Cardiologia Croatica. 2018;13(3-4)

Lars H. Lund, Lars Køber, Karl Swedberg, Frank Ruschitzka

## Preamble The 2016 European Society of Cardiology (ESC) heart failure (HF) guidelines brought to the fore new recommendations for the management of HF with reduced ejection fraction (HFrEF; EF 2, 6MWT, KCCQ score, or NT-proBNP levels. (70) ## Acute heart failure On the basis of the ACS concept of ‘time is muscle’, (1) the initial presentation of acutely decompensated HF may represent a period of substantial myocardial vulnerability. (71) As such, the early intervention with an intravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and myocardial injury, and ultimately long-term prognosis in patients with AHF. (71) In the TRUE-AHF trial, a randomized, double-blind, parallel-group, placebo-controlled, event-driven trial, however, ularitide given at a median of 6 h after evaluation did not reduce the composite endpoint of 48 h clinical course and 15 month CV mortality. (72) Similarly, early administration of serelaxin did not improve the composite endpoint of worsening HF at 5 days or CV death at 6 months in RELAX-AHF2. (73) Interestingly, an observational study suggested that treatment with intravenous loop diuretic within 1-h of presentation to the emergency department was associated with lower in-hospital mortality, (74) but the observational nature of this study precludes any conclusions regarding optimal type or timing of AHF interventions. In BLAST-AHF, a biased ligand of the angiotensin II type 1 receptor did not reduce dyspnoea, worsening HF or hospital length of stay. (75) Another concept is early aldosterone inhibition, but in ATHENA-HF, 100 mg of spironolactone compared to placebo did not improve natriuretic peptides or clinical measures. (76) Thus by end of 2017, numerous interventional strategies in AHF have failed, including continuous diuretics infusion, ultrafiltration, vasodilators and inotropes. ## Advanced heart failure In patients with severe refractory symptoms despite optimal medical management, quality of life and prognosis are dismal. The remaining options include heart transplantation (HTx), durable mechanical circulatory support (MCS), and palliation. After 30 years of remarkable success of HFrEF drug trials, (1, 2) it is notable that In 2017 we celebrate 50 years since the first HTx performed in 1967, and indeed the establishment of HTx as an option paved way for the worldwide HF referral centres and research programs that brought us the subsequent advances in HF pharmacotherapy. Similarly, implantable left ventricular assist devices (LVADs) were introduced already in the 1960s. In recent years, outcomes with HTx (77) and with LVAD both as bridge to transplantation and as destination therapy (78) have improved worldwide. However, HTx is associated with complications and studies are suggesting immunosuppression should be more individualized. (79) The number of HTx procedures performed are stagnant (77) and LVAD use is increasing only modestly. (78) Despite remarkable effect on mortality, LVADs are still limited by complications. Modern small centrifugal continuous flow LVADs appear to reduce the risk of thrombosis in the device, (80) but concerns over stroke and bleeding, right ventricular failure, and infection through the external driveline remain. In the PAL-HF trial, interdisciplinary palliative care compared with usual care showed benefits in quality of life, anxiety, depression, and spiritual well-being (**Figure 3**). (81) It is increasingly recognized that the scarcity of donor organs and the still high cost and complications with durable MCS demand especially careful selection, considering both indications and benefits as well as contraindications and risks. Figure 3. In PAL-HF trial, palliative vas significantly superior to usual care in improving quality of life. ## Novel interventional strategies As much as we need to focus on optimal utilization of existing therapy, HF remains a chronic, incurable, generally irreversible, and still debilitating syndrome, and novel inventive approaches have continued appeal. A new myosin activator which improves impaired contractility, omecamtiv mecarbil, was studied in the phase II study COSMIC-HF. (82) Titration guided by pharmacokinetics resulted in improved cardiac function and decreased NT-proBNP. (82) A Phase III trial is ongoing. Stem cell therapy has generally proven disappointing, but in the exploratory REGENERATE-IHD and CHART-1, intramyocardial injection of autologous bone-marrow derived cells in ischaemic cardiomyopathy appeared safe and improved EF, New York Heart Association (NYHA) class and NT-proBNP, and left ventricular (LV) end-systolic and diastolic volumes. (83–85) Novel radiocarbon (14C) techniques allow assessment of cardiomyocyte turnover dynamics and may provide a future foundation for regenerative strategies. (86) The ESC Task Force for stem cells in myocardial infarction and HF (87) and a global position statement on cardiovascular regenerative medicine (88) outline challenges for the stem cell field, and standardization of animal models, clinical trials and regulatory procedures are put forth as necessary for future success. Gene ‘editing’ targeting Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is a promising technique with broad applications that has been used e.g. to edit hypertrophic cardiomyopathy causing genes in human embryos. (89) ## Conclusions This has been another year with many new trials reporting in HF. However, none of them will change clinical practise at present. A major challenge for the practising physician is to make sure that eligible patients with HFrEF receive guideline recommended care, and a major challenge for the HF community is to develop effective interventions in HFpEF and AHF. ## Acknowledgments The mention of trade names, commercial products organizations, and the inclusion of advertisements in the journal does not imply endorsement by the European Heart Journal, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. The editors and publishers have taken all reasonable precautions to verify drug names and doses, the results of experimental work and clinical findings published in the journal. The ultimate responsibility for the use and dosage of drugs mentioned in the journal and in interpretation of published material lies with the medical practitioner, and the editors and publisher cannot accept liability for damages arising from any error or omissions in the journal. Please inform the editors of any errors. The opinions expressed in the European Heart Journal are those of the authors and contributors, and do not necessarily reflect those of the European Society of Cardiology, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. OUP and the ESC are not responsible or in any way liable for the accuracy of the translation, for any errors, omissions or inaccuracies, or for any consequences arising therefore. Nina Jakuš and Ivo Darko Gabrić solely responsible for the translation published in this reprint. Translation edited by: Mario Ivanuša. Language editing: Tomislav Salopek.

Cecilia Linde, Jan Steffel

## Preamble This traditional overview looks back at the year 2017, summarizing a selection of important and clinically relevant new developments in the fields of cardiac arrhythmias. From new data for the ablation of atrial fibrillation and ventricular tachycardias, over the most recent developments in anticoagulation, to the most recent advances in risk stratification and prevention of sudden cardiac death, we summarize the key findings of relevant studies and put them into perspective for the practicing cardiologist. ## Introduction Once more, numerous relevant contributions on cardiac arrhythmias and devices were presented and published in the year 2017. For the present manuscript the authors identified a selected group of articles with potential impact in daily practice for the readers. ## Cardiac arrhythmias and catheter ablation ## A great loss In early January of 2017, one of the electrophysiology’s greatest pioneers, Mark E. Josephson, passed away at the age of 72. (1) Dr Josephson (**Figure 1**) had a marked influence on both electrophysiology itself, pioneering in various diagnostic and therapeutic interventions, as well as on countless physicians worldwide through his superb educational activities and personal mentorship. One of his last articles, published in print in April 2017, brings him back to the roots of electrophysiology: The first randomized comparison of drug treatment vs. ablation for atrioventricular nodal re-entrant tachycardia (AVNRT). Not surprisingly, AVNRT ablation (one of the most frequently performed ablations worldwide) turned out to be by far superior to antiarrhythmic drug therapy. (2) Another important article in the list of innumerable landmark papers through which Mark left a lasting impression in the field of Cardiology. He will be missed. Figure 1. Mark E. Josephson (1943–2017). (1) THIS figure has been reprinted with permission of Oxford University Press on behalf of European Society of Cardiology. Indeed, also in daily clinical practice, SVT ablation seems safe and effective, as shown in a prospective German Ablation Quality Registry. (3) Success rate of AVNRT ablation was 98.9%; no doubt it needs to be considered standard therapy for this arrhythmia. ## Diagnosis and implications of atrial fibrillation—more than meets the eye What do we call atrial fibrillation (AF)? How long does an atrial arrhythmia at a high rate need to be present, detected by which type of device, until we refer to it as AF? It is astonishing how badly evidence is lacking to answer this arguably simple question. Modern implantable cardiac devices such as pacemakers, implantable cardioverter defibrillators (ICD), and cardiac resynchronization therapy devices (CRTs) are capable of detecting and storing any type of atrial high rate episodes from few seconds to days and weeks. But from which time point on do we refer to it as AF and, more importantly, when does stroke risk increase in these patients? Data from the ASSERT trial published this year shed some new light on this topic, indicating that episodes longer, but not shorter than 24 h were associated with an increased risk of stroke (**Figure 2**). (4) The REVEAL-AF trial (presented at HRS 2017) investigated the prevalence of AF in 385 patients screened with an insertable loop recorder for a median of 22.5 months. The rate of AF detection was 6.2% at 30 days, increasing to 33.6% by 24 months, similar to the figures observed in the CRYSTAL-AF trial of patients post-cryptogenic stroke. (5) Conversely, however, if both patients with and without previous stroke show a similar rate of such short episodes, these findings again raise the question of the importance of short duration ‘AF’ as a predictor of stroke and, consequently, the need for anticoagulation. What to do hence with patients of shorter duration ‘AF’? Currently, the best answer in a device patient would be to enrol them in any of the ongoing studies investigating exactly this question—the ARTESiA or the NOAH trial. (6, 7) These studies focus on device-detected subclinical atrial fibrillation (SCAF) of short duration and studies if a non-vitamin K antagonists oral anticoagulant (NOAC) (apixaban in ARTESiA, edoxaban in NOAH) will be superior in reducing stroke and thrombo-embolic risk compared to control therapy. Until the results of these studies are available, initiation of anticoagulation remains without strong evidence base in such patients. Figure 2. How much atrial fibrillation does it need? Data from ASSERT indicating the risk of stroke to be elevated in patients with device-detected atrial fibrillation >24 h, but not below. (4) SCAF, subclinical atrial fibrillation. THIS figure has been reprinted with permission of Oxford University Press on behalf of European Society of Cardiology. In addition to the duration of AF, the overall risk