G. Acerbi

Prevention of Venous Thrombosis in Long-Haul Flights with Flite Tabs: The LONFLIT-FLITE Randomized, Controlled Trial:

The aim of this study was to evaluate the development of edema, and superficial and deep vein thrombosis (DVT) prophylaxis with an oral profibrinolytic agent (Flite Tabs, 150 mg pinokinase, Aidan, Tempe, AZ, USA) in long-haul flights (7-8 hours), in high-risk subjects. A group of 300 subjects was included; 76 were excluded for several problems including concomitant treat ments ; 204 were randomized into 2 groups (active treatment or placebo) to evaluate the effects of prophylaxis with Flite Tabs. An exercise program was used in both groups. The femoral, popliteal, tibial, and superficial veins were scanned with ultrasound before and within 90 minutes after flights. Of the included subjects, 92 of 103 controls and 94 of 101 treated subjects completed the study. Dropouts were due to connection problems. Age, gender, and risk distribution were comparable in the groups. In the treatment group, no DVT was observed. In the control group, 5 subjects (5.4%) had a DVT and there were 2 superficial thromboses (7 events in 92 subjects; 7.6%). At inclusion, edema was comparable in the 2 groups. After flights there was an increase in score in controls (+12%) in comparison with a decrease (-15%) in the Flite Tabs group (the difference in variation was statistically significant). Intention-to-treat analysis for thrombotic events shows 18 failures in controls (11 lost to follow-up + 7 throm botic events) of 92 subjects (19.6%) in comparison with 7 failures (of 94 subjects, equivalent to 7.4%) in the treatment group (p<0.05). Events were asymptomatic. In conclusion, Flite Tabs were effective in reducing thrombotic events and in controlling edema in high-risk subjects in long flights.

Prevention of Venous Thrombosis with Elastic Stockings During Long-Haul Flights: The LONFLIT 5 JAP Study

The aim of this study was to evaluate deep venous thrombosis (DVT) prophylaxis with specific elastic stockings in longhaul flights (11-13 hours), in high-risk subjects. A group of 300 subjects was included; 76 were excluded for several problems including concomitant treatments; 224 were randomized into two groups (stockings vs. controls) to evaluate prophylaxis with below-knee stockings. An exercise program was used in both groups. Scholl (UK) Flight Socks (14-17 mmHg of pressure at the ankle) were used. DVT was diagnosed with ultrasound scanning. The femoral, popliteal, and tibial veins were scanned before and within 90 minutes after the flights. Of the 205 included subjects, 102 controls and 103 treated subjects completed the study. Drop-outs were due to flight connection problems. Age, gender, and risk distributions were comparable in the two groups. In the treatment group (103 subjects; mean age, 42; SD 9; M:F, 55:48), one limited, distal DVT was observed (0.97%). In the control group (102 subjects; mean age, 42.1; SD 10.3; M:F, 56:46), six subjects (5.8%) had a DVT. There were no superficial thromboses. The difference in DVT incidence is significant (p<0.0025; six times greater in the control group). Intention-to-treat analysis counts 18 failures in the control group (12 lost to follow-up + six thromboses) of 112 subjects (15.8%) versus eight failures (7.3%) in the treatment group (p<0.05). The tolerability of the stockings was very good and there were no complaints or side effects. All events were asymptomatic. Considering these observations, Scholl Flight Socks are effective in reducing the incidence of DVT in high-risk subjects.

Prevention of Venous Thrombosis and Thrombophlebitis in Long-Haul Flights with Pycnogenol®

The aim of this study was to evaluate the occurrence of deep venous thrombosis (DVT) and superficial vein thrombosis (SVT) and its prophylaxis with an oral anti-edema and antithrombotic agent (Pycnogenol®, Horphag, Research Management SA, Geneva, Switzerland) in long-haul flights, in subjects at moderate to high-risk of DVT and SVT. The study pre-included 244 pre-selected subjects; 211 were included (33 were excluded for several reasons due to logistic problems) and 198 completed the study; 13 subjects were lost for follow-up at the end of the flight, all for non-medical problems (i.e., for difficult connections). All subjects were scanned within 90 minutes before the flight and within 2 hours after disembarking. Subjects were supplemented with 100 mg Pycnogenol® per capsule. Treatment subjects received two capsules between 2 and 3 hours before flights with 250 mL of water; two capsules were taken 6 hours later with 250 mL of water and one capsule the next day. The control group received comparable placebo at the same intervals. The flight duration was on average 8 hours and 15 minutes (SD 55 min) (range, 7.45-12.33). In the control group there were five thrombotic events (one DVT and four superficial thromboses) while only nonthrombotic, localized phlebitis was observed in the Pycnogenol®group (5.15% vs. no events; p<0.025). The ITT (intention to treat) analysis detects 13 failures in the control group (eight lost to follow up + five thrombotic events) of 105 subjects (12.4%) vs. five failures (4.7%; all lost, no thrombotic events) in the treatment group (p<0.025). No unwanted effects were observed. In conclusion, this study indicates that Pycnogenol® treatment was effective in decreasing the number of thrombotic events (DVT and SVT) in moderate-to-high risk subjects, during long-haul flights.

