How to treat varicose veins at the first stage. Review of all drugs

I analyze the evidence base for all drugs for the treatment of first-degree varicose veins and chronic venous insufficiency (CVI). How to treat varicose veins at the first stage based on evidence-based medicine.

In this article I do not touch upon compression hosiery, since pre-varicose vein syndrome is not accompanied by compression treatment, but I will definitely prepare material about it later.

We will talk about all active substances for the treatment of the initial stage of varicose veins, having the following ATC classification: C05 - Angioprotectors > C05B - Drugs used for varicose veins, C05C - Capillary stabilizing agents

A brief report on the evidence base. Details in the article

How I look for reliable medical information

My sources are the medical libraries  Pubmed and Cochrane . There is decent material [about evidence-based medicine]( http://encyclopatia.ru/wiki/%D0%94%D0%BE%D0%BA%D0%B0%D0%B7%D0%B0%D1%82%D0% B5%D0%BB%D1%8C%D0%BD%D0%B0%D1%8F_%D0%BC%D0%B5%D0%B4%D0%B8%D1%86%D0%B8%D0%BD% D0%B0) and international databases from neurologist N. Zhukov, which provides answers to all questions about searching for medical information.

Why do I need this: research on medications has more than once saved me from unnecessary expenses in pharmacies and, on the contrary, convinced me of the feasibility of the prescribed treatment. First of all, I do this for myself, I have the time and desire for this. But not everyone can do this kind of work, so I’m sharing my experience here. So let’s get started.

Symptoms of the first stage of varicose veins

Chronic venous insufficiency (hereinafter referred to as CVI) is usually treated according to symptoms, since the causes of varicose veins, strictly speaking, are unknown. Most often they blame a sedentary lifestyle and genetic predisposition, pregnancy, excess weight, and diabetes.

First signs:

• Small vessels of the skin appear as a mesh;
• Previously invisible intradermal veins appear;
• Evening swelling;
• Slight tingling, “stirring” under the skin.

At the first cosmetic problems and slight discomfort, treatment should be started. This is the only way to avoid progression of the disease and further surgery (at least it will delay invasive treatment by a lot).

How to treat varicose veins? Preparations and active ingredients

There are several active ingredients that relieve symptoms. Everything that is available in pharmaceuticals is exclusively symptomatic treatment, working in tandem with lifestyle correction.

CVI and varicose veins at an early stage are treated with the following substances:

• Natural and synthetic flavonoids (quercetin, rutoside, monoxerutin, hesperidin, diosmin, troxerutin, hydrosmin, diosmin and their derivatives)
• Ergot alkaloids (dihydroergocristine, dihydroergotamine, dihydroergocriptine)
• Saponins (escin, or horse chestnut extract)
• Calcium dobesilate (synthetic venotonic)
• Pycnogenol (French maritime pine bark extract)
• Procyanidol oligomers (grape seed extract, red grape leaf extract)
• Tribenoside (semi-synthetic)
• Heptaminol (synthetic alkaloid)

Let’s look at each active substance. Below I “in a nutshell” provide information about them, links to clinical trials and a list of drugs that contain these substances. I will also try to calculate the approximate cost of the course of treatment. This will be useful if you need to compare analogues and generics. My list is relevant for drugs registered in Ukraine, and their trade name and packaging design may differ from Russian and Belarusian ones.

Flavonoids and bioflavonoids

A group of the most popular substances used to treat first-degree varicose veins. Flavonoids give color to plant skins, participate in photosynthesis, apoptosis (the “suicide” of damaged and mutated cells) and seed germination. They accumulate in large quantities in citrus peel, onions, cocoa, and green tea. Bioavailability from products is very high.

Rutin, monoxerutin, rutoside, troxerutin

Spoiler: extremely low efficiency.