of the patients as indicated by the CHA2DS2VASc-Score (8) as well as certain biomarkers (9, 10) will likely play a role in identifying patients at increased risk of events and, ultimately, eligibility for anticoagulation. Also here, prospective randomized studies are required to answer this question at the required highest level of evidence. ## How to stay in sinus rhythm—is upstream therapy the clue? Life style modification is about to become a cornerstone in atrial fibrillation therapy. The open studies from Australia—LEGACY (11) and CARDIO FIT (12)—showed that rigorous exercise and weight loss programs on top of risk factor management reduced re-occurrence of atrial fibrillation in overweight [body mass index (BMI) > 27 kg/m2] patients with paroxysmal or persistent atrial fibrillation patients whether on antiarrhythmic drugs or post-AF ablation. The RACE 3 investigators (van Gelder et al. presented at ESC 2017) took this concept further and focused on patients with symptomatic early persistent atrial fibrillation and early heart failure diagnosed 50 mm in diameter, NYHA IV and LVEF 2-DS2-VASc score ≥ 2 randomized to either continuing NOAC therapy (last intake the evening before the procedure) or interruption for at least 2 days, bleeding as well as other endpoints (including mortality and stroke) was rare and occurred to the same extent in both groups. While other studies are underway assessing a similar question in other surgical settings (e.g. the PAUSE trial; NCT02228798), these data for the first time indicate that continuing NOACs (or at least limiting the time of interruption) may be a safe way to proceed for some interventions. ## Stroke prevention in atrial fibrillation The 2016 ESC guidelines clearly put anticoagulation with NOACs as the preferred therapy for stroke prevention in AF. (8) Could improvements in warfarin therapy such as genotype-guided dosing tip this balance? (25, 26) So far, the evidence is conflicting. In contrast, however, evidence is accumulating that even patients with well controlled INRs are not at zero risk of events. On the contrary, a recent sub-analysis from ARISTOTLE indicated that the vast majority of intracranial haemorrhages (78.5%) occurred at a therapeutic INR (70 000 patients. There are, however, certain differences between the four NOACs that we are only in the process of understanding. Meticulous analyses of existing RCTs as well as new studies shed new light on these differences and improve individualization of NOAC therapy. One remaining problem is that of inappropriate use of the ‘reduced’ dose of NOACs. Data from insurance claims analyses indicate a rate of up to 40% and more of ‘reduced dose’ use, particularly of apixaban, which does not compare to the 4.7% of patients receiving 2 × 2.5 mg of apixaban in the ARISTOTLE trial. (28) Importantly, the effect of using the reduced dose of apixaban or rivaroxaban in patients without the respective dose-reduction criteria leads to completely unpredictable results as this has never been properly studies in a randomized controlled fashion and can hence not be recommended. In contrast, a ‘lower dose’ regimen was studied specifically in the Re-LY as well as in the ENGAGE AF-TIMI 48 trial with dabigatran and edoxaban, respectively. (29, 30) Assessment of the proportion of patients taking the lower dose and/or reduced dose of NOACs in daily clinical practice is one strength of insurance claims database research; indeed, the results serve to remind us to keep up and increase our educational efforts to alert physicians and patients that reproduction of the positive RCT results will only be possibly by using the investigated dosing regimens. In contrast, the assessment of clinical outcomes in the so-called ‘Real World’ research, particularly with insurance claims databases, needs to be viewed with great caution. Independent of statistical methods for adjustment, residual confounding is substantial, severely limits any interpretation of outcomes, and essentially makes assessment of any causal effect impossible, particularly in questions that have never been assessed in an RCT. (31) The same is true for the use of other modalities for stroke prevention in AF, particularly percutaneous as well as surgical left atrial appendage occlusion. Several registry data surfaced in 2017, including the 1-year outcomes of the EWOLUTION registry which demonstrated a low-stroke rate in over 1000 patients undergoing implantation with the Watchman device (Boersma et al., presented at Europace 2017). However, at the same meeting, data from a French registry indicated a high prevalence (6.1%) of device occluder thrombi in 377 consecutive patients implanted with various LAA occluder systems (Fauchier et al., presented at Europace 2017). At the end of the day, the place of the LAA occluder still remains to be determined, even >8 years since publication of the PROTECT-AF study. In view of the available evidence, the current 2016 guidelines appropriately assign a Class IIb recommendation to LAA occlusion for stroke prevention in AF. (8) Further registries are unlikely to change this level of recommendation—this will only be possible with new results from well-designed RCTs. Some trials (CLOSURE-AF, ASAP-TOO) in high-risk patients are now underway; others, particularly comparing LAA occlusion to the current (!) standard of therapy, i.e. NOACs, are urgently required. Similarly, a strategy of combining LAA occlusion with low-level NOAC anticoagulation has never been properly explored but has the potential to strike the golden bridge between the seemingly ‘opposing’, but in fact complementary concepts of anticoagulation and LAA occlusion. Unfortunately, so far, interest and motivation from the industry to sponsor such a trial has been limited. ## Ventricular tachycardia ablation Ablation of ventricular tachycardias (VT) has so far been primarily a domain of idiopathic VTs (particularly outflow tract, fascicular VT) and tachycardias with known structural abnormalities (ischaemic VT, post-myocarditis etc.). In 2017, Pappone et al. (32) reported of the largest series of patients with Brugada syndrome who successfully underwent ablation of an epicardial arrythmogenic substrate in the RVOT—hence in a channelopathy population previously not deemed amenable for ablation. During a median follow-up of 10 months after ablation, elimination of the Brugada ECG phenotype was achieved in 133 of 135 patients undergoing ablation. Will ablation hence become standard therapy for Brugada patients? Will all patients with Brugada syndrome, possibly even ‘only’ with Brugada pattern benefit? What is the natural course of the disease after successful ablation? Many questions remain open, but these results certainly open the door to yet another frontier for ablation therapy in previously believed to be unsuitable patients. Indeed, the RVOT harbours not only ‘idiopathic’ VT, but has been recognized in other entities including Brugada (as mentioned above) as well as early manifestation of ARVC as well as certain forms of exercise-induced arrhythmogenic remodelling. (33) In 57 consecutive patients with scar-related right ventricular VT, the group of Dr Zeppenfeld identified an isolated subepicardial right ventricular outflow tract scar in high-level endurance athletes which was successfully treated by ablation. Furthermore, the scar pattern observed in this exercise-induced arrhythmogenic remodelling demonstrated significant differences compared to that in ARVC and post-inflammatory cardiomyopathy. (33) As with the ablation approach suggested for Brugada, the approach appears attractive, but confirmation in larger series as well as long-term outcomes are eagerly awaited. Indeed, even in ‘typical’ VT ablation patients—those with a ‘structural’ VT—success is far from 100%. In a large cohort, Tzou et al. (34) compared patients undergoing a repeat procedure to those with a first VT ablation. Not surprisingly, the former individuals more frequently presented with non-ischaemic VT, ICD shocks, and amiodarone treatment. Even though the procedural success was similar between the two groups (93% vs. 92%), complications trended to be higher (especially for pericardial effusion and venous thrombosis) and survival was worse (67% vs 78%, P = 0.003). As with virtually all EP procedures—and, as a matter of fact, virtually all procedures in Cardiology—such high-end interventions need to be concentrated at specialized centres to allow for maximum efficacy and safety of the procedure. ## Sudden cardiac death—risk prediction and prevention In 2016, the DANISH trial demonstrated no overall benefit of primary prophylactic ICD implantation in 556 patients with non-ischaemic heart disease. (35) Few studies on cardiac devices have been debated as intensely over the last decade. In a recent meta-analysis of 8567 patients of 11c RCTs (including 3128 patients without ischemic heart disease (IHD)), primary prevention ICD implantation reduced the occurrence of all-cause mortality both in patients with (n = 5439) as well as in those without ischaemic heart disease (n = 3128) by 24%. (36) Is the question answered then? By far not. As elegantly eluted to in an accompanying editorial by Lars Kober (at the same time the principal investigator of the DANISH trial) to the aforementioned meta-analysis: ‘ICDs work—now it is time to find out who needs them’. (37) Indeed, as in the DANISH trial, the question is not as black or white as sometimes presented; what is the role of concomitant CRT? What is the use of CRT in elderly patients and in those with relevant comorbidities (including severe heart failure)? Does the impact of defibrillators on survival become less over time? Indeed, these questions are not only valid for ICD in patients with non-ischaemic cardiomyopathies, which were included in DANISH. Therefore, the aim of the EHRA initiated ‘RESET-SCD’ trial is to test primary prophylactic ICD implantation in patients with ischaemic heart disease and compromised ejection fraction and will deliver urgently needed new data for this important population. And, on another level: Are we at the best that we can do regarding risk stratification of patients at risk of SCD? Indeed, left ventricular ejection fraction—in spite of being the best documented method for primary prevention ICD eligibility—has important shortcomings. Accumulating evidence indicate that imaging, particularly by MRI, may be helpful. In 399 patients with late gadolinium enhancement (LGE) and an EF ≥ 40% had an over nine-fold increased risk of SCD or aborted SCD than those without LGE. (38) The incremental value of using multiple ECG parameters in SCD prediction was tested in the community-based Oregon Sudden Unexpected Death Study. (39) When heart rate, LV hypertrophy, QRS transition zone, QRS-T angle, QTc, and Tpeak-to-Tend interval were added to traditional risk factors, the c-statistics improved significantly from 0.625 to 0.753 (P 87%) not being part of the initial clinical trial. These results also demonstrate the importance of a dedicated structured training program prior to implantation of the system. Some unresolved issues remain, including the feasibility (but also necessity) of extraction, particularly after years of implantation; as well as possible long-term issues that may only surface after years such as the recently discovered premature battery depletion in the SJM/Abbott Nanostim leadless pacemaker. (44) On the tachycardia side, the subcutaneous ICD is gaining momentum for the prevention of sudden cardiac death particularly due to the lack of an intravascular electrode and the associated problems. (45) This year, the mid-term results of the global Evaluation oF FactORs ImpacTing CLinical Outcome and Cost EffectiveneSS of the S-ICD (EFFORTLESS S-ICD) registry were published indicating not only fulfilment of the pre-defined endpoints for efficacy and safety but also a low rate of system extraction due to need for antitachycardia