Cardiologia Croatica. 2017;12(5-6)

Victoria Delgado, Oliver Gaemperli, Massimo Lombardi, Philipp A Kaufmann, Jeroen J Bax

## Preamble Cardiovascular diseases remain the main cause of death in Europe. (1) Current mortality statistics show that more than 4 million people die from cardiovascular diseases every year. Non-invasive cardiovascular imaging plays a central role in the diagnosis and management of patients with cardiovascular diseases. In 2016, many articles focused on prognostic impact of current non-invasive imaging techniques and technological innovations were published. A selection of these articles on the use of non-invasive cardiovascular imaging, including echocardiography, computed tomography (CT), cardiovascular magnetic resonance imaging (CMR), nuclear imaging, and fusion imaging is presented here. ## Echocardiography Echocardiography is the imaging technique of first choice to evaluate patients with cardiovascular diseases. A recent analysis of the largest, publicly available, all-payer inpatient database of the United States has shown that during 2001 and 2011 approximately 7 669 000 echocardiograms were performed and a steady increase in the volume of echocardiograms was noted with an average annual grew rate of 3.41%. (2) Although these numbers would suggest an overuse of this diagnostic procedure, the results from the 2010 nationwide inpatient sample showed otherwise. When analysing five clinical scenarios accounting for 3.7 million hospital admissions (cerebrovascular disease, cardiac arrhythmia, chronic heart failure, acute myocardial infarction, and sepsis), echocardiography was performed only in 8% of the cases indicating a significant underuse of echocardiography. Importantly, the use of echocardiography was associated with significantly lower odds of all-cause in-hospital mortality in these five clinical scenarios. Additional studies will be warranted to provide more information on the association between access to echocardiography and clinical outcomes. Lung ultrasound is another application of echocardiography and is considered a first-line test to assess pulmonary congestion in patients with suspected acute heart failure. (3) The detection of B-lines (reflection of discrete air/fluid interfaces between collapsed, fluid-filled, and well-aerated alveoli) on the anterolateral chest scan indicates a progressive increase of extravascular lung water. The number of B-lines can be summed to generate a semiquantitative score of the extravascular lung water content. (4) The incremental diagnostic and prognostic value of the use of lung ultrasound was investigated in 195 heart failure patients with New York Heart Association (NYHA) class II–IV symptoms evaluated at the outpatient clinic. (5) Of the 185 patients with adequate lung ultrasound data, 59 (32%) had ≥3 B-lines while only 17 (9%) had crackles on auscultation. Patients with higher number of B-lines showed more severe heart failure symptoms and higher levels of NT-pro brain natriuretic peptide. In addition, patients with ≥3 B-lines had a four-fold higher risk of the primary endpoint (hospitalization for worsening of heart failure or all-cause mortality) at 6 months follow-up compared with patients without B-lines (adjusted hazard ratio [HR] 4.08; 95% confidence interval [CI] 1.95–8.54; P CT) continues to raise interest in 2016: in a substudy of the Analysis of Coronary Blood Flow Using CT Angiography: Next Steps (NXT)-trial, Gaur and colleagues evaluated the association between coronary stenosis severity, plaque characteristics and FFRCT in 484 vessels from 254 patients. (19) The presence of low-density non-calcified plaque (≥30 mm3) and FFRCT (≤0.80) increased significantly the diagnostic accuracy of coronary stenoses to detect lesion-specific ischemia (as assessed by invasive FFR), documented by an increase in the area under the receiver operating characteristic curve from 0.71 to 0.90 (P CT: Outcome and Resource IMpacts (PLATFORM) trial assessed the impact of FFRCT on clinical outcomes, downstream resource utilization and costs in two parallel observational arms, one with an intended invasive strategy (n = 380) and one with planned non-invasive testing (n = 204). (20) In the planned invasive stratum, FFRCT lowered mean costs by 33% ($8,127 vs. $12,145; P CT cost weight equal to coronary CTA. Beyond coronary arteries, this year’s CT publications have highlighted the clinical potential of the technique to assess valvular disease. Early hypo-attenuated leaflet thickening (HALT) of trans-catheter aortic valve implants (TAVI) has emerged as a new entity with uncertain prognostic and therapeutic implications. Pache and colleagues followed 156 TAVI patients with early routine coronary CTA (a median of 5 days post-TAVI with a balloon-expandable prosthesis) and found HALT in 16 (10.3%) patients (Figure 2). (21) The occurrence of HALT was not associated with antiplatelet regimen or any of the baseline or procedural characteristics. HALT did not produce any symptoms but was associated with restrictive cusp motion and slightly higher transaortic mean pressure gradient (14.9 ± 5.3 vs. 11.6 ± 3.4 mmHg, P = 0.026). Full anticoagulation restored normal cusp morphology and motion in almost all patients. Gündüz and colleagues investigated the utility of CT to distinguish pannus from thrombus after surgical aortic valve replacement. (22) In 37 patients with mechanical prosthetic aortic valve dysfunction and evidence of periprosthetic mass, CT demonstrated significantly lower attenuation of thrombotic masses (defined as masses which completely resolved upon thrombolysis or were surgically identified as a clot) compared with pannus (87 ± 59 vs. 322 ± 122 Hounsfield units [HU]; P th year examination (2010–2012), 146 (7.9%) individuals showed myocardial scar. (27) In 78% of them, myocardial scar was unrecognized by electrocardiogram or clinical evaluation. Age, male sex, body mass index, hypertension, and CACS (adjusted for age, sex, and ethnicity) at baseline were associated with presence of myocardial scar at year 10. The odds ratio for myocardial scar of a CACS value ≥400 was three-fold higher compared with CACS of 0. The prognostic implications of these findings were not evaluated. The association between presence of midwall myocardial scar/fibrosis and adverse outcomes in patients with aortic stenosis was investigated by Chin et al. (28) From 147 patients with mild-to-severe aortic stenosis and no prior myocardial infarction who underwent LGE CMR, a score including clinical, biomarker, echocardiographic, and electrocardiographic variables independently associated with the presence of midwall myocardial scar/fibrosis was derived. Low risk of myocardial fibrosis was defined by a risk score of 57%. The prognostic value of this score was validated in two cohorts of asymptomatic patients with at least mild aortic stenosis: 127 patients from an internal cohort and 289 patients from an external cohort, resulting in 1560 patient-years. In the internal cohort, a high risk score was associated with seven-fold higher mortality rates compared with patients with low risk score (13 vs. 2.1 all-cause death/100 patient-years; P 0.8 or 123I-meta-iodobenzylguanidine (mIBG) scintigraphy has incremental prognostic information in heart failure patients and may identify patients with increased risk of ventricular arrhythmias or sudden cardiac death. (40) In a sub-study of the ADMIRE-HF trial, Hachamovitch et al. (38) investigated whether the use of 123I-mIBG imaging to guide implantable cardioverter defibrillator (ICD) implantation will result in improved patient prognosis and efficiency of care. Of 777 patients (65% ischaemic heart disease) who did not have an ICD at the time of the index 123I-mIBG scan, 75 (9.6%) died, 23 (3%) presented with sudden cardiac death and 26 (3.3%) with life-threatening arrhythmias during a median of 17 months. Planar 123I-mIBG imaging was an independent and incremental predictor of all-cause mortality. In addition, in the extension study of the ADMIRE-HF trial (ADMIRE-HFX), the prognostic significance of patterns of 123I-mIBG uptake (reflecting myocardial denervation) and 99mTc-tetrofosmin myocardial perfusion imaging was assessed in 619 ischaemic and 319 non-ischaemic heart failure patients. (37) The extent and severity of myocardial denervation were quantified as percentage of total myocardium and the segment denervation score was calculated based on a 17-segment model using a 5-point scale. Moreover, the area of mismatch between 123I-mIBG/99mTc-tetrofosmin uptake was calculated. Mortality was higher in patients with denervation involving >50% of the myocardium. The highest cardiac mortality risk for ischaemic heart failure patients was observed with perfusion defects involving 20–40% of the myocardium. In contrast, non-ischaemic heart failure patients with smaller perfusion abnormalities (70% stenosis in the mid right coronary artery (purple arrow). The infero-septal view shows reduced LV longitudinal strain in the basal segment (colour-coded in orange shades) subtended by this coronary artery. In addition, note a diffuse calcified plaque in the proximal left anterior descending coronary artery present causing reduced LV longitudinal strain in the mid-apical segments of the antero-septal view. Reproduced with permission from Maffessanti et al. (44) This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. Specifically in the field of molecular imaging, hybrid imaging becomes increasingly used to understand pathophysiology in CAD, with specific focus on vulnerable plaque imaging. Bala and colleagues used PET-CT and fluorine-18 labelled vascular cell adhesion molecule (VCAM)-1 (anti-VCAM-1 nanobody, cAbVCAM-1–5), to demonstrate the feasibility in a murine-atherosclerotic model to detect aortic plaque inflammation. (45) Increased tracer uptake was detected in aortic regions with increased atherosclerosis both on PET-CT and on histology. This is just one of the many studies ongoing to obtain further insight in differences between vulnerable and stable atherosclerotic plaques. In the short-term, more animal studies are needed focusing on the coronary arteries, then translational studies to patients, and finally outcome studies. Positron emission tomography-cardiovascular magnetic resonance imaging (PET-CMR) is another modality that is increasingly used, and already some clinical studies in patients have been reported this year. Bulluck and coworkers used PET-CMR and FDG in 21 patients with ST-segment–elevation myocardial infarction (STEMI) 5 days after infarction, and follow-up scans were obtained 1 year later in 12 patients. (46) Cardiovascular magnetic resonance imaging was used to assess the infarct size (using late contrast-enhanced CMR) and the area at risk (using T2-mapping). Immediately after infarction, the area of reduced FDG uptake was significantly larger than the infarct size on late contrast-enhanced CMR (37.2 ± 11.6% vs. 22.3 ± 11.7%; P < 0.001), but was similar to the area at risk on CMR T2-mapping (37.2 ± 11.6% vs. 36.3 ± 12.2%; P = NS). On the 1-year follow-up scans, the area of reduced FDG uptake was significantly smaller as compared with the acute scans (19.5 [6.3–31.8%] vs. 44.0 [21.3–55.3%]; P = 0.002) and correlated closely with the area of infarction on late contrast-enhanced CMR. These findings contribute to our understanding of scar formation over time after acute myocardial infarction. Rischpler et al. (47) used PET-CMR from a different perspective, namely to explore the value of FDG uptake in the infarct area (defined by late contrast-enhanced CMR) as a biosignal to predict functional recovery. In 49 patients, PET-CMR was performed within 5 days after infarction, and follow-up CMR (to assess functional recovery) was performed 6–9 months later. Comparison of PET-CMR with circulating leucocytes and monocytes was performed to measure cellular innate immune response. Fluorodeoxyglucose uptake in the infarcted area exceeded late gadolinium enhancement extent (33.2 ± 16.2% LV myocardium vs. 20.4 ± 10.6%, P < 0.0001) and corresponded to the area at risk (r = 0.87, P < 0.0001), indicating that FDG uptake early after infarction may be a biosignal of myocardial injury. The peripheral blood count of CD14high/CD16+ monocytes correlated with the infarction size and FDG uptake, supporting the hypothesis that FDG uptake reflects injury. Moreover, the FDG uptake in the infarcted myocardium was highest in areas with transmural scar, and was related inversely with functional recovery. All these findings may change our view on FDG uptake early after infarction, namely that it represents myocardial injury rather than viability.