Venoruton® vs Daflon®: Evaluation of Effects on Quality of Life in Chronic Venous Insufficiency:

The aim of this independent study was to investigate differences in efficacy between oxerutins (Venoruton) and 500 mg micronized diosmin + hesperidin (D+H) (Daflon) in patients with chronic venous insufficiency (CVI), evaluating venous-related quality of life (Ve-QOL). A first group of 90 patients with severe venous hypertension (CVI, ankle swelling) was randomized to treatment with oxerutins or D+H. The oxerutins group received oral oxerutins (2 g/day); the D+H group received 3 (500 mg) tablets daily every 8 hours for 8 weeks. A second group of 122 comparable patients was included in a registry following the same study format. The 2 treatments were administered with the same methods and procedures. Clinical conditions were comparable. All patients completing 8 weeks of treatment were included in a registry. Specialists or general practitioners included patients when they considered that clinical conditions were compatible with treatment indications using 1 of the 2 treatments on the basis of their evaluation and experience. When cases were compatible with the registry, the prescribing physician communicated the case to our monitoring center. Patients were evaluated without interfering with their treatment. The main target of evaluation for this study was the change in Ve-QOL (range, 0-100) induced by treatment. A specific Ve-QOL questionnaire was used for this study. Ve-QOL score is a specific expression of the changes in QOL induced by CVI in patients between 35 and 75 years old (defined in our population studies) in which no other significant clinical disease is present (as a confounding factor affecting QOL). Two hundred twelve patients completed the 2 parts of the study. The 2 treatment groups were comparable for age and gender distribution. The mean age was 42 years (SD ±5.5) in the oxerutins group and 41.5 (SD ±6) in the D+H group. There were no differences in the severity of CVI between the treatment groups at inclusion. A significant decrease (46.8%, p<0.05) in Ve-QOL score; that is, improvement, was observed in the oxerutins group. The change in Ve-QOL was significantly less in the D+H group (15.5%). In conclusion, CVI, venous microangiopathy, and edema were significantly improved by the treatment with oxerutins; the improvement in QOL was significantly greater in the oxerutins group. The comparison with D+H indicates that oxerutins is comparatively more effective on Ve-QOL and on signs/symptoms of CVI

Comparison of Pycnogenol® and Daflon® in Treating Chronic Venous Insufficiency: A Prospective, Controlled Study

The aim of this study was to investigate the clinical efficacy of oral Pycnogenol® (Horphag Research Ltd., UK) in patients with severe chronic venous insufficiency (CVI) in comparison to the combination of diosmin and hesperidin (Daflon®, Servier, France). A group of 86 patients with severe chronic venous insufficiency (CVI), venous hypertension, ankle swelling) and previous history of venous ulcerations received either oral Pycnogenol (capsules) 150 mg or 300 mg daily for 8 weeks or Daflon, 1000 mg/day. All patients completed the study without dropouts. At the end of the study, microcirculatory results indicated: a progressive decrease of skin flux at rest (RF); a significant decrease in capillary filtration (RAS); an improvement in the symptomatic venous score (ASLS); a reduction in edema; a significant improvement (increase) in pO2 and a decrease in pCO2 in the Pycnogenol group. A significant level of improvement was reached after 4 weeks of treatment in most patients (p < .05) of the Pycnogenol group while clinical improvement was significant only in 6 subjects in the Daflon group. The positive effects of treatment with Pycnogenol after 8 weeks were significantly larger in comparison with the Daflon group. In conclusion, this study confirms the fast clinical efficacy of Pycnogenol in patients with chronic venous insufficiency and venous microangiopathy and its superiority—considering the evaluated parameters—to the combination of diosmin and hesperidin.

