Sirolimus inhibits key events of restenosis in vitro/ex vivo: evaluation of the clinical relevance of the data by SI/MPL- and SI/DES-ratio's

<p>Abstract</p> <p>Background</p> <p>Sirolimus (SRL, Rapamycin) has been used successfully to inhibit restenosis both in drug eluting stents (DES) and after systemic application. The current study reports on the effects of SRL in various human in vitro/ex vivo models and evaluates the theoretical clinical relevance of the data by SI/MPL- and SI/DES-ratio's.</p> <p>Methods</p> <p>Definition of the SI/MPL-ratio: relation between <b>s</b>ignificant <b>i</b>nhibitory effects in vitro/ex vivo and the <b>m</b>aximal <b>p</b>lasma <b>l</b>evel after systemic administration in vivo (6.4 ng/ml for SRL). Definition of the SI/DES-ratio: relation between <b>s</b>ignificant <b>i</b>nhibitory effects in vitro/ex vivo and the drug concentration in <b>DES </b>(7.5 mg/ml in the ISAR drug-eluting stent platform). Part I of the study investigated in cytoflow studies the effect of SRL (0.01–1000 ng/ml) on TNF-α induced expression of intercellular adhesion molecule 1 (ICAM-1) in human coronary endothelial cells (HCAEC) and human coronary smooth muscle cells (HCMSMC). Part II of the study analysed the effect of SRL (0.01–1000 ng/ml) on cell migration of HCMSMC. In part III, IV, and V of the study ex vivo angioplasty (9 bar) was carried out in a human organ culture model (HOC-model). SRL (50 ng/ml) was added for a period of 21 days, after 21 and 56 days cell proliferation, apoptosis, and neointimal hyperplasia was studied.</p> <p>Results</p> <p>Expression of ICAM-1 was significantly inhibited both in HCAEC (SRL ≥ 0.01 ng/ml) and HCMSMC (SRL ≥ 10 ng/ml). SRL in concentrations ≥ 0.1 ng/ml significantly inhibited migration of HCMSMC. Cell proliferation and neointimal hyperplasia was inhibited at day 21 and day 56, significance (p < 0.01) was achieved for the inhibitory effect on cell proliferation in the media at day 21. The number of apoptotic cells was always below 1%.</p> <p>Conclusion</p> <p>SI/MPL-ratio's ≤ 1 (ICAM-1 expression, cell migration) characterize inhibitory effects of SRL that can be theoretically expected both after systemic and local high dose administration, a SI/MPL-ratio of 7.81 (cell proliferation) represents an effect that was achieved with drug concentrations 7.81-times the MPL. SI/DES-ratio's between 10^-6and 10^-8indicate that the described inhibitory effects of SRL have been detected with micro to nano parts of the SRL concentration in the ISAR drug-eluting stent platform. Drug concentrations in DES will be a central issue in the future.</p

Reduction in downstream test utilization following introduction of coronary computed tomography in a cardiology practice

To compare utilization of non-invasive ischemic testing, invasive coronary angiography (ICA), and percutaneous coronary intervention (PCI) procedures before and after introduction of 64-slice multi-detector row coronary computed tomographic angiography (CCTA) in a large urban primary and consultative cardiology practice. We utilized a review of electronic medical records (NotesMD®) and the electronic practice management system (Megawest®) encompassing a 4-year period from 2004 to 2007 to determine the number of exercise treadmill (TME), supine bicycle exercise echocardiography (SBE), single photon emission computed tomography (SPECT) myocardial perfusion stress imaging (MPI), coronary calcium score (CCS), CCTA, ICA, and PCI procedures performed annually. Test utilization in the 2 years prior to and 2 years following availability of CCTA were compared. Over the 4-year period reviewed, the annual utilization of ICA decreased 45% (2,083 procedures in 2004 vs. 1,150 procedures in 2007, P < 0.01) and the percentage of ICA cases requiring PCI increased (19% in 2004 vs. 28% in 2007, P < 0.001). SPECT MPI decreased 19% (3,223 in 2004 vs. 2,614 in 2007 P < 0.02) and exercise stress treadmill testing decreased 49% (471 in 2004 vs. 241 in 2007 P < 0.02). Over the same period, there were no significant changes in measures of practice volume (office and hospital) or the annual incidence of PCI (405 cases in 2004 vs. 326 cases in 2007) but a higher percentage of patients with significant disease undergoing PCI 19% in 2004 vs. 29% in 2007 P < 0.01. Implementation of CCTA resulted in a significant decrease in ICA and a corresponding significant increase in the percentage of ICA cases requiring PCI, indicating that CCTA resulted in more accurate referral for ICA. The reduction in unnecessary ICA is associated with avoidance of potential morbidity and mortality associated with invasive diagnostic testing, reduction of downstream SPECT MPI and TME as well as substantial savings in health care dollars

Long-term results of carotid stenting versus endarterectomy in high-risk patients

BACKGROUND: We previously reported that, in a randomized trial, carotid stenting with the use of an emboli-protection device is not inferior to carotid endarterectomy for the treatment of carotid artery disease at 30 days and at 1 year. We now report the 3-year results. METHODS: The trial evaluated carotid artery stenting with the use of an emboli-protection device as compared with endarterectomy in 334 patients at increased risk for complications from endarterectomy who had either a symptomatic carotid artery stenosis of at least 50% of the luminal diameter or an asymptomatic stenosis of at least 80%. The prespecified major secondary end point at 3 years was a composite of death, stroke, or myocardial infarction within 30 days after the procedure or death or ipsilateral stroke between 31 days and 1080 days (3 years). RESULTS: At 3 years, data were available for 260 patients (77.8%), including 85.6% of patients in the stenting group and 70.1% of those in the endarterectomy group. The prespecified major secondary end point occurred in 41 patients in the stenting group (cumulative incidence, 24.6%; Kaplan-Meier estimate, 26.2%) and 45 patients in the endarterectomy group (cumulative incidence, 26.9%; Kaplan-Meier estimate, 30.3%) (absolute difference in cumulative incidence for the stenting group, -2.3%; 95% confidence interval, -11.8 to 7.0). There were 15 strokes in each of the two groups, of which 11 in the stenting group and 9 in the endarterectomy group were ipsilateral. CONCLUSIONS: In our trial of patients with severe carotid artery stenosis and increased surgical risk, no significant difference could be shown in long-term outcomes between patients who underwent carotid artery stenting with an emboli-protection device and those who underwent endarterectomy. (ClinicalTrials.gov number, NCT00231270 [ClinicalTrials.gov].)