Giuseppe Ferrante

An optical coherence tomography study of a biodegradable vs. durable polymer-coated limus-eluting stent: A LEADERS trial sub-study

AIMS Incomplete endothelialization has been found to be associated with late stent thrombosis, a rare but devastating phenomenon, more frequent after drug-eluting stent implantation. Optical coherence tomography (OCT) has 10 times greater resolution than intravascular ultrasound and thus appears to be a valuable modality for the assessment of stent strut coverage. The LEADERS trial was a multi-centre, randomized comparison of a biolimus-eluting stent (BES) with biodegradable polymer with a sirolimus-eluting stent (SES) using a durable polymer. This study sought to evaluate tissue coverage and apposition of stents using OCT in a group of patients from the randomized LEADERS trial. METHODS AND RESULTS Fifty-six consecutive patients underwent OCT during angiographic follow-up at 9 months. OCT images were acquired using a non-occlusive technique at a pullback speed of 3 mm/s. Data were analysed using a Bayesian hierarchical random-effects model, which accounted for the correlation of lesion characteristics within patients and implicitly assigned analytical weights to each lesion depending on the number of struts observed per lesion. Primary outcome was the difference in percentage of uncovered struts between BESs and SESs. Twenty patients were included in the analysis in the BES group (29 lesions with 4592 struts) and 26 patients in the SES group (35 lesions with 6476 struts). A total of 83 struts were uncovered in the BES group and 407 out of 6476 struts were uncovered in the SES group [weighted difference -1.4%, 95% confidence interval (CI) -3.7 to 0.0, P = 0.04]. Results were similar after adjustment for pre-procedure lesion length, reference vessel diameter, number of implanted study stents, and presence of stent overlap. There were three lesions in the BES group and 15 lesions in the SES group that had > or =5% of all struts uncovered (difference -33.1%, 95% CI -61.7 to -10.3, P < 0.01). CONCLUSION Strut coverage at an average follow-up of 9 months appears to be more complete in patients allocated to BESs when compared with SESs. The impact of this difference on clinical outcome and, in particular, on the risk of late stent thrombosis is yet to be determined.

High Levels of Systemic Myeloperoxidase Are Associated With Coronary Plaque Erosion in Patients With Acute Coronary Syndromes A Clinicopathological Study

Background— Systemic levels of myeloperoxidase predict prognosis in patients with acute coronary syndromes and are considered a marker of plaque vulnerability. It is not known whether myeloperoxidase is associated with different coronary morphologies (ie, rupture or erosion of the culprit lesion) in patients with acute coronary syndrome. Methods and Results— Twenty-five consecutive patients (aged 67±11 years; 15 men [60%]; 13 [52%] with non-ST-segment elevation acute coronary syndrome and 12 [48%] with acute ST-segment elevation myocardial infarction) were enrolled. Optical coherence tomography classified the culprit lesion as ruptured in 18 (72%) or eroded in 7 patients (28%) and detected intraluminal thrombus in 89% of ruptured plaques and 100% of eroded plaques. Baseline systemic levels of serum myeloperoxidase were significantly higher in patients with an eroded plaque than in those with a ruptured plaque (median, 2500 ng/mL; 25th to 75th percentile, 1415 to 2920 versus median, 707 ng/mL; 25th to 75th percentile, 312 to 943; P=0.001), whereas C-reactive protein levels did not differ significantly (median, 11.3 mg/L; 25th to 75th percentile, 1.3 to 28.5 versus median, 3.9 mg/L; 25th to 75th percentile, 1.3 to 17.8; P=0.76, respectively). In addition, the density of myeloperoxidase-positive cells within thrombi overlying plaques in postmortem coronary specimens retrieved from sudden coronary death victims was significantly higher in lesions with erosion (n=11) than ruptures (n=11) (median, 1584; 25th to 75th percentile, 1088 to 2135 cells/mm2 versus median, 579; 25th to 75th percentile, 442 to 760 cells/mm2; P=0.0012). Conclusions— Systemic myeloperoxidase levels are significantly elevated in patients with acute coronary syndrome presenting with eroded culprit plaque compared with patients presenting with ruptured culprit plaque. Consistently, in postmortem coronary specimens, luminal thrombi superimposed on eroded plaques contain a higher density of myeloperoxidase-positive cells than thrombi superimposed on ruptured plaques. This study supports the concept that elevations in selective inflammatory biomarkers reflect specific acute complications of coronary atherosclerosis.

