Meta-analysis of PTS finds one in five risk of long-term symptoms following isolated distal DVT

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A meta-analysis is first to report the pooled risk of post-thrombotic syndrome (PTS) after isolated distal deep vein thrombosis (DVT). Researchers revealed a one in five risk of long-term PTS after isolated distal DVT, with one in 50 patients progressing to severe PTS, potentially developing to ulceration.

Principal author Benedict R.H. Turner, MBChB, from Imperial College London in London, England, and colleagues evaluated The Cochrane Library, Embase, Google Scholar and MEDLINE databases following PRISMA guidelines to identify eligible prospective cohort studies analyzing the rate of PTS after first episode of isolated distal DVT. Published in the European Journal of Vascular and Endovascular Surgery the study comprised trials held between 2005 and 2021 that included between 52 and 403 participants, with a total of 1,105 included across all seven studies reporting the development of PTS.

Turner et al note that the baseline characteristics of included articles were varied—follow-up periods ranged between one month to four years after first DVT, and several studies additionally reported which of the distal deep veins were thrombosed and corresponding risk factors. Interventions used to treat PTS included stockings, though duration, adherence and degree of compression were heterogenous. Other patients also received anticoagulation, although duration of treatment was unspecified. Among patients who were anticoagulated, direct oral anticoagulants, low molecular weight heparin and vitamin K antagonists were used.

The authors report that one in five patients are at risk of long-term PTS after isolated distal DVT, with one in 50 experiencing severe symptoms that may potentially include ulceration. Going into detail, the authors observed a post-thrombotic rate of 17% (95% confidence interval [CI] 11–26%, p<0.01) across the seven studies, 217 cases and 1,105 participants. Three of these studies (302 patients) reported on the severity of PTS symptoms, 78% posited as mild (Villalta score 5–9), 11% as moderate (10–14) and 11% were severe (15 or more).

Even when modulating the follow-up period, the authors did not see a significant change in the risk of developing PTS (p=0.71). This, they write, suggests shorter follow-up periods may be adequate to collect data on symptom development in clinical trials. The authors note that methods of data collection may have been “confounding” due to recall bias, as most included studies only reported rates of PTS at the average follow-up duration, rather than pinpointing the exact time at which PTS was diagnosed.

Overall, Turner and colleagues state that the risk of PTS after isolated distal DVT appears to be half that in comparison to proximal DVT, although occurring in a similar timeframe. According to the authors, this information is key when considering anticoagulation duration and compression therapy, as  “PTS is noted to be the principal moderator of quality-of-life after VTE [for patients]”.

When considering preventative measures that can be taken by patients, the authors note that the most recent European Society for Vascular Surgery (ESVS) guidance recommends graduated compression stockings in the proximal context of DVT to prevent the onset of PTS, despite the UK National Institute for Health and Care excellence and American College of Chest Physicians withdrawing this treatment option since it demonstrated no additional benefit in the SOX trial. The authors highlight that analysis of stocking use is limited. They detail that trials including CHAPS, SOX and ATTRACT have set about evaluating the treatment for preventing PTS, however they each excluded distal DVT from their eligibility criteria due to assumed lower event rates, although it may constitute up to two thirds of all DVT cases.

Going further, Turner et al comment that the management of isolated distal DVT has been a complex area of consideration in the literature, though there have been no randomized trials to establish the role of therapies preventing PTS in distal DVT. They write that the CACTUS double-blind, randomized trial revealed that outcomes for patients with isolated distal DVT who received six weeks of anticoagulation with Nadroparin were not superior to the placebo group for the composite outcome of venous thromboembolism (VTE) extension, contralateral DVT or pulmonary embolism (PE). Despite a clear risk factor for PTS being poor initial anticoagulation, the author’s meta-analysis shows limited evidence to support its use and benefit when compared with participants who received no anticoagulation.

The investigators note some limitations of their study, including risk of selective reporting due to the inclusion of retrospective studies. Additionally, studies were deemed eligible irrespective of the use of anticoagulation and/or compression stockings, due to little evidence suggesting its effectiveness on reducing rates of PTS unlike proximal DVT.

Although heterogeneity may have been introduced by pooling data in this way, the authors comment on the strengths of the study, noting the “comprehensive inclusion criteria and a thorough statistical analysis that has yielded a credible rate of PTS after distal DVT.” Continuing, they note that future trials of interventional measures to prevent PTS after DVT “should include an isolated distal DVT subgroup considering the established occurrence of PTS in this underserved and clinically significant group […] [and utilize] a survival analysis to delineate the evolution of PTS over time after isolated distal DVT.”

The investigators conclude that randomized trials to analyze and support interventions that can effectively prevent PTS are “urgently needed” to improve patient care and subsequent outcomes after isolated distal DVT.

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