Cardiologia Croatica. 2020;15(5-6)

A. John Camm, Gregory Y.H. Lip, Richard Schilling, Hugh Calkins, Jan Steffel

## Preamble During this last year, there has been much progress with regard to anticoagulant and ablation therapy for atrial fibrillation (AF). Apart from recently issued European Society of Cardiology Guidelines for the management of patients with supraventricular arrhythmias, there has been little progress in research in this field. Ventricular arrhythmias and device therapy have seen modest progress. ## Supraventricular tachycardias This year has seen several publications on the ECG diagnosis of supraventricular tachycardia (SVT) (1–4) and interest in new consumer-led discovery of supraventricular arrhythmias. (5) EP mapping technology has provided better mapping of SVT. (6) There has been a surprising interest in new antiarrhythmic drugs for SVT, ranging for intranasal etripamil (an L-type calcium antagonist) for termination of SVT (7, 8) and nifekalant to increase the refractoriness of accessory pathways and reduce the rate of pre-excited supraventricular arrhythmias. (9) ## Guidelines 2019 saw new European Society of Cardiology guidelines for the management of patients with SVT (10) which had previously been in 2003. However, there was little which was very new. The guidelines insisted that ablation was the best initial management for most re-entrant atrial and AV junctional tachycardia. However atrial tachycardia occurring after ablation for AF should not be considered for ablation until at least 3 months after the AF ablation procedure. The guidelines stressed that ablation for AV nodal re-entrant tachycardia could be achieved in almost all without risk of AV block. An invasive EP risk assessment of Wolff–Parkinson–White syndrome was recommended even in patients who are asymptomatic but have high-risk occupations or are competitive athletes. The guidelines recommend ablation in high risk or symptomatic WPW patients but stop short of recommending ablation of all accessory pathways. It is pointed out that SVT may cause tachycardia mediated cardiomyopathy and that ablation may not only eliminate the tachycardia but restore ventricular function. There are strong Class III recommendations—‘what not to do’, mostly related to antiarrhythmic drug therapy (**Figure 1**). FIGURE 1. Some ‘What not to do’ recommendations from the 2019 ESC Guidelines on the management of patients with supraventricular tachycardia. MRAT, macro re-entrant atrial tachycardia. Reproduced from Brugada et al. (10) ## Atrial fibrillation risk assessment and treatment decisions Various studies have highlighted new developments in the risk assessment for the development of AF and its complications, as well as the use of the non-vitamin K antagonist oral anticoagulants (NOACs) as thromboprophylaxis. ## Risk assessment Numerous clinical factors associated with incident AF have been described (11) but a simple, practical and reliable approach to identifying patients at risk of incident AF is needed. Clinical factors such as change in body mass index have been associated with an increased risk of AF, (12) as has disordered sleep pattern. (13) Various clinical risk scores for identifying incident AF have been described, and as with most clinical scores, all have modest predictive value for identifying high-risk patients and until recently, have been complex models derived from multivariate analyses. The C2HEST score was derived and validated in Asia and has recently been externally validated in a French post-stroke cohort and the Danish nationwide registries. (14, 15) This would facilitate targeted intensive screening for AF, for example, in the post-stroke population with AF, where oral anticoagulation (OAC) as secondary prevention is well established. In contrast, two randomized trials in embolic stroke of unknown source (ESUS) using NOACs failed to show a significant reduction in recurrent stroke, while one trial (NAVIGATE-ESUS) showed an excess of bleeds. (16, 17) Screening for AF has attracted much attention, with population-based approaches and new technologies. (18) The Apple Watch study investigated if a smartwatch-based irregular pulse notification algorithm identified possible AF, and reported that among participants who received notification of an irregular pulse, 34% had atrial fibrillation AF on subsequent ECG patch readings and 84% of notifications were concordant with AF. (19) The Huawei Heart Study also showed the usefulness of photoplethysmographic (PPG) -based technology in population screening for AF, with the positive predictive value of PPG signals being 91.6% and leading to improved anticoagulation use (>80%). (20) Risk assessment continues to evolve, with availability of new data showing stroke risks associated with AF patients with hypertrophic cardiomyopathy (21) and imaging-documented significant coronary artery lesions. (22) There has been much interest into use of sophisticated methods such as machine-learning, even predicting incident AF from a simple 12-lead ECG. (23) More complex risk assessment approaches improve AF stroke risk prediction (at least statistically) but need to be balanced against simplicity and practical application. For now, an independent