Serge Zaugg

Mechanisms of Very Late Drug-Eluting Stent Thrombosis Assessed by Optical Coherence Tomography

Background— The pathomechanisms underlying very late stent thrombosis (VLST) after implantation of drug-eluting stents (DES) are incompletely understood. Using optical coherence tomography, we investigated potential causes of this adverse event. Methods and Results— Between August 2010 and December 2014, 64 patients were investigated at the time point of VLST as part of an international optical coherence tomography registry. Optical coherence tomography pullbacks were performed after restoration of flow and analyzed at 0.4 mm. A total of 38 early- and 20 newer-generation drug-eluting stents were suitable for analysis. VLST occurred at a median of 4.7 years (interquartile range, 3.1–7.5 years). An underlying putative cause by optical coherence tomography was identified in 98% of cases. The most frequent findings were strut malapposition (34.5%), neoatherosclerosis (27.6%), uncovered struts (12.1%), and stent underexpansion (6.9%). Uncovered and malapposed struts were more frequent in thrombosed compared with nonthrombosed regions (ratio of percentages, 8.26; 95% confidence interval, 6.82–10.04; P<0.001 and 13.03; 95% confidence interval, 10.13–16.93; P<0.001, respectively). The maximal length of malapposed or uncovered struts (3.40 mm; 95% confidence interval, 2.55–4.25; versus 1.29 mm; 95% confidence interval, 0.81–1.77; P<0.001), but not the maximal or average axial malapposition distance, was greater in thrombosed compared with nonthrombosed segments. The associations of both uncovered and malapposed struts with thrombus were consistent among early- and newer-generation drug-eluting stents. Conclusions— The leading associated findings in VLST patients in descending order were malapposition, neoatherosclerosis, uncovered struts, and stent underexpansion without differences between patients treated with early- and new-generation drug-eluting stents. The longitudinal extension of malapposed and uncovered stent was the most important correlate of thrombus formation in VLST.

Effect of high-intensity statin therapy on atherosclerosis in non-infarct-related coronary arteries (IBIS-4): a serial intravascular ultrasonography study

AIM The effect of long-term high-intensity statin therapy on coronary atherosclerosis among patients with acute ST-segment elevation myocardial infarction (STEMI) is unknown. The aim of this study was to quantify the impact of high-intensity statin therapy on plaque burden, composition, and phenotype in non-infarct-related arteries of STEMI patients undergoing primary percutaneous coronary intervention (PCI). METHODS AND RESULTS Between September 2009 and January 2011, 103 STEMI patients underwent intravascular ultrasonography (IVUS) and radiofrequency ultrasonography (RF-IVUS) of the two non-infarct-related epicardial coronary arteries (non-IRA) after successful primary PCI. Patients were treated with high-intensity rosuvastatin (40 mg/day) throughout 13 months and serial intracoronary imaging with the analysis of matched segments was available for 82 patients with 146 non-IRA. The primary IVUS end-point was the change in per cent atheroma volume (PAV). After 13 months, low-density lipoprotein cholesterol (LDL-C) had decreased from a median of 3.29 to 1.89 mmol/L (P < 0.001), and high-density lipoprotein cholesterol (HDL-C) levels had increased from 1.10 to 1.20 mmol/L (P < 0.001). PAV of the non-IRA decreased by -0.9% (95% CI: -1.56 to -0.25, P = 0.007). Patients with regression in at least one non-IRA were more common (74%) than those without (26%). Per cent necrotic core remained unchanged (-0.05%, 95% CI: -1.05 to 0.96%, P = 0.93) as did the number of RF-IVUS defined thin cap fibroatheromas (124 vs. 116, P = 0.15). CONCLUSION High-intensity rosuvastatin therapy over 13 months is associated with regression of coronary atherosclerosis in non-infarct-related arteries without changes in RF-IVUS defined necrotic core or plaque phenotype among STEMI patients.

Comparison of a Novel Biodegradable Polymer Sirolimus-Eluting Stent With a Durable Polymer Everolimus-Eluting Stent Results of the Randomized BIOFLOW-II Trial