Marco De Carlo, Lucia Mazzolai, Eduardo Bossone, Marianne Brodmann, Antonio Micari, Maria Lorenza Muiesan, Jean-Baptiste Ricco, Eugenio Stabile, Giancarlo Agnelli, Victor Aboyans

## Preamble In an epidemiological update in 2016, cardiovascular (CV) disease has been estimated as cause of 45% of deaths in Europe, including 12% due to stroke and 14% to other CV diseases, highlighting the major burden of non-coronary artery diseases (i.e. aorta, carotid, and lower extremity arteries) and venous thromboembolism (VTE) in our continent (**Figure 1**). (1) Similar to previous years, (2, 3) relevant scientific evidence in these fields was brought out in 2016 which will affect our daily clinical practice. Figure 1. Proportion of all deaths due to major causes in Europe, latest available year (adapted from Townsend). (1) This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. ## Carotid artery disease In the new ‘2016 European guidelines on cardiovascular disease prevention in clinical practice’, the usefulness of carotid intima-media thickness to stratify CV risk has been strikingly challenged, and this marker is no longer recommended due to its high variability, low intra-individual reproducibility, and lack of added predictive value, even in intermediate risk subjects. (4) In opposition, carotid plaque remains a valuable tool for CV risk stratification. In 2016, the long-term clinical equipoise of carotid artery stenting (CAS) vs. carotid endarterectomy (CEA) was confirmed by the 10 year analysis of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST), reporting similar rates of death, stroke, or MI within 30 days, or ipsilateral stroke up to 10 years for both strategies (11.8% vs. 9.9%; P = 0.51) (**Table 1**). (5) ### Table 1: Summary of major randomized trials in the aorta, peripheral artery diseases, and venous thrombo-embolic disease in 2016. | **Trial** | **Type and aim** | **Challenger** | **Reference** | **N** | **Setting (indication)** | **Primary endpoint** | **Main hypothesis validated?** | | --- | --- | --- | --- | --- | --- | --- | --- | | **Carotid arteries** | | | | | | | | | ACT-1 (6) | Open: non-inferiority (3% margin) of CAS vs. CEA | CAS | CEA | 1453 | Asymptomatic patients at average surgical risk | Death, stroke, or MI within 30 days, or ipsilateral stroke up to 1 year | Yes | | CREST (10 years) (5) | Open: superiority of CAS vs. CEA | CAS | CEA | 2052 | Symptomatic or asymptomatic carotid stenosis | 10 year composite of any stroke, MI, or death | No | | Aorta | | | | | | | | | AARDVARK (24) | Single blind: perindopril vs. amlodipine vs. placebo to reduce AAA growth | Perindopril 10 mg OD | Amlodipine 5 mg OD or placebo | 224 | Patients with AAA (30–54 mm) | Change in AAA diameter | No | | **Lower extremity artery disease** | | | | | | | | | EUCLID (25) | Double blind: superiority of ticagrelor vs. clopidogrel in PAD patients | Ticagrelor 90 mg BID | Clopidogrel 75 mg OD | 13 885 | ABI ≤0.80 or prior revascularization | Efficacy: composite of CV death, MI, or stroke at 3 years | Efficacy: no | | Safety: major bleeding | Safety: yes | | | | | | | | EUCLID prior revascularization subgroup (26) | Double blind: superiority of ticagrelor vs. clopidogrel in LEAD patients | Ticagrelor 90 mg BID | Clopidogrel 75 mg OD | 7875 | Prior revascularization | Efficacy: composite of CV death, MI, or stroke at 3 years; acute limb ischaemia | Efficacy: no | | Safety: major bleeding | Safety: yes | | | | | | | | TRA2°P—qualifying LEAD subgroup (27) | Double blind: superiority of vorapaxar vs. placebo on top of aspirin and/or thienopyridine | Vorapaxar 2.5 mg OD | Placebo | 3787 | Claudicants with ABI ≤0.85 or prior revascularization | Efficacy: acute limb ischaemia up to 3 years | Efficacy: yes | | Safety: severe bleeding | Safety: yes | | | | | | | | TRA2°P—known LEAD subgroup (28) | Double blind: superiority of vorapaxar vs. placebo on top of aspirin and/or thienopyridine | Vorapaxar 2.5 mg OD | Placebo | 5845 | Claudicants with ABI ≤0.85 or prior revascularization | Efficacy: peripheral revascularization up to 3 years | Efficacy: yes | | Safety: severe bleeding | Safety: yes | | | | | | | | IN.PACT SFA I (3 years) (29) | Open: superiority of DEB vs. PTA for FP lesions | DEB | PTA | 331 | Rutherford class 2 to 4 FP lesions | Efficacy: 3 year primary patency; freedom from CD-TLR | Efficacy: yes | | Safety: death, clinically driven TVR, major amputation, thrombosis | Safety: yes | | | | | | | | ZILVER PTX (5 years) (30) | Open: superiority of DES vs. PTA for FP lesions | DES | PTA | 474 | Rutherford class 2 to 6 FP lesions | 5 year primary patency; freedom from CD-TLR | Yes | | **Venous thrombo-embolic disease** | | | | | | | | | CACTUS (37) | Open; superiority of 6 week nadroparine vs. placebo in low-risk patients with symptomatic calf DVT | nadroparine 171 UI/kg OD | Placebo | 259 | Symptomatic first isolated distal DVT event | Efficacy: composite of proximal DVT extension, contralateral DVT, and PE | Efficacy: no | | Safety: bleedings | Safety: no | | | | | | | [†] AAA, abdominal aortic aneurysm; CAS, carotid artery stenting; CD, clinically driven; CEA, carotid endarterectomy; DEB, drug eluting balloon; DVT, deep vein thrombosis; FP, femoro-popliteal; LEAD, lower-extremity artery disease; MI, myocardial infarction; PE, pulmonary embolism, PTA, percutaneous transluminal angioplasty; TLR, target lesion revascularization; TVR, target vessel revascularization. Peri-procedural stroke during CAS is often related to plaque embolization. The randomized Asymptomatic Carotid Trial (ACT) I compared CAS with embolic protection to CEA in 1453 patients with asymptomatic carotid stenosis, not considered at high surgical risk (**Table 1**). (6) The composite endpoint of death, stroke, or MI at 30 days, or ipsilateral stroke at 1 year, was non-inferior in CAS vs. CEA (3.8% vs. 3.4%; P = 0.01 for non-inferiority); however, peri-procedural stroke rates numerically favoured CEA (1.4% vs. 2.8% for CAS, P = 0.23). Notably, in 2016, three small prospective registries reported peri-procedural stroke rates as low as 0–0.9% with the new dual-layered carotid stents, consisting of a thin-strut nitinol stent covered with a nitinol mesh. (7-9) While surgery remains the procedure of choice, the pending question is the risk stratification of patients with asymptomatic carotid stenosis who would benefit from revascularization. ## Aortic diseases The multicentre Normal Reference Ranges for Echocardiography (NORRE) study provided reference values for echocardiographic measures, taking into account different measurements conventions, and timing of the cardiac cycle. (10) Normal values apply also to athletes, as shown by a study on 3281 healthy elite athletes which reported that 1.8% of men and 1.5% of women had ascending aorta diameters >40 mm and 34 mm, respectively. (11) Important data were recently published regarding the assessment of the risk of aortic dissection (AD) in subjects with moderately dilated ascending aorta. (12) Among 4654 individuals, the 5 year risk of AD and/or rupture was 0.4%, 1.1%, and 2.9% at baseline aortic diameters of 45 mm, 50 mm, and 55 mm, respectively. Therefore, the finding of aortic root dilatation indicates the need for a work-up of underlying conditions and scheduled monitoring. Important steps in the understanding of genetic aortic diseases have been taken. In particular, loss-of-function mutations in lysyl oxidase (LOX) genes, involved the regulation of the stability and integrity of elastin and collagen, were identified in families with inherited predisposition for thoracic aortic diseases. (13) Introducing a human LOX mutation in the mouse genome caused ascending aortic aneurysm and spontaneous haemorrhage in mice that were homozygous for the human allele, likely through insufficient cross-linking of elastin and collagen in the aortic wall. (14) In patients with Marfan syndrome (MFS), the impact of genotype on aortic phenotype severity was demonstrated in the Dutch CONgenital CORvitia registry (**Figure 2**). (15) Among 357 patients with mutations of the fibrillin-1 gene, those with mutations causing reduced amount of fibrillin-1 protein had a worse 8 year prognosis than those with dominant-negative mutations (production of abnormal fibrillin-1 protein), with 2.5-fold, 2.4-fold and 1.6-fold increase in the risk of cardiovascular mortality, death or aortic dissection, and any aortic complication, respectively. Figure 2. Prevalence of genetic abnormalities and outcomes according to subgroups in the Dutch CONgenital CORvitia registry (adapted from Franken). (15) This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. Other prognostic data were reported from the GenTAC registry, including 1991 patients with genetically associated thoracic aortic aneurysms (TAA). (16) During an average follow-up of 3.6 years, 1.6% of patients experienced type-A AD; however, only 13% met the guideline criteria on aortic size for TAA repair. Importantly, MFS conferred a seven-fold increase in the risk for AD. Another report from the GenTAC registry described the outcome of 94 women with MFS who had a total of 227 pregnancies, reporting 10.6% pregnancy-related aortic complication rates, with eight-fold increased risk for AD. (17) In type-B AD, standard of care is medical management for uncomplicated cases and thoracic endovascular aortic repair (TEVAR) for complicated ones. However, a recent retrospective study on 338 patients with uncomplicated type-B AD comparing immediate TEVAR (n = 184) to medical therapy (n = 154) showed that 30 day mortality was similar, but medically treated patients had significantly higher mortality (P = 0.01) and aortic-related adverse event rate at 5 year follow-up (P = 0.025). (18) Another retrospective study on 156 patients with uncomplicated acute type B-AD identified an aortic diameter >44 mm as independent predictor of mortality during a median follow-up of 3.7 years; an aortic diameter >44 mm and a false lumen diameter >22 mm were associated with decreased intervention-free survival. (19) These data contribute to the identification of high-risk criteria favouring early TEVAR. A frequent complication of TEVAR, the post-implantation syndrome (PIS)—defined as fever >38 °C, white blood cells >12.0/nL and C-reactive protein >10 mg/dL within 72 h after TEVAR despite negative blood culture—was reported in 16% of cases with type-B AD; PIS did not affect in-hospital outcome, but was associated with increased rates of major adverse events (death, aortic rupture and need for reintervention) at 4 year follow-up (62.5 vs. 25.9%; P = 0.004). (20) Ultrasound screening of abdominal aorta aneurysms (AAA) is recommended in all men >65 years (Class I A), and possibly in women >65 years who smoke (Class IIb C). (21) A Finnish study on 585 patients with ruptured AAA, challenged these recommendations, as 21% of men and 3% of women were 250 ug/L) | 5 (abnormal) | 2 | | Obesity [O] | 1 (BMI≥ 30) | 2.5 (BMI> 30) | | | Age [O] [A] | 1 (≥65 years) | 1→6 (10→90 years) | 0.98 | | Genetic thrombophilia [M] | | 5 | | | Varicose veins [V] | | 2.5 | | | Factor VIII activity [E] | | 1.5→10 (50%→400%) | | | Male sex [S] | | 2 | 2 | | Proximal vein thrombosis or pulmonary embolism | | | 5 | | Time between cessation of anticoagulation and D-dimer measurement (days) | | | 0.74 | | Cut-off value for score | ≥2 | ≥11.5 | – | [†] Numbers represent the value attributed to each characteristic in the scores; capital letters in brackets represent the letter chosen for the score acronym. **Numbers represent hazard ratios and not score values. Unprovoked VTE may be an early sign of cancer. It remains unclear whether a subgroup of high-risk patients with unprovoked VTE could potentially benefit from a more extensive screening strategy. The Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) trial showed that age, smoking status, and prior provoked VTE may be important predictors of occult cancer in patients with first unprovoked VTE (combined effect HR 3.33; P < 0.001). (36) Whether isolated distal deep vein thrombosis (DVT) requires anticoagulation is still debated. The recent CACTUS trial randomized low-risk outpatients (without active cancer or previous VTE) with a first isolated distal DVT to receive subcutaneous low-molecular-weight heparin (LMWH) or placebo for 6 weeks. (37) Rates of symptomatic VTE were not different between the two groups (3% vs. 5%; P = 0.54), while bleeding risk was higher (4% vs. 0%; P = 0.03) (**Table 1**). Although the trial was largely underpowered given the low event rates, it suggests that not all low-risk outpatients with symptomatic isolated distal DVT should receive full-dose LMWH. Alternative strategies such as prophylactic LMWH doses and direct oral anticoagulants (DOAC) need to be investigated. Following large-scale phase-III clinical trials, real-world data confirm safety and effectiveness of DOACs as alternative to standard anticoagulation in a broad range of patients. Recent data pointed out to increased vaginal and heavy menstrual bleeding in women treated with anti-Xa drugs. (38) However, most of patients could be treated conservatively. Among reversal agents, the antiXa andexanet reduced anti-factor Xa activity in acutely bleeding patients and assured effective haemostasis in 79% of cases. (39) In patients with contraindication to anticoagulation, evidence for inferior vena cava filter use remains elusive. Recent data showed that, in non-cancer acute VTE patients, filter use was associated with a significant reduction in 30 day mortality only in case of contraindication to anticoagulation because of bleeding (HR, 0.68). (40) However, risk of subsequent DVT increased by 135%. Pulmonary embolism (PE) is part of the differential diagnosis of syncope; a recent prospective study on 560 patients hospitalized for syncope reported a 17.3% prevalence of PE in this population, supporting the inclusion of PE imaging in the diagnostic workup of syncope. (41)