Not registered as a medicinal product. A separate group includes rutosides. In worldwide practice, rutin, rutoside, monoxerutin and troxerutin are used to relieve swelling before and after surgery on the veins, to reduce, and I quote: “subjective symptoms in patients with chronic venous insufficiency.”

The best-selling drugs based on rutosides

Routines have a slight inhibitory effect on oxidative metabolism in affected veins. Its anti-edematous effect has been proven. The problem lies in the monstrous dosages.

A Cochrane meta-review on rutin and its derivatives was conducted in 2015 ( 1 ). Clinical trials of the drugs Relvene® (France), Venoruton® (Switzerland) and Paroven® (UK) were considered - evidence of the effectiveness of these drugs is questionable.

To get the effect, you need to take 4 grams of rutin per day - 26 tablets of Ascorutin!!!. This does not fit in any way with the therapeutic doses in the medications available to us (Ascorutin - maximum 150 mg per day). In a normal diet, we consume at least 2 grams of flavonoids with plant foods, which makes taking them in dietary supplements unnecessary.

Of the 1,474 studies on rutosides reviewed by Cochrane, only 15 met the rules. According to the cumulative results of these trials, rutin and its derivatives lead to modest improvements in some symptoms of CVI and the first stage of varicose veins (pain, heavy leg syndrome, tingling, swelling).

Addition 02/14/2018: All numbered links are uploaded to Google Drive separately, since articles with so many links have problems with ranking in search engines systems. Search for full texts using the sci-hub service. Thank you for your understanding!

A 2016 review of 66 included studies of the evidence base for phlebotonics found that the most commonly used agents to treat stage 1 varicose veins relieve swelling, cramps, and paresthesia (tingling), but are inferior to compression (2).

A few particularly revealing clinical trials:

• Study of the effect of troxerutin in combination with dihydroergotamine (dosage 3 mg DHET and 300 mg TP). The effect does not exceed the placebo effect (4).
• Antithrombotic effect of rutin (6).
• Rutin is not suitable for the treatment of postthrombotic syndrome (9).
• Rutoside relieves the symptoms of varicose veins during pregnancy but does not prevent complications (11).
• Investigation of the therapeutic potential of rutin, which has everything except the treatment of venous insufficiency (13).
• Rutin derivatives are more effective than diosmin + hesperedin in terms of microcirculation and symptoms of venous insufficiency (clinical trials from the Cochrane database) (14).
• Antioxidant effect of rutin (no changes in plasma antioxidant status were recorded) (15).

Diosmin and hesperidin

Spoiler: the evidence base is lower than rutosides, weak effectiveness.

Citrus flavonoid diosmin (a derivative of hesperidin) appears in medical journals as an antioxidant that can reduce blood glucose levels, a capillary protector, and an antimutagen. Semi-synthetic substance. Increases lymphatic drainage, venous tone, microcirculation of the capillary bed, inhibits inflammatory reactions.

Preparations with diosmin

Diosmin Research:

• Inferior to rutoside in effectiveness in relieving symptoms of venous insufficiency and improving microcirculation (17).
• Treatment of CVI and varicose veins with diosmin. The article was published in the Russian-language medical publication “Angiology and Vascular Surgery” (18).
• Diosmin reduces retinal edema and reduces vascular permeability (19).
• Yugoslav study (the same phrases about improving the quality of life) (22).
• Diosmin for CVI, trophic ulcers and hemorrhoids (23).

A huge number of flavonoid trials end with the following phrase: “It has been proven that the inclusion of the drug “such and such” in the complex treatment of patients statistically significantly increases psychological and social activity and improves the quality of life of patients.” How can you even calculate social activity and other general phrases?

Citrus peel is a rich source of flavonoids

Very weak results of clinical trials do not prevent Phlebodia with Detralex from remaining the most popular drugs for the treatment of veins.

Hesperidin is one of the flavonoids extracted from citrus fruits. Traditional angioprotector, venotonic. Research is weak; in the last decade, the direction of its study has changed towards antioxidant activity.

