Flavio Ribichini

Guidelines on myocardial revascularization.

Guidelines and Expert Consensus Documents summarize and evaluate all available evidence with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition, taking into account the impact on outcome and the risk benefit ratio of diagnostic or therapeutic means. Guidelines are no substitutes for textbooks and their legal implications have been discussed previously. Guidelines and recommendations should help physicians to make decisions in their daily practice. However, the ultimate judgement regarding the care of an individual patient must be made by his/her responsible physician(s). The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC website (http://www.escardio.org/knowledge/ guidelines/rules). Members of this Task Force were selected by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) to represent all physicians involved with the medical and surgical care of patients with coronary artery disease (CAD). A critical evaluation of diagnostic and therapeutic procedures is performed including assessment of the risk benefit ratio. Estimates of expected health outcomes for society are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to predefined scales, as outlined in Tables 1 and 2. The members of the Task Force have provided disclosure statements of all relationships that might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at European Heart House, headquarters of the ESC. Any changes in conflict of interest that arose during the writing period were notified to the ESC. The Task Force report received its entire financial support from the ESC and EACTS, without any involvement of the pharmaceutical, device, or surgical industry. ESC and EACTS Committees for Practice Guidelines are responsible for the endorsement process of these joint Guidelines. The finalized document has been approved by all the experts involved in the Task Force, and was submitted to outside specialists selected by both societies for review. The document is revised, and finally approved by ESC and EACTS and subsequently published simultaneously in the European Heart Journal and the European Journal of Cardio-Thoracic Surgery. After publication, dissemination of the Guidelines is of paramount importance. Pocket-sized versions and personal digital assistant-downloadable versions are useful at the point of care. Some surveys have shown that the intended users are sometimes unaware of the existence of guidelines, or simply do not translate them into practice. Thus, implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations.

Immunosuppressive therapy for the prevention of restenosis after coronary artery stent implantation (IMPRESS study)

OBJECTIVES This study tested the effect of oral prednisone on clinical and angiographic restenosis rate after successful stent implantation in patients with persistent elevation of systemic markers of inflammation after the procedure. BACKGROUND Experimental studies have shown that corticosteroids have the potential to reduce the inflammatory response associated with stent implantation. METHODS Eighty-three patients undergoing successful stenting with C-reactive protein (CRP) levels >0.5 mg/dl 72 h after the procedure were randomized to receive oral prednisone or placebo for 45 days. The primary clinical end point was 12-month event-free survival rate (defined as freedom from death, from myocardial infarction, and from recurrence of symptoms requiring additional revascularization). The angiographic end points were restenosis rate and late loss at six months. RESULTS Twelve-month event-free survival rates were 93% and 65% in patients treated with prednisone and placebo, respectively (relative risk [RR] 0.18, 95% confidence intervals [CI], 0.05 to 0.61, p = 0.0063). Six-month restenosis rate and late loss were lower in prednisone-treated than in placebo-treated patients (7% vs. 33%, p = 0.001, and 0.39 +/- 0.6 mm vs. 0.85 +/- 0.6 mm, p = 0.001, respectively). CONCLUSIONS In patients with persistently high CRP levels after successful coronary artery stent implantation, oral immunosuppressive therapy with prednisone results in a striking reduction of clinical events and angiographic restenosis rate.

Plasma Activity and Insertion/Deletion Polymorphism of Angiotensin I–Converting Enzyme A Major Risk Factor and a Marker of Risk for Coronary Stent Restenosis

BACKGROUND Tissue proliferation is almost invariably observed in recurrent lesions within stents, and ACE, a factor of smooth muscle cell proliferation, may play an important role. Plasma ACE level is largely controlled by the insertion/deletion (I/D) polymorphism of the enzyme gene. The association among restenosis within coronary stents, plasma ACE level, and the I/D polymorphism is analyzed in the present prospective study. METHODS AND RESULTS One hundred seventy-six consecutive patients with successful, high-pressure, elective stenting of de novo lesions in the native coronary vessels were considered. At follow-up angiography, recurrence was observed in 35 patients (19.9%). Baseline clinical and demographic variables, plasma glucose and serum fibrinogen levels, lipid profile, descriptive and quantitative angiographic data, and procedural variables were not significantly different in patients with and without restenosis; mean plasma ACE levels (+/-SEM) were 40.8+/-3.5 and 20.7+/-1.0 U/L, respectively (P<.0001). Diameter stenosis percentage and minimum luminal diameter at 6 months showed statistically significant correlation with plasma ACE level (r=.352 and -.387, respectively P<.001). Twenty-one of 62 patients (33.9%) with D/D genotype, 13 of 80 (16.3%) with I/D genotype, and 1 of 34 (2.9%) with I/I genotype showed recurrence; the restenosis rate for each genotype is consistent with a codominant expression of the allele D. CONCLUSIONS In a selected cohort of patients, both the D/D genotype of the ACE gene, and high plasma activity of the enzyme are significantly associated with in-stent restenosis. Continued study with clinically different subsets of patients and various stent designs is warranted.

