Increased restenosis rates 12 months after coronary implantation of the sirolimus-eluting YUKON-choice stent compared to the paclitaxel-eluting TAXUS Stent.

BACKGROUND: Previously the polymer-free sirolimus-eluting YUKON-Choice stent (A) has demonstrated noninferiority compared to the polymer-based paclitaxel-eluting TAXUS stent (B). To test for long-term equivalency in unselected real-world coronary lesions of various complexities, we retrospectively compared both stents. METHODS: A total of 410 patients with symptomatic coronary artery disease (CAD) were treated with stent A (n = 205) or stent B (n = 205). Baseline clinical characteristics, lesion location, and length and the number of stents implanted per lesion were equally distributed. Clinical follow-up with assessment of major adverse cardiac events (MACE) and noncardiac deaths was obtained at 9 and 12 months. RESULTS: Nominal stent diameter and nominal length of the stented segment were without differences between the groups. The incidence of MACE after 12 months was significantly higher in group A (35.1%) compared to group B (16.6%, P = .001). This was mainly due to increased rates of target-lesion revascularizations in group A (13.7%) vs group B (4.4%, P = .005). No significant differences in target-vessel revascularizations and non-target-vessel revascularizations were observed. In group B, 1 stent thrombosis was documented (0.5%) vs none in group A (P > .05); in each group 1 myocardial infarction (MI), but no cardiac deaths occurred; 3 noncardiac deaths in group A (1.5%) vs 7 in group B (3.4%) were observed (P = .3). CONCLUSIONS: In contrast to our previous findings indicating no differences in MACE between patients treated with the polymer-free sirolimus-eluting YUKON-Choice stent and the polymer-based paclitaxel-eluting TAXUS stent at 6 months, we herewith show that 12 months after percutaneous coronary intervention (PCI) of real-world coronary lesions the YUKON stent appears to be inferior due to increased target-lesion revascularization (TLR) rates as a consequence of delayed restenosis.

Nitinol stent implantation in long superficial femoral artery lesions: 12-month results of the DURABILITY I study.

PURPOSE: To evaluate the long-term efficacy and integrity of the PROTEGE EverFlex stent in superficial femoral artery (SFA) lesions in symptomatic patients with peripheral artery disease (PAD). METHODS: A prospective, multicenter, nonrandomized study enrolled 151 subjects (111 men; mean age 67.8 years, range 42-93) undergoing percutaneous treatment of de novo, restenotic, or reoccluded SFA lesions between August 11, 2006, and June 26, 2007. Subjects were scheduled to receive a single stent and be evaluated through 12 months following the implant procedure. Occlusions were present in 40% of the patients. Mean lesion length was 96.4 mm (range 10-150). RESULTS: A total of 161 stents (158 EverFlex) were implanted in the 151 patients: single stents in 93.4% (141/151) and a second stent in 6.6% (10/151). One-year follow-up information was available for 88.7% (134/151) of the study participants; of the remaining 17 subjects, 6 subjects withdrew from the study, 2 were lost to follow-up, and 9 died. Freedom from restenosis data were available for 99.3% (133/134) of the subjects who completed a 12-month follow-up visit. The mean Rutherford classification fell from 2.8+/-0.8 (range 1-5) at baseline to 0.6+/-1.1 (range 0-5) at 12 months. The mean ankle-brachial index rose from 0.6+/-0.2 (range 0-1.4) at baseline to 0.9+/-0.2 (range 0-1.2) at 12 months. The rates for freedom from >50% restenosis at 6 and 12 months were 91.3% (95% CI 84.9% to 95.2%) and 72.2% (95% CI 63.8% to 79.6%), respectively. The freedom from target lesion revascularization rate at 12 months was 79.1% (95% CI 71.2% to 85.6%). The 1-year stent fracture rate was 8.1% (95% CI 4.0% to 14.4%). CONCLUSION: The high freedom from >50% restenosis and low fracture rate at 12 months suggests that the PROTEGE EverFlex stent offers a safe and acceptably efficacious means of treating SFA lesions in symptomatic subjects with PAD.

One-year follow-up after implantation of the EverFlex nitinol stent in long lesions of the superficial femoral artery.