Patient Cantered Outcome Research Institute (PCORI)-sponsored systematic review and evidence appraisal identified that amongst the commonly used risk stratification schemes in patients with AF, the CHA2DS2VASc and HAS-BLED scores were the best predictors for stroke and bleeding risks, respectively. (24) Bleeding risk prediction only focused on modifiable bleeding risk factors is an inferior strategy to a formal risk assessment using the HAS-BLED score. (25, 26) Stroke and bleeding risk assessments incorporating biomarkers have been proposed based on highly selected anticoagulated clinical trial cohorts but ‘real-world’ studies have not shown the usefulness of such schemes. One study showing sequential addition of biomarkers did not improve the usefulness of stroke and bleeding risk prediction. (27) Also, there are no data across the patient pathway, when first diagnosed and non-anticoagulated, or on aspirin—and following the initiation of OAC. Of note, many risk factors are based on baseline risk assessment but do not remain static and changes with age and incident risk factors. (25, 28) Thus, AF assessment is not a ‘one off’ item and needs to be reassessed at regular intervals, e.g. every 4–6 months. (29) ## Non-vitamin K antagonist oral anticoagulants and atrial fibrillation management in clinical practice The NOACs have changed the landscape of stroke prevention in AF. These drugs are now the preferred OAC option in most guidelines, but challenges remain in its use amongst high-risk subgroups that were under-represented in clinical trials, as well as its adherence and persistence. Clinical trial cohorts are selected populations and may be at lower risk compared to ‘real-world’ clinical practice data. (30) The year also saw the first publications of real-world data for edoxaban, which was the fourth NOAC to enter the market. (31) Increasing data for the NOACs in the elderly have been published, (32, 33) clearly showing their effectiveness and safety even in very elderly subjects, aged ≥80. Additional data emphasize the importance of using the appropriate label-adherent dosing to ensure best outcomes, as well as persistence data with the NOACs, for example, with dabigatran. (34) One trial, AEGEAN showed high adherence and persistence with apixaban (~90%) but did not show additional benefit from interventions to improve adherence/persistence. (35) Also, studies of NOAC use in extremes of renal function, both severe renal impairment and supra-normal renal function. The latter is pertinent given that all three Factor Xa inhibitors showed numerically more ischaemic strokes in the subgroup with CrCl >95 mL/min when compared with warfarin in their pivotal trials, although this is not apparent in real-world observational data. (36) In end-stage renal failure, observational data show better safety for apixaban over warfarin. (37) The last year has seen new trials with NOACs in catheter ablation (CA) for AF, and in the setting of AF patients presenting with an ACS or undergoing PCI/stenting. For CA, an uninterrupted NOAC-based strategy appears to be a safer option compared to a warfarin-based strategy. (38–40) In AF/ACS/PCI patients, the publication to AUGUSTUS and ENTRUST-AF PCI completes the trials of NOACs in this clinical setting. (41, 42) These trials suggest that when OAC is used, a NOAC-based regime or a dual therapy (i.e. OAC plus a P2Y12 inhibitor) is associated with less major bleeding. (43) Of the overall thrombotic or ischaemic outcomes, there is little difference between a triple therapy or dual therapy approach, or a NOAC-based strategy compared to a warfarin-based strategy. However, a dual therapy approach may be associated with an excess of stent thrombosis and myocardial ischaemic events, thus patients who are at high risk of such outcomes may merit a short period of triple therapy at the start. In stable coronary disease, OAC alone is associated with better outcomes compared to dual therapy, in the AFIRE trial. (44) While the concept of integrated AF management has been proposed, its application and implementation in a simple user-friendly manner have not been previously validated. Integrated care has been associated with reduced mortality and hospitalization. (46) One integrated and holistic approach to AF management, streamlining the decision-making management approaches that would be uniformly applicable across the whole AF patient pathway, starting with primary care and linking with secondary care (including cardiologist/non-cardiologists), and understandable for the AF patients per se, is the ABC (Atrial fibrillation Better Care) pathway: Avoid stroke; Better symptom management with patient-centred symptom directed decisions on rate or rhythm control; Cardiovascular and risk factor optimisation, including lifestyle changes (45) (**Figure 2**). The ABC pathway approach has now been shown in independent studies to be associated with a reduction in mortality, hospitalization and adverse outcomes, as well as reduced healthcare costs, when compared to ‘non-ABC’ adherent management. (47–50) The ABC pathway was tested in a cluster randomized trial showing improved clinical outcomes with an ABC pathway management based on an interactive App that included risk