No evidence of association between prothrombotic gene polymorphisms and the development of acute myocardial infarction at a young age

Background—We investigated the association between 9 polymorphisms of genes encoding hemostasis factors and myocardial infarction in a large sample of young patients chosen because they have less coronary atherosclerosis than older patients, and thus their disease is more likely to be related to a genetic predisposition to a prothrombotic state. Methods and Results—This nationwide case-control study involved 1210 patients who had survived a first myocardial infarction at an age of <45 years who underwent coronary arteriography in 125 coronary care units and 1210 healthy subjects matched for age, sex, and geographical origin. None of the 9 polymorphisms of genes encoding proteins involved in coagulation (G-455A &bgr;-fibrinogen: OR, 1.0; CI, 0.8 to 1.2; G1691A factor V: OR, 1.1; CI, 0.6 to 2.1; G20210A factor II: OR, 1.0; CI, 0.5 to 1.9; and G10976A factor VII: OR, 1.0; CI, 0.8 to 1.3), platelet function (C807T glycoprotein Ia: OR, 1.1; CI, 0.9 to 1.3; and C1565T glycoprotein IIIa: OR, 0.9; CI, 0.8 to 1.2), fibrinolysis (G185T factor XIII: OR, 1.2; CI, 0.9 to 1.6; and 4G/5G plasminogen activator inhibitor type 1: OR, 0.9; CI, 0.7 to 1.2), or homocysteine metabolism (C677T methylenetetrahydrofolate reductase: OR, 0.9; CI, 0.8 to 1.1) were associated with an increased or decreased risk of myocardial infarction. Conclusions—This study provides no evidence supporting an association between 9 polymorphisms of genes encoding proteins involved in hemostasis and the occurrence of premature myocardial infarction or protection against it.

Stent Thrombosis With Everolimus-Eluting Stents Meta-Analysis of Comparative Randomized Controlled Trials

Background— Some but not all studies have reported reduced rates of stent thrombosis (ST) with everolimus-eluting stents (EES) compared with other drug-eluting stents (DES). All of these studies were insufficiently powered to reliably detect differences in ST. We therefore performed a meta-analysis of randomized controlled trials comparing the risk of 2-year definite ST between EES and other DES. Methods and Results— Randomized controlled trials comparing EES versus other DES were searched through MEDLINE, EMBASE, Cochrane databases, and proceedings of international meetings. Information on study design, inclusion and exclusion criteria, sample characteristics, and clinical outcomes was extracted. Eleven randomized controlled trials (16 775 patients) were analyzed, including 5 trials (n=7113) of EES versus paclitaxel-eluting stents, 5 trials (n=7370) of EES versus sirolimus-eluting stents, and 1 trial (n=2292) of EES versus zotarolimus-eluting stents. By 2 years definite ST with EES compared with pooled DES occurred in 0.5% versus 1.3% patients, respectively (relative risk, 0.38; 95% CI, 0.24–0.59; P<0.0001). Similar results were observed when the broader definition of definite/probable ST was considered (relative risk, 0.46; 95% CI, 0.33–0.66; P<0.0001). EES compared with other DES reduced the relative risk of early ST (within 30 days), late ST (31 days to 1 year), cumulative 1-year ST, and very late ST (1–2 years). The reduced rate of definite ST observed with EES was consistent across all DES comparators with no interactions apparent during any time interval. Conclusions— EES compared with a pooled group of paclitaxel-eluting stents, sirolimus-eluting stents, and zotarolimus-eluting stents is associated with a significant reduction of definite ST, an effect that appears early and increases in magnitude through at least 2 years.