For treatment of complex superficial femoral artery lesions, suitable stent devices are required. The present study details the first long-term results with the long EverFlex nitinol stent. Forty-one EverFlex stents were implanted in 32 patients with either superficial femoral artery occlusions (n = 20) or stenoses (n = 12); mean lesion length was 13.3 cm (range = 8.0-39.0). Patients presented with clinical stage Fontaine IIb (n = 27), III (n = 4), or IV (n = 1). Stent lengths were 10 cm (n = 18), 12 cm (n = 6), or 15 cm (n = 17). Follow-up after 2 months indicated primary and secondary patency rates of 96.9% (n = 31) and 100% (n = 32); ABI improved from 0.57 to 0.91 (P < .001). After 1 year, revascularization was performed in 6 patients (18.8%). Primary and secondary patency rates were 81.3% (n = 26) and 93.8% (n = 30). In this first long-term evaluation, the long EverFlex nitinol stent achieves excellent clinical results after implantation into complex superficial femoral artery lesions.

The complement factor properdin induces formation of platelet-leukocyte aggregates via leukocyte activation.

Both the complement system and platelet-leukocyte aggregates are involved in chronic and acute stages of atherosclerosis. Properdin, a positive regulator of the complement system, is secreted by leukocytes and endothelial cells. In the present study, the role of properdin in the formation of platelet-leukocyte aggregates was investigated. Incubation of human whole blood with properdin (25-200 microg/ml) resulted in a dose-dependent formation of platelet-leukocyte aggregates, with an increase of up to 2.2-fold compared to controls (p < 0.05), as analysed by flow cytometry. In addition, properdin significantly amplified ADP-induced aggregation of platelets with leukocytes by 53% (p < 0.05), while it had no effect on ADP-induced aggregation of platelets alone. Consistent with these results, properdin did not activate platelets as shown by the expression of activated GPIIb/IIIa (PAC-1 epitope) and P-selectin (CD62P) on the platelet surface. However, properdin significantly induced expression of CD11b (MAC-1) on leukocytes by 12-fold (p < 0.05) as a measure of leukocyte activation. In conclusion, the complement system component properdin induces the formation of platelet-leukocyte aggregates via leukocyte activation. The data establish a link between the complement system and platelet-leukocyte aggregates with potential significance in atherosclerotic vascular disease.

Comparison of a polymer-free rapamycin-eluting stent (YUKON) with a polymer-based paclitaxel-eluting stent (TAXUS) in real-world coronary artery lesions.

BACKGROUND: In selected patient cohorts the polymer-free rapamycin-eluting YUKON stent (A) has demonstrated noninferiority compared with the polymer-based paclitaxel-eluting TAXUS stent (B). To test for equivalency in unselected real-world patients with coronary lesions of various complexities, we retrospectively compared both stent designs. METHODS: A total of 410 patients with symptomatic CAD were successfully treated with A (n = 205) or with B (n = 205). Baseline clinical characteristics, coronary lesion location, lesion length, and the number of stents implanted per lesion were equally distributed between the treatment groups. All patients underwent QCA-analysis at baseline. Clinical follow-up with assessment of MACE and noncardiac deaths was obtained at 30 days and 6 months. RESULTS: Nominal stent diameter was 2.96 +/- 0.38 mm in Group A vs. 3.05 +/- 0.42 mm in Group B (P = 0.2); nominal length of stented segmentwas 22.97 +/-13.0 mm vs. 23.63 +/- 10.0 (P = 0.56). Analysis of MACE after 6 months resulted in one angiographically documented stent thrombosis causing MI in B (0.2%) vs. none in A. No other MI or cardiac deaths occurred in either group, while two noncardiac deaths in A (1.0%) were reported. Fifteen target lesion revascularizations (7.3%) were performed in A vs. 7 (3.4%) in B. Differences in study endpoints at 6 months did not reach statistical significance (P > 0.05). CONCLUSIONS: Up to 6 months after PCI of real-world coronary lesions, there were no statistically significant differences in MACE between patients treated with the polymer-free rapamycin-eluting YUKON stent and the polymer-based paclitaxel-eluting TAXUS stent.

Four-year results after brachytherapy for diffuse coronary in-stent restenosis: will coronary radiation therapy survive?

