A new study demonstrates the efficacy of naftidrofuryl in the treatment of intermittent claudication. Findings of the Naftidrofuryl Clinical Ischemia Study (NCIS).

BACKGROUND: The efficacy and safety of naftidrofuryl were assessed in a double blind, placebo controlled, parallel group study, in patients presenting with intermittent claudication, according to the latest European guidelines. METHODS: The outpatients selected were of both sexes, aged 35 to 85, with moderately severe chronic, stable intermittent claudication and a pain-free (PFWD) and maximum walking distance (MWD) on the treadmill of between 100 and 300 metres. They received naftidrofuryl 200 mg tid or placebo for six months and were then assessed during a six-month follow-up period without treatment. The primary outcome measures were the pain-free walking distance and maximum walking distance. RESULTS: Of the 221 selected patients, 196 were randomised and 181 entered the intention-to-treat analysis. The two groups were well matched for demographic variables, risk factors and history of vascular disease. After six months of treatment, patients who received naftidrofuryl had a 92% im-provement of geometric pain-free walking distance versus 17% in the placebo group (p < 0.001) and an 83% improvement of geometric maximum walking distance versus 14% in the placebo group (p < 0.001). During the follow-up period without treatment, the walking distances of the patients in the naftidrofuryl group significantly decreased. The incidence of adverse events was similar in the two groups. CONCLUSIONS: This study demonstrated the efficacy of naftidrofuryl versus placebo in patients with intermittent claudication with a highly significant and clinically relevant difference and confirmed its good safety profile.

The effect of naftidrofuryl on transcutaneous oxygen tension during a treadmill test in patients with peripheral arterial occlusive disease.

Tissue hypoxaemia can be evaluated by the noninvasive method of transcutaneous oxygen tension (tcpO2) measurement in patients with peripheral arterial occlusive disease (PAOD). The effects of naftidrofuryl (Praxilene) on exercise-induced tissue ischaemia was objectively assessed by continuously measuring the tcpO2 in 30 patients during three treadmill tests over a 3-month period in a randomized double-blind, placebo controlled, parallel group study. To be included in the study, the tcpO2 and total walking distance had to be stable during the washout period (D-15-D0). The area under the tcpO2 curves was scanned and automatically calculated after identification of baseline and the end of the treadmill test. The treadmill test on D30 and D90 was terminated at a similar walking distance to that obtained on D0. On D0 both groups were comparable (p = 0.22). The area under the curve (AUC) reduced significantly in the naftidrofuryl group between D0 and D30 (p < 0.001) and D0 and D90 (p < 0.001). However, no significant tcpO2 AUC reduction was found in the placebo group (D0-D30, p = 0.58; D0-D90, p = 0.50). This was confirmed by calculation of the percentage of patients whose percentage change in the AUC on D90 was higher than the upper limit of the 90% confidence interval, calculated from the percentage change over the washout period. Of the 15 patients receiving natfidrofuryl, 66.6% exceeded this upper limit, compared with only 7% of patients receiving placebo (p = 0.0017). This study shows that naftidrofuryl has a protective effect on exercise-induced tissue ischaemia as measured by the tcpO2 AUC in PAOD stage II patients.

TcPo2 measurement reproducibility during stress in stage II obliterative arterial disease.

Distal transcutaneous oxygen pressure measurement (TcPo2) is a noninvasive method of evaluating tissular hypoxemia in peripheral arterial disease. The poststress area of hypoxemia is a usefull technique for globally quantifying different parameters represented by TcPo2 curves during exercise. Although its use is increasingly widespread, the reproducibility of this method is poorly documented. TcPo2 was monitored three times at twenty-four hour intervals in 5 patients with stage II obliterative arterial disease during a treadmill walking test. In order to get uniform measurement conditions, each patient remained lying and then stood until TcPo2 became stable. The stress duration was calculated so that the pain step could not be reached. TcPo2 curves were digitized and a specific image analyzer was used to make replicate measurements. The area under the curve was computed, the horizontal axis determining the mean TcPo2 value at rest, the vertical axis representing the end of the exercise period. The corresponding areas under the curves ranged from 34 to 2212 mm2 (573.60; SD 826). Significant correlation coefficients were obtained among replicate measurements (first-second day, first-third day). However, owing to the wide range of area values, the authors decided to compute and use the coefficient of variation (STD/mean), since it was more representative of reproducibility. The mean of its value for 5 patients was 21%. Observation of the examination conditions resulted in several findings, especially the ability of certain patients to adapt their efforts to the exercise. These results indicate that TcPo2 poststress area measurements are reproducible, but the conditions of the exercise have to be rigorously defined and may still be improved.