Fernando Alfonso, Karlen Adamyan, Jean-Yves Artigou, Michael Aschermann, Michael Boehm, Alfonso Buendia, Pao-Hsien Chu, Ariel Cohen, Livio Dei Cas, Mirza Dilić, Anton Doubell, Dario Echeverri, Nuray Enç, Ignacio Ferreira-González, Krzysztof J. Filipiak, Andreas Flammer, Eckart Fleck, Plamen Gatzov, Carmen Ginghina, Lino Goncalves, Habib Haouala, Mahmoud Hassanein, Gerd Heusch, Kurt Huber, Ivan Hulín, Mario Ivanuša, Rungroj Krittayaphong, Chu-Pak Lau, Germanas Marinskis, François Mach, Luiz Felipe Moreira, Tuomo Nieminen, Latifa Oukerraj, Stefan Perings, Luc Pierard, Tatjana Potpara, Walter Reyes-Caorsi, Se-Joong Rim, Olaf Rødevand, Georges Saade, Mikael Sander, Evgeny Shlyakhto, Bilgin Timuralp, Dimitris Tousoulis, Dilek Ural, J. J. Piek, Albert Varga, Thomas F. Lüscher

The International Committee of Medical Journal Editors (ICMJE) provides recommendations to improve the editorial standards and scientific quality of biomedical journals. These recommendations range from uniform technical requirements to more complex and elusive editorial issues including ethical aspects of the scientific process. Recently, registration of clinical trials, conflicts of interest disclosure, and new criteria for authorship – emphasizing the importance of responsibility and accountability, have been proposed. Last year, a new editorial initiative to foster sharing of clinical trial data was launched. This review discusses this novel initiative with the aim of increasing awareness among readers, investigators, authors and editors belonging to the Editors´ Network of the European Society of Cardiology.

Vjeran Nikolić Heitzler

The pathomorphological substrate of stable angina pectoris differs significantly from that of unstable angina pectoris. Acute coronary syndrome presents with the clinical picture of unstable angina pectoris and myocardial infarction with or without ST-segment elevation, and the invasive approach through percutaneous coronary intervention or surgical myocardial revascularization with optimal medical therapy is indicated. In contrast, stable angina pectoris develops gradually, and many studies have demonstrated that the long-term results (fatal outcomes) do not differ in comparison with the invasive approach. The main prerequisite is the application of optimal medical therapy. It is based on three medications: extended-release nitrates, beta blockers, and calcium antagonists, in addition to other treatment.