BACKGROUND: Prior to the introduction of drug-eluting stents (DES), diffuse coronary in-stent restenosis (ISR) was mainly treated by brachytherapy (BT), with good short-term and mid-term results. However, there exist limited data on the long-term effects of BT that justify its continuous use. MATERIALS AND METHODS: Two hundred patients with diffuse ISR treated with intravascular BT were retrospectively followed over 4 years. Group A (n=134) was treated with the noncentered (90)Sr/Y BetaCath radiation system, whereas Group B (n=66) was treated with the centered 32P Galileo source wire system. Primary endpoints after 4 years were target lesion restenosis (TLS) and target lesion revascularization (TLR). Secondary endpoints were target vessel revascularization (TVR) and nontarget vessel revascularization (NTVR), as well as major adverse cardiac events (MACE). RESULTS: Follow-up at 4 years yielded a TLS rate of 37.6% (Group A, 40.8%; Group B, 31.1%; P=.48). TLR was performed in 34.8% of patients (37.5% in Group A vs. 29.5% in Group B; P=.55). Ten percent of patients underwent coronary bypass surgery. Percutaneous coronary intervention was performed more often in Group A (27.5%) than in Group B (19.7%), while TVR was less frequent in Group A (10.0%) than in Group B (18.0%). NTVR was undertaken in 25.0% of Group A patients versus 21.3% of Group B patients, and MACE occurred in 1.7% of Group A patients versus 3.3% of Group B patients. These differences were not statistically significant (P>.05). CONCLUSIONS: While excellent short-term and mid-term results after coronary BT are widely accepted, a high TLS rate can be observed after 4 years. The potential superiority of DES to BT will depend on the availability of long-term clinical data.

Ablation of atrial flutter by the femoral approach in the absence of inferior vena cava.

This report describes a case of isthmus-dependent atrial flutter ablation by the femoral approach in a 77-year-old patient with a previously unknown absence of the inferior vena cava (IVC). Multi-row detector CT angiography indicated the absence of the perihepatic IVC, whereas the venous blood is drained into the superior vena cava (SVC) via the vena azygos. An ablation catheter could be advanced through the right femoral vein reaching the right heart via vena azygos and SVC. Despite looping of the catheter, ablation and termination of atrial flutter were performed successfully. This is the first report of an inferior-to-superior approach for ablation of atrial flutter in the absence of the perihepatic IVC.

Closure of guide wire-induced coronary artery perforation with a two-component fibrin glue.

Perforation or rupture of a coronary artery with subsequent pericardial effusion and cardiac tamponade is a potentially life-threatening complication of percutaneous coronary intervention (PCI). Several emergency treatment strategies exist to close the perforation including reversal of anticoagulation, prolonged balloon inflation, implantation of stent grafts, local injection of thrombogenic molecules, placement of microcoils, or open heart surgery. Here we report on a 66-year-old patient who underwent urgent PCI for acute stent thrombosis in the proximal LAD. The artery was reopened, a new stent implanted successfully, and a GPIIb/IIIa-antagonist was given. Shortly thereafter the patient suffered from cardiac tamponade requiring pericardiocentesis and pericardial drainage. The coronary angiogram indicated a severe guide wire-induced perforation and pericardial effusion originating from a distal diagonal branch segment. Prolonged balloon inflation did not stop the leakage. Therefore the monorail balloon was exchanged for an over-the-wire balloon. A two-component commercial fibrin glue consisting of fibrinogen and thrombin was rapidly but separately injected through the wire channel of the balloon into the distal segment of the diagonal branch. The coronary leak was successfully closed and the patient recovered quickly. In comparison with the previously reported cases of thrombin injection important differences should be noticed: (1) a two-component hemostatic seal was used without reversal of anticoagulation, (2) rapid injection instead of prolonged infusion of the hemostatic drugs was performed, and (3) the rescue technique was applied in a cath lab that routinely uses monorail catheter systems. Therefore we consider this a novel and effective approach for closure of coronary ruptures.

Angiotensin II promotes the inflammatory response to CD40 ligation via TRAF-2.