pacing, brady pacing, or CRT. (46) Prospective studies including PRAETORIAN and UNTOUCHED are currently ongoing and will need to confirm these positive results. However, given the likely reduced morbidity compared to conventional transvenous systems, treatment of patients at lower risk of SCD than ‘conventional’ ICD recipients appears to be an attractive option. To this end, MADIT-SICD was launched last year, investigating the efficacy and safety of the S-ICD (compared to the current standard of best medical therapy) in post-myocardial infarction diabetes patients ≥65 years with an LVEF 36–50%. (47) In addition to improving our ways and means of risk stratification for SCD, reducing the morbidity of systems protecting patients from SCD seems to be a logical step to tackle the challenges of the Myerburg-Paradox. (45) While both leadless pacing as well as the S-ICD hence likely represent a glimpse of what the device field will be moving towards in the future, comparative analyses with existing systems (as indicated) are mostly still ongoing. In addition, the higher cost of these systems may be an obstacle in some health care settings preventing the larger volume use of these devices—which, however, is likely to change over the coming years as with every newly introduced therapy. One other concern about cardiac devices seems to be lessened latest since last year, that is the ‘risk’ of MRI in non-MRI-conditional devices (at least in none high-risk patients undergoing 1.5 T MRI). Using a specific standardized protocol for patient selection, programming, observation during MRI and reprogramming, the investigators of the MAGNA-SAFE registry demonstrated no deaths, lead failures, losses of capture, or ventricular arrhythmias during MRI in 1000 pacemakers and 500 ICDs. (48) Whether this is also true for higher risk patients (e.g. pacemaker dependent ICD recipients) remains to be determined. Preliminary data for one such high-risk subgroups appears encouraging: two studies presented at HRS 2017 (Padmanabhan et al. and Brunker et al.) indicate that MRI seems to be safe and feasible in patients with abandoned leads, i.e. patients previously thought to be absolutely contraindicated to undergo MRI scanning. Further studies are required to substantiate these findings, but given the totality of recently provided data, several paradigms seem to be tumbling in this previously uncharted area of MRI scanning in implantable devices. ## Cardiac resynchronization therapy—between guidelines, reality, and alternatives Although standard therapy in heart failure, CRT remains unevenly implemented in ESC countries according to the 2016 EHRA Whitebook. (49) The ESC EHRA HFA CRT Survey II included data on 10 088 new CRT implantations across 42 ESC countries collected between October 2015 and December 2016 (Normand et al., presented at ESC 2017). The results indicate that like in the previous survey (50) doctors go beyond guidelines (51) recommendations when selecting patients for CRT. The most common deviation was to give CRT in LVEF > 35% in 12%, narrow QRS < 120 ms in 8% and NYHA class I in 3%. Of implantations 43% were in patients with a Class I indication according to guidelines, Class II in 21% and Class III meaning implantation is contraindicated in 8%. The results also imply important differences in between countries and centres. The present CRT Survey II is sufficiently big to permit meaningful benchmarking between countries. His Bundle pacing has resurrected over the last years as a possible alternative to CRT in some settings. (52, 53) In a study of 95 patients with an indication for CRT, His bundle pacing was used as a rescue strategy in for failed LV lead or non-response to conventional biventricular pacing (Group I) or as an alternative to the latter for individuals with AV block, bundle branch block, or high ventricular pacing burden. Both groups demonstrated a significant reduction in QRS width, increase in LVEF [30 ± 10% to 43 ± 13% (P = 0.0001)] and improvement in NYHA class. (52) Still, many questions remain. Will this be safe and effective also outside specialized centres with great expertise in this technique? Will this also work in patients requiring ICD therapy? And, most importantly, will it turn out to be as effective in reducing hard clinical endpoints (morbidity and mortality) as conventional CRT has been demonstrated to be. Again, randomized clinical trials assessing these open questions will be required, some of which are already ongoing. ## Acknowledgments The mention of trade names, commercial products organizations, and the inclusion of advertisements in the journal does not imply endorsement by the European Heart Journal, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. The editors and publishers have taken all reasonable precautions to verify drug names and doses, the results of experimental work and clinical findings published in the journal. The ultimate responsibility for the use and dosage of drugs mentioned in the journal and in interpretation of published material lies with the medical practitioner, and the editors and publisher cannot accept liability for damages arising from any error or omissions in the journal. Please inform the editors of any errors. The opinions expressed in the European Heart Journal are those of the authors and contributors, and do not necessarily reflect those of the European Society of Cardiology, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. OUP and the ESC are not responsible or in any way liable for the accuracy of the translation, for any errors, omissions or inaccuracies, or for any consequences arising therefore. Ivica Premužić Meštrović and Karlo Golubić solely responsible for the translation published in this reprint. Translation edited by: Mario Ivanuša. Language editing: Tomislav Salopek.

Lars Søndergaard, Antti Saraste, Christina Christersson, Alec Vahanian

## Preamble A new joint European Society of Cardiology (ESC) and European Association of Cardiothoracic Surgeons (EACTS) guidelines on management of valvular heart disease (VHD) was published in 2017. (1) These guidelines are more focused, and are linked to the upcoming ESC textbook. The main changes concern the role of transcatheter valve treatment, indications for surgery as well as medical therapy. The guidelines present a new concept of Heart Valve Centres with recommended requirements, including multidisciplinary teams with competencies in various interventions and diagnostic techniques for VHD, the availability of important collaborative services, standardized processes and recording of performance data. (2) Some of changes in the latest guidelines are highlighted in this article. ## Epidemiology of valvular disease The association between traditional cardiovascular risk factors and incident, severe aortic stenosis (AS) was highlighted in a large unselected elderly population. (3) Another study found that in a population-based prospective cohort with 1297 incident cases of AS during 15 years of follow-up both overall obesity reflected by body mass index (BMI) and abdominal adiposity based on waist circumference were positively associated with incidence of AS, with similar associations in men and women. (4) Individuals with BMI ≥30 kg/m2 had a significantly [hazard ratio (HR) 1.81, 95% confidence interval (CI) 1.47–2.23] increased risk for incident AS compared with lean individuals. The increasing prevalence of obesity may both determine the increased prevalence of AS and be an important modifiable risk factor for AS. Using data from national statistics, the prevalence of VHD in ESC member countries is approximately 13.3 million. (5) The access to both surgical and transcatheter heart valve treatment is better developed in high-income when compared with middle-income ESC member countries. The health-related burden of rheumatic heart disease has declined worldwide, but high rates of disease persist in some of the developing countries. In a systematically review of fatal and non-fatal rheumatic heart disease over the last 25 years, it was estimated that global age-standardized mortality due to the disease fell by 47.8% from 1990 to 2015. (6) However, there were still more than 30 million cases of rheumatic heart disease and around 300 000 deaths in 2015; the highest mortality was observed in Oceania, South Asia, and central sub-Saharan Africa. ## Aortic stenosis Echocardiography is the first-line imaging technique for the evaluation of patients with VHD, but other imaging modalities can be used to obtain complementary information, and to aid risk stratification in individual patients. (7) Aortic valve calcification detected by cardiac computed tomography (CT) is listed in the guidelines among criteria for differentiating severe low-flow, low-gradient AS from moderate disease, particularly in the presence of preserved ejection fraction (EF). The 2017 VHD guidelines also contain a new recommendation that CT coronary angiography should be considered as an alternative to invasive angiography before valve surgery in patients with a low probability of coronary artery disease; it may also be considered when invasive coronary angiography is either technically not feasible or associated with increased risk. The management of asymptomatic severe AS remains controversial. However, in the 2017 VHD guidelines, markedly elevated plasma natriuretic peptide levels or severe pulmonary hypertension without other explanation have been added as risk factors warranting consideration for surgery in asymptomatic severe AS with normal EF. Currently, aortic valve replacement (AVR) is not indicated in these patients, but it will be evaluated in the randomized EARLY TAVR trial (NCT03042104) and EVoLVeD trial (NCT03094143). An observational study demonstrated that patients with concomitant moderate AS and left ventricle systolic dysfunction are at high risk for clinical events, (8) which is the focus of the transcatheter aortic valve replacement (TAVR)-UNLOAD trial (NCT02661451). Two studies demonstrated the utility of clinical scores for detecting frailty and predicting 1-year mortality after AVR in elderly patients. (9, 10) The burden of mitral annular calcification is also associated with outcomes after AVR; there are now similar data in patients undergoing aortic valve implantation (TAVI). (11) Severe mitral annular calcification was encountered in 10% of patients; this was an independent predictor of both overall mortality (HR 2.35, 95% CI 1.19–4.66) and permanent pacemaker implantation [odds ratio (OR) 2.83, 95% CI 1.08–7.47] following TAVI. Data from surgical registries describe an increase in the use of biological aortic valves even in the age groups were mechanical valves are usually recommended, **Figure 1**. (12, 13) There is still a gap in evidence regarding the optimal age cut-off at which a biological valve prosthesis should be preferred. In a propensity-matched study of patients aged 50–69 years treated with biological and mechanical aortic valve prostheses, survival was higher in the group with mechanical prostheses (HR 1.34, 95% CI 1.09–1.66), and the risk of reoperation was lower. (13) In a sub-analysis the benefit persisted in those aged 50–59 years, but not for those aged 60–69 years. In a meta-analysis of patients aged 18–55 years treated with mechanical valve prostheses, microsimulation was used to calculate life expectancy and lifetime event-risk. (14) Estimated life expectancy was shortened in patients with mechanical prostheses, and the risk of thromboembolism and re-intervention was 18% and 10%, respectively. A recent study stratified patients into different age groups on the basis of valve position [aortic vs. mitral valve (MV)], and found the long-term mortality benefit associated with a mechanical prosthesis, as compared with a biological prosthesis, persisted until 55 years of age among those undergoing aortic-valve replacement, and until 70 years of age among patients undergoing mitral-valve replacement. (15) Figure 1. Number of aortic valve replacements per year. Number of patients aged 50–69 years who had undergone aortic valve replacements with mechanical or bioprosthetic valves in Sweden between 1997 and 2013. From Glaser *et al.