Filippo Crea, Ronald K. Binder, Thomas F. Lüscher

## Preamble The year 2016 brought us several studies on the pathophysiology of acute coronary syndrome (ACS), in particular, on the role of basophils and eosinophils in the mechanism of disease. New puzzling data have also emerged on the pathomechanisms of very late stent thrombosis and the role of neutrophils in ventricular remodelling. New information has also been published on the early diagnosis of ACS by high sensitivity troponin (hsTn) and the role of new exciting biomarkers and clinical scores on risk stratification. With regards to antithrombotic treatment, the year 2016 has brought important new data on the duration of dual antiplatelet therapy (DAPT) and on the management of the growing population of very elderly. Finally, new interesting information has been published on the outcome of specific patient subsets. The studies reported in this review are summarized in **Table 1**. ### Table 1: Summary of the main studies. | **Topic** | **Main messages** | **References** | | --- | --- | --- | | Mechanisms | Allergic immunity is altered in ACS | Niccoli (1) | | VLST is frequently associated to suboptimal stent implantation | Taniwaki (2) | | | In experimental models neutrophil depletion is associated to worse remodelling | Horckmans (3) | | | Early diagnosis | The best hsTn algorithm to rule out ACS remains controversial | Pickering (5), Shah (4) | | Potential role of micro-RNA | Coskunpinar (7) | | | The role of coronary computed tomography angiography in the emergency department in patients with suspected ACS is limited | Dedic (8) | | | Risk stratification | GDF-15 predicts both bleeding and ischemic risk | Hagstrom (11) | | New clinical risk scores to predict in-hospital mortality and medium-term risk of sudden cardiac death in patients admitted with ACS | Hess (10) | | | Treatment | The efficacy of Cangrelor compared to clopidogrel previously found in the CHAMPION PHOENIX trial is independent of the puncture site | Gutierrez (13) | | The pharmacodynamic effects of Ticagrelor are impaired by morphine | Kubica (16) | | | Data from SWEDEHEART database confirm the better efficacy of Ticagrelor as compared to Clopidogrel in ACS in the real world | Sahlen (17) | | | The pharmacodynamic effects of crushed Prasugrel tablets are better than those of intact tablets | Rollini (19) | | | A meta-analysis suggests that dual antiplatelet therapy beyond one year after ACS reduces subsequent ischemic events | Udell (20) | | | The addition of ezetimibe to simvastatin reduced first and subsequent cardiovascular events in ACS patients in the IMPROVE-IT trial | Murphy (31) | | | A sub-study of the LEADERS FREE trial confirms that Biolimus-A9 polymer-free coated stent is superior to bare metal stent in ACS patients with high-bleeding risk on one-month double antiplatelet treatment | Naber (22) | | | A real-world analysis fails to show superiority of bivaluridin as compared to other anti-thrombotic treatments | Sirker (28) | | | The efficacy of early beta-blockers in STEMI remains controversial | Garcia-Ruiz (29) | | | In early STEMI admitted to non-capable PCI centres, transfer for primary PCI is better than fibrinolysis if the delay is less than 140 min | Carrillo (32) | | | In NSTEMI a single-staged compared with a multi-staged PCI is associated with a lower rate of target vessel revascularization during follow-up | Sardella (33) | | | In the very elderly with ACS, an invasive approach is associated to a better outcome as compared to a conservative approach | Tegn (36) | | | PCI in unprotected left main stenosis is associated with comparable clinical outcomes to those observed with coronary artery grafting at long-term follow-up | Pyxaras (34) | | | The outcome of left ventricular assist device implanted in patients with ACS is similar to that observed in stable patients | Acharya (38) | | | Outcomes in specific patient populations | Women: a statement from the American Heart Association on ACS in women summarizes the main differences between men and women in this setting. | Mehta (39) | | Smokers: smoking is independently associated to better left ventricular remodelling | Symons (40) | | | Rheumatoid arthritis: among patients with ACS rheumatoid arthritis is associated to a worse outcome | Mantel (41) | | | Vasospastic angina: among patients with vasospastic angina those who present with aborted sudden cardiac death have a worse outcome during follow up | Ahn (42) | | | Takotsubo syndrome: the outcome of the “happy heart syndrome” is similar to that of the “broken heart syndrome” | Ghadri (44) | | [†] ACS, acute coronary syndrome; NSTEMI, non-ST elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST elevation myocardial infarction; VLST, very late stent thrombosis. ## Mechanisms ## Pathogenesis of ACS Spontaneous ACS can be caused by plaque fissure, plaque erosion, or functional alterations of epicardial coronary arteries or by vasoconstriction of the microcirculation. Activation of inflammatory cells plays a key role in both plaque fissure and erosion although the mechanisms leading to plaque instability are substantially different in these two conditions. Indeed, while monocyte and lymphocyte activation is the key alteration in plaque fissure, neutrophil activation is a crucial player in plaque erosion. The role of eosinophil and basophil activation is still largely unknown. Niccoli et al. (1) found a higher degree of both eosinophil and basophil activation, as assessed by flow cytometry, in patients with ACS than in those with stable angina. Furthermore, in a prospective cohort study they found that higher levels of eosinophil cationic protein (ECP) were associated with a worse outcome during follow-up. This suggests that novel therapies targeting eosinophils should be tested in ACS patients exhibiting raised ECP levels. ## Stent thrombosis It is well known that very late stent thrombosis is a possible cause of ACS. The pathomechanisms underlying very late stent thrombosis after implantation of drug-eluting stents (DES) are incompletely understood. Using optical coherence tomography (OCT), Taniwaki et al. (2) investigated potential causes of this adverse event. They found that the leading associated findings in very late stent thrombosis were in descending order: (**i**) stent malapposition, (**ii**) neoatherosclerosis, (**iii**) uncovered stent struts, and (**iv**) stent underexpansion. The longitudinal extension of malapposed and uncovered struts was the most important correlate of thrombus formation. These findings might further expand the clinical utilization of OCT in optimizing the results of stent implantation. ## Remodelling Another important issue in ACS are the mechanisms responsible for left ventricular remodelling after myocardial infarction (MI). In an elegant experimental study in a mice model of MI, Horckmans et al. (3) found that neutrophil-depleted animals had worsened cardiac function, increased fibrosis, and progressively developed heart failure. Thus, while high neutrophil counts are considered as predictor of adverse clinical outcomes and mortality in patients with ACS and their contribution in the acute inflammatory phase after MI is generally considered detrimental, these data suggest that neutrophils participate in MI repair skewing macrophages towards a resolving phenotype, which mediates efficient clearance of cell debris. This novel role for neutrophils should be taken in account when designing and applying ‘aggressive’ anti-neutrophil treatments in the setting of MI. ## Early diagnosis ## Troponins The evaluation of patients presenting at the emergency department (ED) with suspected ACS remains a clinical challenge. The traditional assessment includes clinical risk assessment based on symptoms, cardiovascular (CV) risk factors with serial electrocardiograms and hsTn measurements, often followed by advanced cardiac testing as inpatients or outpatients. With regards to hsTn, several cohort studies have shown that patients with undetectable plasma hsTn concentrations at presentation are at low risk of MI. However, the optimal approach and threshold of hsTn for the identification of low-risk patients suitable for immediate discharge is still debated. Shah et al. (4) did a prospective cohort study of 6304 consecutively enrolled patients with suspected ACS presenting to 4 secondary and tertiary care hospitals in Scotland. They measured plasma Tn concentrations at presentation using a hsTnI assay and evaluated the negative predictive value of a range of hsTnI concentrations for the primary outcome of index MI, or subsequent MI or cardiac death at 30 days in derivation and validation cohorts. The median time from arrival in the ED to blood sampling for measurement of hsTn was 54 min. They found that a hsTn concentration of less than 5 ng/L at presentation met their pre-specified criteria for a negative predictive value of at least 99.5%. At this threshold, almost two-thirds of patients with suspected ACS could have been discharged with very few cardiac events. Indeed, implementation of this threshold could double the number of patients discharged directly from the ED. In one study, Pickering et al. (5) tested the 0–1 h rule out algorithm proposed by the current European Guidelines on 2015 ESC guidelines for the management of ACS in patients presenting without persistent ST-segment elevation, in 2222 patients with serial hsTnT and hsTnI measurements. The 0-1 h hsTnT algorithm ruled out 1425 patients (64.1%) with a sensitivity of 97.1%. The 0–1 h hsTnI algorithm ruled out 1205 patients (54.2%) with a sensitivity of 98.8%. They concluded that the sensitivity of the European Society of Cardiology rapid assessment 0-1 h algorithm to rule-out AMI with high-sensitivity troponin may be insufficient for some ED physicians to confidently send patients home. Thus, the identification of the optimal rule-out hsTn algorithm in patients with suspected ACS admitted to ED remains debated as well as the optimal rule-in algorithm. (6) Also controversial is the utilization of a second biomarker like copeptin. With regards to new biomarkers in the early diagnosis of ACS, in a proof of concept study Coskunpinar et al. (7) assessed the potential diagnostic role of circulating micro-RNAs in patients with ACS. They found that miR-221-3p was significantly positively correlated with Tn levels, GRACE and SYNTAX Score and inversely correlated with post-MI left ventricular systolic function. They conclude that miR-221-3p may be a promising biomarker for early diagnosing of ACS. ## Coronary computed tomography angiography It is uncertain whether a diagnostic strategy supplemented by early coronary computed tomography angiography (CCTA) is superior to contemporary standard optimal care including hsTn for patients suspected of ACS in the ED. In a prospective, open-label, multicentre, randomized trial, Dedic et al. (8) enrolled 500 patients presenting with symptoms suggestive of an ACS at the ED of 5 community and 2 university hospitals in the Netherlands. The primary endpoint was the number of patients identified with significant coronary artery disease requiring revascularization within 30 days. There was no difference in the primary endpoint. Discharge from the ED was not more frequent after CCTA and length of stay was similar. The authors conclude that in the era of hsTns, CCTA does not identify more patients with significant CAD requiring coronary revascularization, neither does it shorten hospital stay, or allow for more direct discharge from the ED. ## Risk stratification ## Clinical scores McNamara et al. (9) using the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry–GWTG (Get With the Guidelines) database developed a multivariate hierarchical logistic regression model predicting in-hospital mortality. The population (243 440 patients from 655 hospitals) was divided into a 60% sample for model derivation, with the remaining 40% used for model validation. A simplified risk score was created to enable prospective risk stratification in clinical care. Age, heart rate, systolic blood pressure, presentation after cardiac arrest, presentation in cardiogenic shock, presentation in heart failure, presentation with ST-segment elevation MI, creatinine clearance, and Tn ratio were all independently associated with in-hospital mortality. Observed mortality rates varied substantially across risk groups, ranging from 0.4% in the lowest risk group (score 59). This work built upon and extended prior mortality risk models developed for patients with AMI. Although valuable for the selected populations at the time of their original development, changes in patient profiles and AMI management demand updating. The new risk score might serve this purpose. In a pooled cohort analysis which merged individual data from 48 286 participants in 4 trials Hess et al. (10) found that sudden cardiac death (SCD) accounted for about one-third of CV deaths during 1-year follow-up and that reduced left ventricular ejection fraction, older age, diabetes mellitus, lower estimated glomerular filtration rate, higher heart rate, prior MI, peripheral artery disease, Asian race, male sex, and high Killip class were significantly associated with SCD. They also developed an integer-based score from this model, which yielded a calculated SCD probability ranging from 0.1 to 56.7%. This score might help in the identification of candidates for implantable cardioverter defibrillators above and beyond the mere assessment of ejection fraction although prospective assessment of device therapy is warranted because not all sudden death is arrhythmic and may in fact stem from other causes such as recurrent MI or cardiac rupture. ## Biomarkers Hagstrom et al. (11) assessed independent associations between growth differentiation factor-15 (GDF-15) levels and major bleeding and CV events in patients with ACS patients randomized to ticagrelor or clopidogrel in the PLATO (PLATelet inhibition and patient Outcomes) trial. In Cox proportional hazards models adjusting for established risk factors for CV disease and prognostic biomarkers (N-terminal pro B-type natriuretic peptide, cystatin C, high-sensitive C-reactive protein, and hsTn), GDF-15 was associated with increased risk of major bleeding and of the composite of CV death, spontaneous MI, and stroke. The mechanism for the association between GDF-15 and the risk of bleeding might be related to an inhibitory effect on platelet activation mediated via a mechanism similar to glycoprotein IIb/IIIa inhibition resulting in a lower ability of the cells to form a thrombus. These findings give further support to the utilization of this biomarker in the clinical setting of ACS (**Figure 1**). Figure 1. Kaplan–Meier estimated event rates of non-coronary artery bypass grafting-related major bleeding (top panel) and cardiovascular death (bottom panel) by quartiles of growth differentiation factor-15 (ng/L) assessed in 16 876 patients admitted with acute coronary syndrome. CABG = coronary artery bypass grafting; CV = cardiovascular. Reproduced with permission from Hagstrom *et al*. (11) This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. ## Treatments Mechanical reperfusion of the infarct-related artery by percutaneous coronary intervention (PCI) and adjunctive medical management including antithrombotic therapy remain the cornerstones of current ACS management. ## P2Y12 inhibitors Recently the first intravenous P2Y12 inhibitor, Cangrelor, was approved and broadened the armamentarium of antiplatelet agents in patients undergoing PCI. In the CHAMPION PHOENIX trial (12) Gutierrez et al. (13) analysed whether the femoral or radial approach for PCI interacted with the efficacy and safety of cangrelor. Among 11 145 patients randomly assigned to cangrelor or clopidogrel at the time of PCI the primary endpoint, a composite of death, MI, ischemia-driven revascularization, or stent thrombosis (**Figure 2**), occurred in the femoral cohort in 4.8% with cangrelor vs. 6.0% with clopidogrel (odds ratio, OR [95% confidence interval, CI]: 0.79 [0.65–0.96]); in the radial cohort, the primary endpoint was 4.4% with cangrelor vs. 5.7% with clopidogrel (OR [95% CI] 0.76 [0.54–1.06]). *P* for interaction was not significant. The absolute rate of bleedings tended to be lower with radial access. Figure 2. In the CHAMPION PHOENIX trial, Gutierrez *et al.