A plethora of evidence supports a link between inflammation and atherogenesis. Both the vasoactive peptide angiotensin II (ANG II) as well as the CD40/CD154 signaling pathway exhibit proinflammatory properties with a direct influence on atherogenesis. We therefore tested the hypothesis that ANG II interacts with CD40/CD154 in human vascular smooth muscle cells (SMC). ANG II did not increase expression of CD40 in human SMC. However, when SMC were prestimulated with ANG II and thereafter stimulated with CD154, the ligand for CD40, the release of IL-6 as a marker of inflammatory activation was augmented compared to cells not primed with ANG II. TNF receptor-associated factor 2 (TRAF-2), an important adaptor protein involved in CD40 signaling, but not TRAF-5 or -6, was increased by ANG II via activation of the angiotensin II type 1 (AT1) receptor subtype. These results suggest that a signaling pathway downstream of CD40 may be altered by ANG II prestimulation. Thus, ANG II can also indirectly cause inflammatory activation of vascular SMC. The data show a novel link between the proatherogenic vasoactive peptide ANG II and cell-cell contact-mediated inflammatory pathways and implicate options for the prevention and therapy of atherosclerotic disease.

Coronary stent thrombosis related to aspirin resistance: what are the underlying mechanisms?

Acute coronary stent thrombosis represents a serious complication for which aspirin resistance could be a potential cause. The actual case is a myocardial infarction treated with immediate stenting of the right coronary artery followed by elective stenting of the left anterior descending artery 4 days later. Despite standard antiplatelet therapy, stents in both arteries occluded 2 days after the last procedure. The patient's blood samples were analyzed and revealed the presence of aspirin resistance as well as elevated thromboxane B(2) plasma levels. No thrombophilic disorder was detected. Today the mechanism of aspirin resistance is mostly unknown. Further research as well as recommendations for laboratory screening and for alternative pharmacological treatment options are required.

Initial clinical experience with the Protégé EverFlex long self-expanding nitinol stent in the superficial femoral artery.

AIMS: Clinical results following stent implantation in the superficial femoral artery (SFA) are limited due to restenosis, often caused by stent fractures. Therefore new stent devices are desirable. The present study details our initial experience with the routine use of the novel Protégé EverFlex long self-expanding nitinol stent for treatment of long SFA total occlusions or stenoses. METHODS AND RESULTS: Between February and March 2006 a total of 15 EverFlex nitinol stents were implanted in 12 patients with either total SFA occlusions (n = 9) or long stenoses (n = 3), mean lesion length 14.9 cm (+/- 10.4 cm). All patients presented with claudication stage Fontaine IIb (Rutherford category 3). Stent lengths were 10 cm (n = 6), 12 cm (n = 1), or 15 cm (n = 8), stent diameters were 6 mm (n = 14) and 7 mm (n = 1). Access was gained either by the crossover (n = 9), antegrade (n = 2), or popliteal approach (n = 1). After predilatation, stent placement and postdilatation were performed with 100% technical success. Clinical and apparative follow-up after 6-8 weeks indicated the absence of restenosis or reocclusion in all cases. CONCLUSION: The novel long self-expanding EverFlex nitinol stent (10 cm/12 cm/15 cm in length) exhibits excellent technical handling characteristics with good short-term clinical results. Mid-term and long-term clinical results as well as potential stent fractures need to be further examined.

Markers for endothelial dysfunction, but not markers for oxidative stress correlate with classical risk factors and the severity of coronary artery disease. (A subgroup analysis from the Ludwigshafen Risk and Cardiovascular Health Study).

OBJECTIVE: Endothelial dysfunction and oxidative stress are involved in atherogenesis. In the search for predictors of vascular disease markers for endothelial dysfunction and oxidative stress were analyzed. METHODS: Of 208 consecutive patients 22% were controls (CO) without coronary artery disease (CAD), 52% presented with stable angina (SAP) and 26% had acute coronary syndromes (ACS). Nitric oxide (NO), thrombomodulin (TM), von Willebrand factor (vW), sVCAM-1, sICAM-1, sP-selectin, sE-selectin, sL-selectin and C-reactive protein (CRP) were determined as markers for endothelial dysfunction, glutathione (GSH), glutathione peroxidase (Gpx), myeloperoxidase (Mpx), lipid peroxides (Lpx), 8-isoprostane (Iso), superoxide dismutase (SOD), total antioxidant capacity (TAC) and homocysteine (Hc) as markers for oxidative stress. RESULTS: The increases of TM, vW, sVCAM-1, CRP, SOD and Mpx correlated with the CAD status in the order CO < SAP < ACS, whereas NO and sL-selectin were inversely correlated (p < 0.05, resp.). The other markers remained unchanged. For several markers a significant relationship to risk factors was detected. CONCLUSIONS: Markers for endothelial dysfunction rather than those for oxidative stress may serve as indicators for the presence and severity of CAD.

