HR,0-(Beta-Hydroxyethyl)-Rutosides,in Comparison with Diosmin+Hesperidin in Chronic Venous Insufficiency and Venous Microangiopathy: An Independent,Prospective,Comparative Registry Study

Abstract

The aim of this independent study was to investigate differences in efficacy between HR, (0-[beta-hydroxyethyl]-rutosides) and D+H (500 mg, diosmin+hesperidin) in patients with chronic venous insufficiency (CVI). A first group of 90 patients with severe venous hypertension (CVI, ankle swelling) were randomized into an HR or a D+H group. The HR group received oral HR (2 g/day, 8 weeks); the D+H group received a 500 mg tablet 3 times daily for 8 weeks. A second group of comparable patients was included in a registry following the same study format. Patients were openly included; the 2 treatments were administered with the same methods and procedures. Clinical conditions were comparable to those described in the randomized study. Patients treated for at least 8 weeks were included in the registry. A number of physicians (specialists or general practitioners) included patients when they considered that clinical conditions were compatible with using 1 of the 2 treatments on the basis of their personal evaluation and experience. When cases were compatible with the registry, the prescribing physician communicated the case. Patients were evaluated without interfering with the treatment. Main targets of evaluation were skin flux at rest (RF), strain-gauge-derived rate of ankle swelling (RAS), and analogue symptoms score (ASLS). Ninety subjects completed the study in the first group; 122 in the second, registry group (total of 212 patients). The first and second (registry) groups and the 2 treatment groups were comparable for age and sex distribution. The pooled mean age was 42 years (SD ±5.5) in the HR group (46+62 patients) and 41.5 (SD ±6) in the D+H group (44+60 patients). Considering pooled data there were no differences in microcirculatory parameters between the pooled treatment groups at inclusion. A significant decrease (p<0.05) in RF and RAS was observed in the HR group at 8 weeks. The decrease in resting skin flux and in capillary filtration was associated with a significant improvement in signs/symptoms (analogue scale line) from an average of 9.4 (range 3-10) to 3.3 (4-6) (p<0.05). Significantly smaller variations were observed in the D+H group. The decrease in RF was 47.6% in the HR group vs 15.7% in the D+H group. The decrease in RAS was 40.9% in the HR group vs 12.8% in the D+H group. The decrease in ASLS was 64.8% in the HR group vs 12.9% in the comparative group. In conclusion venous microangiopathy and edema were improved by the treatment with HR both in the randomized study and in the pooled analysis. The comparison with D+H indicates that HR is comparatively more effective both on microcirculatory parameters and on signs/symptoms of CVI.

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References

Beckers C , Zijilstra JA : New aspects of the pathogenesis of CVI and the site of action of Venoruton®. Phlebology Digest 14:8-11, 2001.

Belcaro G , Rulo A , Candiani C : Evaluation of the microcirculatory effects of Venoruton in patients with chronic venous hypertension with laser Doppler flowmetry, transcutaneous PO2 and PCO2 measurements, leg volumetry and ambulatory venous pressure measurements. Phlebology 4:23-26, 1989.

Belcaro G , Nicolaides AN , Stansby G (eds): The Venous Clinic. London: Imperial College Press, 1999, pp 22-65.

De Sanctis MT , Cesarone MR , Incandela L , et al : Methods of evaluation and quantification of microangiopathy in high perfusion microangiopathy (Chronic venous insufficiency and diabetic microangiopathy). J Cardiovasc Pharmacol Ther 7(suppl I):S3-S5, 2002.

Belcaro G , Nicolaides AN (eds): Noninvasive investigations in vascular disease. London: Imperial College press, 2001.

Almond NE : A laser Doppler blood flowmeter used to detect thermal entrainment in normal persons and patients with Raynaud's phenomenon. In: Practical Aspects of Skin Blood Flow Measurement, ed. by Spence VA , Sheldon CD. London: Biological Engineering Society, 1985.

Anning ST : The cause and treatment of leg ulcers. Lancet ii:789-791, 1952.

Anning ST : Leg Ulcers. Their Causes and Treatment. London: J & A Churchill Ltd, 1954.

Anning ST : The historical aspect. In: The Pathology and Surgery of the Veins of the Lower Limb, ed. by Dodd H , Cockett FB. Edinburgh: Churchill-Livingstone, 1976.

10.

Belcaro G : The role of transcutaneous PCO2 measurements in association with laser Doppler flowmetry in venous hypertension. Phlebology 3:189-193, 1988.

11.

Belcaro G , Grigg M , Rulo A , et al : Blood flow in the perimalleolar skin in relation to posture in patients with venous hypertension. Ann Vasc Surg 1:5-8, 1989 a.

12.

Belcaro G , Christopoulos D , Nicolaides AN : Skin flow and swelling in postphlebitic limbs. Vasa 18:136-138, 1989 b.

13.

Belcaro G , Nicolaides AN , Volteas N , et al : Skin flow, the venoarteriolar response and capillary filtration in diabetics. A three-year follow-up study. Angiology 43:490-494, 1992.

14.