Short-term evaluation of plaque area measurement reproducibility from computer-assisted sonography.

One reason why quantifying plaque regression is difficult is the poor spatial control of the shooting angle whether in angiography or ultrasonography techniques. A computer-assisted technique has been developed to assess absolute carotid plaque dimensions from B-mode ultrasonography, with enhanced capability of comparative examinations at large time intervals. Plaque area is measured from arterial lumen to adventitia with a real-time tissular detection program. Further measurements on the same patient are made using an echo-specific mask automatically generated by the computer from the original section. For an average sonographer, the manipulation takes no more than ten minutes for each view. In order to determine the reproducibility of this technique, a repeated measurement study (T0, T1, T2) was carried out on 8 patients with moderate to severe atherosclerotic lesions at carotid localizations. The plaque areas ranged from 52.7 to 202.3 mm2 (120.7 +/- 61). The coefficients of correlation between the measurements (T0-T1, T0-T2) were respectively 0.93 and 0.96 (P < 0.0001). The mean coefficient of variation (+/- SD) was 9.8% +/- 4.8. This study shows the feasibility of an accurate follow-up for atherosclerotic patients, with a two-dimensional plaque quantification, closer to the reality of the evolution of the pathology than the usual scoring system.

Study of the antiischemic action of EGb 761 in the treatment of peripheral arterial occlusive disease by TcPo2 determination.

In a randomized, placebo-controlled, double-blind, parallel study of 20 patients, the antiischemic effect of EGb 761 (Ginkgo biloba Extract) was studied by measuring the transcutaneous partial pressure of oxygen (TcPo2) during exercise. Transcutaneous oximetry during exercise provides a good, noninvasive estimation of local arterial perfusion and constitutes a real index of local and regional capillary perfusion. Twenty patients between the ages of forty-four and seventy-three years suffering from claudicating atherosclerotic arterial occlusive disease in stage II according to the Leriche and Fontaine classification, diagnosed for more than a year and stable for three months, were included. The eligible patients received placebo for fifteen days under single-blind conditions. At the end of this preinclusion period, the eligibility criteria were checked and the patients were randomized to two treatment groups. The first group received 320 mg per day of EGb 761 for four weeks and the second group received placebo. The treadmill walking test was performed under standardized conditions at the same time of day and by the same investigator. In a comparison of the differences before and after treatment, the areas of ischemia decreased by 38% in the EGb 761 group but remained essentially stable (+5%) in the placebo group. This difference between groups is significant (F [1.18] = 4.91; P = 0.04) and the 95% confidence interval for the difference ranges from 0.89 to 3.87. This study confirmed significantly the rapid antiischemic action of EGb 761 and its value in the management of peripheral arterial occlusive disease at the stage of intermittent claudication.

Evaluation of ifenprodil efficacy on exercise-induced tissue ischemia in stage II arteriopathy by measurement of transcutaneous oxygen tension during a standard treadmill test: double-blind study of injectable ifenprodil versus placebo.

Measurement of transcutaneous oxygen tension (TcPO2) is a noninvasive and easily reproducible method for objectifying and quantifying exercise ischemia in patients with stage II occlusive arterial disease. This technique is also used at rest to evaluate the therapeutic effect of vasoactive treatments. To objectively assess the effectiveness of a vasoactive treatment on the conditions of tissue perfusion, a randomized double-blind study of ifenprodil tartrate versus placebo was performed in 20 patients, whose TcPO2 was continuously measured while they walked on a treadmill. Patients treated with ifenprodil improved significantly as compared with the placebo group, for both the half-hypoxia area, representing the overall evolution of the tissue ischemia (+34.9% and -16.0%, respectively, p = 0.01), and the half-hypoxia recovery time, estimating the postexercise recovery time (+30.2% and -3.6%, respectively, p < 0.05). This study confirms that the continuous measurement of TcPO2 during the recovery phase after exercise represents an objective method for the evaluation and follow-up of patients with stage II intermittent claudication. The results enabled the objective assessment of ifenprodil efficacy on the evolution of tissue hypoxia.

[Venous endoscopy]. / Endoscopie veineuse.