Aspirin resistance in coronary artery disease is correlated to elevated markers for oxidative stress but not to the expression of cyclooxygenase (COX) 1/2, a novel COX-1 polymorphism or the PlA(1/2) polymorphism.

Aspirin resistance (AR) is estimated to be present in 5-75% of patients and is related to increased cardiovascular mortality. However, the underlying mechanisms are mostly unknown. In the present study, AR was detected in 14 out of 55 patients (25%) with coronary artery disease. The presence of concomitant anti-inflammatory drugs did not affect AR. Plasma levels of thromboxane B(2) as well as the markers for oxidative stress and known platelet activators 8-isoprostane and lipid peroxidation products were significantly higher in aspirin-resistant individuals (349.3 pg/ml, 53.9 pg/ml, and 538 micromol/l) compared to controls (113.7 pg/ml, 10.3 pg/ml, and 32.2 micromol/l; P < 0.05, respectively). Platelet cyclooxygenase-1 (COX-1) and COX-2 mRNA and protein expression were without significant differences between the two groups. DNA sequencing detected a novel platelet COX-1 single nucleotide polymorphism (SNP) resulting in amino acid exchange at position 8 (Arg8/Trp8). The wild-type as well as the heterozygous and homozygous SNP were present in both patient groups without significant differences. The aspirin binding (Arg120) and acetylation site (Ser529) were unaffected in the samples tested. Neither was AR related to the platelet integrin PlA(1)/A(2) polymorphism. In conclusion, AR appears to be unrelated to differences in platelet COX-1 and COX-2 expression or to a novel platelet COX-1 SNP and the PlA(1)/A(2) SNP. However, a correlation exists to elevated eicosanoids generated by oxidative stress indicating COX-1-independent pathways for the generation of platelet activating molecules represent a potential cause for AR.

Percutaneous saphenous vein graft interventions with and without distal filter wire protection.

BACKGROUND: Embolic protection during SVG interventions using distal balloon occlusion and aspiration has shown to reduce periprocedural complications compared to unprotected SVG interventions. A similar effect is expected from filter wires. PATIENTS AND METHODS: A total of 174 SVG interventions carried out with (group A; n=87) or without distal filter wire protection (group B; n=87) were retrospectively matched for the location of distal graft anastomosis and analyzed for baseline and procedural characteristics, for TIMI flow grade before and after PCI, for the post-procedural CK elevation, and for major adverse cardiac events at 30 days and 6 months (primary end point). Location of distal graft anastomosis was the left anterior descending artery in 19.6%, the left diagonal branch in 6.9%, the left marginal branch in 17.2%, the left posterolateral branch in 24.2%, the mid-segment of the right coronary artery in 28.7%, and the posterior descending artery in 3.4%. RESULTS: Baseline clinical demographics showed no relevant differences between both the groups. Mean age of vein grafts was 11.7+/- 4.3 years in group A versus 10.6+/- 4.9 years in group B (P=0.15). The number of stents per lesion was 1.4+/- 0.8 in group A versus 1.0+/- 0.8 in group B (P<0.01). The total length of stents was 32.2+/- 16.2 mm in group A versus 20.9+/-12.1 mm in group B (P<0.01). TIMI flow grade pre was 2.5+/-0.8 in group A versus 2.7+/- 0.6 in group B (P<0.05). TIMI flow grade post was 2.9+/- 0.3 versus 2.9+/- 0.2. Improvement of TIMI flow grade after SVG intervention was 0.4+/- 0.7 in group A versus 0.2+/- 0.6 in group B (P<0.05). Post-procedural CK-MB elevations were observed in 17 patients of group A versus 14 patients of group B (P=0.18). At 30 days, there were no myocardial infarctions (MIs) and no deaths in either group. One patient of group A had to be reoperated and four patients of group A underwent repeat PCI (4.6%) versus one patient of group B (1.2%). At 6 months, there were again no MIs and no deaths in either group. Target lesion revascularization rate was 17.3% in group A versus 11.5% in group B (P <0.02). CONCLUSION: When distal filter wire protection is used in high risk SVG lesions, the clinical outcome of percutaneous interventions may be equal to low risk SVG lesions without filter wire protection.