* (13) analysed among 11 145 patients whether the femoral or radial approach for PCI interacted with the efficacy and safety of cangrelor. (*A*) Kaplan–Meier curves for the primary efficacy endpoint in the subgroup undergoing femoral access (cangrelor vs. clopidogrel). (*B*) Kaplan–Meier curves for the primary efficacy endpoint in the subgroup undergoing radial access (cangrelor vs. clopidogrel). HR = hazard ratio; CI = confidence interval. Reproduced with permission from Gutierrez *et al*. (13) This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. The pharmacodynamics and pharmacokinetics of oral antiplatelet drugs, particularly P2Y12 inhibitors may be affected by absorption and first pass metabolism. Furthermore, a drug–drug interaction between morphine and oral P2Y12 receptor inhibitors, when administered together, has been suggested. (14, 15) In a randomized double-blind trial, Kubica et al. (16) investigated the pharmacokinetics and pharmacodynamics of ticagrelor when administered with or without intravenous morphine in ACS patients. In 70 randomized patients, morphine lowered the total exposure to ticagrelor and its active metabolite by 36% (AUC (0–12): 6307 vs. 9791 ng h/mL; P = 0.003), and 37%, respectively (AUC(0–12): 1503 vs. 2388 ng h/mL; P = 0.008). Despite this impressive interaction, the clinical significance remains to be determined. Concurrently, an analysis of 45 073 ACS patients from the SWEDEHEART registry (17) compared the outcomes of those treated with ticagrelor vs. those receiving clopidogrel. After 2 years, treatment with ticagrelor was associated with a lower rate of death (5.8% vs. 12.9%, adjusted hazard ratio [HR] 0.83 [0.75–0.92]) and a lower rate of MI (6.1 vs. 10.8%, adjusted HR 0.89 [0.78–1.01]) compared to clopidogrel (**Figure 3**). These real-world findings were consistent with previous randomized trial results. (18) Figure 3. Incidence for the primary combined outcome of death, myocardial infarction, or stroke in 45 073 ACS patients from the SWEDEHEART registry. Bottom panels show the individual components of the primary outcome, as well as the primary bleeding outcome of hospitalization with bleeding (bottom right). Treatment with clopidogrel is shown in blue and ticagrelor in yellow. Reproduced with permission from Sahlen et al.17 This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. In STEMI patients undergoing primary PCI delayed antiplatelet effects of oral P2Y12 inhibitors, including prasugrel, have been observed. Rollini et al. (19) investigated the bioavailablity of crushed prasugrel tablets vs. whole prasugrel tablets. The study showed that compared with whole tablets, crushed prasugrel led to reduced P2Y12 reaction units by 30 min post-loading dose, which persisted at 1, 2, and 4 h post-loading dose. Thus, in STEMI patients undergoing primary PCI, crushed prasugrel leads to faster drug absorption, and consequently, more prompt and potent antiplatelet effects compared with whole tablet ingestion. Whether this observation may be associated with clinical endpoints (e.g. acute stent thrombosis) needs to be determined in larger cohorts. ## Optimal dual antiplatelet treatment duration The optimal duration of DAPT after PCI in the setting of ACS is continuously debated as patients considered at high risk of bleeding may benefit from a shortened DAPT duration. In contrast, subsequent ischemic events in stable post ACS patients may be reduced by prolonged DAPT beyond 1 year, as was suggested in a meta-analysis. (20) However, major bleeding occurs significantly more often under prolonged DAPT. In a randomized trial, a Biolimus-A9 drug coated stent (DCS) has shown better outcomes with only one month DAPT compared to a bare metal stent (BMS) in patients at high-bleeding risk. (21) A sub-study focusing on patients with ACS (22) was consistent with the overall findings. At 12-month follow-up, treatment with the DCS in ACS patients was more effective (clinically driven target-lesion revascularization 3.9% vs. 9.0%, *P* = 0.009) and safer (cumulative incidence of cardiac death, MI, or definite or probable stent thrombosis 9.3% vs. 18.5%, *P* = 0.001), than the BMS despite one month DAPT in both groups (**Figure 4**). As the DCS exhibited a better safety and efficacy profile than BMS, the use of BMS has to be questioned for the treatment of coronary artery stenosis. However, the lower cost of the BMS is a favourable argument in an environment with limited resources. Figure 4. In a randomized trial a Biolimus-A9 drug coated stent showed better outcomes with only 1-month dual antiplatelet therapy compared to a bare metal stent, in patients at high-bleeding risk. This sub-study focusing on patients with ACS was consistent with the overall findings. The benefit of the drug coated stent over the bare metal stent was consistent across various sub-groups. ACS = acute coronary syndrome; BMS = bare metal stent; DCS = drug coated stent; NSTEMI = non-ST-elevation myocardial infarction; ST = stent thrombosis; STEMI = ST-elevation myocardial infarction; TLR = target lesion revascularization. Reproduced with permission from Naber et al.22 This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. ## Bivalirudin In primary PCI for ST-segment elevation MI (STEMI), the HORIZONS trial (23) had previously shown a mortality benefit for bivalirudin over heparin with glycoprotein inhibitors (GPI). Subsequent trials (24–27) comparing bivalirudin with other anti-thrombotic strategies rendered divergent results. Now a real-world analysis of 61 136 patients from the UK national PCI registry (28) from 2008 to 2012 showed no significant difference in short- or medium-term mortality between STEMI patients treated with bivalirudin vs. heparin and GPI at primary PCI. Larger randomized trials will be needed to settle the role of bivalirudin vs. heparin in primary PCI. ## Beta-blockade The impact of intravenous beta-blockers before primary PCI on clinical outcomes and infarct size is not well established. A post hoc analysis from the METOCARD-CNIC trial (29) suggested that the sooner metoprolol is administered in the course of an STEMI, the smaller the infarct size. However, the Early-BAMI trial (30) did not show any difference between STEMI patients randomized to early intravenous metoprolol or placebo. In this study, metoprolol reduced the incidence of malignant arrhythmias in the acute phase but was not associated with a reduction in the infarct size (peak and area under the creatine kinase curve). ## Lipid lowering agents Pharmacotherapy that reduces low-density lipoprotein cholesterol has consistently shown benefit for CV endpoints in patients with coronary artery disease. In an analysis of the IMPROVE-IT trial, the addition of ezetimibe to simvastatin not only reduced the rate of first primary endpoint but also reduced the rate of subsequent adverse CV endpoints in ACS patients. (31) Meanwhile a new class of agents—proprotein convertase subtilisin/kexin type 9 inhibitors, which are approved for the treatment of familiar hypercholesterolemia, are under investigation in ACS patients (ClinicalTrials.gov Identifier: NCT01663402). ## Fibrinolysis in non-PCI capable hospitals The preferred reperfusion strategy for ACS patients presenting with STEMI is primary PCI. However, systemic fibrinolysis is still applied in STEMI patients in non-PCI capable hospitals if transfer for primary PCI would lead to unacceptable reperfusion delays. In a prospective multicentre STEMI registry, Carrillo et al. (32) compared the effect of in situ fibrinolysis vs. PCI transfer on 30-day mortality in a real-life consecutive cohort of 2470 STEMI patients. The study showed that patients in the transfer group whose from first medical contact (FMC) to device (PCI) time was achieved within 140 min were associated with significantly lower mortality (2.0% for FMC-device < 99 min, and 4.6% for FMC-device 99–140 min; P = 0.01 and P = 0.03, respectively vs. fibrinolysis). In multivariable logistic regression analysis, reperfusion with fibrinolysis was an independent 30-day mortality predictive factor (OR: 1.91, 95% CI: 1.01–3.50; P = 0.04). These results suggest, that transfer to a PCI-capable hospital should be recommended, if FMC-device delay is less than 140 min. ## Revascularization strategies in ACS A third to half of ACS patients present with multi-vessel disease. The best treatment strategy and the optimal timing for non-culprit lesion PCI in ACS is a matter of debate. In the SMILE trial, (33) 584 patients with non ST elevation MI with multi-vessel disease were randomized to single-stage complete revascularisation vs. multi-stage complete revascularization during the same hospitalization. No significant difference in the one-year incidence of cardiac death (3.41% vs. 5.32% respectively, P = 0.27) and MI (2.65% vs. 3.8% respectively, P = 0.46) was found between groups, although target vessel revascularisation was higher in the multi-stage group (8.33% vs. 15.2%, P = 0.01). However, there was no overall survival benefit of single- vs. multi-staged complete revascularisation. If the culprit lesion of an ACS is located in an unprotected left main coronary artery (ULMCA), the optimal revascularization strategy is a matter of debate. In the DELTA all-comer, multinational registry (34) the long-term outcomes of ACS patients with ULMCA treated with coronary artery bypass grafting (CABG) or PCI was investigated. In 379 ACS patients, no significant differences emerged for the composite endpoint of all-cause death, AMI, and cerebrovascular accident. As patients in this study received first-generation drug eluting stents a lower rate of target vessel revascularisation may be expected with newer-generation stents. ## Treatment of the elderly Schoenenberger et al. (35) analysed the use of guideline-recommended therapies and in-hospital outcomes of 13 662 ACS patients ≥70 years enrolled in the prospective Acute Myocardial Infarction in Switzerland (AMIS) cohort according to 4-year periods (2001–2004, 2005–2008, and 2009–2012). Between first and last 4-year period, PCI use increased as well as use of guideline recommended drugs. At the same time, in-hospital mortality of the overall population decreased from 11.6% in the first to 10.0% in the last 4-year period, and in-hospital major adverse cardiac and cerebrovascular events from 14.4 to 11.3%. This study indicates that increasing use of guideline-recommended therapies is appropriate in the elderly. It remains to establish whether this notion is also valid for octogenarians. One aspect in the very elderly population was investigated by Tegn et al. (36) They studied whether patients aged 80 years or older presenting with an ACS without ST-segment elevation would benefit from an early invasive strategy compared to an initially conservative management. During a median follow-up of 1.53 years, the primary outcome, a composite of MI, need for urgent revascularization, stroke, and death, occurred in 93 (40.6%) of 229 patients assigned to the invasive group and 140 (61.4%) of 228 patients assigned to the conservative group (HR 0.53 [95% CI 0.41–0.69], P = 0.0001). The two strategies did not differ in terms of bleeding complications. In conclusion, in line with the ESC Guidelines, (37) an invasive strategy in patients aged 80 years or older presenting with non-ST segment elevation MI was superior to a conservative strategy. ## Left ventricular assist device Patients who present with acute heart failure or cardiogenic shock refractory to reperfusion and medication may require mechanical circulatory support. In the INTERMACS registry patients who received a durable ventricular assist device (VAD) in the setting of an ACS were compared to those who received a VAD for non-ACS indications. (38) In an unadjusted analysis the ACS group had higher early phase hazard (HR: 1.24; P = 0.04) but reduced late-phase hazard of death (HR: 0.57; P = 0.04) than the non-ACS group. Despite being more critically ill before VAD implantation, ACS patients had similar outcomes compared to non-ACS patients. Therefore, VAD implantation is a valuable strategy in ACS patients with cardiogenic shock or heart failure refractory to medical therapy. ## Outcomes in specific patient populations ## Women An interesting scientific statement from the American Heart Association on ACS in women (39) summarizes the main differences between men and women in this setting. In particular, it is highlighted that regardless of age, within a year of a first AMI, more women than men die; within 5 years of a first AMI, more women than men die, have heart failure, or suffer from a stroke, although the higher mortality for women compared with men is explained partially by differences in risk factors, clinical presentation, and treatment. Indeed, the prevalence of diabetes mellitus, heart failure, hypertension, depression, and renal dysfunction is higher in women compared with men. Compared with men, women more commonly present with NSTEMI and non-obstructive coronary artery disease. Women are also more likely to have unusual pathophysiological mechanisms of ACS such as spontaneous coronary artery dissection or coronary artery spasm. ## Smokers Symons et al. (40) assessed the effect of smoking in 471 STEMI patients by cardiac magnetic resonance. Smoking was associated with intramyocardial haemorrhage (IMH) at baseline even after correction for other factors associated with ischemia-reperfusion injury. Unexpectedly, smoking was an independent protective predictor against adverse left ventricular remodelling consistent with the ‘smoker’s paradox’, although the presence of IMH at baseline abolished this paradoxical, beneficial effects of smoking. It remains to establish what mediates these intriguing protective effects of smoking in STEMI in order to identify new therapeutic targets. ## Rheumatoid arthritis Despite a wealth of studies describing an increased incidence of ACS in rheumatoid arthritis (RA), considerably less is known about the clinical characteristics and their association with short-term outcome of such ACS. Mantel et al. (41) compared the clinical presentation of incident ACS in a cohort of 1135 subjects with prevalent RA and in a cohort of 3184 matched general population comparators. RA subjects more frequently presented with SCD, STEMI, had higher levels of hsTn and higher frequencies of in-hospital complications compared with the general population comparators. Furthermore, the short-term mortality was higher among RA-associated ACS. The higher risk of RA-associated ACS is consistent with the important role of inflammation in the pathogenesis of ACS and should stimulate further research for the identification of personalized forms of treatment. ## Vasospastic angina Ahn et al. (42) compared the outcomes of 188 patients with vasospastic angina and aborted SCD and 1 844 patients with vasospastic angina without aborted SCD enrolled from 13 heart centres in South Korea. The former had a much higher risk of death than the latter. Predictors of SCD included age, hyperlipidaemia, family history of SCD, multi-vessel spasm, and left anterior descending artery spasm. It remains to establish which mechanisms make the myocardium more susceptible to malignant arrhythmias in these patients. ## Takotsubo syndrome Finally, an emerging notion is that ACS are not only caused by epicardial anatomic or functional alterations but also by coronary microvascular dysfunction (**Figure 5**). This seems to be the case, in particular for takotsubo cardiomyopathy (TTC) (43) (**Figure 6**). To this regards, one study illustrated that TTC can be triggered by not only negative but also positive life events. (44) While patient characteristics and also short- and long-term outcomes were similar between groups, the midventricular TTC type was more prevalent among the ‘happy hearts’ than among the ‘broken hearts’. Presumably, despite their distinct nature, happy and sad life events may share similar final common emotional pathways, which can ultimately trigger TTC. Figure 5. Typical angiographic presentation of ST-segment elevation myocardial infarction (STEMI), non-STEMI, Takotsubo syndrome, and Prinzmetal angina. Reproduced with permission from Luscher and Templin.43 This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. Figure 6. Macrovascular and microvascular ischemia in patients with ST-segment elevation myocardial infarction (STEMI), non-STEMI, Takotsubo syndrome and Prinzmetal angina, respectively. Reproduced with permission from Luscher and Templin.43 This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. ## Perspectives Major progress has been made in the understanding of ACS. In particular, novel data indicate that both basophils and eosinophils may play a pathogenetic role in ACS suggesting new potential therapeutic targets. Further efforts are also needed in the early diagnosis of ACS when it remains undetermined after optimal Tn assessment. The demonstration that GDF-15 predicts both ischemic and bleeding risk is exciting although its role in daily practice remains to be established. With regards to antithrombotic treatment, it remains challenging to tailor DAPT duration according to individual risk. Finally, the worse outcome of patients with RA as compared to those without RA indicates that the former need more aggressive forms of treatment to be defined in future studies.