Background—Biodegradable polymers for release of antiproliferative drugs from drug-eluting stents aim to improve vascular healing. We assessed noninferiority of a novel ultrathin strut drug-eluting stent releasing sirolimus from a biodegradable polymer (Orsiro, O-SES) compared with the durable polymer Xience Prime everolimus-eluting stent (X-EES) in terms of the primary end point in-stent late lumen loss at 9 months. Methods and Results—A total of 452 patients were randomly assigned 2:1 to treatment with O-SES (298 patients, 332 lesions) or X-EES (154 patients, 173 lesions) in a multicenter, noninferiority trial. The primary end point was in-stent late loss at 9 months. O-SES was noninferior to X-EES for the primary end point (0.10±0.32 versus 0.11±0.29 mm; difference=0.00063 mm; 95% confidence interval, −0.06 to 0.07; Pnoninferiority<0.0001). Clinical outcome showed similar rates of target-lesion failure at 1 year (O-SES 6.5% versus X-EES 8.0%; hazard ratio=0.82; 95% confidence interval, 0.40–1.68; log-rank test: P=0.58) without cases of stent thrombosis. A subgroup of patients (n=55) underwent serial optical coherence tomography at 9 months, which demonstrated similar neointimal thickness among lesions allocated to O-SES and X-EES (0.10±0.04 mm versus 0.11±0.04 mm; −0.01 [−0.04, −0.01]; P=0.37). Another subgroup of patients (n=56) underwent serial intravascular ultrasound at baseline and 9 months indicating a potential difference in neointimal area at follow-up (O-SES, 0.16±0.33 mm2 versus X-EES, 0.43±0.56 mm2; P=0.04). Conclusions—Compared with durable polymer X-EES, novel biodegradable polymer–based O-SES was found noninferior for the primary end point in-stent late lumen loss at 9 months. Clinical event rates were comparable without cases of stent thrombosis throughout 1 year of follow-up. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01356888.

The association between in-stent neoatherosclerosis and native coronary artery disease progression: a long-term angiographic and optical coherence tomography cohort study

AIMS The purpose of the present study was to investigate the relationship between in-stent neoatherosclerosis (NA) and native atherosclerosis progression of untreated coronary segments. METHODS AND RESULTS In-stent NA was assessed by optical coherence tomography (OCT) among patients included in the SIRTAX-LATE OCT study 5 years after drug-eluting stent (DES) (sirolimus-eluting and paclitaxel-eluting stents) implantation. Neoatherosclerosis was defined as the presence of fibroatheroma or fibrocalcific plaque within the neointima of stented segments with a longitudinal extension >1.0 mm. Atherosclerosis progression in untreated native coronary segments was evaluated by serial quantitative coronary angiography (QCA). The change in minimal lumen diameter (MLD) was serially assessed within matched segments at baseline and 5-year angiographic follow-up. The key clinical endpoint was non-target lesion (non-TL) revascularization throughout 5 years. A total of 88 patients with 88 lesions were available for OCT analysis 5 years after DES implantation. In-stent NA was observed in 16% of lesions with the majority of plaques being fibroatheromas (11.4%) followed by fibrocalcific plaques (5.7%). A total of 704 non-TL segments were serially evaluated by QCA. Between baseline and 5-year follow-up, the reduction in MLD was significantly more pronounced in patients with NA (-0.25 mm, 95% CI -0.36 to -0.17 mm) when compared with patients without NA (-0.13 mm, 95% CI -0.17 to -0.10 mm, P = 0.002). Similarly, non-TL revascularization was more frequent in patients with NA (78.6%) when compared with patients without NA (44.6%, P = 0.028) throughout 5 years. CONCLUSIONS In-stent NA is more common among patients with angiographic and clinical evidence of native atherosclerosis progression suggesting similar pathophysiological mechanisms.SIRTAX trial is registered at http://www.clinicaltrials.gov/ct2/show/NCT00617084.

Impact of local endothelial shear stress on neointima and plaque following stent implantation in patients with ST-elevation myocardial infarction: A subgroup-analysis of the COMFORTABLE AMI-IBIS 4 trial

BACKGROUND Numerous studies have demonstrated an association between endothelial shear stress (ESS) and neointimal formation after stent implantation. However, the role of ESS on the composition of neointima and underlying plaque remains unclear. METHODS Patients recruited in the Comfortable AMI-IBIS 4 study implanted with bare metal stents (BMS) or biolimus eluting stents (BES) that had biplane coronary angiography at 13 month follow-up were included in the analysis. The intravascular ultrasound virtual-histology (IVUS-VH) and the angiographic data were used to reconstruct the luminal surface, and the stent in the stented segments. Blood flow simulation was performed in the stent surface, which was assumed to represent the luminal surface at baseline, to assess the association between ESS and neointima thickness. The predominant ESS was estimated in 3-mm segments and was correlated with the amount of neointima, neointimal tissue composition, and with the changes in the underlying plaque burden and composition. RESULTS Forty three patients (18 implanted with BMS and 25 with BES) were studied. In both stent groups negative correlations were noted between ESS and neointima thickness in BMS (P < 0.001) and BES (P = 0.002). In BMS there was a negative correlation between predominant ESS and the percentage of the neointimal necrotic core component (P = 0.015). In BES group, the limited neointima formation did not allow evaluation of the effect of ESS on its tissue characteristics. ESS did not affect vessel wall remodeling and the plaque burden and composition behind BMS (P > 0.10) and BES (P > 0.45). CONCLUSIONS ESS determines neointimal formation in both BMS and BES and affects the composition of the neointima in BMS. Conversely, ESS does not impact the plaque behind struts irrespective of stent type throughout 13 months of follow-up.