Relationship between size of myocardial infarctions assessed by delayed contrast-enhanced MRI after primary PCI, biochemical markers, and time to intervention.

BACKGROUND: The quantitative assessment of myocardial infarctions using delayed contrast-enhanced magnetic resonance imaging (MRI) has recently been validated using postmortem histopathological animal studies. In a prospective study, we investigated the correlation between infarct size as assessed by delayed contrast-enhanced MRI, elevation of creatine kinase (CK), and c-reactive protein (CRP) as well as the time from onset of symptoms to intervention. METHODS: Four to 10 days after immediate PCI in 45 acute ST-segment elevation myocardial infarction (STEMI) patients (<24 hour) with stenting of the infarct-related artery and treatment with abciximab, we performed gadolinium contrast-enhanced three-dimensional inversion recovery gradient-echo MR sequences with complete coverage of the LV-myocardium in short-axis slices. The mass of infarcted tissue based on the volume of hyperenhanced myocardium was calculated and linear regression analysis was performed to assess the correlation between absolute size of infarctions (g) as well as relative size (LV%) with peak values of CK, CRP, and the time to PCI. RESULTS: There was a significant correlation between absolute size of infarctions (g) and peak CK values (r = 0.72; P < 0.001) as well as the relative size (LV%) and peak CK (r = 0.77; P < 0.001). No correlations were found between absolute size (r = 0.33) as well as relative size (r = 0.27) of infarctions and peak CRP. There was also no correlation between absolute (r = 0.29) as well as relative size of infarctions (r = 0.27) and the time from onset of symptoms to PCI. CONCLUSIONS: In patients with acute STEMI (<24 hour) undergoing immediate PCI with stenting and treatment with abciximab, peak CK values correlated well with infarct size as assessed by delayed contrast-enhanced MRI. There were no correlations between infarct size and peak CRP as well as the time to intervention.

Endovascular interventions in iliac and infrainguinal occlusive artery disease.

Percutaneous endovascular procedures are increasingly applied to treat symptomatic peripheral occlusive artery disease. While the primary technical success and recanalization rates in iliac and infrainguinal interventions are high, differences in the long-term patency rates exist with respect to the anatomic localization, separating the iliac, femoropopliteal, and infrapopliteal arterial regions. In iliac arteries, even complex lesions can be recanalized with good long-term patency rates, especially when using self-expanding nitinol stents. In the infrainguinal arteries the method of choice is still under debate (e.g., balloon angioplasty vs stent implantation). A high restenosis rate represents one of the major limitations in femoropopliteal and infrapopliteal interventions. Therefore, additional methods and treatment strategies for peripheral interventions with the potential for future applications are under investigation and will be discussed such as drug-eluting stents, brachytherapy, subintimal angioplasty, laser angioplasty, atherectomy/thrombectomy, cutting balloon, polytetrafluoroethylene (PTFE)-covered stent grafts, biodegradable stents, and cryoplasty. The increasing amount of data on successful peripheral interventions supports the necessity to adapt and reevaluate the current consensus guidelines that were put together in 2000.

[Interactions of statins with antithrombotic drugs]. / Beeinflussen Statine die Effekte antithrombotischer Pharmaka?

Due to a wealth of scientific clinical data, statins are being extensively used for the primary and secondary prevention of ischemic events. Therefore, statins play a major part in the pharmacological treatment of cardiovascular disease. Even before it became apparent that statins are effective despite normal baseline lipid levels, it was known that statins exert additional effects on the vascular wall that are independent of lipid lowering and protective toward the arteriosclerotic plaque. Some of these pleiotropic effects are related to hemostasis: through profibrinolytic, antiadhesive and antiaggregatory mechanisms, statins act antithrombotic. Based on experimental results, concerns were brought forward Simthat atorvastatin interferes with the antithrombotic effects of the ADP-receptor inhibitor prodrug, clopidogrel, due to competitive affinity to liver enzymes. So far, however, other experimental as well as clinical data do not support the hypothesis that atorvastatin or any other statin affects the antithrombotic potency of clopidogrel. The aforementioned issues will be discussed.