Preparations with hesperidin

Hesperidin Research:

• Treatment of hemorrhoids with a mixture of flavonoids (diosmin, troxerutin, hesperidin) (24).
• Evaluation of the effectiveness of diosmin + hesperidin for the treatment of CVI. Swiss study (25).
• Hesperidin against diabetes (Canadian study on diabetic rats) (26).
• Clinical trial of diosmin + hesperidin (Russian, 66 patients, no numbers) (27).

Synthetic flavonoid hydrosmin

Spoiler: little studied, no better than other flavonoids

Hydrosmin is a synthetic flavonoid. It was synthesized not so long ago; there are few clinical trials for the treatment of varicose veins. Rarely produces side effects compared to natural flavonoids (this is due to the fact that the synthesized substances do not have ballast impurities that cause allergic reactions).

Links to studies:

• Hydrosmin therapy for CVI (Spain).
• Treatment of chronic lymphedema (edema) with hydrosmin (29).

Drug available on the market: Venosmil capsules with 200 mg hydrosmin. The course of treatment takes at least 3 months and will cost 1100 UAH/2800 rubles.

Preparations with hydrosmin

Quercetin

Spoiler: not a cure. Efficacy not proven

An antioxidant flavonoid, according to in vitro experiments, helps reduce the permeability of cell membranes and prevents the formation of free radicals. It has a cumulative effect; taking medications with quercetin should be long-term. Registered as a dietary supplement, it is not a medicine; no high-quality clinical trials have been conducted. Its weak anti-inflammatory and anti-allergenic properties have been proven.

Preparations with quercetin

In the list of patents containing quercetin, the names of dietary supplements are as follows: antioxidant compositions that lower cholesterol (paired with statins, unexpectedly), a method for increasing physical performance, restoring the immune system, treating drug addiction (30). Not a word about venous insufficiency, blood vessels, capillaries. I read about the treatment of varicose veins with quercetin exclusively in the Russian journal Angiology and Vascular Surgery, with links to specific trade names of the drugs.

The bioavailability of quercetin from foods is very high. Red onion is a source of flavonoids

Publications:

• Does not exhibit antioxidant activity, but reduces blood pressure in patients with stage 1 hypertension (at placebo level) (33).
• Effect of a quercetin-rich diet on oxidative damage to human DNA (no effect). Cambridge study (34).
• Reduced uric acid levels (36).
• Quercetin reduces the size of prostate walls in benign hyperplasia (Iranian study).
• Vasodilator effect is less than the statistical minimum (38).
• Vasodilator effect on the coronary artery (39).
• Anti-atherosclerotic efficacy was not confirmed (Polish study) (40).
• Red grape leaf extract (quercetin, isoquercitrin) against CVI (41).

Saponins: escin

Spoiler: The best substance for the prevention of varicose veins

Of the dozens of saponins, including poisons, the most famous is escin. It is synthesized from horse chestnut bark, seeds and flowers. The effect on venous insufficiency is associated with the protection of the endothelium (escin increases the permeability of endothelial cells to calcium) and the ability to produce venous compression.

Horse chestnut extract is one of the most studied substances in the history of medicine.

Medicines with escin

Clinical trials of escin:

• Comparison of horse chestnut extract and compression therapy. The bottom line: escin therapy at the zero stage of CVI helps to avoid the use of compression hosiery at the zero and first stages of varicose veins. Support with the extract should begin from the first signs of edema (43).
• Local use for venous insufficiency and arterial hypertension (46).
• Reducing swelling, complementing compression.
• Effect of beta-escin on venous insufficiency (49).
• Pharmacokinetics (50, 51).
• Effect of escin on microcirculation (52, 53).
• Reduced capillary filtration (54, 55).

There is a systematic review from the Cochrane database on horse chestnut seed extract for chronic venous insufficiency. In one peer-reviewed study, the extract showed the same results as compression garments.