assessments, patient decision aids, educational materials and dynamic tracking of risk (mAFA-II trial (20); presented as Late Breaking Science at the ESC congress, September 2019). FIGURE 2. Please see the original article (Eur Heart J. 2020 Feb 1;41(5):619-625c.). ## Ablation ## Clinical outcomes A number of publications have described AF CA outcomes and impact on prognosis. Probably the most eagerly awaited was the CABANA study. (51) This multicentre study randomized 2204 patients to CA or drug therapy. As designed, intention to treat, the study was neutral for CA impacting on the primary composite endpoint of death, disabling stroke, serious bleeding, or cardiac arrest. This type of study is incredibly difficult to recruit for because the clinicians most likely to recruit are seeing a patient referred for a CA, so even if they are prepared to enter the study, the cross-over rate is likely to be high from drug to ablation, as it was in this study (27.5%). When analysing by treatment, there was a prognostic benefit, but this subverts the principle of randomization and increases bias. The cerebral micro-emboli associated with AF CA do not appear to have much impact and CA itself may improve cognitive impairment as in 308 patients studied and followed for 1 year. (52) Most electrophysiologists continue to tell patients that the primary goal of AF ablation is quality of life (QOL). The first randomized controlled trials (RCT) of AF CA vs drugs to examine QOL as the primary endpoint was published in 2019 and favoured CA. (53) While this was a small study, 155 patients, it does open the way for double-blind RCTs of AF CA with QOL as the primary outcome. The use of cryoablation for AF has accumulated more evidence this year: it is faster than RF CA, (54) associated with lower risk of pericardial effusion, (55, 56) and has superior outcomes (54, 55) regardless of centre volume. (57) Several large registries have published this year. The Swedish registry reveals CA procedure complications and death were low and that AF, ventricular tachycardia (VT), and premature ventricular complex (PVC) CA numbers increased with AF having the highest repeat procedure rate (41%). (58) A European registry demonstrated that cryoablation is as effective for female patients but is associated with higher complication rates. (59) The Danish registry confirmed that success rates for AFL ablation were 90% but that AF is a common presentation (13%) within 2 years after. (60) The German Helios registry showed that pericardial effusion rates were 0.9% in 21 141 AF CA, and was more likely in low volume centres, but only if RF was used rather than cryo. (55) CA of VF storm after myocardial infarction was reported in a multicentre study of 110 patients. (61) In-hospital mortality (27%) and 2-year follow-up mortality (36%) were high and associated with the time taken to perform CA. A retrospective study of 110 patients demonstrated CA of recurrent VT in patients with arrhythmogenic ventricular cardiomyopathy is no more effective than drugs but is more likely to be successful if both epicardial and endocardial approaches are used. (62) ## New mapping technologies It is recognized that the primary reasons for failure of CA in complex arrhythmia are a lack of understanding of the mechanism. There continues to be huge effort to solve this. This year ripple mapping has been used successfully used in persistent AF (18 months 53% vs. 39% conventional), (64) atrial tachycardia, (65) and VT in arrhythmogenic right ventricular cardiomyopathy (ARVC). (66) Non-contact mapping is returning to clinical practice with an observational trial showed good outcomes for persistent AF CA at 12 months (59%). (67) The STAR mapping system (**Figure 3**), presented its feasibility clinical trial of 35 patients showing freedom from AF after persistent AF CA guided by STAR of 80% at 18 months. (68) It remains to be seen whether any of these make it to widespread clinical use. FIGURE 3. Please see the original article (Eur Heart J. 2020 Feb 1;41(5):619-625c.). ## Energy sources High power short-duration RF may make point-by-point AF CA faster and, at least so far, not being associated with worse outcomes. (63) Electroporation is also showing promise as a novel energy source that is highly effective with low complication rates. (69) The use of radiotherapy to treat intractable VT is an exciting innovation, showing promising results in a small prospective study of 19 patients. (70) ## Guidelines and consensus statements A number of guidelines have been published this year and while these are useful reviews of the literature, the temptation to accept them as dogma has to be resisted given that they are often drive by consensus of a well-intentioned writing group rather than hard data. CA of ventricular arrhythmia (VA) guideline suggests that programmed electrical stimulation may come back into fashion as a method for prognostic prediction, this time in patients with frequent PVCs and structural heart disease, and also recommends use of ICE for VA ablation although much of the world does not use ICE without any apparent compromise to their outcomes. (71) The sex differences in arrhythmia consensus highlighted that although outcomes may