New antithrombotic drugs on the horizon.

Venous and arterial thromboembolism are a major cause for morbidity and mortality. The list of established drugs for the prevention of thrombus formation and embolisation includes heparins, hirudin and derivatives, aspirin, ADP and glycoprotein IIb/IIIa receptor antagonists, as well as vitamin K antagonists. Several limitations exist for these drugs that have stimulated the search for new and better anticoagulants. A series of selective clotting factor Xa inhibitors and direct factor IIa (thrombin) inhibitors are on the horizon, two of which are getting close to broad clinical application. Additional therapeutics that are still under preclinical and clinical investigation include inhibitors of the tissue factor pathway/factor VII complex, clotting factor VIII and XIII inhibitors and modulators of the protein C pathway or of endogenous fibrinolysis, as well as novel antiplatelet drugs. This review is focused on the current status of development of novel antithrombotics and their clinical potential. Even though only a few of a broad array of antithrombotic agents have reached clinical testing, some hold the potential for significant improvement in efficacy and safety of anticoagulant therapy.

Abciximab, eptifibatide, and tirofiban exhibit dose-dependent potencies to dissolve platelet aggregates.

Platelet GPIIb/IIIa antagonists are not only used to prevent platelet aggregation, but also in combination with thrombolytic agents for the treatment of coronary thrombi. Recent data indicate a potential of abciximab alone to dissolve thrombi in vivo. We investigated the potential of abciximab, eptifibatide, and tirofiban to dissolve platelet aggregates in vitro. Adenosine diphosphate (ADP)-induced platelet aggregation could be reversed in a concentration-dependent manner by all three GPIIb/IIIa antagonists when added after the aggregation curve reached half-maximal aggregation. The concentrations chosen are comparable with in vivo plasma concentrations in clinical applications. Disaggregation reached a maximum degree of 72.4% using 0.5 microg/ml tirofiban, 91.5% using 3.75 microg/ml eptifibatide, and 48.4% using 50 microg/ml abciximab (P < 0.05, respectively). A potential fibrinolytic activity of the GPIIb/IIIa antagonists was ruled out by preincubation with aprotinin or by a plasma clot assay. A stable model Chinese hamster ovary (CHO) cell line expressing the activated form of GPIIb/IIIa was used to confirm the disaggregation capacity of GPIIb/IIIa antagonists found in platelets. Not only abciximab, but also eptifibatide and tirofiban have the potential to disaggregate newly formed platelet clusters in vitro. Because enzyme-dependent fibrinolysis does not appear to be involved, competitive removal of fibrinogen by the receptor antagonists is the most likely mechanism.

Potential of gold-bound microtubules as a new ultrasound contrast agent.

Contrast agents based on gas-filled microspheres share the problem of time limited opacification due to low stability of microbubbles. The aim of this study was to test if gold-bound microtubules provide backscattering that allows microtubules to be potentially useful as an ultrasound (US) contrast agent. Gold colloids were immobilized on protein microtubule walls. Latex balloons were filled with gold-bound microtubules or conventional left heart contrast agent and were ultrasonographically imaged in fundamental and harmonic modes. Feasibility of anti-beta-tubulin antibody conjugation to gold-bound microtubules was confirmed using immune fluorescence analysis. Gold particles were successfully bound to microtubules. Contrast intensities in latex balloons filled with gold-bound microtubules (141 +/- 35) were comparable to those with Levovist (180 +/- 35) and did not decrease significantly during continuous US imaging for 20 min (135 +/- 34 vs. Levovist 5.0 +/- 2.0). Anti-beta-tubulin antibodies were successfully conjugated to gold-bound microtubules. Gold-bound microtubules provide a persistent contrast effect, suggesting their use as an ultrasonic contrast agent with the feasibility of antibody conjugation.