Daily Duration of Compression Treatment in Chronic Venous Disease Patients: A Systematic Review

Background: There are no data on the daily regimen of compression therapy in patients with chronic venous disease. This systematic review aimed to establish the optimal daily duration of compression treatment. Methods: A systematic search of CENTRAL and MEDLINE was performed to identify RCTs, non-RCTs, reviews, systematic reviews, meta-analyses, and guidelines evaluating the use of compression regimens in the treatment of varicose veins. Results: Thirty-two RCTs, three non-RCTs, four observational studies, and two crossover trials reporting the duration and regimes of compression treatment fulfilled the inclusion criteria. The daily duration of compression was reported in patients after invasive treatment, for venous ulcer treatment, in patients with venous symptoms. The quality of the studies varied. We could not conduct a meta-analysis due to the heterogeneity of the research data and their quality. Twenty-three studies reported results of compression usage after invasive procedures. Eight studies reported daily duration regimens in patients with venous ulcers. Nine studies reported the impact of compression on venous symptoms and/or edema or limb volume change. One study was conducted to assess if compression improves QoL in venous patients. While there was a clear difference found in the daily duration depending on the clinical scenario, no data in support of exact regimens were found. Conclusions: There are no reliable data supporting exact daily regimens of compression treatment in various cohorts of CVD patients.

On the other hand, patients' adherence to compression treatment is often poor [18]. Wearing compression garments often leads to significant discomfort due to itching, sweating, skin dryness, and irritation [19]. Adverse events of compression make patients less compliant with treatment [18,[20][21][22]. One possible way to improve adherence could be the adjustment of a daytime compression regimen, i.e., determining an optimal daytime duration effective at controlling CVD symptoms and signs. Nevertheless, although guidelines recommend compression as a first-line treatment for many patients, they do not detail the optimal day duration of compression [15][16][17]23].
This study aimed to investigate the optimal duration and regimens of compression treatment in CVD patients.

Search Strategy
For reporting the study results, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used [24]. Randomized clinical trials (RTCs), non-RCTs, reviews, systematic reviews, meta-analyses, and guidelines were searched using the Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed (MEDLINE) databases to identify studies that evaluated the use of compression hosiery in the treatment of varicose veins. In addition, references in identified or related publications were reviewed to highlight any additional studies.

Inclusion Criteria
Full-text articles reporting the duration and regimes of compression treatment published in English and not limited by year were included.

Exclusion Criteria
Studies were excluded if they reported compression treatment for asymptomatic varicose veins or in CVD patients with coexisting peripheral arterial disease.

Data Extraction
Datasets included first author, year of publication, study design, description of the cohort by CEAP classification, basic description of the studied population, treatment methods, class of compression, compression regimes, and assessment period, and the study results were extracted by two researchers (S.M. and A.A.). All disagreements were resolved by adjudication by a third reviewer (I.A.).

Statistical Analysis
It was impossible to draw any statistical analysis due to the variability of the compression products used, the different regimes used, and the different outcomes assessed.

Literature Search
A systematic review of the literature identified 424 potential records, of which 103 were rejected as duplicates, 16 as not reported in English, and 162 unacceptable after reviewing the title and abstract. Of the remaining 143 papers, a total of 41 papers were finally eligible for inclusion ( Figure 1).

Statistical Analysis
It was impossible to draw any statistical analysis due to the variability of t pression products used, the different regimes used, and the different outcomes as

Literature Search
A systematic review of the literature identified 424 potential records, of wh were rejected as duplicates, 16 as not reported in English, and 162 unacceptable viewing the title and abstract. Of the remaining 143 papers, a total of 41 papers nally eligible for inclusion ( Figure 1).

Included Studies
The analysis included 41 studies of which 32 were RCTs, three were non-R were observational studies, and two were crossover designed trials. The daily dur compression was reported in patients after invasive treatment, for venous ulce ment, and in patients with venous symptoms. The main information extracted f studies is presented in Tables 1-4.