be different, this should not influence provision of CA for females. (72) ## Ventricular arrhythmias ## Arrhythmogenic cardiomyopathy This has been an exciting year in arrhythmogenic cardiomyopathy (ACM). There are major publications to be aware of. The first is the Heart Rhythm Society Consensus Document on Arrhythmogenic Cardiomyopathy. (73) This document, which was led by McKenna and Towbin redefines ACM as a condition that presents with symptomatic and/or asymptomatic arrhythmias in association with some degree of cardiac dysfunction. This ‘big tent’ approach includes classic ARVC, the more recently described arrhythmogenic left ventricular cardiomyopathy, as well as other subgroups of patients. Included within ACM are sarcoidosis, Chagas disease, myocarditis, and a large number of inherited cardiomyopathies. This is a comprehensive and provocative article that is important to be aware of. One of the writing groups goals was to encourage having patients present with arrhythmias and a cardiomyopathy to a specialized centre that perform comprehensive evaluation, arrange for genetic testing, and determine a patient’s arrhythmic risk and need for an ICD. (74) Another important publication was authored by Cadrin-Tourigny et al. (74) Through the combined efforts of five international ARVC registries, an ARVC risk calculator was developed to help estimate arrhythmic risk and inform decisions regarding ICD implantation (www.ARVCrisk.com). More than 500 ARVC patients from five registries in North America and Europe were enrolled. During 5 years of follow-up, 28% experienced sustained VT, sudden death, or received an appropriate ICD therapy. A prediction model to estimate annual arrhythmic risk was developed (**Figure 4**). The variables at baseline included in the model are recent syncope, age, gender, non-sustained VT, the number of PVCs in 24 h, and right ventricular ejection fraction. And a final paper by Chatterjee et al. (75) investigated the diagnostic value of an anti-Desmoglein-2 antibody in diagnosing ARVC. An antibody to DSG-2 was identified in 12/12 and 25/25 ARVC cohorts and 7/8 borderline subjects. The antibody was absent in 11/12 and 20/20 control cohorts. The authors concluded that anti-DSG-2 antibodies are a sensitive and specific marker for ARVC. Before this test can be used clinically, it will need to be tested in more control populations including those with cardiac sarcoidosis. FIGURE 4. Prediction of sustained ventricular arrhythmia in arrhythmogenic right ventricular dysplasia/cardiomyopathy. ARVC, arrhythmogenic right ventricular dysplasia/cardiomyopathy; INV., inversion; PVC, premature ventricular complex; RVEF, right ventricular ejection fraction; VT, ventricular tachycardia. (74) ## Cardiac arrest Sondergaard et al. (76) examined the use of bystander CPR among patients who experience out of hospital cardiac arrest in Denmark. More than three-fourths of cardiac arrests occurred in residential locations. Bystander CPR increased between 2001 and 2004 from 36% to 84% in public locations and from 16% to 61% in residential locations. Not surprisingly, the increased use of CPR resulted in an increased 30-day survival from 6% to 25% for arrests in public locations and from 3% to 10% in residential locations. ## Cardiac devices What is the evidence behind current guideline recommendations for primary prevention ICD implantation in our present day and age? Can patient populations, background therapies and treatment algorithms, particular in heart failure, underlying trials conducted well over a decade ago be extrapolated to current daily clinical practice? (**Figure 5**) (77) According to a large analysis from the French-British-Swedish-Czech CRT Network, death due to progressive heart failure remains the leading cause of death for the majority of patients. (78) Moreover, increasing evidence indicate left ventricular (LV) remodelling as a main driver or arrhythmogenic events leading to sudden cardiac death (SCD), which may be reduced by modalities aimed at preventing (or even reversing) these processes, i.e. neurohormonal blockade and cardiac resynchronization therapy (CRT). (79) These concepts and findings call into question the validity of the available randomized clinical trial evidence underlying current recommendations for primary prevention ICD implantation in heart failure patients. On a conceptual level, they additionally raise the question if trials should generally come with a ‘due date’ after which they would require re-validation. On the flipside, however, device therapies have advanced over the last decades, including better algorithms to detect ventricular arrhythmias and to prevent inadequate shocks, as well as the development of extravascular systems such as the S-ICD and the extravascular (EV-) ICD. (80) Indeed, even entirely leadless CRT systems appear to be feasible. (81) If proven safe and effective in the (ongoing) large RCTs, these novel modalities will come with a substantially reduced system-related morbidity, which may again tip the scale towards device-based SCD prevention. Indeed, inadequate shocks, as well as infections, remain the most devastating complications of current ICD systems, which come along with a substantial impact