* (13) This figure has been reprinted with permission of Oxford University Press on behalf of European Society of Cardiology. The choice of intervention with TAVI and surgical AVR (SAVR) depends on careful individual evaluation by the Heart Team, taking into consideration the risks and benefits of each approach (**Table 1**). Although, TAVI is an accepted alternative to surgery in patients with severe AS who are at high surgical risk, the SURTAVI trial provided additional data concerning intermediate risk patients. (16) The SURTAVI trial included 1746 patients and showed that TAVI with a self-expanding prosthesis was non-inferior to SAVR with regards to estimated incidence of all-cause mortality and disabling stroke at 24 months (12.6% vs. 14.0%). Surgery was associated with higher rates of acute kidney injury, atrial fibrillation, and transfusion requirements, whereas TAVI had higher rates of residual aortic regurgitation (AR) and need for pacemaker implantation. ### TABLE 1: Aspects to be considered by the Heart Team for the decision between surgical aortic valve replacement and transcatheter aortic valve implantation in patients at increased surgical risk. | **Clinical characteristics** — STS/EuroSCORE II a — STS/EuroSCORE II ≥4% (logistic EuroSCORE I ≥10%)a — Presence of severe comorbidity (not adequately reflected by scores) — Age aSTS score (calculator: http://riskcalc.sts.org/stswebriskcalc/#/calculate); EuroSCORE II (calculator: http://www.euroscore.org/calc.html); logistic EuroSCORE I (calculator: http://www.euroscore.org/calcge.html). Scores have major limitations for practical use in this setting by insufficiently considering disease severity and not including major risk factors such as frailty, porcelain aorta, chest radiation etc. EuroSCORE I markedly overestimates 30-day mortality and should therefore be replaced by the better performing EuroSCORE II with this regard; it is nevertheless provided here for comparison since it has been used in many TAVI studies/registries and may still be useful to identify the subgroups of patients for decision between intervention modalities and to predict 1-year mortality. Even though randomized trials support the use of TAVI for the treatment of AS in high- and intermediate-risk patients, the generalizability of these results to clinical practice may be challenged. However, in 9464 propensity-matched intermediate- and high-risk U.S. patients who underwent TAVI or SAVR, there were similar rates of death, stroke, and days alive and out-of-hospital to 1 year, but TAVI patients were more likely to be discharged home. (17) With the increased clinical experience and newer generation devices, (18–20) TAVI is expected to expand to younger patients, where bicuspid aortic valves are more common. Early experience with TAVI in bicuspid aortic valves revealed difficulties with optimal valve positioning and more paravalvular leak. In a multi-centre registry, 561 patients with bicuspid AS and 4546 patients with tricuspid AS were compared after propensity score matching, assembling 546 pairs of patients with similar baseline characteristics. (21) Compared with TAVI for tricuspid AS, treatment in bicuspid AS was associated with a similar prognosis, but a lower device success rate. However, expansion of TAVI to younger patients can only be supported with the availability of long-term data, which are still lacking. Longevity of bioprosthetic heart valves is an extremely important issue. However, comparisons of valve brands, as well as surgical and transcatheter implantation, have been difficult because different valve durability criteria have been used. The definitions of bioprosthetic valve dysfunction and failure have now been standardized for use in future studies in a consensus publication from the European Association of Percutaneous Cardiovascular Interventions (EAPCI) endorsed by ESC and EACTS, (22) **Figure 2**. Valve-in-valve TAVI should be considered as an option by the Heart Team for treating degenerated surgical bioprostheses depending on the risk of reoperation and the type and size of prosthesis. Thus, TAVI for bioprosthetic aortic valve failure has been associated with a relatively low complication rates and mortality, improved haemodynamics, and excellent functional and quality-of-life outcomes. (23, 24) Furthermore, transcatheter closure may be considered for clinically significant paravalvular leaks in surgical high-risk patients. (25) FIGURE 2. (A) Causes of bioprosthetic valve dysfunction. (B) Suggested assessment of bioprosthetic valve failure (BVF) in outcome studies of transcatheter aortic valve implantation or surgical aortic valve replacement (SAVR). SVD, structural valve deterioration. From Capodanno *et al*. (22) This figure has been reprinted with permission of Oxford University Press on behalf of European Society of Cardiology. ## Aortic regurgitation The 2017 VHD guidelines recommends that, in selected cases and in experienced centres, aortic valve repair, and valve-sparing aortic surgery, rather than AVR, should be considered by Heart Team for the treatment of severe AR. Consideration of valve sparing surgery, using re-implantation or remodelling with aortic annuloplasty techniques, is especially recommended in young patients with aortic root dilatation and tricuspid aortic valves, when performed by experienced surgeons. The timing of surgery in asymptomatic patients with severe AR and preserved EF remains controversial, although long-term (mean follow-up 6.6 years) survival after surgery is similar to an age- and sex-matched population. (26) TAVI for non-calcified native aortic valve regurgitation has been challenging with prosthesis embolization and high rate of paravalvular leakage. However, newer generation TAVI systems has improved the outcome with fewer patients needing a second valve (10%) and having significant residual AR (3%). (27) ## Mitral regurgitation Echocardiography is essential to assess the aetiology of mitral regurgitation (MR), but quantitative grading remains challenging. The 2017 VHD guidelines state that the thresholds used to define severe secondary MR remain controversial and need to be evaluated with regards to their impact on prognosis after MV intervention. Integration of echocardiography-derived Doppler mitral flow and CT-derived cross-sectional mitral anatomical regurgitant orifice area to calculate mitral regurgitant volume has been evaluated. (28) In 73 patients undergoing TAVI, who also had either primary or secondary MR, this approach resulted in reclassification of MR from severe to non-severe in 10% and from non-severe to severe in 14% of the patients providing a proof-of-concept of this integrated approach. A study validated a risk score (The Mitral Regurgitation International Database (MIDA) mortality risk score) integrating various clinical and echocardiographic parameters endorsed by guidelines for predicting short- and long-term mortality risk in patients with severe degenerative MR either under medical or surgical treatment. (29) In patients with severe MR and preserved left ventricular EF, worsening of global longitudinal strain using speckle-tracking resting echocardiography is independently associated with mortality during 8.3 years of follow-up, providing additive prognostic utility to reduced capacity on exercise testing and other previously known predictors. (30) Importantly, in the recent guideline, MV surgery in patients with moderate secondary MR undergoing coronary artery bypass surgery is no longer recommended in the guidelines. Mitral valve repair is recommended over MV replacement in degenerative MR and this recommendation is backed-up by multicentre registry data analysed with propensity score matching. (31) The operative mortality was lower in the MV repair group (0.2% vs. 4.4%, P 111In imaging of endocarditis. A study evaluated the feasibility and diagnostic accuracy of simultaneous imaging of inflammation with 111In-labelled white blood cells and myocardial perfusion with 99mTc, for localization of white blood cells relative to the valve plane in suspected endocarditis. (52) The results support the usefulness of a novel approach to increase sensitivity and accuracy of white blood cell imaging in endocarditis. Work has also considered the risks of endocarditis in patients with prosthetic valves. In a population-based cohort study of 138 867 patients with a prosthetic valve (median follow-up 1.7 years) the incidence rate of oral streptococcal IE was 93.7/100 000 patient-years. (53) No increased rate of IE was found within three months of exposure to invasive dental procedure, but in a case crossover analysis a dental procedure was more frequent in IE periods (5.1% vs. 3.2%, OR 1.66; 95% CI 1.05–2.63; P = 0.03). In the CONCOR registry, including patients with congenital heart disease, the incidence of IE was 1.33 cases/1000 patient-years. (54) Prosthetic valves were associated with an increased risk of IE (HR 5.48, 95% CI 3.58–8.38) compared with no prosthetic valve. This increased risk was found both early and during long-term follow-up after surgery. In a registry-based observational study of both biological and mechanical aortic prostheses (mean follow-up 6.2 years), the incidence of prosthetic valve IE was 0.57%/person-year; the risk was highest during the first year after surgery. (55) The risk of prosthetic valve IE was higher in the group with biological prostheses (HR 1.54, 95% CI 1.29–1.83) as compared with those with mechanical prostheses. These studies have confirmed the risk of IE in patients with prosthetic valves and support the continued recommendation of antibiotic prophylaxis in all such patients. ## Perspectives With the rapid adaptation of TAVI in patients with AS and increased surgical risk, the role of TAVI in patients at low surgical risk is currently being explored. Since patients in these trials have longer life-expectancy, these trials may also add important information on longevity of bioprosthetic aortic valves. As several transcatheter repair and replacement techniques are emerging, evidence for the benefit of intervention in particular functional MR is still missing. The COAPT and French MITRA-FR trials investigate MitraClip in this setting and study results are foreseen during 2018. Furthermore, the impact of transcatheter MV replacement and tricuspidal valve repair is also under investigation. ## Acknowledgments The mention of trade names, commercial products organizations, and the inclusion of advertisements in the journal does not imply endorsement by the European Heart Journal, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. The editors and publishers have taken all reasonable precautions to verify drug names and doses, the results of experimental work and clinical findings published in the journal. The ultimate responsibility for the use and dosage of drugs mentioned in the journal and in interpretation of published material lies with the medical practitioner, and the editors and publisher cannot accept liability for damages arising from any error or omissions in the journal. Please inform the editors of any errors. The opinions expressed in the European Heart Journal are those of the authors and contributors, and do not necessarily reflect those of the European Society of Cardiology, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. OUP and the ESC are not responsible or in any way liable for the accuracy of the translation, for any errors, omissions or inaccuracies, or for any consequences arising therefore. Ivo Planinc is solely responsible for the translation published in this reprint. Translation edited by: Mario Ivanuša. Language editing: Tomislav Salopek.

