Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial.

OBJECTIVE: Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is superior to ASA alone in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. We sought to determine whether clopidogrel plus ASA conferred benefit on limb outcomes over ASA alone in patients undergoing below-knee bypass grafting. METHODS: Patients undergoing unilateral, below-knee bypass graft for atherosclerotic peripheral arterial disease (PAD) were enrolled 2 to 4 days after surgery and were randomly assigned to clopidogrel 75 mg/day plus ASA 75 to 100 mg/day or placebo plus ASA 75 to 100 mg/day for 6 to 24 months. The primary efficacy endpoint was a composite of index-graft occlusion or revascularization, above-ankle amputation of the affected limb, or death. The primary safety endpoint was severe bleeding (Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries [GUSTO] classification). RESULTS: In the overall population, the primary endpoint occurred in 149 of 425 patients in the clopidogrel group vs 151 of 426 patients in the placebo (plus ASA) group (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.78-1.23). In a prespecified subgroup analysis, the primary endpoint was significantly reduced by clopidogrel in prosthetic graft patients (HR, 0.65; 95% CI, 0.45-0.95; P = .025) but not in venous graft patients (HR, 1.25; 95% CI, 0.94-1.67, not significant [NS]). A significant statistical interaction between treatment effect and graft type was observed (P(interaction) = .008). Although total bleeds were more frequent with clopidogrel, there was no significant difference between the rates of severe bleeding in the clopidogrel and placebo (plus ASA) groups (2.1% vs 1.2%). CONCLUSION: The combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis suggests that clopidogrel plus ASA confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk.

The safety and efficacy of a paclitaxel-eluting wrap for preventing peripheral bypass graft stenosis: a 2-year controlled randomized prospective clinical study.

OBJECTIVES: To compare the safety and efficacy of a bioresorbable paclitaxel-eluting wrap implanted with a synthetic vascular graft (treatment) versus the graft implanted alone (control). DESIGN: Prospective, randomized, controlled, multicentre, 2-year clinical study conducted in adults scheduled to undergo femoropopliteal peripheral bypass surgery with a polytetrafluoroethylene (PTFE) graft. MATERIALS AND METHODS: Hundred and nine subjects were randomized 2:1 to treatment or control. All subjects were implanted with a 6mm expanded PTFE vascular graft; in addition, treated subjects had a 2.5 cm x 4 cm paclitaxel-eluting wrap (1.6 microg/mm(2)) placed around the distal graft anastomosis. RESULTS: The overall incidence of adverse events was similar in both groups. Treated subjects required fewer limb amputations than controls (15.5% vs 18.4%) and time to amputation for those that required amputation was twice as long (153 days vs 76 days). Among diabetics, this effect was pronounced with 13.8% of treated subjects requiring limb amputations compared with 23.5% of controls. Over the course of study, the diameter at the distal graft anastomosis was greater in treated subjects than in controls (difference of 2.1mm at 2 yr, p=0.03). CONCLUSIONS: The paclitaxel-eluting wrap maintained graft patency at the distal anastomosis and was safe to use in patients who had received a peripheral bypass PTFE graft.

Sarpogrelate, a 5-hT2A receptor antagonist in intermittent claudication. A phase II European study.

This was a multinational, multicentre, double-blind Phase II study in Europe to evaluate the efficacy and safety of two dose regimens (200 mg bid and 200 mg tid) of sarpogrelate (MCI-9042, 5-HT2A receptor antagonist) compared to placebo in patients with stable, moderately severe intermittent claudication. Following a single-blind placebo run-in period of 6 weeks, 364 (309 male and 55 female) patients (59.2 +/- 8.4 years, mean +/- SD) were randomized to receive sarpogrelate 200 mg bid, 200 mg tid or placebo for 24 weeks with a follow-up of 8 weeks. The primary objective was the increase of absolute claudication distance (ACD) at the end of treatment (week 24) compared to placebo. Analysis of covariance (ANCOVA) was performed on the log-transformed percentage of baseline ACD: loge(ACD/baseline). A responder analysis (defined as a > or = 50% improvement in ACD) was also performed. There was a marked training/placebo effect on the ACD which persisted up to 16 weeks. At 24 weeks the primary objective did not reach statistical significance (200mg bid vs placebo, p = 0.225; 200mg tid vs placebo, p = 0.580). In the responder analysis, 200 mg bid showed a statistically significant difference vs placebo (p = 0.035). In the exploratory analysis with completers (patients completing all treadmill tests), there was a statistical difference in ACD/baseline change for 200 mg bid (p = 0.035) and in the responder analysis for 200 mg tid (p = 0.044) at 24 weeks compared to placebo. Both treatments showed a carry-over effect for ACD during the 8-week follow-up (weeks 28-32). The treatment was well tolerated and no clinically significant safety concerns were reported. In conclusion, the study results confirm that sarpogrelate is well tolerated and although the primary endpoint failed to reach statistical significance, the responder analysis showed an increased absolute walking distance, which makes a further trial warranted, including a larger population, and possibly also a longer treatment period.

