Antiplatelet and anticoagulant drugs for prevention of restenosis/reocclusion following peripheral endovascular treatment.

BACKGROUND: Peripheral arterial disease (PAD) is frequently treated by balloon angioplasty. Restenosis/reocclusion of the dilated segments occurs often, depending on length of occlusion, lower leg outflow, stage of disease and presence of cardiovascular risk factors. To prevent reocclusion, patients are treated with antithrombotic agents. This is an update of a review first published in 2005. OBJECTIVES: To determine whether any antithrombotic drug is more effective in preventing restenosis or reocclusion after peripheral endovascular treatment, compared to another antithrombotic drug, no treatment, placebo or other vasoactive drugs. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched 14 February 2012) and CENTRAL (2012, Issue 1). SELECTION CRITERIA: We selected randomised controlled trials (RCTs). Participants were patients with symptomatic PAD treated by endovascular revascularisation of the pelvic or femoropopliteal arteries. Interventions were anticoagulant, antiplatelet or other vasoactive drug therapy compared with no treatment, placebo or any other vasoactive drug. Clinical endpoints were reocclusion, restenosis, amputation, death, myocardial infarction, stroke, major bleeding and other side effects, such as minor bleeding, puncture site bleeding, gastrointestinal side effects and haematoma. DATA COLLECTION AND ANALYSIS: We independently extracted and assessed details of the number of randomised patients, treatment, study design, patient characteristics and risk of bias. Analysis was based on intention-to-treat data. To examine the effects of outcomes such as reocclusion, restenosis, amputation and major bleeding, we computed odds ratios (OR) with 95% confidence intervals (CI) using a fixed-effect model. MAIN RESULTS: Twenty-two trials with a total of 3529 patients are included (14 in the original review and a further eight in this update). For the majority of comparisons, only one trial was available so results were rarely combined in meta-analyses. Individual trials were generally small and risk of bias was often unclear due to limitations in reporting. Three trials reported on drug versus placebo/control; results were consistently available for a maximum follow-up of only six months. At six months post intervention, a statistically significant reduction in reocclusion was found for high-dose acetylsalicylic acid (ASA) combined with dipyridamole (DIP) (OR 0.40, 95% CI 0.19 to 0.84), but not for low-dose ASA combined with DIP (OR 0.69, 95% CI 0.44 to 1.10; P = 0.12) nor in major amputations for lipo-ecraprost (OR 0.89, 95% CI 0.44 to 1.80). The remaining trials compared different drugs; results were more consistently available for a longer period of 12 months. At 12 months post intervention, no statistically significant difference in reocclusion/restenosis was detected for any of the following comparisons: high-dose ASA versus low-dose ASA (OR 0.98, 95% CI 0.64 to 1.48; P = 0.91), ASA/DIP versus vitamin K antagonists (VKA) (OR 0.65, 95% CI 0.40 to 1.06; P = 0.08), clopidogrel and aspirin versus low molecular weight heparin (LMWH) plus warfarin (OR 0.31, 95% CI 0.06 to 1.68; P = 0.18), suloctidil versus VKA: reocclusion (OR 0.59, 95% CI 0.20 to 1.76; P = 0.34), restenosis (OR 1.87, 95% CI 0.66 to 5.31; P = 0.24) and ticlopidine versus VKA (OR 0.71, 95% CI 0.37 to 1.36; P = 0.30). Treatment with cilostazol resulted in statistically significantly fewer reocclusions than ticlopidine (OR 0.32, 95% CI 0.13 to 0.76; P = 0.01). Compared with aspirin alone, LMWH plus aspirin significantly decreased occlusion/restenosis (by up to 85%) in patients with critical limb ischaemia (OR 0.15, 95% CI 0.06 to 0.42; P = 0.0003) but not in patients with intermittent claudication (OR 1.73, 95% CI 0.97 to 3.08; P = 0.06) and batroxobin plus aspirin reduced restenosis in diabetic patients (OR 0.28, 95% CI 0.13 to 0.60). Data on bleeding and other potential gastrointestinal side effects were not consistently reported, although there was some evidence that high-dose ASA increased gastrointestinal side effects compared with low-dose ASA, that clopidogrel and aspirin resulted in fewer major bleeding episodes compared with LMWH plus warfarin, and that abciximab resulted in more severe bleeding episodes. AUTHORS' CONCLUSIONS: There is limited evidence suggesting that restenosis/reocclusion at six months following peripheral endovascular treatment is reduced by use of antiplatelet drugs compared with placebo/control, but associated information on bleeding and gastrointestinal side effects is lacking. There is also some evidence of variation in effect according to different drugs with cilostazol reducing reocclusion/restenosis at 12 months compared with ticlopidine and both LMWH and batroxobin combined with aspirin appearing beneficial compared with aspirin alone. However, available trials are generally small and of variable quality and side effects of drugs are not consistently addressed. Further good quality, large-scale RCTs, stratified by severity of disease, are required.