Ante Silić

The concept of somatic illnesses that is separate from mental illness is a concept that harms the optimal treatment of our patients. There are more and more arguments showing that the mental is inseparable from the somatic in the context of diagnostics and treatment.

Gordana Bačić, Vjekoslav Tomulić, Igor Medved, Luka Zaputović, Teodora Zaninović, Jurjević, David Gobić

Extracorporeal membrane oxygenation (ECMO) is a procedure that provides extracorporeal mechanical circulatory or respiratory support and is used primarily in patients with life-threatening forms of heart or respiratory failure. There are two basic types of ECMO support: veno-venous (VV) and veno-arterial (VA) ECMO. VV ECMO ensures blood gas exchange and is applied in cases of severe reversible respiratory insufficiency. VA ECMO supports the function of the heart and lungs; other than in reversible forms of damaged heart function, it can also be used in irreversible forms of heart failure as a bridge to heart transplantation or to the implantation of mechanical circulatory support device. ECMO is an invasive and technically complex procedure that is performed in critically ill patients and thus has a high risk of complications. Results of ECMO treatment vary depending on the indications for the procedure itself. Patients in whom ECMO was applied for respiratory support show better outcomes compared with those with cardiogenic shock or cardiac arrest. Despite a lack of evidence based on large randomized studies to support its application, in clinical practice ECMO represents a life-saving method of treatment in well-selected critical patients.

Dubravko Petrač

Atrial fibrillation (AF) is often present in patients with cardiac resynchronization therapy (CRT), and may have a significant negative impact on the prognosis and CRT response. Management of AF in CRT patients includes the optimal pharmacological heart failure therapy, anticoagulation therapy, and rate or rhythm control therapy with specific goal to ensure a high percentage (≥98%) of biventricular (BiV) pacing. In heart failure patients with AF, a rhythm control with antiarrhythmic drugs has failed to show any survival benefit compared with a rate control drugs. In this context, a rate control with drugs is preferred as first-line therapy in CRT patients with persistent or permanent AF. However, the observational prospective studies and meta-analyses indicate that AV junction ablation is superior to rate control drugs in achieving adequate BiV pacing and reducing mortality. Therefore, an ablation of AV junction should be considered as the first therapeutic choice in CRT patients with permanent AF. Amiodarone and dofetilide are the lone antiarrhythmic drugs suitable for the rhythm control in CRT patients, but with a moderate efficacy and significant side effects. Catheter ablation of AF is another option for the rhythm control, which can improve CRT response by promoting adequate atrioventricular and interventricular synchrony. According to randomized controlled studies in heart failure patients, AF ablation should be considered in CRT patients with paroxysmal AF, who are non-responders to antiarrhythmic drugs, or in selected patients with persistent AF before accepting a rate control therapy.