CagA antigen of Helicobacter pylori and coronary instability: insight from a clinico-pathological study and a meta-analysis of 4241 cases.

BACKGROUND Cytotoxin-associated gene-A (CagA) antigen is expressed by some virulent strains of Helicobacter pylori (H. pylori). The role of CagA antigen in coronary instability is unknown. We performed a clinico-pathological study and a meta-analysis in the attempt to shed new light on this complex issue. METHODS In the clinico-pathological study, 38 patients with unstable angina (UA), 25 patients with stable angina (SA), 21 patients with normal coronary arteries (NCA) and 50 age and sex matched healthy volunteers were enrolled. Serology for CagA was assessed in all patients. Specimens of atherosclerotic plaques were obtained from all patients by directional coronary atherectomy, and prepared for immunohistochemistry using anti-CagA monoclonal antibodies. The meta-analysis includes 9 studies assessing the association between seropositivity to CagA strains and acute coronary events. RESULTS The titre of anti-CagA antibodies was significantly higher in patients with unstable angina (161+/-90 RU/ml) compared to those with stable angina (83+/-59 RU/ml p<0.02), NCA (47.3+/-29 RU/ml p<0.01) and healthy controls (73+/-69 p<0.02). Anti-CagA antibodies recognized antigens localized inside coronary atherosclerotic plaques in all specimens from both stable and unstable patients. In the meta-analysis, seropositivity to CagA was significantly associated with the occurrence of acute coronary events with an odds ratio (OR) of 1.34 (95% CI, 1.15-1.58, p=0.0003). CONCLUSIONS Taken together these findings suggest that in a subset of patients with unstable angina, an intense immune response against CagA-positive H. pylori strains might be critical to precipitate coronary instability mediated by antigen mimicry between CagA antigen and a protein contained in coronary atherosclerotic plaques.

A multicentre evaluation of the safety of intracoronary optical coherence tomography.

AIMS Optical coherence tomography (OCT) is increasingly being applied to the coronary arteries. However, the risks associated with the imaging procedure are not yet well defined. The purpose of the present multicentre registry was to assess the acute complications associated with the clinical use of intra-coronary OCT in a large number of patients. METHODS AND RESULTS Consecutive patients from six centres who had OCT examination were retrospectively included. All adverse events and complications, even if transient, were noted. Risks were categorised into: 1) self-limiting 2) major complications including major adverse cardiac events (MACE) and 3) mechanical device failure. A total of 468 patients underwent OCT examination for evaluation of: plaque (40.0%), percutaneous coronary intervention (28.2%) or follow-up stent tissue coverage (31.8%). OCT was performed using a non-occlusive flush technique in 45.3% with a mean contrast volume of 36.6+/-9.4ml. Transient chest pain and QRS widening/ST-depression/elevation were observed in 47.6% and 45.5% respectively. Major complications included five (1.1%) cases of ventricular fibrillation due to balloon occlusion and/or deep guide catheter intubation, 3 (0.6%) cases of air embolism and one case of vessel dissection (0.2%). There were no cases of coronary spasm or MACE during or within the 24 hour period following OCT examination. CONCLUSIONS OCT is a specialised technique with a relatively steep learning curve. Major complications are uncommon and can be minimised with careful procedural planning and having an awareness of the potential contributory risks, especially deep guide catheter intubation during contrast flushing. Upcoming developments will make OCT more practical and less procedurally demanding, also potentially conserving contrast volume considerably.

The Evolving Role of Inflammatory Biomarkers in Risk Assessment After Stent Implantation

The main adverse reactions to coronary stents are in-stent restenosis (ISR) and stent thrombosis. Along with procedural factors, individual susceptibility to these events plays an important role. In particular, inflammatory status, as assessed by C-reactive protein levels, predicts the risk of ISR after bare-metal stent implantation, although it does not predict the risk of stent thrombosis. Conversely, C-reactive protein levels fail to predict the risk of ISR after drug-eluting stent (DES) implantation, although they appear to predict the risk of stent thrombosis. Of note, DES have abated ISR rates occurring in the classical 1-year window, but new concern is emerging regarding late restenosis and thrombosis. The pathogenesis of these late events seems to be related to delayed healing and allergic reactions to polymers, a process in which eosinophils seem to play an important role by enhancing restenosis and thrombosis. The identification of high-risk individuals based on biomarker assessment may be important for the management of patients receiving stent implantation. In this report, we review the evolving role of inflammatory biomarkers in predicting the risk of ISR and stent thrombosis.