Endovascular stent graft repair of iatrogenic popliteal artery injuries--a report of 2 cases.

Popliteal artery injury during total knee replacement (TKR) is rare. We report 2 cases of post-TKR popliteal artery occlusions treated endovascularly with Viabahn stent grafts. Long-term duplex follow-up and secondary re-intervention may be necessary.

Successful extra-anatomical recanalization of occluded superficial femoral arteries using the Outback device--a report of 2 cases.

INTRODUCTION: We report 2 cases where the Outback catheter facilitated extra-anatomical bypass after vessel perforation during attempted subintimal vessel dissection. REPORT: Attempted subintimal angioplasty of the superficial femoral artery (SFA) resulted in vessel perforation in 2 patients with chronic SFA occlusion and limb ischemia. Due to the lack of other endovascular or surgical options, the Outback catheter was used to reenter the patent lumen distal to the perforation. A stent graft was then deployed from proximal to the perforation to beyond the reentry point with successful outcomes. DISCUSSION: Although the reentry devices are typically used to enter the lumen from the subintimal plane, this novel technique involves using the Outback catheter to enter from the extravascular compartment and facilitate bypass of the SFA occlusion via an extra-anatomical route. This novel technique can be used to restore in-line blood flow when attempted endovascular revascularization failed due to vessel perforation.

Exogenous and endogenous cannabinoids suppress inhibitory neurotransmission in the human neocortex.

Activation of CB(1) receptors on axon terminals by exogenous cannabinoids (eg, Δ(9)-tetrahydrocannabinol) and by endogenous cannabinoids (endocannabinoids) released by postsynaptic neurons leads to presynaptic inhibition of neurotransmission. The aim of this study was to characterize the effect of cannabinoids on GABAergic synaptic transmission in the human neocortex. Brain slices were prepared from neocortical tissues surgically removed to eliminate epileptogenic foci. Spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) were recorded in putative pyramidal neurons using patch-clamp techniques. To enhance the activity of cannabinoid-sensitive presynaptic axons, muscarinic receptors were continuously stimulated by carbachol. The synthetic cannabinoid receptor agonist WIN55212-2 decreased the cumulative amplitude of sIPSCs. The CB(1) antagonist rimonabant prevented this effect, verifying the involvement of CB(1) receptors. WIN55212-2 decreased the frequency of miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin, but did not change their amplitude, indicating that the neurotransmission was inhibited presynaptically. Depolarization of postsynaptic pyramidal neurons induced a suppression of sIPSCs. As rimonabant prevented this suppression, it is very likely that it was due to endocannabinods acting on CB(1) receptors. This is the first demonstration that an exogenous cannabinoid inhibits synaptic transmission in the human neocortex and that endocannabinoids released by postsynaptic neurons suppress synaptic transmission in the human brain. Interferences of cannabinoid agonists and antagonists with synaptic transmission in the cortex may explain the cognitive and memory deficits elicited by these drugs.

Purine receptor-mediated endocannabinoid production and retrograde synaptic signalling in the cerebellar cortex.

BACKGROUND AND PURPOSE: Presynaptic CB1 cannabinoid receptors can be activated by endogenous cannabinoids (endocannabinoids) synthesized by postsynaptic neurones. The hypothesis of the present work was that activation of calcium-permeable transmitter-gated ion channels in postsynaptic neurones, specifically of P2X purine receptors, can lead to endocannabinoid production and retrograde synaptic signalling. EXPERIMENTAL APPROACH: GABAergic inhibitory postsynaptic currents (IPSCs) were recorded with patch-clamp techniques in Purkinje cells in mouse cerebellar slices. Purine receptors on Purkinje cells were activated by pressure ejection of ATP from a pipette. KEY RESULTS: ATP evoked an inward current in Purkinje cells, most likely due to P2X receptor activation. The ATP-evoked currents were accompanied by currents via voltage-gated calcium channels. ATP suppressed electrical stimulation-evoked IPSCs and miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin, and these effects were prevented by the CB1 antagonist rimonabant and the calcium chelator BAPTA (applied into the Purkinje cell). ATP also suppressed mIPSCs when voltage-gated calcium channels were blocked by cadmium, and intracellular calcium stores were depleted by thapsigargin. However, ATP failed to suppress mIPSCs when the extracellular calcium concentration was zero. CONCLUSIONS AND IMPLICATIONS: ATP elicits CB1 receptor-dependent retrograde synaptic suppression, which is probably mediated by an endocannabinod released by the postsynaptic neurone. An increase in intracellular calcium concentration in the postsynaptic neurone is necessary for this retrograde signalling. We propose that ATP increases the calcium concentration by two mechanisms: calcium enters into the neurone via the P2X receptor ion channel and the ATP-evoked depolarization triggers voltage-gated calcium channels.