Daily Duration of Compression after Invasive Procedures
Twenty-three studies reported the results of compression usage after invasive procedures including high ligation and stripping, phlebectomy, laser and radiofrequency ablation, and foam sclerotherapy (Table 1). For "daytime" and "during the day", compression was prescribed in five [25][26][27][28][29] and two studies [30,31], respectively. The "day and night", "24 h", and "continuously" regimens were used in two [32,33], one [11], and two studies [34,35], respectively. In five studies, daily duration regimes changed consecutively, from "day and night" to "daytime" in two studies [36,37], from "day and night" to "8 h a day" in one [38], from "24 h" to " daytime" in one [39], and from "24 h" to "while ambulatory" in one [40]. Other daily regimens used were "during walking hours" [41], "removed at night" [42], "throughout the day" [43], and "all day" [44]. In a study from Elderman et al., a mean daily duration of 12.48 h was registered [14]. Reich-Schupke et al. reported that, when patients were asked to use compression for the "whole day, for at least 8 h/day", 29.3-42.6% of them wore stockings for 6-12 h a day, while 53.2-68% wore stockings for 12-18 h a day [45]. No comparison of the outcomes depending on different daily durations was made.

Daily Duration of Compression in Patients with Venous Symptoms/Edema
Nine studies were conducted to assess the impact of compression on venous symptoms and/or edema or limb volume change ( Table 3). Four of them reported "8 h a day" as a prescribed regimen [54][55][56][57]. Other regimens used were "from morning to bedtime" [52,58], "during waking hours" [59], "from morning before going to bed" [60], and "day and night, then removed overnight" [61]. In the study of Belczak et al., there were two groups where Class-2 stockings were prescribed for 6 h/day and 10 h/day, while the third group did not use compression [62]. Evening edema was reduced in the treatment groups compared with no compression. Wearing stockings for 10 h/day was more effective than for 6 h/day.
One study was conducted to assess if compression improved QoL in venous patients. Patients were recommended to wear stockings no less than 8 h a day for six months. The authors measured the mean daily duration of compression treatment in patients with all C classes from C1 to C6. It varied from 9.33 to 10.4 h [63].

Risk of Bias
Twenty-four RCTs were labelled as having a moderate risk of bias ( Figure 2) [11,14,[25][26][27][30][31][32][33][34][35][36]38,[40][41][42][43]45,47,48,50,52,58,61]. This was mainly due to no blinding of patients and/or researchers and a lack of descriptive information regarding study drop-out or withdrawals. Most studies were likely to include an appropriate randomization approach with attempts to create balanced groups at the baseline and to use allocation concealment and analysis by intention to treat. Five RCTs were classified as being at a low risk of bias overall, with all risk-of-bias domains were judged to be of low risk [37,39,44,51,55]. Three RCTs had a high overall risk of bias due to blinded outcome assessment [56,62], incomplete outcome data [62], and deviation from the treatment plan [46].  Of the two crossover trials, one had a high risk of bias due to deviations from the intended interventions and the measurement of the outcome [59] (Figure 3). It was also unclear whether randomization was carried out. Another study had moderate risk and was designated as randomized, but the exact method was not specified [54].   All non-randomized studies had a moderate risk of bias ( Figure 4). In all cases, there was a risk of bias due to the measurement of outcomes [28,29,49,53,57,60,63]. Four studies had risks associated with the classification of the interventions [29,49,53,63]. Three studies had domains alleged to be biased due to deviations from the intended interventions after assessment [29,57,63]. One study had bias regarding the selection of participants into the study [49], and the other one was due to missing data [29].

Meta-Analysis
Due to the heterogeneity of the data in terms of different indications for the compression treatment, regimes, and garments used and the differences in the outcomes reported, it was impossible to perform a meta-analysis to compare the results of different daily duration prescriptions.