Victoria Delgado, Juhani Knuuti, Sven Plein, Stephan Achenbach, Jeroen J. Bax

## Preamble This Year in Cardiology 2017 review article provides a broad overview of the novelties published in non-invasive cardiovascular imaging. While it is well established that echocardiography is the imaging technique of first choice to evaluate patients with cardiovascular symptoms, other techniques (nuclear imaging, cardiovascular magnetic resonance, and computed tomography) are needed to image specific-disease characteristics or pathophysiological mechanisms that may impact on the patient’s management. The evidence showing the incremental diagnostic and prognostic value of combination of imaging techniques or fusion imaging is growing exponentially. Advances in non-invasive cardiac imaging have provided important new insights in the pathophysiology of valvular heart disease and cardiomyopathies, risk stratification of patients with suspected coronary artery disease and diagnosis of implanted device- or bioprosthesis-related complications; this article provides an overview of the most relevant articles published in 2017. ## Introduction Advances in non-invasive cardiac imaging have provided important new insights in the pathophysiology of valvular heart disease and cardiomyopathies, risk stratification of patients with suspected coronary artery disease (CAD), and diagnosis of implanted device- or bioprosthesis-related complications. The evidence showing the incremental diagnostic and prognostic value of combination of imaging techniques or fusion imaging is growing rapidly. This Year in Cardiology 2017 review article provides a broad overview of the novelties published in non-invasive cardiovascular imaging. ## Echocardiography The role of echocardiography in the diagnosis of valvular heart disease was underscored in the OxValve Population Cohort Study which recruited 2500 patients aged 65 years and older without known valvular heart disease. (1) One in two of the elderly population had newly diagnosed (predominantly mild) valvular heart disease: 34% presented aortic sclerosis, 22% mitral regurgitation, and 15% aortic regurgitation. Moderate and severe undiagnosed valvular heart disease was identified in 6.4% of patients. Interestingly, moderate and severe valvular heart disease was three times more common in patients with atrial fibrillation (AF), which could be considered as a marker of silent significant valvular heart disease. Projections based on the OxValve Population Cohort Study suggest that the number of individuals aged 65 years or more in the UK will increase from 1.5 million in 2015 to 3 million by 2046. The results of this study provide further insights in the pathophysiology and natural history of valvular heart disease and have important implications for the management of elderly patients in the current era with growing advances in transcatheter therapies. Selection of patients who may benefit from valvular intervention relies on symptoms and effects of the abnormal loading conditions on the cardiac chambers. The extent of cardiac damage caused by the abnormal valve haemodynamics is an important determinant of the morbi-mortality of patients with heart valve disease. From the Placement of Aortic Transcatheter Valves (PARTNER)-2 trials, 1661 patients with severe stenosis were classified into four stages based on the cardiac damage assessed with echocardiography: no extra-valvular cardiac damage (Stage 0, n = 47), left ventricular (LV) damage characterized by increased LV mass index (Stage 1, n = 212), left atrial (LA), or mitral damage, including LA dilation, moderate, and severe mitral regurgitation and AF (Stage 2, n = 814), pulmonary vasculature or tricuspid damage characterized by systolic pulmonary hypertension and moderate or severe tricuspid regurgitation (Stage 3, n = 413) and right ventricular damage characterized by moderate and severe right ventricular dysfunction (Stage 4, n = 145). (2) One-year mortality rates after aortic valve replacement increased along with progression of cardiac damage stage: from 4.4% in stage 0 to 24.5% in Stage 4. Each increment in cardiac damage stage was independently associated with increased mortality [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.27–1.67; n 99mTc-PYP) cardiac scintigraphy was performed to evaluate the presence of concomitant transthyretin cardiac amyloidosis and tissue Doppler echocardiography, as well as LV global longitudinal strain (GLS) with two-dimensional speckle tracking echocardiography to assess LV systolic function. (5) Sixteen percent of patients had a 99mTc-PYP scan positive for transthyretin cardiac amyloidosis. Compared to patients with isolated severe aortic stenosis, patients with concomitant transthyretin cardiac amyloidosis showed more LV hypertrophy, lower stroke volume, more advanced LV diastolic dysfunction, and reduced LV function [lower LV ejection fraction (EF), more impaired LV GLS and lower peak systolic velocity on tissue Doppler imaging, S′] (**Figure 1A** – **Take home figure**). A value of S′ ≤6 cm/s on tissue Doppler echocardiography was strongly associated with a positive 99mTc-PYP scan. The clinical implications of these findings need to be evaluated in larger studies confirming that patients with concomitant transthyretin cardiac amyloidosis have worse prognosis after aortic valve replacement as compared to patients with isolated aortic stenosis. Figure 1A. **Take home figure.** Transthyretin cardiac amyloidosis in patients with severe aortic stenosis. Panels **A** and **B** show the technetium-99m pyrophosphate (99mTc-PYP) cardiac scintigraphy and the left ventricular global longitudinal strain bull’s eye plot of a patient without transthyretin cardiac amyloidosis. A 99mTc-PYP cardiac scintigraphy positive for transthyretin cardiac amyloidosis shows an increased heart-to-contralateral ratio (H/CL) (panel **C**) and more impaired left ventricular global longitudinal strain (panel **D**). Panel **E** shows the receiver operating curves for several echocardiographic parameters of left ventricular systolic and diastolic dysfunction. The S′ measured on tissue Doppler imaging had the largest area under the curve to predict 99mTc-PYP cardiac scintigraphy positive for transthyretin cardiac amyloidosis. Reproduced with permission from Castano *et al.* (3) AS, aortic stenosis; ATTR-CA, transthyretin cardiac amyloidosis; AUC, area under the curve; CI, confidence interval; Decel, deceleration; H/CL, heart-to-contralateral ratio; LS, longitudinal strain; MCF, myocardial contraction fraction; VMR, voltage-mass ratio. This figure has been reprinted with permission of Oxford University Press on behalf of European Society of Cardiology. The role of three-dimensional transoesophageal echocardiography to better characterize the mitral valve anatomy and dynamics in mitral regurgitation was highlighted in several publications. For example, Kagiyama et al. (6) demonstrated the presence of insufficient remodelling of the mitral leaflets assessed with three-dimensional transoesophageal echocardiography in 28 AF patients with moderate and severe mitral regurgitation compared to 56 AF patients without mitral regurgitation. The ratio between the total leaflet area and the mitral annulus area was significantly smaller among patients with moderate and severe mitral regurgitation than in patients without (1.29 ± 0.10 vs. 1.65 ± 0.24, P 99mTc-tetrofosmin stress/rest single photon emission computed tomography (SPECT) was evaluated in 184 patients with single vessel CAD. (12) Total plaque volume and burden, and specifically for non-calcified, low-density non-calcified and calcified plaques, remodelling index, contrast density difference, lesion length, and diameter stenosis were significantly larger in those coronary arteries supplying ischaemic territories on myocardial perfusion imaging as compared with arteries supplying non-ischaemic territories. However, on multivariable analysis, non-calcified plaques (odds ratio 2.6), low-density non-calcified plaques (odds ratio 3.9) and contrast density difference (odds ratio 2.7) were significantly associated with ischaemia, whereas the degree of stenosis was not. The study demonstrated that other plaque characteristics than only coronary luminal narrowing are major determinants of myocardial ischaemia. These results provide interesting support for the concept that ischaemia reflects not only luminal narrowing but also relates to vulnerable plaques. Cardiac sarcoidosis remains one of the major diagnostic challenges in cardiology. Cardiovascular magnetic resonance (CMR) and PET imaging are increasingly used to detect cardiac involvement of sarcoidosis. Imaging of active sarcoidosis with PET is based on detection of myocardial inflammation using 18F-fluorodeoxyglucose (FDG). However, 18F-FDG uptake is not specific for sarcoidosis. Although special patient preparation is applied to minimize myocardial glucose utilization, some degree of physiological 8F-FDG uptake is commonly present in the heart. Schildt et al. (13) demonstrated the diagnostic accuracy of heterogeneity of myocardial 18F-FDG uptake in 271 consecutive patients with suspected cardiac sarcoidosis referred for PET-computed tomography (CT). By quantifying the maximum, minimum, mean, and standard deviation of the segmental, 18F-FDG uptake values of each of the 17 LV segments, the coefficient of variation of the entire left ventricle was calculated as the average of each segmental standard deviation divided by the average of each segmental mean. This coefficient of variation is a measure of LV metabolic heterogeneity. The investigators proposed a cut-off value of 0.184 to have the best accuracy to detect cardiac sarcoidosis (75% sensitivity, 51.4% specificity). 