Belcaro G , Bollinger A , Hoffman U , et al (eds): Laser Doppler Flowmetry. London: Med-Orion, 1994.

15.

Bergan JJ , Schmid-Schonbein GW , Takase S : Therapeutic approach to chronic venous insufficiency and its complications: Place of Daflon 500 mg. Angiology 52(suppl 1):S43-S45, 2001.

16.

Belcaro G , Cesarone MR , Bavera P , et al : HR (Venoruton 1000, Paroven, 0-[beta-hydroxyethyl]-rutosides) vs Daflon 500 in chronic venous disease and microangiopathy: An independent prospective, controlled, randomized trial. J Cardiovasc Pharmacol Ther 7:139-145, 2002.

17.

Bollinger A , Jager K , Geser A , et al : Transcapillary and interstitial diffusion of Na-Fluorescein in chronic venous insufficiency with white atrophy. Int J Microcirc I:5-8, 1982.

18.

Fagrell B : Microcirculatory disturbances—the final cause for venous leg ulcers? Vasa 11:101-103, 1982.

19.

Fagrell B : Problems using laser Doppler flowmetry on the skin in clinical practice. In: Laser Doppler, ed. by Belcaro G , Hoffman U , Nicolaides AN , et al. London: Med Orion, 1994, pp 49-53.

20.

Franzeck U , Bollinger A , Huch R , et al : Transcutaneous oxygen tension and capillary morphologic characteristics and density in patients with chronic venous incompetence. Circulation 70:806-809, 1984.

21.

Hendriksen O : Local reflex in microcirculation in human subcutaneous tissue. Acta Physiol Scand 97:446-449, 1976.

22.

Rayman G , Hassan A , Tooke JE : Blood flow in the skin of the foot related to posture in patients with diabetes mellitus. Br Med J 292:87-91, 1986.

23.

Thulesius O : Capillary filtration under normal and pathological conditions. Angiologia 10:198-201, 1973.

24.

Garner RC , Garner JV , Gregory S , et al : Comparison of the absorption of micronized (Daflon 500 mg) and nonmicronized 14C-diosmin tablets after oral administration to healthy volunteers by accelerator mass spectrometry and liquid scintillation counting. J Pharm Sci 91:32-37, 2002.

25.

Danielsson G , Jungbeck C , Peterson K , et al : A randomized controlled trial of micronized purified flavonoid fraction vs placebo in patients with chronic venous disease. Eur J Vasc Endovasc Surg 23:73-79, 2002.

26.

Incandela L , Belcaro G , Renton S , et al : HR (Paroven, Venoruton; 0-[beta-hydroxyethyl]-rutosides) in venous hypertensive microangiopathy: A prospective, placebo-controlled, randomized trial. J Cardiovasc Pharmacol Ther 7(suppl I):S7-S10, 2002.

27.

Incandela L , Cesarone MR , Belcaro G , et al : Treatment of diabetic microangiopathy and edema with HR (Paroven, Venoruton; 0-[beta-hydroxyethyl]-rutosides): A prospective, placebo-controlled, randomized study. J Cardiovasc Pharmacol Ther 7(suppl I):S11-S13, 2002.

28.

Cesarone MR , Belcaro G , Incandela L , et al : Flight microangiopathy in medium-to-long-distance flights: Prevention of edema and microcirculation alterations with HR (Paroven, Venoruton; 0-[beta-hydroxyethyl]-rutosides). J Cardiovasc Pharmacol Ther 7(suppl I):S17-S19; 2002.

29.

Cesarone MR , Incandela L , De Sanctis MT , et al : Treatment of edema and increased capillary filtration in venous hypertension with HR (Paroven, Venoruton; 0-[beta-hydroxyethyl]-rutosides): A clinical, prospective, placebo-controlled, randomized, dose-ranging trial. J Cardiovasc Pharmacol Ther 7(suppl I):S21-S25, 2002.

30.

Cesarone MR , Incandela L , De Sanctis MT , et al : Variations in plasma free-radicals in patients with venous hypertension with HR (Paroven, Venoruton; 0-[beta-hydroxyethyl]-rutosides): A clinical, prospective, placebo-controlled, randomized trial. J Cardiovasc Pharmacol Ther 7(suppl I):S25-S28, 2002.

31.

Poynard T , Valterio C : Meta-analysis of hydroxyethylrutosides in the treatment of chronic venous insufficiency. Vasa 23:244-260, 1994.

32.

Ekestrom S , Welti R : The affinity of hydroxyethyl-rutosides for the venous wall and its efficacy in preventing early occlusion of aorto-coronary vein bypass grafts. Phlebology 5(suppl 1):41-48, 1990.

33.

Nees S , Juchem G , Fink R , et al : Influence of polymorphonuclear leukocytes and platelets on the barrier function of cultured venular endothelial cells. Proceedings 6th World Congress for Microcirculation. Monduzzi, Bologna, 1996, pp 401-404.

34.

Roland IH , Bougelet C , Ninane N , et al : Effect of hydroxyethylrutosides on hypoxial-induced neutrophil adherence to umbilical vein endothelium. Cardiovasc Drugs Ther 12:375-381, 1998.