Publications

To propose standardized consensus definitions for important clinical endpoints in transcatheter aortic valve implantation (TAVI), investigations in an effort to improve the quality of clinical research and to enable meaningful comparisons between clinical trials. To make these consensus definitions accessible to all stakeholders in TAVI clinical research through a peer reviewed publication, on behalf of the public health.Transcatheter aortic valve implantation may provide a worthwhile less invasive treatment in many patients with severe aortic stenosis and since its introduction to the medical community in 2002, there has been an explosive growth in procedures. The integration of TAVI into daily clinical practice should be guided by academic activities, which requires a harmonized and structured process for data collection, interpretation, and reporting during well-conducted clinical trials.The Valve Academic Research Consortium established an independent collaboration between Academic Research organizations and specialty societies (cardiology and cardiac surgery) in the USA and Europe. Two meetings, in San Francisco, California (September 2009) and in Amsterdam, the Netherlands (December 2009), including key physician experts, and representatives from the US Food and Drug Administration (FDA) and device manufacturers, were focused on creating consistent endpoint definitions and consensus recommendations for implementation in TAVI clinical research programs. Important considerations in developing endpoint definitions included (i) respect for the historical legacy of surgical valve guidelines; (ii) identification of pathophysiological mechanisms associated with clinical events; (iii) emphasis on clinical relevance. Consensus criteria were developed for the following endpoints: mortality, myocardial infarction, stroke, bleeding, acute kidney injury, vascular complications, and prosthetic valve performance. Composite endpoints for TAVI safety and effectiveness were also recommended.Although consensus criteria will invariably include certain arbitrary features, an organized multidisciplinary process to develop specific definitions for TAVI clinical research should provide consistency across studies that can facilitate the evaluation of this new important catheter-based therapy. The broadly based consensus endpoint definitions described in this document may be useful for regulatory and clinical trial purposes.

AimsTo investigate the incidence of incomplete stent apposition and to explore the impact of the presence of thrombus and protruding plaque after stent implantation on neointima formation at follow-up in ST-segment elevation myocardial infarction (STEMI) patients with serial optical frequency domain imaging (OFDI) investigations.

Validation of new three-dimensional (3-D) bifurcation quantitative coronary angiography (QCA) software.Cardiovascular Angiography Analysis System (CAAS 5v10) allows 3-D angiographic reconstructions based on two or more 2-D projection images. Measurements for minimal lumen diameter (MLD), reference vessel diameter (RVD), percent diameter stenosis (DS) and bifurcation angle (BA) were validated against precision manufactured phantom bifurcations. Length measurements were validated against angiographic measurement catheters inserted into a plexiglas bifurcation phantom. In 3-D reconstructions based on two 2-D images, acquired at variable rotation and angulation, accuracy and precision (mean difference ± SD) of the 11-segment model for MLD, RVD and DS were 0.013±0.131 mm, -0.052±0.039 mm and -1.08±5.13%, respectively; inter-observer variability was 0.141 mm, 0.058 mm and 5.42%, respectively. Adding the antero-posterior (optimal) projection to these basic reconstructions resulted in reduced variability (0.101 mm, 0.041 mm and 3.93% for MLD, RVD and DS, p<0.01 for all) and showed a trend towards improved precision (0.109 mm, 0.031 mm and 4.26%, respectively, p>0.05 for all). In basic reconstructions, accuracy and precision for BA was -1.3±5.0°, whereas inter-observer variability was 7.5°; respective measures for length were 0.15±0.26 mm and 0.54 mm. Adding the antero-posterior projection resulted in decreased precision (0.47 mm, p<0.01) and increased variability (1.03 mm, p<0.01) for length measurements; precision (5.4°) and variability (7.9°) for BA did not change significantly (p>0.30).Advances in the methodology of 3-D reconstruction and quantitative analysis for bifurcation lesions translated into highly accurate, precise and reproducible measures of diameter, length and BA.

COPD is associated with glucocorticosteroid insensitive inflammation. CXCR3 chemokines are elevated in COPD and may drive recruitment of CD8+ lymphocytes. Expression of CXCR3 chemokines is regulated by IFNγ. This study investigated the effect of JAK-STAT inhibitors PF95 and PF13 on CXCR3 chemokine production from human bronchial epithelial cells. Beas-2B and primary human bronchial epithelial cells (HBEC) were pre-treated with PF95, PF13, or Dexamethasone (DEX) then stimulated with IFNγ or IFNγ+TNFα. After 24h, cytokines were measured by ELISA. Inhibition of the JAK-STAT pathway was measured by immunoblotting for phosphorylated and total STAT-1 and STAT DNA binding using Trans-AM kits. DEX had no effect on the release of CXCL9, 10 or 11, however all were inhibited by the JAK-STAT inhibitors stimulated with either IFNγ or IFNγ+TNFα (Table 1). HBEC responded similarly to Beas-2B. Both inhibitors attenuated phosphorylation of STAT-1 in a concentration dependent manner. DNA binding of STAT-1 and STAT-3was inhibited but not of STAT5a or STAT5b. JAK-STAT inhibitors therefore attenuate release of CXCR3 chemokines from airway epithelial cells under conditions of glucocorticosteroid insensitivity and have potential as a new anti-inflammatory treatment in COPD patients.