The miniaturization of endoscopic equipment now allows exploring the superficial venous system and visualizing the endovein in situ and in vivo. This type of venous endoscopy is an ambulatory procedure, performed during a simple outpatient consultation of angiology, after which the patient is immediately discharged. Although this examination is invasive, non-physiological and expensive, it allows the video recording of the morphology, dynamics and kinetics of the values, of the endovein and of the liquid flows (blood, washing fluid and sclerosing products). The new examination has already enabled us to propose an functional classification of the parietal valves of the great saphenous vein. It makes an intraoperative three-dimensional mapping of the vessels possible, which is sometimes difficult in such particular anatomical regions as the popliteal fossa. It allows performing sclerosis with a visual control and following up the evolution of the immediate endoparietal lesions in situ.

Objectifying exercise ischemia in peripheral vascular disease: a study in 120 patients.

This study presents the results of transcutaneous oxygen pressure (TcPO2) monitoring during a treadmill test walk performed in the early stages of peripheral obliterative vascular disease. The study population consisted of a first group of 50 known arteriopathic patients presenting, on questioning, with intermittent claudication; a second group of 50 known arteriopathic patients void of any symptoms of intermittent claudication; and a third group, which was a control cohort of 20 nonarteriopathic, nonclaudicating patients. Though resting TcPO2 cannot be used to aid the clinical diagnosis of exercise ischemia it may be useful in revealing asymptomatic chronic resting ischemia (9% of cases in this series). On the other hand, a posteffort (recovery phase) fall in TcPO2 had a predictive positive diagnostic accuracy for ischemia on exercise in 99% of the cases reported here versus 87% for clinical appraisal. In the light of these results, TcPO2 measurements coupled to a treadmill test walk perfectly ascertain exercise ischemia in arteriopathic patients, whether asymptomatic or not, and avoid the false-positive results obtained by clinical evaluation.

[Hormones and venous system]. / Hormones et système veineux.

Sex hormones have an effect on venous "content" and "container" according to their chemical nature, their dosage and their mode of administration: 17 beta-estradiol (endogenous): protective effect; synthetic estrogens, at normal or low doses: thrombogenic; oral natural estrogens: thrombogenic; extra-digestive natural estrogens: non thrombogenic; non steroid progestagens (androgenic): thrombogenic; non androgenic progestagens: non thrombogenic. Clinically, the venous disease si characterized by sudden episodes occurring at key-periods of the hormonal life: puberty, pregnancy, menopause, oral contraceptives intake, substitute treatments of menopause, premenstrual syndrome. Evaluation of these different situations shows that an early treatment is possible and needed, which, although not providing a new venous wall for these constitutionally fragile patients, may act effectively at two levels: 1) correction of the haemodynamic disorder (venous reflux in the saphenous arches and the perforators; 2) resorption of tissue infiltration. As primary prevention, in a patient with hormonal disorders or who must be treated with estrogens or progestagens, the objective of our treatment is to protect the venous wall and encourage the return circulation. One must: 1) reinforce the vaso-constrictive effect and the parietal tone, 2) limit collagen and elastin alteration, 3) reinforce capillary permeability and decrease the interstitial edema, 4) normalize the haemorheological constants, 5) restore the balance hemostasis-fibrinolysis. The opinion of a phlebologist seems essential before prescribing a hormonal treatment and monitoring the effects of the treatment. Cooperation between gynaecologists and phlebologists is particularly essential in the interpretation of the clinical disorders as well as discussing the venous risk, the dosage and the administration route of sex hormones.

[Modification of the level of adenosine triphosphate in digital pulp capillary blood in patients with microcirculatory disorders following i.v. injection of coenzyme A (CoA 1000)]. / Modification du taux d'adénosine tri-phosphate (ATP) dans le sang capillaire prélevé au niveau de la pulpe digitale, dans les troubles de la microcirculation, après injection i.v. de coenzyme A (CoA 1000).

Capillary blood ATP assay was performed in 2 groups of patients (diabetic and non-diabetic) with disorders of microcirculation, before and several minutes after 2 mg I.V. of Coenzyme A (CoA 1000). Values obtained showed a significant increase in both groups. The hypothesis advanced, based on previous experimental data indicating an action of CoA on intracellular calcium movement, is that CoA 1000 acts by elevation of the membrane ATP/Ca+ ratio of red corpuscles, and possible activation of their deformability and flow rate in the microcirculation.