Discussion
The present review was conducted to evaluate data on the impact of the daily duration of compression treatment in patients with CVD. To our knowledge, this is the first attempt to assess if treatment results depend on how many hours a day compression is prescribed.
This question arises from routine clinical practice observations and is supported by logical speculations. On the one hand, every patient for whom compression is prescribed asks a physician how long it has to be used during the day. No recommendations have been made by guidelines on this up to now. The decision is at the physicians' discretion, whose recommendations are usually "for daytime", "from wake up until going to bed", etc. This prescription seems to be justified for patients with venous ulceration or severe edema. However, many patients experience signs and symptoms of much-less severity. For example, those who had deep venous thrombosis several months ago may have edema and symptoms, but no trophic disturbances. Compression may also be prescribed for symptomatic C1-C2 patients with a primary CVD. For such patients, the above-mentioned recommendations seem rather uncertain, confusing, and even redundant.
Daytime may significantly differ depending on geographical area and the season of the year. Waking time is an indefinite term also. Its duration may vary widely in patients of different ages, social statuses, occupations, physical conditions, etc. On the other hand, the lack of an exact daily "dosage" may lead to an increase in discomfort related to compression garments. Compression used from waking up until going to bed in the wintertime is not the same as in hot weather conditions. Practical observations confirm that patients' compliance in warm weather is not good. Some patients report discomfort independently of environmental conditions, which makes them less compliant. What happens if compression is prescribed not for 15-16 h (from waking up till going to bed), but for 8-10 h a day, which is close to the average time of active orthostasis? It can be assumed that compression of a lesser duration would lead to less discomfort, thus increasing patients' compliance with the treatment. To discuss if compression for several hours a day (and for how many hours) is reasonable, we should have data on whether this regimen is as effective as the commonly recommended daytime wearing. This systematic review was conducted to establish whether such data have been already obtained.
We found 40 studies in which daily duration of compression treatment were specified. Four groups of studies depending on the patients' cohorts and end-points were identified. There were three main clinical scenarios, i.e., the period after invasive procedure, venous ulcer, or symptomatic CVD and/or edema. We also found one study that was designed to register QoL in all C classes.
Interestingly, recommendations for the daily duration of compression were quite different ( Figure 5). Continuous (day and night, 24 h) and daytime (during the day, all day, etc.) regimens were mainly used after invasive procedures and in venous ulcer patients. However, continuous compression was never prescribed for symptomatic patients and edema. A regimen with a duration in hours per day was used for symptomatic disease and edema control. In two other scenarios, such a regimen was used only once after an initial period of continuous compression. This reflects the difference in what the patients need in different clinical situations. The post-procedural period is characterized by slight or moderate pain/discomfort, which may be reduced by elastic compression. Compression is also useful to control exudation from incisions in the first post-procedural days. This explains the prescription of compression for continuous use after invasive treatment. In a venous ulcer patient, the main goal of compression was to diminish the orthostatic loading of the venous system. Therefore, it is justifiable to recommend compression for the time when the patient is in the upright position, no matter whether standing or sitting, i.e., from waking up until going to bed. As for symptoms and/or edema control, it is generally assumed that it is enough to cover the working hours by compression. This leads to the use of daily dosage measured in hours, mainly 8 h a day, which is close to the common working day duration.
The general view of the findings from the literature confirms a connection between the daily duration of compression with the clinical situation. On the other hand, there are still no definite recommendations that can be used by physicians in routine clinical practice. The only regimen that is precisely defined with no interpretations possible is continuous (day and night, 24 h) compression.
When it comes to the daytime regimen, an important issue arises. Compression beyond nighttime was defined in fully different terms for patients who had undergone invasive treatment (daytime, during the day, whole day) and for those with ulceration (entire day, walking hours, compression removed at night at bedtime, wakefulness). This may indicate a need for different daily durations in these two cohorts. Interpreting daytime as working hours, i.e., from around 9 am to around 5 pm, needs exact definitions as patients may accept it their own way. For example, Elderman et al. prescribed daytime compression after EVLA and then measured the mean duration of wear. This resulted in 12.48 h a day [14]. This is also clearly different from what, for example, wakefulness means. In the study of Belczak et al., a duration of 10 h/day was also called "entire day" [62]. The nuances in using different terms cannot be caught by those physicians whose native language is not English. On the other hand, if one interprets daytime as the period between sunrise and sunset, then the geographical and seasonal conditions must also be taken into consideration. Thus, the lack of precise definitions of the mentioned terms may lead to a misinterpretation of the