Background. Little is known about the long-term natural history of asthma and the long-term clinical and functional consequences in non-smoking patients. From a functional point of view, non-smoking asthmatic patients may have a significantly greater decline in forced expiratory volume in one second (FEV1) compared with nonasthmatic subjects and may develop chronic irreversible (fixed) airflow limitation. This has been related to the physiological consequences of chronic airway inflammation causing airway remodeling. However these lesions are all potentially reversible and there is little radiological evidence indicating lung destruction (pulmonary emphysema), which is potentially irreversible, in non-smoking asthmatics. Severe chronic respiratory failure is the major cause of mortality in patients with severe chronic lung diseases. Domiciliary long-term oxygen therapy (LTOT) is an accepted treatment for patients with severe chronic respiratory failure. Our reasoning, therefore, was that if asthma is a cause of severe chronic respiratory failure in nonsmokers we should be able to find non-smoking asthmatics within a large population of patients on LTOT. The aim of our study (Asthma and Long-term Oxygen Therapy, “ALOT”) was to investigate the prevalence of non-smoking asthmatics in patients on LTOT in a multicentre, cross-sectional study. Methods. Between June and September 2003 we screened all subjects on long-term domiciliary oxygen therapy in three different hospitals in the North-East area of Italy (within the provinces of Ferrara and Bologna). Taken collectively, we have found one-hundred and eighty-four patients on LTOT. We have reviewed their clinical data (age, sex, smoking, history and physical examination, arterial blood gas analysis, pulmonary function). Results. 114 patients (all smokers) fulfilled the diagnostic criteria for COPD. Seventy patients (all smokers) had other diseases. We were unable to find any non-smokers in our screened population of subjects on long-term domiciliary oxygen therapy. Furthermore, there was no past history of asthma and/or acute wheezing episodes in either of the patient groups. Conclusions. This data suggests that asthma is an uncommon cause of severe chronic respiratory failure necessitating long-term domiciliary oxygen therapy in nonsmokers and supports the current consensus that asthma and COPD are different diseases with differing stages of severity and the concept that long-term avoidance of active smoking is fundamental for the prevention of severe chronic respiratory failure.

An increasing number of patients are referred for percutaneous aortic valve replacement (PAVR). Although case studies are available on outcome of selected patients, little is known about the demographics, treatment assignment and survival of the total referred population.This was a prospective observational cohort study. From September 2005 to September 2007, 100 patients were referred for PAVR of whom 39 underwent PAVR, 14 surgical valve replacement (AVR) and three balloon valvuloplasty (PABV). Another 16 refused treatment and 28 were no candidate (non severe aortic stenosis [n=11], asymptomatic and normal ventricular function [n=3], comorbidity [n=12], technically PAVR not feasible [n=2]). The logistic EuroSCORE (Mean, sd) was: 15 +/- 6% (PAVR), 9 +/- 11% (AVR), 22 +/- 15% (PABV), 25 +/- 14% (refusals) and 17 +/- 12% (no-candidate). The mean follow-up was 13 months (range 0-30 months). Cumulative survival at six months was 97%, 85% and 70%, for PAVR, AVR and refusals, respectively. At 12 months, it was 87%, 62% and 40% respectively.Not all patients referred for PAVR finally receive it. Approximately 15% of the patients received AVR and 30% were considered not eligible. This may reflect the lack of sufficient data and need for an improvement in the technology in order to offer PAVR to both lower and higher risk patients. Considering risk and outcome, it is conceivable that patients who refused treatment could have benefited the most from it.

Background In the GLOBAL LEADERS trial, ticagrelor monotherapy beyond 1 month compared with standard antiplatelet regimens after coronary stent implantation did not improve outcomes at intention‐to‐treat analysis. Considerable differences in treatment adherence between the experimental and control groups may have affected the intention‐to‐treat results. In this reanalysis of the GLOBAL LEADERS trial, we compared the experimental and control treatment strategies in a per‐protocol analysis of patients who did not deviate from the study protocol. Methods and Results Baseline and postrandomization information were used to classify whether and when patients were deviating from the study protocol. With logistic regressions, we derived time‐varying inverse probabilities of nondeviation from protocol to reconstruct the trial population without protocol deviation. The primary end point was a composite of all‐cause mortality or nonfatal Q‐wave myocardial infarction at 2 years. At 2‐year follow‐up, 1103 (13.8%) of 7980 patients in the experimental group and 785 (9.8%) of 7988 patients in the control group qualified as protocol deviators. At per‐protocol analysis, the rate ratio for the primary end point was 0.88 (95% CI, 0.75–1.03; P =0.10) on the basis of 274 versus 325 events in the experimental versus control group. The rate ratio for the key safety end point of major bleeding was 1.00 (95% CI, 0.79–1.26; P =0.99). The per‐protocol and intention‐to‐treat effect estimates were overall consistent. Conclusions Among patients who complied with the study protocol in the GLOBAL LEADERS trial, ticagrelor plus aspirin for 1 month followed by ticagrelor monotherapy was not superior to 1‐year standard dual antiplatelet therapy followed by aspirin alone at 2 years after coronary stenting. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01813435.

