Stent restenosis

Horvath C, Welt FG, Nedelman M, Rao P, Rogers C. Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates inhibitory potential depends on type of injury and leukocytes targeted. Circ Res 2002 90(4) 488 494. 

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. 

While drug eluting stents effectively tackled the problem of stent restenosis, other issues have emerged in recent times. In 2003, the FDA issued a warning regarding cases of sub-acute thrombosis (SAT) with the CYPHER stent that resulted in some deaths. This... 

Fischman DL, Leon MB, Bairn DS, et al., for the Stent Restenosis Study Investigators. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994 331 496-501. 

Kereiakes D, Linnemeier TJ, Bairn DS, et al. Usefulness of stent length in predicting in-stent restenosis (the MULTI-LINK stent trials). Am J Cardiol 2000 86 336-341. 

Kornowski R, Hong MK, Tio FO, Bramwell O, Wu H, Leon MB. In-stent restenosis contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol 1998 31 224-230. 

In a study by Bartunek et al. [134], 35 patients were infused with AC 133 bone marrow cells after AMI. The mean dose was 12.6 million cells, and the mean infusion was 11.4 days after the index event. At 4-month follow-up, treated patients had an improved mean LVEF but higher rates of stent restenosis, stent reocclusion, and de novo coronary artery lesions than did the controls. 

George J, Herz I, Goldstein E, Abashidze S, Deutch V, Finkelstein A, Michowitz Y, Miller H, Keren G. Number and adhesive properties of circulating endothelial progenitor cells in patients with in-stent restenosis. Arterioscler Thromb Vase Biol 2003 23 e57-60. 

ACE inhibitors are widely prescribed for patients with atherosclerosis, hypertension, or diabetes, and after myocardial infarction, because of proven beneficial effects in each of these groups. In light of the results in the setting of stent restenosis, whether a patient with hypertension or some other target disorder who carries the DD genotype derives less benefit from ACE inhibitor therapy warrants consideration. 

Vascular stenting has become a common procedure during percutaneous transluminal angioplasty (PTA) and percutaneous transluminal coronary angioplasty (PTCA) procedures because it has been found to reduce restenosis (Narins et al., 1998). In both the STRESS (Stent Restenosis Study) and BENESTENT... 

Gene therapy offers new possibilities for the treatment of cardiovascular diseases. This area of research has focused mainly on the treatment of postangioplasty restenosis, in-stent restenosis, and vein graft thickening. First clinical trials have shown that vascular gene transfer to humans is generally safe and well tolerated. Even... 

The ERASER Investigators, Acute platelet inhibition with abcix-imab does not reduce in-stent restenosis (ERASER study). Circulation 1999 100 799,... 

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. 

Douglas JS, Holmes DR, Kereiakes DJ, et al. Coronary stent restenosis in patients treated with Cilostazol. Circulation 2005 ... 

Kuchulakanti B Wolfram R, "lorguson R, et al. Bivalirudin compared with llb/llla inhibitors in patients with in-stent restenosis undergoing intracoronary brachytherapy. Cardiovasc Revasc Med 2005 6 154-159. 

Lange H, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004 350(26) 2673-2681. 

As previously mentioned, for SMC proliferation after coronary angioplasty, cell activation and cell-to-cell interaction of platelets and leukocytes mediated by adhesion molecules are considered to be important. Coronary stenting produces the release of an adhesion molecule, P-selectin, from d-granule of activated platelets. P-selectin-mediated platelet-leukocyte interaction has a crucial role in the development of stent restenosis. Cilostazol is an antiplatelet, antithrombotic, phosphodiesterase III inhibitor that by inhibiting P-selectin release has inhibitory effects on SMC migration. In addition, cilostazol may directly act to inhibit intimal hyperplasia. 

Hoffmann R, Mintz GS, Dussaillant GR, et al. Patterns and mechanisms of in-stent restenosis a serial intravascular ultrasound study. Circulation 1996 94 1247-1254. 

Marx SO, Marks AR, Bench to bedside the development of rapamycin and its application to stent restenosis. Circulation 2001 8 852-855. 

Acute vessel recoil, chronic remodeling, and intimal hyperplasia were the mechanisms involved in this process (1-4). However, after the introduction of stents in the daily practice during interventional procedures, intimal hyperplasia became the mechanism associated in the pathophysiology of in-stent restenosis (5-9). Therefore, its prevention should be related with therapies that inhibit smooth muscle cell proliferation. 

First, there was a consistent benefit in clinical and angiographic binary restenosis data. As we can see in Table 2, in-stent restenosis of the two pilot studies, which comprised only de novo lesions, angiographic restenosis was in only a single digit of restenosis, with a late loss of around 0.6 mm. All these numbers represent, compared to the average restenosis rate of control arm from the more recent DES trials, a reduction of 81 % of in-stent restenosis and a 42% reduction of late loss, and also represent a reduction of 90% of MACCE. 

A small pilot trial from Brazil reporting 6.6% of in-stent restenosis with 0.61 mm of late loss and with no target lesion revascularization or any major events after two years of follow-up (47) also confirmed these positive results. 

In patients with in-stent restenosis, the first pilot trial reported negative results in a small population of inpatients presenting restenosis after brachiterapy failure however, of note, in this population, even with DES therapy, they also had negative results, some of them, such as those reported by the Thorax Center, with high incidence of restenosis and stent thrombosis (29,48). 

Among these 76 patients, 109 bare-coronary stents were deployed in 103 de novo lesions in an equal number of major native epicardial vessels. Patients with in-stent restenosis, bifurcation lesions, vein graft lesions, lesion length of >0.20 mm, acute myocardial infarction in the previous 72 hours, poor left ventricular function (ejection fraction <35%), renal failure defined as creatinine concentration of >2 mg, or under immunosuppressive treatment were excluded from the study. 

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