## Preamble The year 2016 was characterized by numerous relevant contributions in cardiac arrhythmias. A selected group of articles providing information with potential impact in daily practice has been identified by the authors and is reported in the present article. ## Cardiac arrhythmias and catheter ablation ## Supraventricular tachycardia: diagnosis and treatment Supraventricular tachycardia (SVT) continues to be a frequent cause of emergency hospital admission. The REVERT study evaluated the best and most efficient acute treatment strategy for SVT and compared postural modification (leg elevation and supine positioning applied for 15 sec at the end of 15 sec) with standardized strain Valsalva manoeuvre (i.e. pressure of 40 mm Hg sustained for 15 s by forced expiration measured by aneroid manometer with the target pressure visible to the treating team). (1) The modified treatment was found to terminate SVTs in a significantly larger proportion of patients (43% of 214) than using conventional manoeuvres (17% of 214; *P* < 0.0001). As a consequence, significantly less patients in the study arm required adenosine (50% vs. 69%) or emergency anti-arrhythmic treatment (57% vs. 80%) to terminate the incident arrhythmia (1) and no differences in time to discharge from hospital. This finding may considerably affect daily practice and reduce drug-related patient discomfort at time of emergency treatment in patients with SVT. The full scope of up-to-date diagnosis and treatment of SVTs can be reviewed best in 2016 EHRA/ESC consensus document on SVT management (Katritsis *et al.*, EHJ 2016 in press) ## Atrial fibrillation: pathophysiology, risks, treatment opportunities, and the new ESC AF guidelines The intense scientific discussion about the pathophysiology of atrial fibrillation and particularly the drivers for AF progression was enriched and stimulated by a very interesting experimental and clinical study on atrial remodeling. (2) It was shown that atrial adipose tissue, which has been previously identified as a strong risk factor for AF development, is progressively replaced by fibrotic tissue that serves as the substrate for AF progression. (2) These data may further explain the link between obesity and AF recently described in clinical studies. (3) However, those studies also showed a significant reduction of AF burden with weight loss and it is now of particular interest whether or not the reduction in AF burden may coincide with reversed structural re-modelling—and vice versa (**Figure 1**). MRI-based fibrosis detection and quantification holds some promise to document the substrate changes over time and may give further insights into this important aspect of AF pathology in the future (**Figure 2**). (4) However, various methodological hurdles need to yet be overcome, mainly due to the thin wall of the atria, and appropriate protocols are indispensable. Rate control is the most frequent treatment options chosen for and by AF patients world-wide. Data about the best medication to support rate control therapy by symptom relief and reducing AF-related risks are limited and somewhat controversial. (5) A recent nationwide study from Taiwan investigated the long-term effects of beta-blockers, calcium-channel blockers or digitalis given for the rate control in ongoing atrial fibrillation on mortality. (6) After adjustment for baseline differences, the risk of mortality was found to be significantly lower in the 43 879 patients receiving beta-blockers and in the 18 466 patients receiving calcium-channel blockers than in a control population of 168 678 patients not receiving any rate-control drug. On the contrary, patients receiving digoxin had a higher risk of mortality. Especially the effects observed for beta-blockers are interesting as a recent meta-analysis on rate control medications did not show such beneficial effects for beta-blockers. (7) These findings contribute to the ongoing controversy about the impact of rate-control drugs on the risk of all-cause death in patients with ongoing AF and prompt for the need of future randomized trials to address this relevant question. Figure 1. Different dynamics of scar progression with progressive fibrosis over a time period of 3 years in the years after atrial fibrillation ablation. Panel (*A*) depicts a patient with little to no increase in cardiac fibrosis while panel (*B*) depicts a patient with massive increase in cardiac fibrosis at 1 year and 3 years (green colour) coinciding with multiple AF recurrences. Reproduced with permission from Gal and Marrouche. (4) This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. Figure 2. MRI-based imaging of atrial wall fibrosis. MRI cross section at the level of the left atrium (left side) and 5-chamber view (right side). Atrial fibrosis can be detected in various regions of the atrial wall (white spots). Only the left atrial appendage (LAA) is largely free of scar. This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. Patients with aortic stenosis often also have pre-existing AF which may be ‘silent’ or develop AF (so-called ‘new-onset AF’) early after surgical or transfemoral aortic valve replacement (TAVI). Indeed, when compared with patients in sinus rhythm, patients with AF undergoing surgical or TAVI interventions have been shown to be at higher risk for stroke and bleeding but also for having a higher total mortality. (8) A recent clinical update on this topic pointed out that the incidence of new-onset AF may be lower with TAVI as compared with surgical valve replacement. (8) However, the optimal treatment strategy of such patients with respect to rhythm or rate control is still unclear. Particularly the role of amiodarone both for the peri-procedural prevention of AF and for classical rhythm control as well as the role of catheter ablation as a rhythm control strategy needs further evaluation in clinical studies and trials. Another field of controversy relates to the optimal anticoagulation regimen especially for TAVI patients: are AF patients after TAVI eligible for NOAC therapy or are vitamin K antagonists the better choice? While there are good arguments in favour of NOACs after TAVI convincing data from specific and large clinical trials are still lacking to answer this important question. (9) Catheter ablation of paroxysmal AF: burn it down or freeze it? The comparative effect of catheter-based point-by-point radiofrequency ablation and balloon-based cryo-ablation for the treatment of paroxysmal AF was unknown and had been intensely debate over years. We now know that both ablation techniques result in the same rhythm outcome and have similar complication rates. (10) In the FIRE AND ICE international, multicentre, clinical trial 762 patients with paroxysmal AF were randomly assigned to undergo pulmonary vein isolation with RF-ablation or cryo energy. During 1.5 years of follow-up, no differences were found between the two groups in the incidence of post-ablation clinical failure (i.e. recurrence of AF, occurrence of atrial flutter or atrial tachycardia, use of anti-arrhythmic drugs, or repeat ablation): 34.6% in the cryo-balloon arm and 35.9% in the RF arm. The two techniques also proved similarly safe, with an aggregate incidence of death, cerebrovascular events, or serious treatment-related adverse events of 10.2% and 12.8%, respectively (P = ns). This relatively high incidence of side effects is in line with previous data of prospectively investigated populations. Quality-of-life assessment post-ablation did not differ between the two study arms. In a subsequent study, the same authors reported a lower incidence of repeat ablations, direct-current cardioversions, and all-cause rehospitalization during follow-up in the cryo-balloon study arm. (11) Similarly, a non-inferiority of cryo-balloon-assisted vs. RF-assisted ablation was also documented in the Freeze AF study which randomized 315 patients with paroxysmal AF. (12) The results of these two studies, which are characterized by a limited adoption in the RF arm of the most recently introduced technologies, will contribute to establish cryoballoon-assisted ablation as a valuable alternative to RF-assisted ablation of paroxysmal AF. However, it still needs to be evaluated whether substrate-based ablation strategies in patients with paroxysmal AF and low-voltage areas may add benefits with respect to rhythm outcome after RF-based ablation techniques. (13) In patients with persistent AF, the efficacy of catheter-based PVI using RF current was comparatively assessed with that of PVI plus linear ablation and that of PVI plus complex fractionated atrial electrogram (CFAE) ablation in the STAR AF II study. (14) In the 589 study patients randomly assigned to the three study arms according to a 1:4:4 randomization ratio, no differences were found in the proportion of patients who were free from recurrent AF after 18-month follow-up (59%, 49%, 46%). These results diverge with those reported in a recent meta-analysis (15) on limited series showing a 51% relative risk reduction in the incidence of recurrent AF in patients receiving linear ablation in addition to PVI when compared with patients receiving PVI only. The discrepancy of findings between these two studies highlights the value of performing randomized studies in order to validate findings from previous studies using less rigorous methodology. Establishing on a large scale the role of a simpler procedure as the first ablation step in patients with persistent AF may have relevant clinical implications with regard to patient safety. New studies are required to confirm the present findings, investigate new ablation designs and identify the best strategy in patients with persistent AF who failed the first one. The optimal antiarrhythmic management following ablation also still remains to be determined. In the Efficacy of Antiarrhythmic Drugs Short-Term Use After Catheter Ablation for Atrial Fibrillation trial, a total of 2038 patients were randomly assigned to antiarrhythmic drug therapy of control following radiofrequency catheter ablation for paroxysmal, persistent, or long-lasting AF. (16) The risk of recurrent atrial tachyarrhythmias was reduced in the antiarrhytmic drug therapy group during the treatment period of 3 months, however without an effect on clinical outcomes at later time points. Does catheter ablation of AF have any effect on stroke rate and/or mortality? In a recent nationwide Swedish Patient Register identifying 361 913 patients, Friberg et al. evaluated the possible influence of AF ablation on clinical outcome. (17) Using propensity score matching, two cohorts of equal size (2836 patients each) were extracted of which one had received AF ablation and one not. The two cohorts presented similar characteristics in 51 dimensions. After adjustment for known confounders AF ablation was found to be associated with a significantly lower incidence of all-cause mortality (HR = 0.50; 95% CI = 0.37–0.62) and ischemic stroke (HR = 0.69; 95% CI = 0.51–0.93). Reduction in the risk of ischemic stroke by means of AF ablation was most pronounced in sub-groups with CHA2DS2VASc score ≥ 2 (HR = 0.39; 95% CI = 0.19–0.78) and among patients without a new cardioversion beyond 6 months after ablation (HR = 0.68; 95% CI = 0.48–0.97). These results are encouraging and prompt for the implementation that adequately sized randomized studies may provide to this controversial topic in the next future. Until those trials have arrived and fully reported clinical practice should include continuing life-long anticoagulation after ablation in at risk patients according to the CHADS-VASc Score—a point of view which is strongly supported by the 2016 ESC AF management guidelines. (5) The new AF guidelines strengthen a personalized, precision driven approach to patients with atrial fibrillation. Importantly, the role of new AF risk factors and the importance of life style changes for reduction of AF burden and potentially for reduction of AF related risks is intensely described. Moreover, the benefits resulting from integrated AF care, AF heart teams and patient engagement for shared decision-making are presented and specific action is recommended to deliver the best care for AF patients. (5) ## Stroke prevention An interesting finding referred to as the ‘obesity paradox’ was recently reported in a sub-analysis from the ARISTOTLE trial. (18) Out of 17 913 patients enrolled in this study, 7159 were categorized as obese, 6702 overweight and 4052 normal. During 1.8 years follow-up, higher body masses were associated with a lower risk of all-cause mortality (overweight, HR = 0.67; 95% CI = 0.59–0.78; obese, HR = 0.63; 95% CI = 0.54–0.74). Such benefit extended to the risk of stroke in the female (P = 0.048), but not in the male gender. No measure of adiposity was associated with a different risk of bleeding. Among possible explanations for this finding are an earlier more rigorous use of co-medications and life-style modification (19) and better metabolic reserve, (20) which may ultimately affect intermediate-term prognosis in obese patients. Another interesting finding was observed in a recent sub-analysis from the Engage AF-TIMI 48 trial. (21) In this study, a higher degree of protection from all-cause mortality vs. vitamin K antagonist (VKA) therapy was found in the edoxaban 30 mg arm (HR = 0.87; 95% CI = 0.79–0.96, P = 0.006) than in the edoxaban 60 mg arm (HR = 0.92; 95% CI = 0.83–1.01, P = 0.08). This benefit occurred in spite of an evident increased risk of ischemic stroke (HR = 1.41; 95% CI = 1.19–1.67, *P* < 0.001) at the lower edoxaban dose, which was not found at the higher dose (HR = 1.00; 95% CI = 0.83–1.19, P = 0.97). The fewer total deaths observed with edoxaban were predominantly due to a significantly lower rate of fatal bleeding in the edoxaban groups and particularly in the low dose group. These findings raise our attention on the delicate balance between risk and benefit associated with administration or oral anticoagulants and shift the objective of their use from thromboembolic events to cardiovascular morbidity as a whole. In addition, further subgroup analyses were able to demonstrate a consistent net clinical efficacy and safety of edoxaban in other high risk subgroups such as the elderly (22) and patients at increased risk of falls, (23) hence establishing the drug as a valuable alternative in our armamentarium for stroke prevention in AF. A recent randomized controlled study (Ensure AF) (24) showed that oral edoxaban 60 mg once daily presented similar efficacy and safety outcomes as VKAs when administered during the peri-procedural phase on cardioversion of atrial fibrillation. In the 30 days following cardioversion using either an early or delayed strategy, 1095 patients assigned to edoxaban presented a 0.5% incidence of aggregate stroke, myocardial infarction, peripheral embolism or cardiovascular death vs. a 1.0% observed in 1104 patients assigned to VKA therapy (OR 0.46; 95% CI = 0.12–1.43). Similarly low incidences of peri-procedural major bleeding (0.3% and 0.5%) were observed in the two arms (OR 0.61; 95% CI = 0.09–3.13). These results are similar to those recently reported by Cappato et al. in the X-VeRT trial investigating oral rivaroxaban vs. VKA therapy in the same clinical setting. (25) Both trials were not numerous enough to test a non-inferiority hypothesis. However, the high reproducibility of primary efficacy and safety outcomes in the two studies make these NOACs a valuable alternative to VKAs in these patients. After the authorization for market release of three of the four novel oral anti-coagulants (NOACs) previously investigated in large phase III trials, a number of post-authorization studies have been published providing real-life evidence for efficacy and safety of these new drugs. In a previous registry investigating the real-life efficacy and safety of rivaroxaban, Camm et al. had shown that during about 1-year follow-up, the incidences of major bleeding (2.1 per 100 patient-years) and stroke events (0.7 per 100 patient-years) were low and superimposable to those observed in Rocket AF. (26, 27) Most recently, the results from three studies using claims database as data source were reported. (28-30) In the REVISIT-US registry, (28) a measure of net clinical benefit was inferred by the aggregate estimate of ischemic stroke and intracranial haemorrhage reported in the investigated populations. Real life treatment with rivaroxaban and apixaban was associated with a 39% (HR 0.61; 95% CI = 0.45–0.82) and a 37% (HR 0.63; 95% CI = 0.35–1.12) risk reduction in the aggregate incidence of ischemic stroke and intracranial haemorrhage as calculated in 22 822 patients and in 8166 patients, respectively. More recently, results showing a similar benefit of dabigatran vs. VKA were presented by the same authors. Another real world analysis performed a propensity-matched analysis comparing apixaban (15 390 patient), dabigatran (28 614 patients), and rivaroxaban (32 350 patients) each with warfarin in OptumLabs Data Warehouse (OLDW). (29) They found a similar risk for ischemic stroke for dabigatran vs. warfarin (HR 0.98, 95% CI 0.76–1.26, P = 0.98) and for rivaroxaban vs. warfarin (HR 0.93, 95% CI 0.72–1.19, P = 0.56), and a lower risk for apixaban vs. warfarin (HR 0.67, 95% CI 0.46–0.98, P = 0.04). The risk of major bleeding was similar for rivaroxaban vs. warfarin (HR 1.04, 95% CI 0.90–1.20], P = 0.60), and lower for dabigatran vs. warfarin (HR 0.79, 95% CI 0.67–0.94, P < 0.01) as well as apixaban vs. warfarin (HR 0.45, 95% CI 0.34–0.59, P < 0.001). Finally, a very recent FDA analysis in 52 240 dabigatran- and 66 651 rivaroxaban-treated elderly (≥ 65 years). Medicare patients revealed a trend for lower risk of thromboembolic stroke with rivaroxaban compared with dabigatran (HR, 0.81; 95% CI, 0.65–1.01; P = 0.07). (30) At the same time, however, intracranial haemorrhage (HR, 1.65; 95% CI, 1.20–2.26; P = 0.002) as well as major extracranial bleeding (HR, 1.48; 95% CI, 1.32–1.67; P < 0.001) were increased with rivaroxaban compared with dabigatran, with a trend towards an increased all-cause mortality (HR, 1.15; 95% CI, 1.00–1.32; P = 0.051). While comparisons between large phase III study and post-authorization outcome measures are recommended, statistics on ‘head-to-head’ comparison among NOACs should clearly be discouraged. The available evidence, in fact, demonstrates that any ‘real world’ analysis equally comes with a number of possible limitations, including residual confounding, short follow-up, selected patient populations, inconsistency of outcome measures (i.e. major bleeding definition), lack of external adjudication, and incomplete follow-up, hence limiting the generalizability of such comparative data. The primary—and likely the only—conclusion that can be drawn from data from post-authorization studies is that their findings are consistent with the safety and efficacy of NOACs observed in the large-scale randomized clinical trials after their adoption in daily practice by large segments of the medical community across the world. As such, the current 2016 guidelines for the management of atrial fibrillation recommend the use of NOACs as first line therapy in patients who newly start anticoagulation treatment for AF, with a Class I recommendation, level of evidence A. (5) In contrast, the use of aspirin newly received a class III recommendation (possible harm) given its limited efficacy and frequently underestimated bleeding risk. ## Ventricular arrhythmias and sudden cardiac death Catheter ablation of ventricular tachycardia (VT) is an important technique to manage patients with recurrent VT (**Figure 3**). (31) However, randomized clinical trials evaluating the potential benefits of catheter ablation as compared with antiarrhythmic drug therapy are scarce. The recently published VANISH trial randomized patients with drug refractory ventricular tachycardia in the setting of ischemic cardiomyopathy and defibrillator protection to VT catheter ablation with continuation of baseline antiarrhythmic medications vs. escalated antiarrhythmic drug therapy. (32) In the latter group, amiodarone was initiated if another drug had been used previously. The dose of amiodarone was increased up to 300 mg/day and mexiletine was added thereafter, if clinically required. During 27-month follow-up, significantly more deaths, VT storm events or appropriate ICD shocks were reported in the 127 patients assigned to the escalated therapy arm than in the 132 patients assigned to the ablation arm (69% vs. 59%; HR = 0.72; 95% CI = 0.53–0.98). However, although such beneficial effects on VT recurrence could be observed in the ablation group there was no difference in overall survival indicating that additional factors such as progression of structural heart disease and progressive heart failure may also play an important role for the prognosis of these patients. Figure 3. Endo- and epicardial VT ablation. Three-dimensional mapping of the left ventricular endocardial surface (*A*) as well as the epicardium (*B–D*), with superimposed coronary angiograms to detect the epicardially located coronary arteries. While only a small area of low-voltage is detectable on the endocardium (*A*, red area), the epicardial surface shows extensive fibrosis (*D*). Pink points denote sites of ablation. This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. Recurrent ventricular tachycardia in patients with repaired tetralogy of Fallot is a significant risk factor for sudden cardiac death. Treatment with catheter ablation is difficult due to the complex anatomy after surgical repair. However, as recently shown detailed electroanatomical reconstruction and mapping of the conduction properties in the operated areas effectively identifies critical conduction isthmus that promotes VT. (33) In one of the largest patient series of Fallot patients with VT reported so far it could be shown that discrete ablation of the isthmus results in VT termination and rendered VT non-inducible in the majority of patients. In patients with effective ablation VT recurrence was very low proving the benefits of this approach. In a recent study, Kudenchuck et al. compared parenteral amiodarone, lidocaine, and saline placebo, along with standard of care, in adults with out-of-hospital cardiac arrest, shock refractory ventricular fibrillation (VF) or pulseless VT after at least one shock. (34) Of 3026 enrolled patients, 974 were assigned to amiodarone, 993 to lidocaine and 1059 to placebo. No differences in survival to hospital discharge (24%, 24% and 21%, respectively) or neurologic outcome were found among the three groups. Interestingly, active drug administration was associated with a higher survival rate among patients with by-stander witnessed cardiac arrest (P = 0.05), but not among those with unwitnessed cardiac arrest. These findings offer a serious argument against the administration of intravenous antiarrhythmic drugs in unwitnessed out-of-hospital cardiac arrest victims, but leave the door open for their possible use in by-stander witnessed victims. ## Cardiac electronic devices ## Implantable defibrillator therapy Who benefits from an ICD and who does not? The final jury is not out on this ever moving target. In a randomized study of 1116 patients with symptomatic systolic heart failure not caused by coronary artery disease (the DANISH trial), Kober et al recently showed that implantable cardioverter defibrillator (ICD) therapy in addition to usual care did not confer a significant protection from all-cause mortality as compared with usual care only during long-term follow-up (68 months). (35) In this study, the 50% (highly significant) relative reduction of sudden death risk in patients assigned to an ICD was offset by a larger proportion of patients in this same group presenting with deaths caused by other cardiovascular causes and, above all, by non-cardiovascular death. All time-to-event curves tended to diverge in favour of the ICD population during the first 5 years of follow-up and then to converge. These results contribute significantly to the ongoing debate on the usefulness of ICD therapy for the primary prophylaxis of patients with non-ischemic cardiomyopathy. (36, 37) The relatively old age at entry (64 years) and the long duration from time to diagnosis of heart failure to enrolment (19 years) make the investigated population of this study a highly selected one and one with a relatively low life-expectancy (ejection fraction at entry, 0.25). Indeed, a subgroup analysis focusing on patient age revealed a significant statistical interaction, with younger patients (< 59 years old) deriving a benefit from ICD in terms of all-cause mortality which was not evident in the elderly patients. In addition, the variety of reported cardiomyopathies makes the investigated population rather heterogeneous. Further studies are needed to evaluate the protective efficacy of ICD therapy in patients in whom a non-ischemic dilated cardiomyopathy is diagnosed at a younger age and whose eligibility for primary prophylaxis is raised at a relatively short time interval from diagnosis of heart failure. Previous studies investigating such a population were not numerous enough to test a superiority hypothesis by the ICD system vs. pharmacological therapy only. (38) In summary, the results of the DANISH trial are important, but in the end reinforce clinical practice which should ideally already be in place—i.e. to take into consideration competing risk and modes of death, particularly non-cardiovascular as well as pump failure, when deciding to opt for ICD implantation, especially in patients with non-ischemic heart disease. These results are in line with a recent large prospective, multicentre registry of patients with cardiac resynchronization therapy (CRT). In a total of 1705 consecutive patients implanted with either a CRT-P (535 patients) or CRT-D (1170 patients), the adjusted morality hazard 1.54 in CRT-P vs. CRT-D (CI 1.07–2.21, P = 0.0209). (39) However, 95% of the excess mortality in CRT-P recipients was due to an increase in non-sudden cardiac death, hence re-iterating the importance of an individualized ‘competing risk’ analysis prior to the right device for each patient. In a recent report, Vehmemeijer et al. performed a comprehensive review and meta-analysis on the indications, efficacy and safety of ICD therapy in adults with congenital heart disease. (40) Overall, 2162 patients (66% males) with a mean age of 37 years at implant were included from 24 studies. The devices were implanted for primary prevention in 53% of patients (95% CI = 43.5–62.7%), with non-sustained VT representing the most frequent indication, followed by impaired LV function, inducible VT, syncope, and palpitations or presyncope. The most frequent substrate was tetralogy of Fallot, followed by transposition of great arteries, congenitally corrected transposition of great arteries, ventricular or atrial septal defects and others. During 3.6-year follow-up, 24% of patients received an appropriate and 22% an inappropriate ICD intervention, inclusive of shock and/or anti-tachycardia pacing. All-cause mortality occurred in 10% of patients. These data offer the rationale for a thoughtful decision process concerning the relatively high rate of complications and inappropriate ICD therapy in these patients. ## Subcutaneous implantable cardioverter defibrillators In a recent study, Friedman et al. evaluated the trends and in-hospital outcomes associated with early adoption of the S-ICD in USA. (41) Out of 393 734 ICD implants reported to the National Cardiovascular Data Registry ICD Registry between September 2012 (US Food and Drug Administration S-ICD approval date) and March 2015, the investigators performed a 1:1:1 propensity-matched analysis of 5760 patients to compare in-hospital outcomes among patients with S-ICD with those of patients with single chamber (SC)-ICD and dual chamber (DC)-ICD. The proportion of patients receiving an S-ICD among all ICD patients during the investigated period was 0.9%. Compared with SC-ICD and DC-ICD, patients receiving an S-ICD were younger, more prevalently female, black, undergoing dialysis and survivors of cardiac arrest. Interestingly, many patients presented with a high number of co-morbidities. DFT testing resulted in a successful defibrillation in 99.7% of 2629 patients undergoing induction of ventricular arrhythmias at time of implant. In-hospital complication rates associated with an S-ICD were low (1.1%), similar to those associated with a SC-ICD (1.0%), and lower than those associated with a DC-ICD (1.2, P < 0.001). These figures provide an initial perspective of the impact of S-ICD in daily practice and offer an encouraging view on their safety at implant. Another, preliminary report on the use of a subcutaneous ICD in a limited population of young patients (mean age, 34 years) with congenital heart disease recently showed a 100% success rate of device implant, and a 100% conversion rate with ≤ 80J of induced arrhythmias. (42) Randomized trials are required to confirm these results and evaluate the clinical impact of S-ICD during long-term follow-up. (43) The still young technology of the S-ICD is at the same time evolving rapidly. A novel high pass filter (SmartPass, available for Gen 2 and Gen 2.5 of the EMBLEM S-ICD) was introduced this year designed to reduce the risk of T-wave oversensing in S-ICD patients (Theuns et al., presented at HRS 2016). Modelling of inappropriate shock episodes recorded in the large EFFORTLESS registry demonstrated a reduction in inappropriate shocks by 81% compared with the first generation S-ICD. One of the (perceived) major limitations of current S-ICD systems is the lack of pacing capability, hence limiting its use in patients with known monomorphic VT or an indication for bradycardia pacing. This year it was demonstrated for the first time in an animal model that communication of an S-ICD with a leadless cardiac pacemaker is possible, resulting in adequate termination of a monomorphic VT as well as in normal VVI functionality of the leadless pacer. (44) These data are highly encouraging on the way to a further improvement of the current S-ICD system. ## Leadless pacemaker Leadless pacing has taken centre stage in the field of bradycardia pacing for the last years, and important new data surfaced during the year 2016. The primary results of the Micra experience in 725 patients, published in print early in the year, (45) demonstrated favourable electrical values (threshold, sensing, impedance) in 292 of 297 patients with paired 6-month data. About 28 major complications occurred in 25 of 725 patients (4.0%), including 11 (1.9%) cardiac perforation or effusion and 1 death (0.1%). These positive results were reinforced by additional follow-up which were presented at Cardiostim, with an average follow-up duration of 7.7 ± 3.9 months. There was no signal apparent with very few additional clinical events; most importantly, no macro dislodgement and no embolization occurred. With now over 2000 Micra pacemakers implanted, the latter is also mirrored in the ‘real world’ outside the clinical trial, hence reinforcing particularly the safety of the device. ## Wearable cardioverter defibrillators Several studies have documented the efficacy and safety of wearable cardioverter defibrillators. (46-48) In a large German registry, 94 patients (1.6%) were treated by the WCD due to ventricular tachyarrhythmias, an incidence of 8.4 (95% confidence interval, 6.8–10.2) per 100 patient-years (German life vest Circulation 2016). About 112 of the 120 (93%) shocked patients survived 24 h after treatment, whereas asystole was observed in two patients (0.03%) with one resulting death. Taking together the available data, a recent science advisory from the American Heart Association, (49) suggested a list of conditions for which this therapy may be recommended, which is in great parts similar to the ESC guidelines for the prevention of sudden cardiac death. (50) Among them are the following circumstances: (**i**) as a bridging therapy in situations associated with risk of death in which ICDs have been shown to reduce sudden cardiac death but not overall mortality such as within 40 days of myocardial infarction; (**ii**) when there is a clear indication for an implantable device accompanied by a transient contraindication or need for interruption in ICD care such as infection; (**iii**) when there is concern about a heightened risk of sudden cardiac death that may resolve over time or with treatment of left ventricular dysfunction, e.g. in ischemic heart disease with recent revascularization, newly diagnosed non-ischemic dilated cardiomyopathy in a patient starting guideline-directed medical therapy, or secondary cardiomyopathy (tachycardia mediated and thyroid mediated) in which the underlying cause is potentially reversible; (**iv**) as a bridge to more definitive therapy such as cardiac transplantation. In light of the non-definitive nature of the studies conducted in this field, the authors recognize that their document provides a tentative framework to assist in decision-making of an increasingly used therapy for the protection from sudden cardiac death during a transient clinical phase, but further studies are required to support these recommendations.

