registry (ISRCTN73041168). Eligibility criteria are detailed in Table S1. During recruitment, the age of entry was dropped from 18 to 16 years and the time from diagnosis of first acute DVT was relaxed from less than 2 weeks to less than 3 weeks. Participants were enrolled by local research nurses and electronically randomized 1 : 1 to either the control arm (standard of care) or the intervention arm. Allocation was performed using Research Electronic Data Capture (REDCap), a secure, web-based platform hosted by the Edinburgh Clinical Trials Unit, after anticoagulation had commenced. An independent assessor at each site performed the primary outcome assessment, blind to participant allocation10.
Participants in the intervention arm received a fitted GCS providing 23–32 mmHg pressure at the ankle plus oral anticoagulation as recommended by their local haematologist. Participants were reviewed at 2 weeks to remeasure their leg and give further advice, a donning aid, or an alternative GCS. Further information on adherence can be found in the study protocol.
Participants in the control arm received oral anticoagulation alone as recommended by their local haematologist. All participants were followed up at 6, 12, and 18 months. The primary outcome measure was the cumulative incidence of PTS using the Villalta scale. Secondary endpoints were serious adverse events related to GCS, GCS reordering, self-reported adherence, venous ulceration, and disease-specific Venous Insufficiency Epidemiological and Economic Study-Quality of Life (VEINES-QoL) and generic (EQ-5D) quality-of-life measures.
Results
Between March 2020 and May 2022, some 2332 patients were screened. Of these, 152 participants from 19 centres were randomized into the trial (Fig. 1). The main reasons for non-enrolment included: ‘Other reason’ the majority of which were classified as COVID-19 pressures, followed by participants not meeting the inclusion/exclusion criteria and clinician decision (for example isolated DVT below the popliteal vein). Baseline demographics are shown in Table S2.
CONSORT diagram for the CHAPS RCT
*A total of 53 randomized patients were not included in the screening database.
At the request of the funder, the CHAPS RCT was terminated early due to poor recruitment during the COVID-19 pandemic. At the time of trial closure, 152 of the planned 864 participants had been recruited. The Statistical Analysis Plan was updated to remove formal statistical comparisons and the results presented are descriptive.
As the trial was stopped early, around one-quarter of participants did not reach the first follow-up at 6 months. Follow-up data were available for 55 participants in the control arm and 56 participants in the intervention arm.
The cumulative incidence of PTS was 51% (28 of 55) in the control arm versus 30% (17 of 56) in the intervention arm at last follow-up (Table 1). Rates of all categories of PTS (mild, moderate, and severe) were lower in the intervention arm; the rate of severe PTS in the intervention arm was 0%.
Cumulative incidence of post-thrombotic syndrome at last follow-up (intention-to-treat analysis)
| Control arm (n = 55) | Intervention arm (n = 56) | |
|---|---|---|
| Any PTS | 28 (51) | 17 (30) |
| Mild PTS | 21 (38) | 15 (27) |
| Moderate PTS | 4 (7) | 2 (4) |
| Severe PTS | 3 (6) | 0 (0) |
| Control arm (n = 55) | Intervention arm (n = 56) | |
|---|---|---|
| Any PTS | 28 (51) | 17 (30) |
| Mild PTS | 21 (38) | 15 (27) |
| Moderate PTS | 4 (7) | 2 (4) |
| Severe PTS | 3 (6) | 0 (0) |
Values are n (%). Only participants with at least one complete follow-up Villalta-scoring assessment (for one leg or for both legs) are included.
Cumulative incidence of post-thrombotic syndrome at last follow-up (intention-to-treat analysis)
| Control arm (n = 55) | Intervention arm (n = 56) | |
|---|---|---|
| Any PTS | 28 (51) | 17 (30) |
| Mild PTS | 21 (38) | 15 (27) |
| Moderate PTS | 4 (7) | 2 (4) |
| Severe PTS | 3 (6) | 0 (0) |
| Control arm (n = 55) | Intervention arm (n = 56) | |
|---|---|---|
| Any PTS | 28 (51) | 17 (30) |
| Mild PTS | 21 (38) | 15 (27) |
| Moderate PTS | 4 (7) | 2 (4) |
| Severe PTS | 3 (6) | 0 (0) |
Values are n (%). Only participants with at least one complete follow-up Villalta-scoring assessment (for one leg or for both legs) are included.