Depolarizing GABAergic synaptic input triggers endocannabinoid-mediated retrograde synaptic signaling.

Endocannabinoids released by postsynaptic neurons inhibit neurotransmitter release from presynaptic axon terminals. One typical stimulus of endocannabinoid production is an increase of calcium concentration in postsynaptic neurons. The aim of the present study was to clarify whether depolarizing GABAergic synaptic input, by increasing calcium concentration in postsynaptic neurons, can trigger endocannabinoid production. Spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) were recorded in Purkinje cells in mouse cerebellar slices with patch-clamp pipettes containing 151 mM chloride (a usual recording mode). sIPSCs were depolarizing inward currents under this condition. Combined electrophysiological and fluorometric calcium imaging experiments indicated that sIPSCs frequently triggered calcium spikes. After the calcium spikes, a short-term suppression of sIPSCs occurred. This suppression was prevented by the CB(1) cannabinoid receptor antagonist rimonabant and the diacylglycerol lipase inhibitor orlistat, but not changed by URB597, an inhibitor of anandamide degradation. It is, therefore, likely that CB(1) receptors and 2-arachidonoylglycerol were involved. For testing the physiological significance of the above observation, we carried out experiments on brains of 3- to 5-day-old mice. The gramicidin-induced perforated patch-clamp mode was used for preserving the physiological intracellular chloride concentration of the neurons. Depolarizing GABAergic sIPSCs occurred under this condition, but at a very low rate. Rimonabant did not change the frequency of these sIPSCs, arguing against the persistence of an endocannabinoid tone. The results point to a new kind of trigger of endocannabinoid production: depolarizing GABAergic synaptic input can elicit endocannabinoid production in postsynaptic neurons by activating calcium channels. The produced endocannabinoid suppresses GABA release from presynaptic axon terminals.

Effects of colloid solutions on ischemia-reperfusion-induced periosteal microcirculatory and inflammatory reactions: comparison of dextran, gelatin, and hydroxyethyl starch.

OBJECTIVE: To compare the microhemodynamics and possible anti-inflammatory reactions of colloid resuscitation with 4% gelatin, 6% dextran, or 6% hydroxyethyl starch 130/0.4 solutions. DESIGN AND SETTING: A randomized control in vivo animal study in a university research laboratory. ANIMALS: Adult male Wistar rats (280 +/- 20 g). INTERVENTIONS: Sodium pentobarbital-anesthetized animals were subjected to a 60-min complete hindlimb ischemia and a 180-min reperfusion. Volume resuscitation, either with a colloid (dextran, gelatin, or hydroxyethyl starch, 25 mL kg(-1) during 3 hr intravenously) or with lactated Ringer's solution, was initiated 10 min before reperfusion. Fluorescence intravital videomicroscopy was performed before ischemia and 30, 60, 120, and 180 min postresuscitation to quantify the tibial periosteal functional capillary density, the capillary red blood cell velocity changes, and leukocyte rolling and firm adherence in postcapillary venules. In a separate series blood samples were drawn to determine the release of soluble intercellular adhesion molecule-1 (enzyme-linked immunosorbent assay technique), and the surface expression of CD11b (flow cytometry) on peripheral blood granulocytes. MEASUREMENTS AND MAIN RESULTS: Reperfusion significantly increased the leukocyte rolling and firm adhesion (by 2.6 and 7.1-fold, respectively), evoked marked decreases in periosteal functional capillary density and red blood cell velocity (56% and 39%, respectively), and increased the CD11b expression on the circulating leukocytes (by 85%). Hydroxyethyl starch, but not gelatin or dextran pretreatment, significantly inhibited the firm adherence of the leukocytes and reduced the elevated CD11b expression. Hydroxyethyl starch pretreatment also effectively attenuated the decreases in functional capillary density and red blood cell velocity, whereas gelatin and dextran did not improve the microhemodynamics. Finally, ischemia had no direct effect on the soluble intercellular adhesion molecule-1 levels, whereas gelatin treatment increased significantly this parameter. CONCLUSIONS: When compared with gelatin or dextran solutions, hydroxyethyl starch provided a therapeutic advantage in this setting by exerting an inhibitory effect on the ischemia-reperfusion-induced local and systemic leukocyte reactions and the postischemic periosteal microvascular dysfunction.