Association between C-reactive protein and angiographic restenosis after bare metal stents: an updated and comprehensive meta-analysis of 2747 patients

BACKGROUND Previous studies have shown conflicting results about the relationship between baseline C-reactive protein (CRP) and restenosis after stenting with bare metal stent (BMS). METHODS We assessed the association between serum CRP and angiographic restenosis after BMS by meta-analysis. Studies that reported basal serum CRP levels, above a prespecified cutoff value, before BMS deployment were included. An inverse random weighted meta-analysis was performed by entering the logarithm of the odds ratio (OR) of angiographic restenosis with its standard error for each study. RESULTS Nine studies enrolling 2747 patients were selected. CRP threshold value was around 3 mg/l in three studies, 5 mg/l in four studies, and 6.98 and 10 mg/l in one study. Follow-up duration was 6.2+/-3.0 (mean+/-S.D.) months. Higher preprocedural CRP levels were a significant predictor of angiographic restenosis: OR 1.59, 95% confidence interval 1.21-2.07, P=.001. Heterogeneity was found: chi2 14.47, P=.07; I2=44.7%. Publication bias was also detected (P=.01, Eggers test). A sensitivity analysis, after excluding each study in turn, confirmed the predictive value of higher CRP levels, in agreement with the results of the main analysis. CONCLUSIONS Among patients with coronary artery disease, undergoing percutaneous coronary intervention with BMS, higher baseline CRP levels are associated with higher risk of angiographic restenosis. A targeted therapeutic approach to patients with high baseline CRP, based on statins, oral corticosteroids, or PPAR gamma agonists, or selective use of drug-eluting stents, aiming at abating the higher risk of in-stent restenosis should be considered.

Effects of cobalt-chromium everolimus eluting stents or bare metal stent on fatal and non-fatal cardiovascular events: patient level meta-analysis

Objectives To examine the safety and effectiveness of cobalt-chromium everolimus eluting stents compared with bare metal stents. Design Individual patient data meta-analysis of randomised controlled trials. Cox proportional regression models stratified by trial, containing random effects, were used to assess the impact of stent type on outcomes. Hazard ratios with 95% confidence interval for outcomes were reported. Data sources and study selection Medline, Embase, the Cochrane Central Register of Controlled Trials. Randomised controlled trials that compared cobalt-chromium everolimus eluting stents with bare metal stents were selected. The principal investigators whose trials met the inclusion criteria provided data for individual patients. Primary outcomes The primary outcome was cardiac mortality. Secondary endpoints were myocardial infarction, definite stent thrombosis, definite or probable stent thrombosis, target vessel revascularisation, and all cause death. Results The search yielded five randomised controlled trials, comprising 4896 participants. Compared with patients receiving bare metal stents, participants receiving cobalt-chromium everolimus eluting stents had a significant reduction of cardiac mortality (hazard ratio 0.67, 95% confidence interval 0.49 to 0.91; P=0.01), myocardial infarction (0.71, 0.55 to 0.92; P=0.01), definite stent thrombosis (0.41, 0.22 to 0.76; P=0.005), definite or probable stent thrombosis (0.48, 0.31 to 0.73; P<0.001), and target vessel revascularisation (0.29, 0.20 to 0.41; P<0.001) at a median follow-up of 720 days. There was no significant difference in all cause death between groups (0.83, 0.65 to 1.06; P=0.14). Findings remained unchanged at multivariable regression after adjustment for the acuity of clinical syndrome (for instance, acute coronary syndrome v stable coronary artery disease), diabetes mellitus, female sex, use of glycoprotein IIb/IIIa inhibitors, and up to one year v longer duration treatment with dual antiplatelets. Conclusions This meta-analysis offers evidence that compared with bare metal stents the use of cobalt-chromium everolimus eluting stents improves global cardiovascular outcomes including cardiac survival, myocardial infarction, and overall stent thrombosis.

Benefits and risks of long-term duration of dual antiplatelet therapy after drug-eluting stenting: A meta-analysis of randomized trials