Changes of coronary plaque composition correlate with C-reactive protein levels in patients with ST-elevation myocardial infarction following high-intensity statin therapy

OBJECTIVES Levels of inflammatory biomarkers associate with changes of coronary atheroma burden in statin-treated patients with stable coronary artery disease. This study sought to determine changes of plaque composition in vivo in relation to high-sensitivity C-reactive protein (hs-CRP) levels in patients with ST-elevation myocardial infarction (STEMI) receiving high-intensity statin therapy. METHODS The IBIS-4 study performed serial (baseline and 13-month), 2-vessel intravascular ultrasound (IVUS) and radiofrequency-IVUS of the non-infarct-related arteries in patients with STEMI treated with high-intensity statin therapy. The present analysis included 44 patients (80 arteries) with serial measurements of hs-CRP. RESULTS At follow-up, median low-density lipoprotein cholesterol (LDL-C) levels decreased from 126 to 77 mg/dl, HDL-C increased from 44 to 47 mg/dl, and hs-CRP decreased from 1.6 to 0.7 mg/L. Regression of percent atheroma volume (-0.99%, 95% CI -1.84 to -0.14, p = 0.024) was accompanied by reduction of percent fibro-fatty (p = 0.04) and fibrous tissue (p < 0.001), and increase in percent necrotic core (p = 0.006) and dense calcium (p < 0.001). Follow-up levels of hs-CRP, but not LDL-C, correlated with changes in percent necrotic core (p = 0.001) and inversely with percent fibrous tissue volume (p = 0.008). Similarly, baseline-to-follow-up change of hs-CRP correlated with the change in percent necrotic core volume (p = 0.02). CONCLUSIONS In STEMI patients receiving high-intensity statin therapy, stabilization of VH-IVUS-defined necrotic core was confined to patients with lowest on-treatment levels and greatest reduction of hs-CRP. Elevated CRP levels at follow-up may identify progression of high-risk coronary plaque composition despite intensive statin therapy and overall regression of atheroma volume.

Variability in the measurement of minimum fibrous cap thickness and reproducibility of fibroatheroma classification by optical coherence tomography using manual versus semi-automatic assessment

AIMS The minimum fibrous cap thickness (FCT) is considered a major criterion of coronary plaque vulnerability according to autopsy studies. We aimed to assess the reproducibility in the measurement of the optical coherence tomography (OCT)-detected minimum FCT and the agreement in the classification of thin-cap fibroatheroma (TCFA), by a software-based semi-automatic method compared with the manual method. METHODS AND RESULTS A total of 50 frames with fibroatheromas (FA) were randomly selected from the Integrated Biomarker Imaging Study-4 (IBIS-4). Two experienced OCT analysts independently measured the minimum FCT at two different time points, manually and by three different semi-automatic software-based algorithms, based on the assessment of light intensity along the axial scan line. A TCFA was defined as an FA with minimum FCT <65 μm. The inter- and intra-observer reproducibility of the manual measurement of the minimum FCT was moderate with an intra-class correlation coefficient (ICC) of 0.71 and 0.79, respectively. The corresponding ICCs by either one of the three semi-automatic algorithms were 0.99. When categorising FA according to the minimum FCT based on the manual assessment, the inter- and intra-observer agreement was poor (κ=0.23) and moderate (κ=0.50), respectively. In contrast, the semi-automatic assessment showed perfect agreement for both inter- and intra-observer assessments (κ=0.90-1.00 and 1.00, respectively). CONCLUSIONS While semi-automatic assessment of FCT and TCFA classification was associated with excellent reproducibility and agreement, manual measurements were associated with a moderate reproducibility and agreement in the quantification of FCT and classification of TCFA.

A comparison of an ultrathin-strut biodegradable polymer sirolimus-eluting stent with a durable polymer everolimus-eluting stent for patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: rationale and design of the BIOSTEMI trial

AIMS A novel ultrathin-strut biodegradable polymer sirolimus-eluting stent (BP-SES) (Orsiro; Biotronik, Bülach, Switzerland) was shown to be superior to a thin-strut durable polymer everolimus-eluting stent (DP-EES) (XIENCE Xpedition/Alpine; Abbott Vascular, Santa Clara, CA, USA) with respect to the primary endpoint of target lesion failure (TLF) at 12 months in the pre-specified subgroup of patients with ST-segment elevation myocardial infarction (STEMI) included in the BIOSCIENCE trial. We designed a large-scale, randomised, clinical trial to assess the clinical superiority of ultrathin-strut BP-SES over thin-strut DP-EES among patients with STEMI undergoing primary percutaneous coronary intervention (PPCI). METHODS AND RESULTS BIOSTEMI (NCT02579031) is a prospective, multicentre, randomised, controlled, superiority trial that will randomly assign 1,250 patients with STEMI undergoing PPCI to treatment with BP-SES or DP-EES. The primary endpoint of TLF, a composite of cardiac death, target vessel reinfarction, and clinically indicated target lesion revascularisation within 12 months, will be analysed with Bayesian models applied to the BIOSTEMI data set (n=1,250) using robust historical priors to incorporate historical information from the BIOSCIENCE STEMI subgroup (n=407). CONCLUSIONS The BIOSTEMI trial will determine whether ultrathin-strut BP-SES are superior to thin-strut DP-EES with respect to TLF in patients with STEMI undergoing PPCI.

