by Seema Belani, BA and Suresh Vedantham, MD
Post-thrombotic syndrome (PTS) is a chronic, burdensome consequence of deep vein thrombosis (DVT).1 PTS typically is characterized by chronic leg pain, swelling, fatigue and/or heaviness, and can be accompanied by physical signs of venous hypertension, including venous ectasia, skin hyperpigmentation, subcutaneous fibrosis and ulceration. R ecent studies have shown that about 40 percent of patients with symptomatic lower extremity DVT develop PTS, but it is poorly understood why some patients develop this condition and others do not (1). Of importance, PTS has been shown to significantly impair health-related quality of life (QOL) in DVT patients, with the degree of QOL impairment paralleling the severity of PTS.2
In recent years, a number of clinical studies have evaluated the abilities of noninvasive and invasive strategies to reduce a patient’s likelihood of developing PTS. In some of these studies, the results of formal QOL assessments have been presented. However, the assessment of QOL offers certain complexities that need to be understood to be confident that one can fully appreciate what a study’s findings say about the impact of a particular treatment upon patients’ wellbeing. The purpose of this article is to summarize important considerations that should be weighed when interpreting the results of QOL studies in patients with DVT.
First and foremost, it is important to distinguish disease severity from QOL impact of a disease, since these are entirely separate attributes. While the two attributes may often parallel one another for major diseases, this is not always the case. For example, many patients with PTS describe robust daily leg aching and swelling, but are able to maintain a high level of function and a positive attitude. Other patients may have their activity severely limited and/or become depressed by comparatively modest symptoms. This apparent discordance reflects the fact that the phenotypic features of PTS can vary greatly from person to person in ways that are not well understood, and the fact that QOL is a complex attribute with many contributing factors. QOL may be influenced greatly by concomitant medical conditions (e.g. mild PTS on top of a recent hip arthroplasty may add substantially to functional limitations), life circumstances (e.g. changes in family health, relationships and/or employment status), baseline ps chological health and individual patient expectations for what level of functional impairment can be tolerated.
Clinical treatment trials are usually designed to answer a single “primary question” about an estimate of treatment effect with use of a particular therapeutic intervention. A common approach taken for well-designed studies is to actively control factors that are known to affect the primary outcome, and beyond this to allow randomization to otherwise “equalize” the study cohorts. What this means is that the ideal way to determine the impact of a particular treatment upon QOL would be to actively ensure that patients with factors that are known to affect QOL are balanced in the two treatment arms. However, for PTS studies, the downside is that since QOL is multifactorial, a negative study might then miss an effect of the treatment upon PTS prevention. For this reason, most PTS prevention studies have utilized a validated measure of PTS as the primary outcome, with QOL assessments reported as a secondary outcome. This approach makes sense; however, we must realize that in such studies the diverse factors that affect QOL may not be perfectly balanced among the different treatment arms.
Another reason why PTS severity must be considered separately from QOL is that some medical treatments that prevent or reduce PTS may be associated with uncomfortable side effects or inconveniences that, if sufficiently severe, could adversely affect QOL. For example, there is limited evidence that the long-term use of tinzaparin, an injectable low molecular weight heparin (LMWH), may provide better protection against PTS than warfarin therapy; however, LMWH injections are painful and can cause substantial bruising in some patients.5 Compression stockings are difficult to don and are very uncomfortable for some patients. Endovascular procedures, while delivered over a shorter time period, can produce local aching and limitation of mobility at the site of catheter placement that could conceivably impact short-term to medium-term QOL if resolution is slow (e.g. if local hematomas are frequent). Such considerations are not unique to PTS prevention therapies – for instance, many cancer chemotherapy regimens reliably reduce disease extent, but with substantial impact to the patient in terms of side effects.
