Pharmacological Treatment of Primary Chronic Venous Disease: Rationale, Results and Unanswered Questions

Perrin M, Ramelet AA. Eur J Vasc Endovasc Surg. 2011;41:117-125.

Reviewed by Peter NEGLEN, Trimiklini, Cyprus

To view PubMed abstract, please Click here

Drs Perrin and Ramelet have written a comprehensive review that tries to pin down the importance of pharmacological treatment (vasoactive drugs; VADs) in the management of primary chronic venous disease (PCVD). The use of VADs varies between countries and the type of specialist treating PCVD. The overwhelming reason for this is the lack of robust scientific support for its use, but also ignorance of the potential benefits. The authors give a balanced view of the present status of the use of VADs and suggestions on how to improve future evaluations, which are warranted.

Primary chronic venous disease and insufficiency (PCVI) are defined and the difference is pointed out.  The introduction describes initially how the CEAP system is used to classify clinical severity, with underlying etiology, affected anatomical sites, and pathological findings (obstruction and/or reflux). This is important since the CEAP classification is presently the only way to describe and select patients with venous disease adequately for inclusion in studies.  The lack of this information in available reports on VADs is the major obstacle to comparing published studies and performing a meta-analysis. In the future it will be necessary to use the CEAP classification, adhere to Consolidated Standards of Reporting Trials (CONSORT) for randomized studies, find validated tools to assess swelling and diffuse symptoms (cramp, itching, heaviness, and restless legs) and define what constitutes a clinically relevant improvement of these tools. In lieu of the latter, appropriate quality of life questionnaires have to be used. Not until then will we be able to assign the appropriate indication for VAD in the treatment of PCVD.

The authors also give a well-illustrated, excellent report on the present view of the pathophysiology of PCVD. The common denominator is venous hypertension caused by reflux and/or obstruction. The main cause in PCVD is venous reflux due to valve and vein wall changes, although the importance of iliofemoral venous outflow obstruction may be underestimated. The actual trigger for the structural changes of the venous wall is not known, but it appears that inflammatory events play a major role. Leukocyte rolling, adhesion, and trapping in the capillaries followed by transmural migration and release of enzymes combined with extravasation of macromolecules result in skin hyperpigmentation, dermatitis, fibrosis and, perhaps, ulcer. “Venous” pain is also hypothesized to be related to inflammation. It is not rare for patients to complain of tender and painful tributaries without any clinical or ultrasound findings of thrombophlebitis. If this inflammatory response could be controlled, the patient may have relief from symptoms and perhaps the progress of the disease could be delayed or prevented.

VADs can increase the venous tone, reduce capillary filtration, decrease blood viscosity, and increase cell velocity in the capillaries. Micronized purified flavonoid fraction (MPFF) treatment in animal models has been shown to reduce reflux and decrease inflammatory mediators. All these actions may theoretically improve symptoms of PCVD.  There are a plethora of studies and several reviews and meta-analyses have been performed. Statistically significant improvement of swelling, pain, cramps, itching, heaviness, etc. has been shown. Whether or not these are numerical significances alone or there is truly a significant clinical impact is hard to evaluate, especially since substantial relief is also noted in the placebo groups. There are no quality of life data. All of these studies also have many of the deficiencies discussed above. There is presently no adequate high-quality evidence supporting the use of VADs in any indication related to PCVD. The MPFF and rutosides have a tentative strong recommendation to relieve clinical symptoms and edema (1B of the GRADE system) and MPFF has the same recommendation for healing of small ulcers in PCVD as an adjuvant to standard treatment. The strong recommendation is made because the risk of important inadvertent complications is minimal (the risk as well as the benefit is part of the GRADE system).

The authors end with an appeal for appropriate future studies with proper use of validated tools of symptom assessment, the CEAP classification, and generic and specific quality of life scales to define the ultimate role of VADs in the treatment of PCVD. Endovascular or open surgery, when possible, is the first choice in PCVD with obvious venous pathology and has been shown to give excellent relief. MPFF and rutosides may be used in patients with chronic leg symptoms typical of PCVD, but with minimal or no findings of venous disease, and MPFF in patients with small recalcitrant leg ulcers as adjuvant to standard treatment.