Improvement of diabetic microangiopathy with pycnogenol® : A prospective, controlled study

The aim of this study was to investigate the clinical efficacy of oral Pycnogenol® (Horphag Research Ltd, United Kingdom) in patients with diabetic microangiopathy. Patients without a history of diabetic ulcerations were treated with Pycnogenol. Patients received oral Pycnogenol (50 mg capsules, 3 times daily for a total of 150 mg daily for 4 weeks). A group of 30 patients was included (severe microangiopathy); 30 comparable patients were observed as controls (no treatment during the observation period). All patients (age, 59 years; range, 55-68 years; male:female = 18:12) included in the treatment group completed the 4-week study. Also, all controls completed the follow-up period. There were no drop-outs. All included subjects had signs and symptoms of diabetic microangiopathy. The duration of diabetes—from the first signs/symptoms—was on average 7.5 years (SD = 3). After 4 weeks, microcirculatory and clinical evaluations showed a progressive decrease in skin flux at rest in the foot (indicating an improvement in the level of microangiopathy), a significant decrease in capillary filtration, and a significant improvement in the venoarteriolar response in all treated subjects. There were no visible effects in controls except a slight reduction in skin flux at rest in the foot. Treatment was well tolerated in both groups. In conclusion, this study confirms the clinical efficacy of Pycnogenol in patients with diabetic microangiopathy. The study indicates the clinical role of Pycnogenol in the management, treatment, and control of this common clinical problem. The treatment may be also useful to prevent diabetic ulcerations by controlling the level of microangiopathy.

Rapid relief of signs/symptoms in chronic venous microangiopathy with pycnogenol: a prospective, controlled study.

The aim of this study was to investigate the clinical efficacy of oral Pycnogenol® (Horphag Research Ltd, UK) in patients with severe chronic venous insufficiency. Patients with severe venous hypertension (chronic venous insufficiency, ankle swelling) and history of venous ulcerations were treated with Pycnogenol. Patients received oral Pycnogenol (50 mg capsules, 3 times daily for a total of 150 mg daily) for 8 weeks. A group of 21 patients was included in the treatment group and 18 equivalent patients were observed as controls (no treatment during the observation period). All 21 patients (age 53 years; range, 42-60 years; M:F=11:10) in the treatment group completed the 8-week study. Also the 18 controls completed the follow-up period. There were no drop-outs. The average ambulatory venous pressure was 59.3 (SD 7.2; range 50-68) with a refilling time shorter than 10 seconds (average 7.6; SD 3). There were no differences in ambulatory venous pressure or refilling time between the treatment and control patients. The duration of the disease—from the first signs/symptoms—was on average 5.7 years (SD 2.1). At 4 and 8 weeks, in all Pycnogenol-treated subjects, microcirculatory and clinical evaluations indicated a progressive decrease in skin flux, indicating an improvement in the level of microangiopathy; a significant decrease in capillary filtration; a significant improvement in the symptomatic score; and a reduction in edema. There were no visible effects in controls. In conclusion, this study confirms the fast clinical efficacy of Pycnogenol in patients with chronic venous insufficiency and venous microangiopathy. The study indicates the significant clinical role of Pycnogenol in the management, treatment and control of this common clinical problem. The treatment may be also useful to prevent ulcerations by controlling the level of venous microangiopathy.

Management of superficial vein thrombosis and thrombophlebitis : Status and expert opinion document