The multifactorial nature of QOL also creates important challenges in its measurement. Self-reported measures that assess “generic QOL” are well-validated as reflecting an individual’s overall state of well-being. On one hand, they can be relatively insensitive to the impact of a particular disease upon overall QOL. On the other, “disease-specific” QOL measures tend to facilitate the detection of changes in QOL as they relate to a particular disease, but are less well-suited to consider the impact of that disease upon a patient’s overall well-being in the context of other important factors. For these reasons, QOL measurement experts generally recommend that both types of measures be used to estimate QOL in any particular study.
Finally, most QOL measures are in the form of patient self-reported questionnaires, which may be vulnerable to reporting bias. In the more rigorous studies, the staff members administering the questionnaires have been blinded to the patient’s allocated treatment arm, but very few studies have mandated patient blinding. It therefore remains possible that the self-evaluation of QOL could be prone to various forms of reporting bias, including a placebo effect, depending upon the design and implementation methods of the specific study.
Recent Clinical Trials of DVT Therapies
A number of studies have demonstrated that DVT patients who develop PTS experience impaired healthrelated QOL. Of particular interest, the Venous Thrombosis Outcomes (VETO) Study was a rigorous multicenter, observational study in which 387 patients with first-episode symptomatic lower extremity DVT were followed for two years and evaluated with measures of PTS and QOL.1,2 This study found that, a) approximately 40 percent of patients developed PTS over two years using the Villalta PTS Scale; b) patients with PTS experienced significantly worse QOL compared with patients without PTS at all timepoints (assessed using the generic SF-36 and venous diseasespecific VEINES-QOL measures); and c) the presence and severity of PTS were the leading predictors of QOL during the two-year period.6-8 Against the background of previous studies which are largely concordant, this contemporary study provides compelling evidence of a strong relationship between PTS and impaired QOL.
The daily use of elastic compression stockings (ECS) after an episode of symptomatic lower extremity proximal DVT has been hypothesized to reduce the risk of PTS, with previous open-label trials providing suggestive evidence of such a benefit.9,10 However, more recently, the SOX Trial evaluated the efficacy of ECS in a much larger (n=806) multicenter, randomized, double-blind, placebocontrolled trial11. In this study, patients were randomized to receive either an active (30-40mmHg) stocking or a placebo (identical in appearance but with <5mmHg ankle pressure) stocking. The SOX Trial, which used the Ginsberg PTS measure and the Villalta PTS Scale, found no difference in PTS rates or severity between the two treatment arms over a two-year follow-up. As might be expected, there was also no difference in health-related QOL between the two treatment arms that were assessed using the SF-36 and VEINES-QOL measures.
Over the years, a few studies have evaluated catheterbased therapies that have been hypothesized to prevent PTS and preserve QOL. In 1999, a prospective multicenter registry documented the safety and anatomic efficacy outcomes of 473 patients with proximal DVT who received urokinase catheter-directed thrombolysis (CDT) infusions between 1994 and 1997.12 In a follow-up investigation, Comerota et al. evaluated health-related QOL in a 68-patient subgroup of patients from that registry who underwent anatomically successful CDT for acute iliofemoral DVT. The results were compared with those from a retrospectively-identified, 30-patient “matched” control sample of patients who had been treated with anticoagulant therapy alone (no CDT). In this study, the CDT-treated patients experienced superior health-related QOL at mean 16 months follow-up, including fewer PTS symptoms (p=0.006), better physical functioning (p=0.046), less stigma of chronic venous insufficiency (p=0.033), and less health distress (p=0.022).13 As seen in later studies of pharmacomechanical CDT (PCDT) methods by the same group, successful lysis correlated with improved QOL.14 However, the control arm patients were older than the CDT-treated patients (61 years + 6 versus 53 years + 17, p=0.039). Since QOL is known to decline with advancing age, this is a potentially relevant limitation. The modest sample size and patient selection method (e.g. inclusion only of patients who had “successful” CDT, retrospective selection of the control cohort) are also issues that limit the inferences that can be drawn from this study about the effect of CDT upon QOL.