18F-fluorodeoxyglucose PET has become one of the standard imaging tests in patients with suspected endocarditis. (14) It has been shown earlier that PET provides important diagnostic information in patients with suspected prosthetic valve endocarditis. In contrast, the sensitivity of 18F-FDG PET is low in native valve endocarditis if no annular involvement or extra-cardiac infection focus exist. In prosthetic valve endocarditis, relatively little information is available about the physiological 18F-FDG uptake. Mathieu et al. (15) characterized 18F-FDG uptake patterns in non-infected prosthetic heart valves. The authors identified 54 prosthetic valves without endocarditis that have undergone 18F-FDG PET imaging. Some degree of peri-prosthetic FDG uptake was present in majority of prosthetic valves. The tracer uptake using quantitative analysis was significant in many patients and somewhat greater in mechanical than in biological valves (standardized uptake value 4.0 [2.4–8.0] and 3.3 [2.1–6.1], respectively). However, the pattern was typically homogeneous. Therefore, not only the intensity of 18F-FDG uptake but also its heterogeneity is the important criteria for prosthetic valve endocarditis. Furthermore, Dell’Aquila et al. (16) demonstrated that quantitative 18F-FDG PET-CT is an optimal diagnostic tool to detect superficial and deep driveline infections in heart failure patients recipients of continuous flow LV assist device. In contrast, the accuracy of quantitative 18F-FDG PET-CT to diagnose pump housing infection is limited and a qualitative approach together with the clinical information should be considered in this situation (**Figure 1B**). In addition, 18F-FDG PET is increasingly used for the diagnosis of cardiac implantable electronic device infection. Juneau et al. (17) performed a systematic review and meta-analysis of the accuracy of PET and SPECT to detect cardiac implantable electronic device infection. A total of 13 articles (11 studies for 18F-FDG PET-CT and 2 for labelled leucocyte scintigraphy) met the inclusion criteria. The pooled sensitivity of 18F-FDG PET-CT for the diagnosis of cardiac implantable electronic device infection was 87% (95% CI 82%–91%) and pooled specificity was 94% (95% CI 88%–98%). The receiver operating characteristics curve analysis demonstrated good accuracy overall, with an AUC of 0.935. For labelled leucocyte scintigraphy, both studies reported sensitivity above 90% and specificity of 100%. The authors concluded that both 18F-FDG PET-CT and leucocyte scintigraphy yield high sensitivity, specificity, and accuracy, but limited data is available on the latter. The authors recommended to use 18F-FDG PET as preferred method when available. Also leucocyte scintigraphy appears useful tool for the diagnosis of cardiac implantable electronic device infection. Figure 1B. 18F-fluorodeoxyglucose positron emission tomography–computed tomography to diagnose left ventricular assist device infection. On maximum intensity projections and fused transaxial positron emission tomography–computed tomography images, the pathological uptake of 18F-fluorodeoxyglucose is visualized at the piercing site of the driveline and along the intracorporeal course in panel *A* whereas panel *B* shows pathological 18F-fluorodeoxyglucose accumulation at all the levels including the pump housing. Reproduced with permission from Dell’Aquila *et al.* (16) This figure has been reprinted with permission of Oxford University Press on behalf of European Society of Cardiology. ## Cardiovascular magnetic resonance Among the established clinical applications of CMR, the measurement of cardiac iron loading has become an integral part of the management of patients with thalassaemia major and CMR guided management has dramatically reduced mortality in this patient population. In a recent cohort of 481 thalassaemia patients on contemporaneous treatment, Pepe et al. (18) described which CMR findings are independently associated with the occurrence of heart failure and arrhythmias. Overall, the rate of adverse outcomes was low with only 16 patients experiencing heart failure and 16 presenting with an arrhythmia during 6 years follow-up. Myocardial fibrosis on late gadolinium enhancement (LGE) CMR was associated with adverse outcomes (HR = 10.9, P 50% stenoses, had superior prognostic value than clinical risk scores, including the NCEP ATP III, Framingham, and Morise scores (C-statistic: 0.696, 0.675, 0.610, and 0.606, respectively). Application of the CONFIRM score led to reclassification of 34% of patients when compared with the NCEP ATP III score alone. An interesting new approach to risk stratification based on CCTA was described by Motwani et al. (33) Machine learning was applied to build a model from clinical data and CCTA of 10 030 patients included in the CONFIRM registry. Twenty-five clinical variable (such as age, gender, and Framingham risk score) and 44 CCTA-derived parameters (such as segment stenosis score, segment involvement score, modified Duke index, number of segments with non-calcified, mixed or calcified plaques). Machine learning involved automated feature selection, model building, and 10-fold stratified cross-validation. During a mean follow-up of 5.4 years, 745 patients died. Machine learning yielded a higher AUC compared with the Framingham risk score or any single CCTA-derived severity scores alone (such as the segment involvement score) for predicting all-cause mortality (machine learning: 0.79; Framingham Risk Score: 0.61; segment involvement score: 0.64; P 18F-FDG. Fusion imaging could represent the fusion or integration of different images that were acquired in isolation and then later on fused or integrated for assessment of cardiovascular pathophysiology. For example, van Rosendael et al. (42) described the integrated use of CT and echocardiography for improved assessment of severity of mitral regurgitation in 73 patients. When the effective regurgitant orifice was assessed by direct planimetry from CT, and this orifice size was then integrated with the velocity of the regurgitant flow on echocardiography (**Figure 6**), the severity of mitral regurgitation was downgraded from severe to non-severe in 10% of patients and upgraded from non-severe to severe in 14% of patients. Thus the fusion of the two techniques altered severity assessment in 24% of patients; the prognostic value of this fusion imaging remains to be demonstrated. Figure 6. Integration of the Doppler echocardiography and computed tomography data to quantify mitral regurgitant volume. By echocardiography, the proximal isovelocity surface area method was used for the assessment of the effective regurgitant orifice area of the mitral regurgitation.(Panels *A, B*, and *F*) The velocity time integral of the magnetic resonance jet was assessed on the continuous wave Doppler images (Panel *B*). By aligning the multiplanar reformation planes on the multi-detector computed tomography data, a double oblique transverse plane parallel to the narrowest part of the mitral regurgitant orifice was reconstructed. The anatomical mitral regurgitant orifice area was measured by planimetry at this level (Panels *C–E*). The echocardiography and integrated regurgitant volume of magnetic resonance were assessed by multiplying the echocardiographic effective regurgitant orifice area and the multi-detector computed tomography derived mitral regurgitant orifice area with the velocity time integral, respectively (Panel *F*). Reproduced with permission from van Rosendael *et al.* (42) VTI, velocity time integral; CT, computed tomography; ROA, regurgitant orifice area; RVol, regurgitant volume; EROA, effective regurgitant orifice area. This figure has been reprinted with permission of Oxford University Press on behalf of European Society of Cardiology. The majority of the literature reports on hybrid imaging, mostly with PET and CT, but also with PET and CMR. These new machines permit direct fusion of both images, which are acquired simultaneously or sequentially (in the same session). Various examples were reported in 2017. Singh et al. (43) reported on integrated imaging of coronary plaque morphology and inflammation using PET-CT with 18F-FDG: 55 patients underwent imaging before and after 12 weeks of statin (atorvastatin) use. The 18F-FDG uptake (target-to-background ratio) was assessed in the left main coronary artery, which was significantly higher in non-calcified or partially calcified lesions on CCTA (considered high-risk) as compared to calcified lesions (target-to-background ratios 1.95 ± 0.43 vs. 1.67 ± 0.32, P = 0.04). After 12 weeks of statin use, there was a significant reduction in 18F-FDG uptake in the high-risk lesions. Patients (n = 25) with possible sarcoidosis were evaluated with PET-CMR; (44) active sarcoidosis was defined as having increased 18F-FDG uptake in areas with delayed contrast-enhancement on CMR (present in eight patients); all other patients did not show active sarcoidosis. This approach may enable identification of patients with active sarcoidosis and permit selective treatment. Positron emission tomography–computed tomography enabled accurate detection of endocarditis in patients who underwent transcatheter aortic valve replacement. (45) Computed tomography demonstrated leaflet thickening (as marker of thrombosis), whereas 18F-FDG indicated active inflammation; the imaging approach was superior over routine assessment of endocarditis (according to the modified Duke criteria). In the EValuation of INtegrated Cardiac Imaging for the Detection and Characterization of Ischaemic Heart Disease (EVINCI) study, 14 centres from nine European countries included 252 patients with stable angina and intermediate pre-test likelihood of CAD. (46) The patients underwent SPECT or PET perfusion imaging and CCTA, and these images were fused on a dedicated workstation. These non-invasive imaging data were compared with quantitative invasive coronary angiography with assessment of FFR (to detect haemodynamically significant stenosis). Hybrid imaging excluded functionally significant CAD in 41% of patients, which provided a negative predictive value of 88%, and included in significant disease in 24% of patients, which yielded a positive predictive value of 87%. To establish the role of hybrid imaging in the detection of significant CAD, additional studies are needed focusing on the influence of this imaging modality on the downstream of patients (avoiding unnecessary invasive coronary angiography and interventions). ## Acknowledgments The mention of trade names, commercial products organizations, and the inclusion of advertisements in the journal does not imply endorsement by the European Heart Journal, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. The editors and publishers have taken all reasonable precautions to verify drug names and doses, the results of experimental work and clinical findings published in the journal. The ultimate responsibility for the use and dosage of drugs mentioned in the journal and in interpretation of published material lies with the medical practitioner, and the editors and publisher cannot accept liability for damages arising from any error or omissions in the journal. Please inform the editors of any errors. The opinions expressed in the European Heart Journal are those of the authors and contributors, and do not necessarily reflect those of the European Society of Cardiology, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. OUP and the ESC are not responsible or in any way liable for the accuracy of the translation, for any errors, omissions or inaccuracies, or for any consequences arising therefore. Dora Fabijanović and Saša Pavasović are solely responsible for the translation published in this reprint. Translation edited by: Mario Ivanuša. Language editing: Tomislav Salopek.