Superficial vein thrombosis is characterized by clotting of superficial veins (ie, following direct trauma) with minimal inflammatory components. Superficial thrombophlebitis is a minimally thrombotic process of superficial veins associated with inflammatory changes and/or infection. Treatments generally include analgesics, elastic compression, anti-inflammatory agents, exercise and ambulation, and, in some cases, local or systemic anticoagulants. It is better to avoid bed rest and reduced mobility. Topical analgesia with nonsteroidal, anti-inflammatory creams applied locally to the superficial vein thrombosis/superficial thrombophlebitis area controls symptoms. Hirudoid cream (heparinoid) shortens the duration of signs/symptoms. Locally acting anticoagulants/antithrombotics (Viatromb®, Lipohep ®, spray Na-heparin) have positive effects on pain and on the reduction in thrombus size. Intravenous catheters should be changed every 24 to 48 hours (depending on venous flow and clinical parameters) to prevent superficial vein thrombosis/superficial thrombophlebitis and removed in case of events. Low molecular weight heparin prophylaxis and nitroglycerin patches distal to peripheral lines may reduce the incidence of superficial vein thrombosis/superficial thrombophlebitis in patients with vein catheters. In case of superficial vein thrombosis/superficial thrombophlebitis, vein lines should be removed. In neoplastic diseases and hematological disorders, anticoagulants may be necessary. Exercise reduces pain and the possibility of deep vein thrombosis. Only in cases in which pain is very severe is bed rest necessary. Deep vein thrombosis prophylaxis should be established in patients with reduced mobility. Antibiotics usually do not have a place in superficial vein thrombosis/superficial thrombophlebitis unless there are documented infections. Prevention of superficial vein thrombosis should be considered on the basis of patients history and clinical evaluation.

Cramps and muscular pain: prevention with pycnogenol in normal subjects, venous patients, athletes, claudicants and in diabetic microangiopathy.

The aim of this study was to assess the preventive action of Pycnogenol® (Horphag Research Ltd, UK) on cramps and muscular pain in different groups of subjects and patients. The study included a 5-week observation period (4 weeks treatment and one follow-up week after the suspension of treatment) to evaluate the efficacy of Pycnogenol after its withdrawal. Four 50 mg capsules (total dose 200 mg/day) were prescribed with suggestion to drink at least 1.5 liters of water every day. In the first part of the study 66 healthy subjects completed a 5-week follow-up period. The difference between number of cramps attacks recorded within the 2 weeks before inclusion and the number of episodes during the fourth (p<0.05) and fifth (p<0.05) week were statistically significant. In normal subjects the average number of episodes was reduced from 4.8 (1.2) events per week to 1.3 (1.1) at 4 weeks (p<0.05). In venous patients the decrease in events was from 6.3 (1.1) to 2.6 (0.4) per week (p<0.05). In athletes the number of episodes decreased from 8.6 (2) to 2.4 (0.5) (p<0.05). The decrease was still present at 5 weeks in the 3 groups, to levels significantly lower than inclusion values (p<0.05). In the second part of the study, patients with intermittent claudication and diabetic microangiopathy were evaluated and treated (4 weeks). The groups treated with Pycnogenol and the control, placebo groups were comparable. There was a significant decrease in the number of cramps episodes (p<0.05) and in the score concerning muscular pain (p<0.05) in claudicants and diabetics. No significant effects were observed in the placebo groups. In conclusion, cramps and muscular pain, common in these 2 types of patients, were decreased by the use of Pycnogenol. Globally, these results suggest that the use of Pycnogenol prevents cramps, muscular pain at rest, and pain after/during exercise in normals, in athletes prone to cramps, in patients with venous disease, in claudicants, and in diabetics with microangiopathy. The difference is statistically significant considering objective observations (cramps episodes) and evaluating more subjective aspects (score). This indicates that Pycnogenol is effective in reducing pain and cramps during retraining and rehabilitation increasing its efficiency. In starting any physical rehabilitation program, particularly in vascular subjects, the limitation in mobility associated with muscular pain and with cramps tends to be relevant, and controlling these symptoms is useful to speed up the retraining process.

Methods of Evaluation and Quantification of Microangiopathy in High Perfusion Microangiopathy (Chronic Venous Insufficiency and Diabetic Microangiopathy)

Noninvasive macro- and microcirculatory tests provide quantitative information that offers answers to most questions posed in venous diseases. Duplex scanning is used to assess the macrocirculation, and microcirculatory methods are used to assess and quantify venous microangiopathy. Laser Doppler flowmetry is used to assess perfusion. Transcutaneous Po2 and Pco2 measurements are used to study venous hypertension, and strain-gauge plethysmography is used to assess capillary filtration. In venous hypertension, fluid filtration into the extracapillary compartment is increased. The increase in filtration is associated with a decreased venoarteriolar response. To quantify capillary filtration, two methods have been developed: venous occlusion plethysmography and rate of ankle swelling. These methods quantify filtration into the extracapillary compartment and, therefore, are an indication of the formation of edema, the most frequent sign in venous hypertension. Other methods, such as the vacuum suction chamber and the edema tester, can be used to assess changes due to treatments in venous hypertension. The techniques described in this article should be used in controlled environmental conditions