In general, escin is the most suitable substance of plant origin for the prevention of diseases of veins and blood vessels with a half-century history of testing. Quote from the Cochrane review: “The evidence presented shows that ESCC is an effective short-term treatment for CVI.”

Hundreds of dietary supplements are produced using plant extracts with mono and combined compositions for the treatment of venous insufficiency and varicose veins. If you trust any manufacturer, then you can take them too (the manufacturer of dietary supplements is not required to conduct clinical trials of the product, remember this and remain skeptical).

Calcium dobesilate

Spoiler: effectiveness is questionable.

Calcium dobesilate (DC) is a synthetic venotonic, which means that it does not contain any untested impurities, its pharmacokinetics and dynamics have been thoroughly studied. Used in the treatment of vascular diseases caused by diabetes, CVI. The substance reduces capillary permeability and blood viscosity, slows down the process of platelet adhesion, and dilates blood vessels. Side effects are rare.

Clinical trials, mostly with a small sample of patients, are not detailed. A meta-review has not yet been published, so it is difficult to judge how effective calcium dobesilate is for the treatment of varicose veins and chronic venous insufficiency.

Preparations with calcium dobesilate

There is a Cochrane study of all venotonics based on clinical trials, and DC was included in the list. Conclusion: calcium dobesilate in qualitative tests does not show significant results in the “quality of life” parameter. Follow the link for the full text of the review, which I highly recommend viewing for yourself. Such reviews are “evidence-based medicine”: verification is very important, 115 clinical trials were rejected and they explain why. It’s possible that, based on my links to articles from PubMed, something even ended up on Cochrane’s blacklist in this meta-review, I don’t exclude that (57).

Calcium dobesylate research:

• Confirmation of the therapeutic effect of calcium dobesilate in the initial stage of varicose veins using plethysmography (reduction of the vein distensibility index, etc.) (58).
• Fragility of blood vessels in diabetes mellitus. Dobesylate therapy (59).
• Calcium dobesilate for chronic venous insufficiency and varicose veins (60, 61, 62, 6 3, 64, 66).
• In vitro study of calcium dobesilate on oxidative/inflammatory stress in varicose veins, antioxidant effect (68).
• The effect of calcium dobesilate on “quality of life” (scientists found that the group receiving placebo felt better at the end of treatment than those who took the drug (after 3 months). But after 9 months, dobesilate slightly outperformed placebo. The trial was double/blind.) This study was commissioned by the manufacturer of Doxium. See the link for the full text of the clinical trial (69).

Pycnogenol. French maritime pine bark extract

Spoiler: nothing is clear, expensive, exclusive. Not a medicine

French maritime pine bark extract (pycnogenol) consists of procyanidins, dihydroquercetin and phenolic acids and has a complex multi-level formula. Extracted exclusively from pine trees in Les Landes de Gascogne in southwest France, the formula is patented.

A substance with high bioavailability, quickly absorbed, and has low toxicity. The monopolist manufacturer claims that the substance is effective in the treatment of CVI and microhemorrhages. Antioxidant that absorbs free radicals. Anti-inflammatory activity has been proven in vitro and in vivo in humans. Alleviates asthma, reduces platelet aggregation, and gently reduces blood pressure (70).

There is a systematic Cochrane review. It included 15 studies with 791 participants on asthma, CVI, etc. Conclusion: studies are weak, need to be studied further. The substance is tested frequently, but with a sample size of 20 people. This is not evidence-based medicine.

Preparations with pycnogenol

Science articles:

• Comparative study of pycnogenol and escin (72).
• Prevention of venous thrombosis (73, 74).
• Troxerutin + pycnogenol is effective in treating venous insufficiency and varicose veins (75).
• Treatment of chronic venous insufficiency (76, 77, 78, 79, 80, 81).
• Improved microcirculation (82).
• Capillary resistance in hypertension (83).
• Healing of trophic ulcers (84).