Arteriogenic gene therapy in patients with unreconstructable critical limb ischemia: a randomized, placebo-controlled clinical trial of adenovirus 5-delivered fibroblast growth factor-4.

The objectives of this study were to assess the safety and potential clinical efficacy of adenovirus-delivered fibroblast growth factor-4 (Ad5FGF-4) by intramuscular injection into patients with critical limb ischemia (CLI). This study was a double-blind, randomized, placebo-controlled study with escalating dose groups of 2.87 x 10(8) to 2.87 x 10(10) viral particles. Thirteen patients with CLI were randomized to receive active drug (n = 10) or placebo (n = 3). Safety evaluations and efficacy parameters (ankle-brachial index, digital subtraction angiograms, magnetic resonance imaging, and scintigraphy) were performed at baseline and for 12 weeks after treatment. Injections of Ad5FGF-4 were generally well tolerated and considered safe. Transfection efficacy at these concentrations may have been limited or local. The small sample size did not allow any firm conclusions regarding clinical efficacy but a trend toward more and slightly larger blood vessels was observed in the angiograms. It is concluded that intramuscular injection of Ad5FGF-4 into CLI patients seemed safe, but transfection efficacy was limited at the assessed doses. Conclusions regarding clinical efficacy are impossible to draw from this small patient cohort.

Multibaker map for shear flow and viscous heating.

A consistent description of shear flow and the accompanying viscous heating as well as the associated entropy balance is given in the framework of a deterministic dynamical system. The laminar shear flow is modeled by a Hamiltonian multibaker map which drives velocity and temperature fields. In the appropriate macroscopic limit one recovers the Navier-Stokes and heat conduction equations along with the associated entropy balance. This indicates that results of nonequilibrium thermodynamics can be described by means of an abstract, sufficiently chaotic, and mixing dynamics. A thermostating algorithm can also be incorporated into this framework.

Thermodynamic cross effects from dynamical systems

We give a thermodynamically consistent description of simultaneous heat and particle transport, as well as of the associated cross effects, in the framework of a chaotic dynamical system, a generalized multibaker map. Besides the density, a second field with appropriate source terms is included in order to mimic, after coarse graining, a spatial temperature distribution and its time evolution. An expression is derived for the irreversible entropy production in a steady state, as the average of the growth rate of the relative density, a unique combination of the two fields.

Multibaker map for thermodynamic cross effects in dynamical systems

A consistent description of simultaneous heat and particle transport, including cross effects, and the associated entropy balance is given in the framework of a deterministic dynamical system. This is achieved by a multibaker map where, in addition to the phase-space density of the multibaker, a second field with appropriate source terms is included in order to mimic a spatial temperature distribution and its time evolution. Conditions are given to ensure consistency in an appropriately defined continuum limit with the thermodynamic entropy balance. They leave as the only free parameter of the model the entropy flux let directly into the surroundings. If it vanishes in the bulk, the transport properties of the model are described by the thermodynamic transport equations. Another choice leads to a uniform temperature distribution. It represents transport problems treated by means of a thermostating algorithm, similar to the one considered in nonequilibrium molecular dynamics.

[A new method for the management of perforated veins in the lower extremities]. / Uj módszer az elégtelen alsó végtagi perforans vénák ellátására.

Elimination of incompetent perforating veins is the effective therapeutic method in the treatment of lower leg ulceration and trophic skin disorders associated with chronic venous insufficiency. The subfascial endoscopic ligation is a new surgical method to treat patients with incompetent perforating veins. 19 patients with severe chronic venous insufficiency or protracted venous ulceration of lower leg were treated. Through an incision of the skin the proximal 1/3 of the lower leg-far away from the dermatosclerotic area-an endoscope is inserted after which the perforating veins are ligated by clips under direct vision. The method is recommended due to its reduced invasiveness and the fair results.