Objectives We sought to evaluate the impact of mixed aortic stenosis (MAS) on postprocedural aortic regurgitation (PPAR) and clinical outcomes after transcatheter aortic valve implantation (TAVI). Background The impact of MAS of TAVI outcomes is unknown. Methods and Results Data from a multicenter registry were retrospectively analysed. Outcomes were compared between patients with pure aortic stenosis (PAS; associated AR &lt; 1+/3+) and MAS (associated AR ≥ 1+/3+). Study objectives were PPAR incidence and short‐ and long‐term mortality. Overall, 1,062 patients were included: 419 (39.4%) with MAS and 643 (60.5%) with PAS. At 30 days, there were no differences in mortality, however, a higher incidence of major bleeding (22.7% vs. 16.8%; P = 0.016), PPAR ≥ 1+/3+ (42.6% vs. 26.5%; P &lt; 0.001) and lower device success (89.3% vs. 93.3%; P = 0.019) was observed in patients with MAS. Of note, MAS was an independent predictor of PPAR ≥ 1+/3+ at multivariable analysis (OR: 2.882; CI: 1.851–4.488; P &lt; 0.001). At 2 years of follow‐up, no survival differences were present between MAS and PAS groups. Similarly, following stratification for PPAR ≥ 1+/3+, MAS had no protective effect on survival as compared with PAS. Conclusions MAS was associated with lower device success and higher PPAR incidence. However, despite these findings, it had no influence on long‐term postoperative outcomes. © 2015 Wiley Periodicals, Inc.

Drug-eluting stents (DESs) have been shown to reduce the rate of repeat revascularization compared with bare-metal stents (BMSs) after multivessel percutaneous coronary intervention in carefully selected patients. However, the long-term safety and efficacy of DESs in patients with multivessel disease outside the setting of randomized trials was unknown. Therefore, all patients undergoing multivessel percutaneous coronary intervention with BMSs, sirolimus-eluting stents (SESs), or paclitaxel-eluting stents (PESs) from January 2000 to December 2005 were investigated. The primary end point was all-cause mortality. A total of 1,720 patients were recruited in 3 consecutive sequential groups of BMS (n = 701; January 2000 to April 2002), SES (n = 293; April 2002 to February 2003), and PES (n = 726; February 2003 to December 2005). Overall median follow-up was 1,440 days. There was improved 3-year survival in the SES group (93.7%) compared with both the BMS (86.1%) and PES groups (87.3%), which remained significant after propensity score adjustment for differences in baseline and procedural characteristics (SES vs BMS, adjusted hazard ratio 0.53, 95% confidence interval 0.30 to 0.94; SES vs PES, adjusted hazard ratio 0.49, 95% confidence interval 0.28 to 0.87). There was no difference in mortality between the PES and BMS groups. Both DES types significantly reduced the need for clinically driven target-vessel and target-lesion revascularization without an excess in myocardial infarction or stent thrombosis. In conclusion, both SESs and PESs significantly reduced the need for repeated revascularization in these patients with no excess in mortality. SESs might reduce mortality in patients undergoing multivessel percutaneous coronary intervention.

Background: Individualized risk prediction is central to personalized decision-making in patients with left main coronary artery disease being considered for revascularization. Purpose: To examine the prognostic performance and treatment interactions with the anatomic SYNTAX score in patients with left main disease undergoing PCI vs CABG. Methods: Individual patient data from the four major trials comparing PCI with DES to CABG in patients with left main disease (SYNTAX, PRECOMBAT, NOBLE, EXCEL) were combined. Patients were categorized by core lab-determined SYNTAX score categories (low: ≤22; intermediate: 23-32; high: ≥33). KM event rates were calculated in each treatment arm through 5 years. Hazard ratios were generated using a Cox model with trial as a random effect; absolute risk differences were calculated. Heterogeneity between randomized treatment effect and baseline score was tested. Results: 4,394 patients were randomized to PCI or CABG. The SYNTAX score identified a gradient of risk for death (~2-fold) and for major coronary events (spontaneous MI or revasc; MCE) ( Fig ). The risk gradient for MCE was only apparent after PCI and not after CABG, leading to differential absolute risk reductions with CABG from 5.5% (95%CI 2.3-8.7%) to 16.2% (11.1-21.3%) in those with low vs high SYNTAX scores (P int =0.002). There was no significant heterogeneity across SYNTAX score categories for risk of stroke, protocol-defined procedural MI, or UDMI-defined procedural MI after PCI vs CABG. Conclusion: The anatomic SYNTAX score identified risk for death and coronary events following PCI and CABG for left main disease. Mortality was similar after PCI and CABG across SYNTAX score categories. In contrast, MCE risk increased with higher SYNTAX scores after PCI but not after CABG, and the anatomic SYNTAX score thus identified high-risk patients with greater relative and absolute MCE reductions with CABG.