Pulmonary Artery Hypertension in Adult Patients With Symptomatic Valvular Aortic Stenosis

Pulmonary hypertension (PH) has been reported in patients with valvular aortic stenosis (AS) and has been found to be associated with a more severe clinical picture and a poor prognosis after aortic valve replacement. The aim of this study was to assess the prevalence of PH in adult patients with symptomatic AS undergoing cardiac catheterization, and to evaluate the relation between pulmonary artery (PA) systolic pressure and hemodynamic and clinical variables to further clarify the pathogenetic mechanisms. We assessed right-sided heart hemodynamics during cardiac catheterization in 388 patients with symptomatic isolated or predominant AS. PA systolic pressure between 31 and 50 mm Hg was used to define mild to moderate PH, whereas PA systolic pressure >50 mm Hg was used to define severe PH. PA systolic pressure showed no significant difference according to age and sex, although it was significantly higher in patients in New York Heart Association functional classes III and IV and in patients with coexistent systemic hypertension than in the others. PH was absent in 136 patients (35%, group 1), mild to moderate in 196 patients (50%, group 2), and severe in 58 patients (15%, group 3). Only the prevalence of overt heart failure was significantly higher in group 3 patients. AS severity was similar among the 3 groups, and PA systolic pressure showed no relation to aortic valve area in the entire population. Also, a poor correlation was found between PA pressure and left ventricular (LV) ejection fraction (r = -0.28), with several patients having moderate or severe PH despite a preserved LV systolic function. PA systolic pressure significantly correlated with LV end-diastolic pressure (r = 0.50) and with PA wedge pressure (r = 0.84). Furthermore, transpulmonary pressure gradient, an index of resistance across the pulmonary vascular bed (obtained as the difference between PA mean and PA wedge pressure), was significantly higher in patients with PH, especially in those with a marked increase in PA systolic pressure, suggesting a reactive component of PH.

Drug-eluting stent safety: findings from preclinical studies

After pivotal clinical trials, drug-eluting stents (DES) are now considered the standard of care for the management of acute coronary syndrome. However, late stent thrombosis has emerged as a major concern. Preclinical testing is an important regulatory process that determines the safety and efficacy of devices prior to human clinical trials. Histopathologic analysis following placement of DES has typically been performed in porcine coronary artery models to ensure safety in these devices. The recently issued consensus report from the US FDA, for the approval of DES recommends the use of the porcine model for the safety assessment of these devices in the vascular bed for which they are intended. Other models are also recommended, as vascular responses to stents are much slower in man than in animals, and no animal truly elicits the response seen in humans. The rabbit iliac artery can provide further data, especially regarding endothelialization, which is slower in the rabbit model than in the porcine model. Furthermore, inflammation is not as extensive in the rabbit and may thus be a closer model of humans than the porcine models. The FDA recognizes that it may be more appropriate to test these devices in atherosclerosis. The choice of animal model may mask the serious drawbacks of the devices; therefore, we suggest the use of both models to understand the healing following DES implantation, with emphasis on endothelialization, inflammation and neointimal formation and, whenever possible, to complement the observations in the environment of atherosclerosis.

European expert consensus on rotational atherectomy.

The interest in rotational atherectomy (RA) has increased over the past decade as a consequence of more complex and calcified coronary stenoses being attempted with percutaneous coronary interventions. Yet adoption of RA is hampered by several factors: amongst others, by the lack of a standardised protocol. This European expert consensus document stems from the awareness of the large heterogeneity in the protocols adopted to perform rotational atherectomy. The objective of the present document is to provide some points of consensus among highly experienced operators on the most controversial steps of RA in an attempt to build the basis of a standardised and universally accepted protocol.

Impella ventricular support in clinical practice: Collaborative viewpoint from a European expert user group

Mechanical circulatory support represents an evolving field of clinical research and practice. Currently, several cardiac assist devices have been developed but, among different institutions and countries, a large variation in indications for use and device selection exists. The Impella platform is an easy to use percutaneous circulatory support device which is increasingly used worldwide. During 2014, we established a working group of European physicians who have collected considerable experience with the Impella device in recent years. By critically comparing the individual experiences and the operative protocols, this working group attempted to establish the best clinical practice with the technology. The present paper reviews the main theoretical principles of Impella and provides an up-to-date summary of the best practical aspects of device use which may help others gain the maximal advantage with Impella technology in a variety of clinical settings.

Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Aims Cardiopoietic cells, produced through cardiogenic conditioning of patients’ mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. Methods and results This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein–Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann–Whitney estimator 0.54, 95% confidence interval [CI] 0.47–0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200–370 mL (60% of patients) (Mann–Whitney estimator 0.61, 95% CI 0.52–0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. Conclusion The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.