Victor Aboyans, Sigrid Braekkan, Lucia Mazzolai, Henrik Sillesen, Maarit Venermo, Marco De Carlo

## Preamble More than 83 million people live with cardiovascular (CV) disease in the ESC member countries, with peripheral vascular diseases as the most predominant condition (more than 35 million) followed by ischaemic heart disease (>29 million), underlining the public health burden of the former in our continent. (1) The ESC collaborated with European Society of Vascular Surgery (ESVS) to publish the most comprehensive guidelines document on the management of peripheral arterial diseases (PADs), encompassing all the peripheral territories. (2) Compared to the 2011 version, major changes regard risk stratification for patients with asymptomatic carotid disease, and those with critical limb-threatening ischaemia (CLTI), and a new specific chapter on cardiac diseases in patients with PADs. Any presentation of PADs is associated with a very high risk for CV events, and all patients require best medical therapy for secondary prevention. In this respect, the VIVA (3) and COMPASS (4) trials are definitely the two seminal randomized controlled trials (RCTs) of the year. The VIVA trial demonstrated the interest of multiple vascular screening to improve population longevity (**Table 1**). (3) Over 50 000 Danish men were randomized to receive an invitation for vascular screening or not. Vascular screening consisted of arm blood pressure and ankle-brachial index (ABI) measurement, and abdominal aorta ultrasound. Positive cases were invited to consult their general practitioners, while large abdominal aorta aneurysm (AAA) were referred to vascular surgeons. After 4.4 years, the mortality was significantly lower in the screening group (**Table 1**). The number needed to screen to prevent one death was 169, far below the one necessary for any cancer screening. ### TABLE 1: Summary of major randomized trials in peripheral intervention in 2017. | **Trial’s acronym** **(or first author)** | **Type and aim** **of the study** | **Challenger** **(n)** | **Reference (n)** | **Setting** **(indication)** | **Primary outcome (+ secondary outcomes of interest)** | | --- | --- | --- | --- | --- | --- | | **Multiple localization** | | | | | | | COMPASS-PAD (4) | Double-blind: interest of low-dose rivaroxaban (alone or with aspirin) in patients with PADs | Rivaroxaban 2.5 mg x 2 + Aspirin 100 mg (R + A: 2492) or Riva 5 mg x 2 (R: 2474) | Aspirin 100 mg (A: 2504) | LEAD (past revascularization, claudication with proven LEAD, or CAD with ABI 50%) | CV death, MI or Stroke: R+A vs. A = -28% (P = 0.0047); R vs. A = −14% (P = 0.19). -46% reduction of MALE for R + A vs. A. +61% bleeding risk, but not fatal bleeding. | | VIVA (3) | Open: interest of vascular screening in general population | Screening for hypertension, LEAD and AAA (25 078) | No screening (25 078) | Men aged 65–74 years in Central Denmark | Mortality (HR 0.93; 95% CI 0.88–0.98) | | **Carotid artery disease** | | | | | | | Moresoli (5) | Meta-analysis: CAS versus CEA in patients with asymptomatic carotid stenosis | CAS (1881) | CEA (1138) | Asymptomatic carotid stenosis | Any peri-procedural stroke and long-term stroke (RR 1.24; 95% CI 0.76–2.03) or death (RR 1.72; 95% CI 0.95–3.11) | | **Lower extremities artery disease** | | | | | | | EMPA-REG (LEAD subgroup) (6) | Double-blind: efficacy and safety of empagliflozin on top of standard care in type 2 diabetic patients with LEAD | Empagliflozin (982) | Placebo (479) | LEAD (past revascularization or amputation, stenosis > 50%, or ABI aDefined as absence of target lesion restenosis, measured by duplex ultrasonography-derived peak systolic velocity ratio ≤ 2.5 and freedom from CD-TLR. bDefined as the absence of target lesion restenosis on duplex ultrasound (peak systolic velocity ratio ≤ 2.5). cWith blinded assessors. The COMPASS trial randomized 27 395 patients either with coronary artery disease (CAD) or PADs [lower-extremity artery disease (LEAD) or carotid stenosis or prior carotid revascularization] to three different antithrombotic strategies. In the pre-defined sub-analysis of patients with PADs, the results were consistent with those obtained in the entire population (**Table 1**): the combination of rivaroxaban 2.5 mg b.i.d. + aspirin 100 mg was associated with a significant 28% reduction of a combination of CV death, myocardial infarction, or stroke and a 46% reduction of major adverse limb events (MALE), including amputation, as compared to aspirin 100 mg. (4) Bleeding events were higher under the combination therapy, except for fatal bleeding. The net benefit including ischaemic and major bleeding events remained in favour of the combination strategy. The clinical implication for the management of these patients needs further analyses to select specific subgroups with an optimal benefit/risk ratio (RR). Also, the external applicability of these results is important; among REACH participants with LEAD, 68% were COMPASS-compatible, fulfilling inclusion, and exclusion criteria. (15) The main reason for not being COMPASS-compatible was a high-bleeding risk. Hence, the bleeding risk stratification is of paramount importance. ## Other specific studies in lower-extremity artery disease The 2017 ESC guidelines (1) emphasize the optimal management of risk factors in patients with PADs. A new analysis of the FOURIER trial underscored the importance of lowering LDL-cholesterol in patients with LEAD, with significant benefits with evolocumab, a PCSK-9 inhibitor (**Table 1**). (7) This new analysis in patients with LEAD showed similar benefits in terms of CV events reduction, and a significant reduction of MALE. This is the first trial showing the benefits of a lipid-lowering drug to reduce MALE, including amputation. Many patients with LEAD are diabetic. Recently strikingly positive results on the CV benefits of sodium glucose cotransporter 2-inhibitors have been presented, although concerns were raised regarding the increased risk of amputation (mostly minor) with canaglifozin. (16) A new analysis of patients with LEAD enrolled in the EMPA-REG trial confirmed the benefits of empagliflozin in terms of mortality and CV events (**Table 1**), without any difference in amputation rates as compared to placebo. (6) The need for improved diabetes care was underlined by a recent registry on 15 332 CLTI patients (47% diabetic), showing that in spite of a 60% higher risk of infection and 40% higher amputation rate (both in-hospital and at 4-year follow-up), diabetic patients were revascularized less often (46% vs. 54%, P 11 × 109/L | 1 | 1 | 1 | 1 | | Pre-chemotherapy platelet count ≥350 × 109/L | 1 | 1 | 1 | 1 | | Body mass index >35 kg/m2 | 1 | 1 | 1 | | | D-dimer >1.44 µg/mL | | 1 | | | | Soluble P-selectin ≥53.1 ng/mL | | 1 | | | | World Health Organization (WHO) performance status ≥2 | | | | 1 | | Gemcitabine chemotherapy | | | 1 | | | Platinum-based chemotherapy | | | 1 | | | Cut-off for classification of high-risk patients (points) | ≥3 | ≥5 | ≥3 | ≥3 | [†] Numbers represent the value attributed to each characteristic in the scores. aThe Vienna CATS also included brain cancer as a high-risk site. Diagnostic algorithms are frequently used to identify patients in whom pulmonary embolism (PE) can be ruled out without the use of computed tomography pulmonary angiography (CTPA). In a study of 3465 patients with suspected PE, the YEARS decision rule (based on three clinical items combined with two D-dimer cut-offs) yielded a 14% decrease in CTPA examinations compared to conventional strategies (**Figure 3**) with a negative predictive value of 99.4%. (46) Whether negative CTPA is sufficient to exclude PE in patients with likely pretest probability is debated. Pulmonary embolism was excluded with CTPA in 37% of patients with likely clinical probability, and the 3-month VTE risk was 0.6%, indicating that a negative CTPA safely excludes PE in this patient group. (47) Figure 3. The YEARS diagnostic strategy in case of suspicion for pulmonary embolism. CTPA, computed tomography pulmonary angiography; DVT, deep vein thrombosis; PE, pulmonary embolism. The prevalence of PE in patients presenting with syncope has been highly debated this year, following the PESIT trial, reported last year, (39) describing a 17% rate of PE in syncope cases referred to emergency rooms, after excluding cases with evident aetiology. A meta-analysis including 6608 emergency department patients and 975 patients hospitalized for syncope reported a PE prevalence <1%. (48) Two other studies reported a PE prevalence of 1.4% among patients with syncope. (14, 49) Routine screening for PE in all patients presenting with syncope may not be justified. The PEITHO trial investigated long-term prognosis in patients with intermediate-risk PE randomized to receive thrombolysis or placebo. (50) Thrombolytic treatment did not decrease long-term mortality rates, persisting dyspnoea, chronic thromboembolic pulmonary hypertension, or right ventricular dysfunction. ## Acknowledgments The mention of trade names, commercial products organizations, and the inclusion of advertisements in the journal does not imply endorsement by the European Heart Journal, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. The editors and publishers have taken all reasonable precautions to verify drug names and doses, the results of experimental work and clinical findings published in the journal. The ultimate responsibility for the use and dosage of drugs mentioned in the journal and in interpretation of published material lies with the medical practitioner, and the editors and publisher cannot accept liability for damages arising from any error or omissions in the journal. Please inform the editors of any errors. The opinions expressed in the European Heart Journal are those of the authors and contributors, and do not necessarily reflect those of the European Society of Cardiology, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. OUP and the ESC are not responsible or in any way liable for the accuracy of the translation, for any errors, omissions or inaccuracies, or for any consequences arising therefore. Sandra Makarović and Kristina Selthofer-Relatić are solely responsible for the translation published in this reprint. Translation edited by: Mario Ivanuša. Language editing: Tomislav Salopek.