Procyanidin and procyanidol oligomers. Grape seed extract

Procyanidol oligomers, or procyanidins, are flavonoids found in grape seed extract. This group of bioflavonoids has a pronounced antithrombotic effect associated with the protection and regeneration of the endothelium, preventing platelet aggregation. Grape seed extract slows down the growth of inflammatory cells and the “clumping” (adhesion) of blood clots. The antioxidant property of grape seed polyphenols is 20 times stronger than vitamin E and 50 times stronger than vitamin C. It is a UV filter ( source ).

Literature about procyanidin:

• Biochemistry and pharmacodynamics of grape seed flavonoids (85).
• Treatment of chronic arterial insufficiency with Endotelon (86).
• Effect of procyanidol oligomers on vascular permeability (87).
• Effect of grape seed extract on the permeability of the blood-brain barrier (88).

Heparin and heparinoids

Heparin does not treat the zero stage of varicose veins, but it can be prescribed additionally for increased blood viscosity, when the liver does not synthesize enough of its heparin. The drug is very serious and without a direct prescription from a doctor, I would not even smear myself with a gel containing heparin.

When I was looking for studies on heparin, I did not at all expect a devastating systemic review from Cochrane.

I quote the conclusion from the attached large-scale study: “Overall, trial quality was disappointing”: in general, the quality of the trials was depressing." That’s it. The conclusion also indicated that there is insufficient evidence of protection against thrombosis of the arteries and deep veins, but there is a possibility that a positive effect is present for the veins of the lower extremities.

According to most independent studies, heparin is not very effective as a targeted treatment, but creates a lot of problems with microbleeding, bruising and bleeding intestines.

List of drugs containing heparin and heparinoids:

Venogepanol, Viatromb, Heparil 1000, Heparin ointment, Heparoid Zentiva, Hepatrombin, Dermaton, Dioflan, Lyogel 1000, Lyoton, Liotromb, Trombles, Esphatil.

Tribenoside

Tribenoside is a synthetic capillary protector. The pharmacology of tribenoside was studied back in the 70s, but there are very few modern clinical trials to talk about its effectiveness and safety. Most of the few studies are devoted to osteoarthritis and hemorrhoids, almost all studies before the 90s. Therefore, the full texts were not found in electronic form.

Side effects often include Quincke’s edema, urticaria, dermatitis - 10% of patients. This may be the reason for the rare use of tribenozide. From an article in 1977 in “Pharmacology” it is known: tribenoside/glivenol has anti-inflammatory, analgesic, wound-healing, anti-arthrosis, membrane-stabilizing effects, and is a mild venotonic. These statements are not supported by anything.

There have been several studies on hemorrhoids, but no results or texts.

• Human hemodynamics after taking glivenol (no changes in volume parameters of central hemodynamics) (89).

With heptaminol the situation is approximately the same. Heptaminol is always paired with diosmin or troxerutin, making the drug more expensive, but it is not clear whether it is more effective. Well, Ginkgo biloba is generally bullshit; Cochrane reviews universally deny its effectiveness.

• German study on heptaminol (90).

Preparations with heptaminol

Conclusions

You need to start working on your feet as early as possible, even with cosmetic creams containing escin - there are hundreds of them. Judging by the collected material, the oldest and most proven remedies are the best: chestnut extract and compression stockings.

We have not yet learned how to treat varicose veins without surgery. Dietary supplements with flavonoids can become a good placebo assistant if you engage in simple prevention of venous insufficiency.

Simple prevention of varicose veins:

1. Whenever possible, raise your legs higher.
2. Drink a little more water than you want.
3. Set a reminder on your smartphone or computer every 40 minutes to get up and stretch, or vice versa, sit down and raise your legs higher.
4. Take off your heels when sitting at your desk.
5. Stop smoking. Resins make vessels brittle.

I hope the material will be useful.

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