available data and the incorrect implementation in routine use of elastic compression. The post-procedural period is characterized by slight or moderate pain/discomfort, which may be reduced by elastic compression. Compression is also useful to control exudation from incisions in the first post-procedural days. This explains the prescription of compression for continuous use after invasive treatment. In a venous ulcer patient, the main goal of compression was to diminish the orthostatic loading of the venous system. Therefore, it is justifiable to recommend compression for the time when the patient is in the upright position, no matter whether standing or sitting, i.e., from waking up until going to bed. As for symptoms and/or edema control, it is generally assumed that it is enough to cover the working hours by compression. This leads to the use of daily dosage measured in hours, mainly 8 h a day, which is close to the common working day duration.
The general view of the findings from the literature confirms a connection between the daily duration of compression with the clinical situation. On the other hand, there are still no definite recommendations that can be used by physicians in routine clinical practice. The only regimen that is precisely defined with no interpretations possible is continuous (day and night, 24 h) compression.
When it comes to the daytime regimen, an important issue arises. Compression beyond nighttime was defined in fully different terms for patients who had undergone invasive treatment (daytime, during the day, whole day) and for those with ulceration (entire day, walking hours, compression removed at night at bedtime, wakefulness). This may indicate a need for different daily durations in these two cohorts. Interpreting daytime as working hours, i.e., from around 9 a.m. to around 5 p.m., needs exact definitions as patients may accept it their own way. For example, Elderman et al. prescribed daytime compression after EVLA and then measured the mean duration of wear. This resulted in 12.48 h a day [14]. This is also clearly different from what, for example, wakefulness means. In the study of Belczak et al., a duration of 10 h/day was also called "entire day" [62]. The nuances in using different terms cannot be caught by those physicians whose native language is not English. On the other hand, if one interprets daytime as the period between sunrise and sunset, then the geographical and seasonal conditions must also be taken into consideration. Thus, the lack of precise definitions of the mentioned terms may lead to a misinterpretation of the available data and the incorrect implementation in routine use of elastic compression.
In symptomatic CVD patients, the "dosage" in hours a day was most-often recommended. This seems quite reasonable, taking into account that venous symptoms are usually of light/moderate intensity and can be effectively managed by less-prolonged compression during the day. The goal of compression is to prevent symptoms from appearing by supporting venous return during orthostasis. The 8 h/day regimen reflects the common working day duration. However, no evidence exists about the effectiveness of this duration, especially in comparison with other regimens, i.e., 6, 10, or 12 h/day. The intensity of venous symptoms may differ, as well as the working day duration. It seems reasonable to adjust the daily duration accordingly. Belczak et al. found that a 10 h/day duration was more effective than 6 h/day in preventing edema after working hours in C0-C1 patients [62]. This is the only study that compared different regimens measured in hours a day. Thus, using compression 6 h/day seems to be insufficient in the early CVD stages. However, how many hours are enough for these patients? What is an optimal duration for C2-C3 patients-8, 10, 12, or more hours a day? Unfortunately, no studies have addressed this important practical issue yet.
Another issue related to the absence of definite recommendations is how patients follow physicians' prescriptions. Being recommended to wear stockings no less than 8 h/day, C1 patients wore them 9.33 h/day on average, C2 9.3 h/day, C3 9.66 h/day, C4 10.2 h/day, C5 9.7 h/day, and C6 10.4 h/day [63]. In the study of Reich-Schupke et al., patients received the same recommendation to use compression for the "whole day, for at least 8 h/day", but followed them differently. Some patients used compression for 6-12 h per day, while others wore stockings for 12-18 h per day [45]. It is clear that "daytime", "entire day", or "whole day" prescriptions are followed differently by patients.

Limitations
There is only one study that reported the impact of different daily durations of compression treatment on the outcomes. The study had a high risk of biases. Furthermore, there are many definitions that are used to describe the same regimens. This makes it difficult to compare data from different studies. Moreover, patients' compliance with the daily duration prescription was not measured objectively in either study. Improved reporting of daily compression regimens is essential to assess the treatment results.

Conclusions
This systematic review outlined the lack of data on the impact of different daily duration regimens on the effect of compression treatment in CVD patients. While, for different clinical scenarios, different duration regimens are used, no evidence exists of which regimen is optimal. The definitions of the same regimen may vary, which makes it difficult to compare the results from published studies. Future studies are needed to establish which exact daily duration of compression is optimal for patients with different clinical classes of CVD, especially for those with non-severe disease.

Data Availability Statement:
No new data were created or analyzed in this review. Data sharing is not applicable to this article.

Conflicts of Interest:
The authors declare no potential conflict of interest with respect to the research, authorship, and/or publication of this article.