Børge G. Nordestgaard, Francesco Cosentino, Ulf Landmesser, Ulrich Laufs

## Preamble During 2017 several landmark studies have been published that have practical implications for atherosclerotic cardiovascular disease (ASCVD) prevention and risk factor control, such as lipids and lipoproteins, inflammation, diabetes, hypertension, and healthy lifestyle. We use the term ‘ASCVD’ where relevant to simplify the reading of this article for the non-specialist, although the exact definition as ASCVD differ slightly from study to study. However, in sections where ASCVD clearly is not the relevant endpoint (e.g. in hypertension research) we do not use ‘ASCVD’, but instead of use other words to describe endpoints. All relevant trials have been performed on a background of optimal medical therapy, such as described in the European Society of Cardiology(ESC)/European Atherosclerosis Society (EAS) guidelines on ASCVD prevention and management of dyslipidaemia for lipid-lowering. (1, 2) For example, important new evidence for additional risk reduction relates to lipid-lowering [proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, (3) cholesteryl ester transfer protein (CETP) inhibition (4)] to the reduction of systemic inflammation (interleukin-1β inhibition (5)) and to anti-thrombotic therapy (low-dose factor Xa antagonism (6)). Since these novel treatments have not yet been tested in combination and because of the practical and economic limitations, an important challenge for the years to come is patient selection. Also, the benefit to risk dimension of any new therapeutic agent needs to be considered. This review article is intended to provide the practicing physician with the information needed to identify patients in secondary prevention that may benefit the most from additional novel treatments (**Figure 1**), and at the same time give a comprehensive update of novel insights relevant both to primary and secondary prevention of ASCVD. Use and accessibility of novel treatments will depend critically on whether patients live in high income, upper middle-income or lower middle-income countries, as levels of cardiovascular risk factors, cardiovascular mortality rates, and thus the prevention potential differ between such countries. (7) Figure 1. A 2017 optimally treated patient with coronary heart disease on statin, aspirin, angiotensin-converting enzyme inhibitor, and beta-blocker. Do new trials suggest that we should add additional drugs or lifestyle modification, and what in whom? PCSK9, proprotein convertase subtilisin/kexin type 9; LDL-C, low-density lipoprotein cholesterol; ACE, angiotensin converting enzyme. This Figure has been reprinted with permission of Oxford University Press on behalf of European Society of Cardiology. This Figure has been reprinted with permission of Oxford University Press on behalf of European Society of Cardiology. ## Lifestyle Observational epidemiology in the field of lifestyle is difficult to trust due to the high-risk of confounding (a third factor influences both disease risk and lifestyle) and reverse causation (diseases will change a person’s lifestyle), and therefore only randomized intervention trials and genetic Mendelian randomizations studies can be trusted. However, each of these study designs have limitations. (8–10) Importantly, as randomized intervention trials are very difficult to conduct for lifestyle factors, we often are left with observational and genetic studies in this field. Below is what we choose to highlight for 2017. The concept of ‘metabolically healthy obesity’, namely that in the absence of metabolic dysfunction, individuals with excess adiposity are not at greater cardiovascular risk, has been controversial. A recent pan-European case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition study (EPIC-CVD), observed higher cardiovascular risk with increasing general and central adiposity. (11) Other cohort studies have challenged this concept reporting an excess of cardiovascular risk in metabolically healthy obese as compared to normal weight individuals. (12–15) These results highlight the importance of population-wide prevention of obesity with lifestyle intervention targeting eating behaviour and physical activity. Importantly however, steady and sustained weight loss is preferable as in patients with coronary heart disease the highest vs. lowest variation in body weight was associated with 64% more coronary and 124% more mortality events. (16) Coffee consumption is observationally associated with reduced all-cause, cardiovascular and other cause-specific mortality. (17–19) However, both reverse causation and confounding by other lifestyle factors may bias such results. Interestingly therefore, Mendelian randomization studies free of confounding found no causal effect of coffee intake on all-cause or cardiovascular mortality, or on cardiovascular disease. (19) Likewise, in Mendelian randomization studies milk intake appears not to influence risk of hypertension or cardiovascular disease. (20, 21) Alcohol intake: novel findings include that acute beer alcohol consumption during the Munich Octoberfest was associated with cardiac arrhythmias and sinus tachycardia. (22) Large UK and USA cohorts found moderate alcohol intake associated with less of most cardiovascular disease endpoints while heavy and binge drinking or alcohol abuse were associated with more cardiovascular disease or deaths. (23–25) A Mendelian randomization study of genotypes associated with higher education suggested that low education is causally associated with ASCVD events. (26) Using UK-Biobank participants, it was observed that the association between physical activity and mortality was strongest in those with lowest strength and lowest cardiorespiratory fitness, suggesting that these subgroups would benefit the most from more physical activity (27); preventing or delaying cardiovascular disease or diabetes seemed to delay cognitive decline and possibly dementia. (28) Adherence to a healthy lifestyle consisting of non-smoking, light to moderate alcohol intake, high physical activity, fruit and vegetables intake, and normal body weight was associated with a substantially lower burden of ASCVD in Chinese, (29) like previously observed in Europeans. Interestingly, in Spain skipping breakfast was associated with more non-coronary and generalized atherosclerosis, independent of other cardiovascular risk factors. (30) Importantly however, lifestyle can be difficult to change, even for patients with acute coronary syndrome and/or revascularization. (31) Further, in the PURE study covering all major parts of the World and recruiting 135 335 individuals between 2003 and 2013 with follow-up until 2017, higher intake of fruit, vegetables, and legumes was associated with lower non-cardiovascular and total mortality, with a non-significant trend for cardiovascular mortality. (32) The findings also included that as little as three servings per day consisting of only 375 g per day were associated with similar benefit. This indicate that optimal health benefits may be achieved with a more modest consumption of fruit, vegetables, and legumes than that recommended in high-income Europe and the USA, an approach that is more likely to be affordable in low-income and middle-income countries. In contrast to popular opinion, higher fat intake was not associated with ASCVD or death. Finally, air pollution, noise, and other environmental stressors, depending on where a person choose to live, may influence cardiovascular health and mortality. (33, 34) For example, long-term exposure to road traffic noise and ambient air pollution were associated adversely with cardiovascular biochemical risk factors (35) and self-reported hypertension. (36) Worldwide ambient air pollution with aerodynamic diameter 2.6 mmol/L (100 mg/dL)] treated with intense statin therapy, were randomized to evolocumab or placebo (3): LDL cholesterol was reduced 59% to 0.8 mmol/L (30 mg/dL), ASCVD events 15% (absolute risk reduction 1.5%), and myocardial infarction was reduced 27% (absolute risk reduction 1.2%). Moreover, a pre-specified secondary analysis of FOURIER suggested reduced ASCVD at achieved LDL cholesterol 50 000 men aged 65–74 to screening or not for abdominal aortic aneurism, peripheral arterial disease, and hypertension; those diagnosed in the screening group were offered relevant follow-up and treatment including surgery and antihypertensive medication, which was associated with a 7% reduced all-cause mortality (absolute risk reduction 0.6%) primarily linked to initiation of pharmacological therapy. (133) Importantly, mortality related to abdominal aortic aneurism may differ from country to country, and can be influenced by rate of surgical repair and aneurysm diameter at repair. (134) A low ankle-brachial index help identify patients with abdominal aortic aneurism and peripheral arterial disease and predict ASCVD events, although to a lesser extent than increased coronary artery calcification. (135) Arterial thrombosis depends on atherosclerotic plaque vulnerability, which likely differs in individuals taking statins or not due to reduced lipid-driven plaque inflammation in those on statins. (136) Interestingly, new data support that a chronically affected haematopoietic system potentially drive low-grade inflammation in patients with atherosclerosis. (137) For venous thromboembolism, meta-analyses of observational studies found a 27% reduced risk of recurrent venous thromboembolism associated with statin use, (138) in accordance with findings in the randomized JUPITER trial. (139) Finally, in patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was reduced approximately 70% by rivaroxaban compared with aspirin, without a significant increase in bleeding rates; (140) this confirms previous studies with other novel oral anticoagulants. ## Guidelines and consensus statements Despite evidence-based recommendation for widespread use of statins in both primary and secondary prevention of ASCVD, (1, 2) statin compliance is a major problem worldwide, (141, 142) partly due to negative press (143, 144) and in consequence discontinuation of statin use and increased risk of myocardial infarction and cardiovascular mortality. (143–146) In support, in the ASCOT-LLA trial muscle-related adverse events were similar in those receiving atorvastatin and placebo during blinding, however, after un-blinding and follow-up for an additional 2.3 years muscle-related adverse events were now 41% higher in those who knew they were receiving atorvastatin. (147) Therefore, any patient claiming statin intolerance including muscle symptoms needs careful counselling with his or her physician, including better diagnostics of statin intolerance and advice on how to continue statin therapy despite perceived side effects. (141, 142, 148) Various updates of major guidelines for prevention of cardiovascular disease has occurred lately, (1, 149–154) and despite use of the same scientific evidence to guide lifestyle changes and medical intervention advise tend to differ between guidelines. For example, the ACC/AHA guidelines compared with the ESC/EAS guidelines placed higher priority for assigning statins in primary prevention to those who later developed ASCVD (155); this difference was mainly explained by the fact that the American guidelines assigned statin therapy to more individuals that the European guidelines. That said, the European guidelines is limited by using the SCORE algorithm for ASCVD risk assignment based only on ASCVD mortality in cohorts recruited many years ago, and limited to only 40–65 years old. (156, 157) Although the risk of ASCVD increases with increasing age above 65 years (156) with age as the most important ASCVD risk predictor, arguments differ with respect to how important age should be in determining statin assignment. (158, 159) Although the American ACC/AHA risk score overestimates ASCVD risk, particularly in Chinese, (160) the European ESC/EAS SCORE may in some populations overestimate risk even more. (155) Therefore, ideally risk scores for ASCVD needs to be recalibrated to each country and ethnic group before it is used to assign statin therapy. In 2017, exactly that has happened for the UK QRISK3 risk prediction algorithms for the NICE guidelines, (149) using current data from 981 general practices and 7.9 million patients aged 25–84 in England to develop new scores and another 328 practices and 2.7 million patients to validate the new score algorithms. (161) By 2017, the use of non-fasting rather than fasting lipid profiles is now recommended in many guidelines and consensus statements worldwide, (89) including in the UK, (149) Europe, (1, 2, 162) Canada, (150, 151) Brazil, (163) and in the USA. (153, 164, 165) Finally, new USA guidelines have lowered the threshold for the definition of hypertension to ≥130/80 mmHg systolic/diastolic BP (earlier 140/90 mmHg), (166) placing very large proportions of adult populations in potential need for BP-lowering medication or intensified BP-lowering in the USA. ## Conclusion 2017 has been a very exciting year for studies in ASCVD prevention, including landmark clinical trials, genetic Mendelian randomization studies, and observational prospective cohort studies. **Figure 1** illustrates some of the new concepts for additional preventive measures in secondary prevention in a patient with coronary heart disease already on statin, aspirin, ACE inhibitor, and beta-blocker. Naturally, many new concepts await confirmation by additional studies and their test in clinical practice. Importantly, considerable inter-individual variability has been noted in the response to a number of the agents discussed in this review. Therefore, for all new (and old) drugs, it is important to monitor response, particularly at a time when economic pressures oblige clinicians to use therapeutic agents in an optimal manner on a personalised basis. ## Acknowledgments Published on behalf of the European Society of Cardiology. All rights reserved. © The Author. For permissions please email: journals.permissions@oup.com