In the multicenter CAVENT Trial, patients with firstepisode proximal DVT were randomized to receive anticoagulation and compression or anticoagulation, compression and additional CDT.15 One hundred eighty nine patient outcomes were reported. The use of CDT was associated with a relative PTS risk reduction of 26 percent and a 3 percent rate of major, but non-fatal bleeding over a two-year follow-up using the Villalta PTS Scale (55.6 percent versus 41.1 percent, p=0.04). A subsequent health economic analysis of this study was performed and found that the use of CDT was associated with an additional 0.63 qualityadjusted life-years with an incremental cost-effectiveness ratio of $20,429 per QALY gained. This translates to an 82 percent likelihood that CDT is cost-effective at a willingnessto-pay threshold of $50,000.16 A study of job absenteeism in trial participants found that CDT-treated patients were less likely to have taken paid leave after their DVT than control arm patients (26.5 percent versus 40.4 percent, p=0.046).17 Together, these findings point to CDT as being fairly costeffective, at least in Norway.
On the other hand, a third study summarized the CAVENT Trial’s QOL analysis.18 Patients in both arms were given the EQ-5D and VEINES-QOL/Sym measures over a two-year follow-up. Like previous studies, this study confirmed that patients with PTS fared more poorly than patients without PTS in terms of QOL (p < 0.001). However, although the study found significantly better disease-specific QOL in CDT recipients over the first six months (mean VEINES-QOL score 51.3 CDT versus 48.9 control, p=0.048), this effect did not extend to generic QOL (EQ-5D score 0.82 CDT versus 0.81 control, p=0.893) and was not sustained over 24 months (no difference in scores on either measure). These findings will undoubtedly surprise many CDT proponents, since it has been expected that any QOL benefits associated with endovascular thrombus removal would accrue over the long-term in parallel with avoidance of the most severe PTS manifestations (e.g. venous ulcers). Limitations of the QOL assessment in CAVENT include the modest sample size, and it has been speculated by some that the infusion CDT technique used in that study, which did not incorporate use of mechanical thrombectomy devices and which saw very limited use of stents, may not provide the same level of efficacy as the pharmacomechanical methods that are more widely used in the United States and other countries. All that said, it should be remembered that CAVENT was a very rigorously performed multicenter, randomized trial with explicit efforts to minimize bias, so its finding that the impact of CDT upon QOL may be time-limited should be considered carefully in future studies.
The NIH-sponsored ATTRACT Study is a multicenter, randomized controlled trial evaluating the ability of adjunctive PCDT to reduce the risk of PTS in patients with proximal DVT.19 The study includes a robust QOL assessment at baseline and at 1, 6, 12, 18, and 24 months post-randomization. As of March 31, 2014, ATTRACT had enrolled 589 patients out of a planned sample of 692 patients. With multiple rigorous assessments of PTS (Villalta, Venous Clinical Severity Score, and Clinical-Etiologic-Anatomic-Pathophysiologic Classification) and use of both generic (SF-36) and venous disease-specific (VEINES-QOL) measures, ATTRACT is expected to provide even more robust information about the impact of PCDT upon QOL.20-22
PTS is a leading determinant of QOL in patients with DVT. PTS and QOL are distinct attributes that should both be routinely assessed in DVT treatment trials. The concomitant use of measures to assess PTS disease severity, generic QOL and venous disease-specific QOL can help to provide a comprehensive assessment of the impact of therapy upon a patient’s well-being. Important considerations to bear in mind in interpreting QOL data are the extent to which a particular study expressly minimized bias from factors that are known to affect QOL, the degree to which blinding and other measures were used to minimize reporting bias for patientreported measures, and the possibility that the nature of the treatment itself may produce side effects or inconveniences that impact the QOL assessment. It is hoped that ongoing studies will enable more definitive conclusions to be drawn concerning the impact of CDT and PCDT upon QOL.
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