Rehospitalizations Following Primary Percutaneous Coronary Intervention in Patients With ST-Elevation Myocardial Infarction: Results From a Multi-Center Randomized Trial.

Background Rehospitalizations (RHs) after ST‐elevation myocardial infarction carry a high economic burden and may deteriorate quality of life. Characterizing patients at higher risk may allow the design of preventive measures. We studied the frequency, reasons, and predictors for unplanned cardiac and noncardiac RHs in ST‐elevation myocardial infarction patients undergoing primary percutaneous coronary intervention. Methods and Results In this post‐hoc analysis of the COMFORTABLE AMI (Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST‐Elevation Myocardial Infarction; NCT00962416) trial including 1137 patients, unplanned cardiac and noncardiac RHs occurred in 133 (11.7%) and in 79 patients (6.9%), respectively, at 1 year. The most frequent reasons for unplanned cardiac RHs were recurrent chest pain without evidence of ischemia (20.4%), recurrent chest pain with ischemia and coronary intervention (16.9%), and ischemic events (16.9%). Unplanned noncardiac RHs occurred most frequently attributed to bleeding (24.5%), infections (14.3%), and cancer (9.1%). On multivariate analysis, left ventricular ejection fraction (22% increase in the rate of RHs per 10% decrease; P=0.03) and angiographic myocardial infarction Syntax score (34% increase per 10‐point increase; P=0.01) were independent predictors of unplanned cardiac RHs. Age emerged as the only independent predictor of unplanned noncardiac RHs. Regional differences for unplanned cardiac RHs were observed. Conclusions Among ST‐elevation myocardial infarction patients undergoing primary percutaneous coronary intervention in the setting of a randomized, clinical trial, unplanned cardiac RHs occurred in 12% with recurrent chest pain being the foremost reason. Unplanned noncardiac RHs occurred in 7% with bleeding as the leading cause. Left ventricular ejection fraction and Syntax score were independent predictors of unplanned cardiac RHs and identified patient subgroups in need for improved secondary prevention. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00962416.

A randomized multicenter trial comparing the XIENCE everolimus eluting stent with the CYPHER sirolimus eluting stent in the treatment of female patients with de novo coronary artery lesions: The SPIRIT WOMEN study

Background The comparative performance of different drug-eluting stents (DES) among female patients has not been assessed in a randomized manner. Objectives The SPIRIT Women Clinical Evaluation trial compared the durable polymer everolimus-eluting XIENCE stent (DP-EES) with the durable polymer sirolimus-eluting Cypher stent (DP-SES) in women undergoing percutaneous coronary intervention (PCI). Methods A total of 455 female patients with stable CAD were randomly assigned to receive DP-EES (n = 304) or DP-SES (n = 151). The powered angiographic outcome of the trial was in-stent late lumen loss (LLL) at 9 months after the index procedure. Secondary angiographic end points included in-segment LLL, in-stent and in-segment binary restenosis and percent diameter stenosis. The primary clinical outcome was a composite of all-cause death, myocardial infarction (MI) or target vessel revascularization (TVR). Results At 9-month follow-up, in-stent LLL was 0.19±0.38 mm and 0.11±0.37 mm in patients assigned to DP-EES and DP-SES, respectively. The one-sided upper 95% CI of the difference in in-stent LLL between the groups of 0.08 mm was 0.15 and therefore within the pre-specified non-inferiority margin of 0.17 mm (p for non-inferiority = 0.013). However, the test for superiority showed a borderline significant difference in terms of LLL between DP-EES and DP-SES (p for superiority = 0.044). There were no significant differences in binary restenosis (2.0% vs. 0.72%, p = 0.44) and percent diameter stenosis (14.97±12.17 vs. 13.36±10.82, p = 0.19). The rate of definite stent thrombosis at 12 months was lower in patients treated with DP-EES (0% vs. 2.0%, p = 0.036). Conclusions Among women undergoing PCI, DP-EES was associated with a small but probably clinically relevant increase in in-stent LLL at 9 months as compared to DP-SES and with a lower risk of definite stent thrombosis at 12 months. Trial registration ClinicalTrials.gov NCT01182428. https://clinicaltrials.gov/