In-stent thrombosis

Rapamycin (sirolimus), a macrolide antibiotic, has been used recently in organ transplantation for its potent immunosuppressive actions by inhibiting both cytokine mediated and growth factor mediated proliferation of smooth muscle cells and lymphocytes [55, 56]. In the RAVEL trial of non-acute single vessel lesions, the Sirolimus-eluting stent was compared to bare metal stent (BMS) in a 1 1 fashion [57]. One-year major adverse cardiovascular events and 6 month neointimal proliferation as assessed by late luminal loss (-0.01 0.33 mm in Sirolimus stent versus 0.80 0.53 mm in BMS) were improved. The Sirolimus-eluting stent thus virtually eliminated in-stent restenosis with no evidence of edge effect, dissection, or in-stent thrombosis. 

The addition of ticlopidine to aspirin has been shown to have a synergistic effect on the inhibition of platelet aggregation after stent insertion (6), and this combination has also been found to be superior in terms of prevention of in-stent thrombosis to both aspirin alone and aspirin combined with warfarin (7). However, due to the rare but serious side effect of agranulocytosis associated with ticlopidine (8), and its slow onset of action, ticlopidine is no longer used in most countries. The combination of clopidogrel and aspirin has been proved to be as effective as aspirin and ticlopidine in the prevention of intrastent thrombosis (9). 

Patient selection is crucial in reducing rates of stent thrombosis. The SCAAR registry initially showed increased rates of stent thrombosis with DES however, as practice patterns changed, this increase disappeared and there was no difference in stent thrombosis between DES and BMS (38). Nevertheless, given these findings, the duration of dual antiplatelet therapy with clopidogrel and aspirin is recommended for at least 12 months. 

In contrast to the efficacy of abciximab in the electrically induced thrombosis model and in stent thrombosis (see above), aspirin and heparin, or combinations of the two, were ineffective in these models. However, in the electrically induced thrombosis model in the dog, combination of 7E3... 

Fig. 2 Four years clinical outcome of BMS when compared to DES (A) in-stent thrombosis reached 1.2% using DES compared to 0.6% using BMS, (B) death risk of patients with BMS was at 5.3% after 4 years while DES was at 6.7% but the difference was not considered to be significant, (C) myocardial infarction of both was same all over the time period of 4 years, and (D) Restenosis levels were drastically higher for BMS than DES, with a 23% probability over 4 years [93].

Despite the success of DES, still better prevention of restenosis and in stent thrombosis is searched for by scientists. In addition to that, the metallic stent matrix that remains in the vessels is still considered to be a foreign body, thus having potential disadvantages. 

Metallic stents covered with stem cells were proposed as a plausible solution for preventing in-stent thrombosis and restenosis. Raina et al. published in 2014 in vivo results of 152 implanted hTEC covered stents and compared the outcomes with BMS. The preliminary results showed earlier strut coverage with endothelial cells and no increased neointimal proliferation compared to BMS [92],... 

DBS have reduced the occurrence of restenosis and the need of repeated revascularization procedures by 50-70% (Moses et al. 2003 Stone et al. 2004). One of the current concerns about DBS is the increase of delayed in-stent thrombosis manifesting more than 30 days after stent implantation. This late manifestation of stent thrombosis may be related to delayed endothe-lialization of the stent and typically occurs when antiplatelet therapy is discontinued. 

We have recently prepared an open-label phase 1/lla clinical trial (the INDOR study a phase I/Ha open-label multicenter study to assess the inhibitory effects of NF-kB decoy ODN on restenosis after stenting in coronary artery) to evaluate the safety and efficacy of NF-kB decoy ODN. Seventeen patients were treated with NF-kB decoy ODN after percutaneous coronary intervention (PCI) using bare metal stents. As a result, the stenosis improved to 1.4 5.9% after the intervention. Serum monocyte chemotactic protein-1 (MCP-1) levels were significantly suppressed in NF-kB decoy ODN-treated patients on day 3 after the PCI. Significant restenosis was found in (Mily one of the 17 patients after 6 months, and the average restenosis rate was 39.6 22.3%. No in-stent thrombosis was found and no... 

For patients undergoing primary PCI, clopidogrel is administered as a 300-to 600-mg loading dose followed by a 75 mg/day maintenance dose, in combination with aspirin 325 mg once daily, to prevent subacute stent thrombosis and long-term cardiovascular events. 

The pivotal US trial for the Paclitaxel stent was the TAXUS IV trial, which enrolled 1,314 patients with single de novo coronary lesions (Length 10-28 mm and diameter 2.5-3.75 mm) [67] (Fig. 5.7). Target vessel revascularization based on ischemic symptoms was reduced from 12 to 4.7% p < 0.001). The rate of restenosis by angiography was considerable lower (7.9% versus 26.6% p < 0.001), with no difference in the rate of cardiac death, myocardial infarction, or stent thrombosis. 

In 2006, however, focus shifted to another rare but potentially catastrophic event known as late stent thrombosis, which, in contrast to subacute thrombosis, occurs months to years after stent placement. It usually occurs before endothelialization is complete. For bare metal stents, this takes a few weeks. However, in drug eluting stents, this process of endotheliazation is delayed [68]. This complication... 

Over the ensuing months, new criterion was proposed for defining stent-thrombosis in an attempt to establish uniformity, eliminate inappropriate censoring, and improve sensitivity. 

One of the significant factors promoting late stent thrombosis has been found to be premature discontinuation of dual antiplatelet therapy (aspirin and clopidrogel). In an analysis of 4,666 of patients undergoing initial PCI with BMS or DES, researchers from the Duke Heart center reported that longterm risk for death and major cardiac events was significantly increased among patients in the DES... 

Serruys PW, Daemen I. Are drug-eluting stents associated with a higher rate of late thrombosis than bare metal stents Late stent thrombosis a nuisance in both bare metal and drug-eluting stents. Circulation 2007 115 1433-1439. 

Mauri L, Hsieh WH, Massaro IM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007 356 1020-1029. 

Waksman R, Ajani AE, White RL, et al. Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary gamma-radiation in patients with in-stent restenosis Washington Radiation for In-Stent Restenosis Trial plus 6 months of clopidogrel (WRIST PLUS). Circulation 2001 103 2332-2335. 

I 5 Gurbel PA, Bliden KR Samara W, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis results of the CREST Study. J Am Coll Cardiol 2005 46 1827-1832. 

Ajzenberg N, Aubry R Huisse MG, et al. Enhanced shear-induced platelet aggregation in patients who experience subacute stent thrombosis a case-control study J Am Coll Cardiol 2005 45 1753-1756. 

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