Self-reported adherence to GCS was a mean(s.d.) of 6(2) days per week before the study visit. On these days, 60% of participants reported wearing GCS for greater than 8 h. GCS were reordered at 6 months by 64% (36 of 56) of participants (Table S3 and Fig. S1). Reasons given for not wearing GCS were (in order of frequency): participants finding them too hot, participants finding them uncomfortable, damage to them, participants forgetting to wear them, participants being unable to put them on, and problems washing them. No serious adverse events related to GCS were reported.
Generic and disease-specific quality-of-life scores were similar at 6 and 12 month time points between the groups (Tables S4, S5).
Discussion
Although failing to complete recruitment, the descriptive data from the CHAPS RCT show that fewer patients in the GCS arm had PTS. These data have the potential to be added to further summation analysis. The fact that more patients had PTS in the control arm is concordant with other studies11,12.
The strengths of this study are that it is a pragmatic, high-quality trial of typical patients in the UK National Health Service, with a validated primary endpoint and blinded assessment of outcome. In addition, it examined adherence in two independent ways. Aids to the intervention were made available to patients and a process evaluation was included. Unfortunately, this important study was not completed, but it was well informed by pilot data and should be considered by anyone undertaking trials in this area. The limitations of this study are that it did not achieve its target recruitment and therefore its findings are uncertain. The eligibility criteria (Table S1) were similar to those of three other studies, which recruited to target, and, under normal circumstances, the sample size is achievable.
Protracted delays in research and development affected site set-up and the study eligibility criteria were amended during the trial to widen the inclusion window from less than 2 weeks to less than 3 weeks from diagnosis of first acute DVT.
A further limitation is that one-quarter of participants randomized were not enrolled long enough to provide data on the primary endpoint or adherence.
After closure of the trial, all of the CHAPS sites were surveyed to explore their interest in taking part in a remodelled version of the trial; 77% of the sites said the research question was still important and 73% of the sites expressed interest in acting as a recruitment site.
The CHAPS RCT provides descriptive data in line with earlier trials that suggest compression hosiery reduce the likelihood of PTS in patients when used alongside anticoagulation. It calls into question the results of the SOX trial, which have influenced certain recommendations6,8,9,13 and not others14, and it demonstrates that, under the right circumstances, a trial could successfully answer the research question.
Funding
The CHAPS RCT was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (17/147/47). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
Acknowledgements
A.T. and R.L. are joint first authors.
Author contributions
Ankur Thapar (Conceptualization,Methodology, Writing-review & editing), Rebecca Lawton (Project administration, Writing—original draft, Writing—review & editing), Andrew Bradbury (Conceptualization, Investigation), Nicky Cullum (Conceptualization, Investigation), Manjit Gohel (Conceptualization, Investigation), Robert Horne (Conceptualization, Investigation), Beverley J. Hunt (Conceptualization, Investigation), John Norrie (Conceptualization, Investigation, Formal analysis, Writing—review & editing), Joseph Shalhoub (Conceptualization, Investigation), and Alun H. Davies (Conceptualization, Funding acquisition, Methodology, Investigation, Writing—original draft)
Disclosure
Stockings for the study were supplied by Medi UK at a discount. The authors declare no other conflict of interest.
Supplementary material
Supplementary material is available at BJS online.
Data availability
Anonymized data are available upon written request. All requests should be submitted to the corresponding author for consideration. Data are housed in the REDCap repository https://redcap.clinicaltrials.ed.ac.uk/ hosted by the Edinburgh Clinical Trials Unit (ECTU) at the University of Edinburgh.