BACKGROUND The potential benefits and risks of at least 1-year dual antiplatelet therapy (DAPT) duration after drug-eluting stent (DES) implantation remain uncertain. METHODS AND RESULTS PubMed, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched from database inception to December 2011 for randomized controlled trials that compared longer DAPT versus shorter DAPT duration after DES. Unpublished data were obtained from investigators. Trial-specific odds ratios (ORs) with 95% confidence interval (CI) were calculated and pooled using fixed-effects or random-effects model as appropriate. Data were independently extracted by 2 reviewers. Three randomized controlled trials comprising 5622 participants were included. Compared with patients receiving short-term therapy, participants receiving longer DAPT duration had a pooled OR of 1.26 (95% CI, 0.88 to 1.80; P=0.21, random-effects) for the primary outcome of cardiac death, myocardial infarction or stroke, OR of 1.29 (95% CI, 0.85 to 1.93; fixed-effects) for all-cause death, 1.23 (95% CI, 0.78 to 1.93; fixed-effects) for cardiac death, 0.91 (95% CI, 0.58 to 1.42; random-effects) for myocardial infarction, 1.93 (95% CI, 1.01 to 3.69; fixed-effects) for stroke and 2.51 (95% CI, 1.10 to 5.71, fixed-effects) for TIMI major bleeding. The number needed to treat for an additional harmful outcome was 217.6 for stroke and 243 for TIMI major bleeding. CONCLUSIONS This meta-analysis provides no evidence of benefits with longer DAPT duration as compared with a shorter course of therapy. It also reports significant harms with respect to major bleeding and stroke associated with prolonged DAPT use.

Coronary atherosclerotic burden in patients with infection by CagA-positive strains of Helicobacter pylori

ObjectivesCytotoxic associated gene-A (CagA)-positive strains of Helicobacter pylori emerged as a possible atherosclerotic stimulus. Nevertheless, whether CagA-positivity is associated with more extensive or severe atherosclerotic coronary burden has never been studied. MethodsForty consecutive patients with coronary artery disease (CAD) and twenty consecutive patients with normal coronary arteries undergoing coronary angiography were enrolled. All patients underwent evaluation of classical atherogenic risk factors and assessment of anti-urease B and anti-CagA antibodies titer. Either the severity of coronary stenosis (stenosis score) or the extent of coronary atherosclerosis (extent score) was evaluated in CAD patients. ResultsThe anti-CagA antibody titer was significantly higher in patients with CAD as compared with normal coronary arteries patients [85 (10–108.75) vs. 47.3 (17–64) RU/ml, P=0.02], whereas there were no differences in anti-urease B titer between the two groups. A significant correlation was found between anti-CagA antibody titer and extent score (R=0.35, P=0.03), whereas stenosis score was similar (R=0.25, P=0.11). On the contrary, no significant correlation was found between anti-urease B antibody titer and either extent or stenosis score. Moreover, CagA-positive patients had a more extensive CAD (P=0.029) when compared with CagA-negative patients. Interestingly, whereas serum glucose, LDL levels, anti-urease B, and anti-CagA antibodies were predictors of extent score at univariate analysis, at multivariate analysis anti-CagA antibody titer only was an independent predictor of the extent of coronary atherosclerosis (B=0.051, standard error of B=0.042, P=0.04). ConclusionThese results support the association between CagA-positive H. pylori infection and coronary atherosclerotic burden. Further studies are needed to better elucidate the mechanism by which CagA-positive strains may promote atherosclerosis.

Pre-intervention eosinophil cationic protein serum levels predict clinical outcomes following implantation of drug-eluting stents

AIMS Eosinophils have been identified in post-mortem studies as important players of both restenosis and thrombosis after drug-eluting stent (DES) implantation. We aimed at assessing the association between baseline levels of eosinophil cationic protein (ECP), a marker of eosinophil activation, and recurrence of clinical events in a consecutive series of patients who underwent DES implantation. METHODS AND RESULTS Two hundred patients (age 63 +/- 10.4, males 75%) undergoing implantation of first-generation DES (Taxus or Cypher stents) were enrolled. We measured serum levels of ECP and total IgE by enzyme-linked immunosorbent assay and of C-reactive protein by high-sensitivity nephelometry prior to percutaneous coronary intervention. A clinical follow-up was planned 18 months after discharge. Major adverse cardiac events (MACEs), such as cardiac death, recurrent myocardial infarction, or clinically driven target lesion revascularization, were the endpoint of the study. Twenty-two patients (11%) had MACEs and showed higher serum levels of ECP compared with those without MACEs [30.5 (14.4-50) vs. 12.2 (4.4-31) microg/L, P = 0.004]. At simple Cox regression analysis, serum levels of ECP were a significant predictor of MACEs (hazard ratio 1.016, 95% confidence interval 1.003-1.03, P = 0.018). CONCLUSION This study shows for the first time an association between baseline ECP levels and the occurrence of MACEs in patients undergoing implantation of DES. Further studies are warranted to establish whether in this setting ECP is a risk marker or plays a contributory pathogenetic role.