Ottavio Alfieri, Alec Vahanian

## Preamble A large number of studies addressing various aspects of the diagnosis and treatment of valvular heart disease (VHD) have been published since the ESC Annual congress in 2015. As expected in this era of rapidly evolving therapeutic modalities and technologies, many scientific contributions are related to the expanded role of percutaneous interventions. New data are now available, consolidating the validity of the transcatheter approach in a variety of subsets of patients and therefore offering new strategies and perspectives in management. The most relevant articles have been selected for this review. ## Epidemiology It is well known that ageing of the population is associated with a higher prevalence of VHD. A large-scale echocardiographic screening involving 2500 individuals aged > 65 years was conducted to detect undiagnosed VHD (**Figure 1**). (1) Clinically significant (moderate or severe) undiagnosed VHD was identified in 6.4%. In addition, 4.9% of the cohort had pre-existing VHD (a total prevalence of 11.3%). Projecting these findings using population data, the prevalence of clinically significant VHD is estimated to double before 2050. The unique data of this study confirm the scale of the emerging epidemic of VHD, with widespread implications for clinicians and healthcare resources. In this scenario of predominantly elderly people affected by significant VHD, percutaneous modalities of treatment are expected to play a major role. Figure 1. UK population projections of diagnosed and undiagnosed significant valvular heart disease. The OxValve Population Cohort Study. Diagnosed estimates are based on the number excluded from participation in the present study due to a prior diagnosis of valvular heart disease. Undiagnosed estimates are based on the number with newly diagnosed significant valvular heart disease in OxVALVE-PCS. Reproduced with permission from D’Arcy JL *et al*. (1) This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. ## Aortic stenosis The mechanisms responsible for aortic valve calcification and development of aortic stenosis (AS) have been explored, and an association between valvular iron resulting from intraleaflet haemorrhage and the degree of aortic valve calcification has been demonstrated. (2) Iron uptake by valvular interstitial cells produces proliferation and extracellular matrix remodelling leading to calcification and progressive narrowing of the valve. These findings emphasize the pathophysiological role of valvular haemorrhages and suggest iron transporters as a novel potential therapeutic target to slow the haemodynamic progression of AS. Some subsets of patients with AS deserve special consideration and may require different patterns of treatment. An analysis of the Duke Echocardiographic Database revealed that in patients with moderate/severe AS and left ventricular dysfunction mortality was definitely substantial and aortic valve surgery was associated with a significant survival benefit even in the presence of only moderate AS (mean gradient >25 and 1.5 mg/dL, peripheral artery disease, left ventricular ejection fraction <30%, severe tricuspid regurgitation and procedural failure. Quality of life improved remarkably after MitraClip implantation. Importantly, a significant proportion of patients regained complete independence in self-care. The efficacy of percutaneous edge to edge repair, as well as its impact on the natural history, is strongly dependent on the acute reduction of MR. Residual 2+ MR immediately after MitraClip implantation is associated with more unfavourable outcomes (survival, symptom relief, and recurrence of MR) during follow-up compared with residual 1+ or less MR. (21) The absence of mitral valve annuloplasty is a concern regarding the durability of MitraClip treatment. Furthermore, some patients are not eligible for MitraClip therapy due to excessive annular dilatation. In well-selected patients, annuloplasty alone can completely eliminate or at least remarkably reduce MR. Therefore, the introduction of a reliable annuloplasty device into the percutaneous armamentarium of mitral valve repair definitely offers new perspectives in the field of transcatheter mitral interventions. Early results obtained with the Cardioband system, a direct, adjustable annuloplasty device, in 31 high-risk patients with moderate-to-severe or severe secondary MR have been reported. (22) Following Cardioband adjustment (29 of 31 patients), MR was none or trace in six patients (21%), mild in 21 (72%), and moderate in 2 (7%). Procedural mortality was zero and in-hospital death (neither procedure nor device-related) occurred in two patients. Another method of direct percutaneous annuloplasty, performed with the Mitralign system, has been investigated in 71 high-risk patients with moderate to severe secondary MR. (23) The procedure appeared to be feasible and safe. In addition, left ventricular reverse remodelling and significant clinical improvement have been documented during a 6-month follow-up. Transcatheter mitral valve replacement in native mitral valve disease represents a rapidly moving field of great interest for the cardiological community. Encouraging early clinical experiences with different devices are presently ongoing worldwide, and results in consistent clinical series are expected to be published in the near future. The importance of multimodality imaging will also be a key factor for the selection of patients and planning of the procedure. (24) ## Mitral stenosis Pre-operative pulmonary hypertension has been shown to affect the long-term outcome in a large series of patients operated on for mitral stenosis (MS). (25) Ten-year survival after mitral valve surgery was significantly lower in the moderate-severe pulmonary hypertension group, compared with the normal pulmonary artery pressure-mild pulmonary hypertension group (58% vs 83%; *P* = 0.001). According to this finding, patients with MS and mild pulmonary hypertension should be considered for mitral valve surgery. A multicentre retrospective review of clinical outcomes of 64 patients with MS and severe mitral annular calcification submitted to transcatheter mitral valve replacement using balloon-expandable TAVI valves was performed. (26) Access was transatrial in 15.6%, transapical in 43.8% and transseptal in 40.6%. In this preliminary experience, the procedure was associated with significant adverse events, and 30-day all-cause mortality was 29.7%. Obviously, only very symptomatic patients with limited therapeutic options should be considered for this modality of treatment at this stage. ## Tricuspid regurgitation Following the recommendations of the European and American Guidelines for the management of VHD, tricuspid regurgitation (TR) should be addressed early in the disease process to prevent the development of right-sided heart failure. A recent study showed that in patients with moderate TR or tricuspid annular dilatation undergoing mitral valve repair, concomitant tricuspid annuloplasty was safe, effective and associated with improved long-term right-sided remodelling. (27) Tricuspid annuloplasty can either be carried out with suturing techniques or with the implantation of prosthetic rings. Controversy remains regarding the effectiveness of one method compared with the other. No difference in patient survival, late functional status, progression of TR or tricuspid valve reoperations has been found in a recent retrospective study comparing patients treated with suture annuloplasty and those submitted to ring annuloplasty. (28) Both techniques have been shown to yield good results. Suture annuloplasty can be performed easily and rapidly with a lower cost compared with ring annuloplasty which requires a commercially available prosthetic device. When isolated severe TR occurs in a context of right heart failure or develops late following left-sided valve surgery, the surgical risk is generally high. In these settings percutaneous therapeutic options to correct or at least reduce TR are badly needed. Although the clinical experiences with new procedures and devices are quite preliminary, some important attempts and contributions in this field have to be recognized. The TriCinch device allows transfemoral fixation of a corkscrew in the annulus of the tricuspid valve in proximity to the antero-posterior commissure. Following deployment of a self-expandable nitinol stent in the inferior vena cava, appropriate traction is exerted and the antero-posterior diameter of the valve is reduced with improvement of leaflet coaptation. (29) Tricuspid regurgitation can also be treated with edge-to-edge repair using the MitraClip system. (30) Another device used to reduce TR is the FORMA System, which is a valve spacer/occluder positioned within the tricuspid orifice, creating a platform for native leaflet coaptation to reduce the regurgitant jet. (31) Feasibility and safety of these procedures have been demonstrated, but the experience is limited and more data are necessary to assess their efficacy. In total there was a lot of new evidence in the domain of VHD during the past year and it is expected that it will be incorporated into the upcoming ESC/EACTS on VHD to be published next year. Conflict of interest: Prof. Alfieri has no conflicts of interest to declare. Prof. Vahanian declares the following conflict of interest — Consultancy for Edwards Lifesciences, Abbott Vascular and Valtech Cardio.