on quality of life, morbidity, and mortality. (82) FIGURE 5. Two-year cause-specific mortality and non-fatal vascular events for patients with cardiovascular disease according to New York HeartAssociation class. Numbers and proportions are a conceptual representation of absolute and relative risk and are not strictly evidence based. Note that for patients in New York Heart Association Class 4, interventions for sudden arrhythmic death may be ineffective or fail to lead to a meaningful prolongation of life because the patient is likely soon to die of worsening heart failure. CRD, congestion-related death, otherwise called death due to worsening heart failure; NFVE, non-fatal vascular event (e.g. myocardial infarction and stroke; note that events are more likely to be suddenly fatal as heart failure progresses); NON-CVD, non-cardiovascular death; RSAD, resuscitatable sudden arrhythmic death; SVD, sudden vascular death; TSAD, terminal (non-resucitatable) sudden arrhythmic death. In addition, better means of risk prediction for SCD above and beyond left ventricular ejection fraction (LVEF) are desperately needed in order to better protect those patients who need it (and prevent those who do not from unnecessary device implantation). One such risk prediction model for patients post-myocardial infarction with preserved LVEF has recently been put forward using electrocardiographic non-invasive risk factors (PVCs, non-sustained VT, late potentials, prolonged QTc, increased T-wave alternans, reduced heart rate variability, and abnormal deceleration capacity with abnormal turbulence) combined with programmed ventricular stimulation. (83) The algorithm yielded an excellent sensitivity and negative predictive value (arguably the most important parameter) of 100%, as well as a specificity of 93.8%; on the downside, positive predictive value was only 22%. Modern imaging modalities such as MRI may further yield added value in identifying patients at increased risk of ventricular arrhythmias who may benefit from ICD implantation. (84) Similar algorithms are being developed also for rarer disease entities such as arrhythmogenic right ventricular cardiomyopathy (ARVC). (74) If proven positive in randomized clinical outcome trials, these concepts may move the field closer to venturing beyond the current (suboptimal) standard of LVEF for risk stratification. Until such outcome trials are available, however, it may be prudent to stick to the currently available evidence and guideline recommendations; at the same time, recruitment into ongoing trials is encouraged in order to accelerate the generation of high-level evidence which may potentially alter current clinical practice. Cardiac resynchronization therapy remains an important treatment modality for heart failure patients to induce reverse LV remodelling and to improve morbidity and mortality. However, the rate of so-called ‘non-responders’ remains in the order of 20–30%, depending on definitions and cut-offs. (85) The MORE-CRT MPP trial investigated the effect of stimulating the LV from two sites instead of one to reduce the number of non-responders. (86) Five hundred and forty-four patients classified as non-responders (defined as an LV end-systolic volume reduction by <15%) 6 months after CRT implantation were randomized to receive the ‘Multipoint’™ algorithm turned on (MPP ON) or off (standard of care group). While the conversion rate to ‘responders’ was no different between the two groups (31.8% vs. 33.8%) patients in the MPP group programmed to a wide electrode distance were significantly more likely to convert to responders than those programmed to other vector combinations (45.6% vs. 26.2%, P = 0.006). (86) Although interesting and biologically plausible, these findings have to be viewed as hypothesis-generating in view of the negative primary endpoint. ## Acknowledgments Reproduced from: Camm AJ, Lip GYH, Schilling R, Calkins H, Steffel J. The year in cardiology: arrhythmias and pacing. Eur Heart J. 2020 Feb 1;41(5):619-625c. https://doi.org/10.1093/eurheartj/ehz931, by permission of Oxford University Press on behalf of the European Society of Cardiology. ® The Authors(s) 2020. All rights reserved; no part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission of the Publishers. For Permissions, please email: journals.permissions@oup.com The opinions expressed in the Journal item reproduced as this reprint 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. The mention of trade names, commercial products or organizations, and the inclusion of advertisements in this reprint do not imply endorsement by the Journal, the editors, the editorial board, Oxford University Press or the organization to which the authors affiliated. The editors and publishers have taken all reasonable precautions to verify drugs 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 this reprint 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 or in this reprint. Please inform the editors of any errors. Oxford University Press, OPL., and the European Society of Cardiology are not responsible or in any way liable for the accuracy of the translated reprint, for any errors, omissions, or inaccuracies, or for any consequences arising therefrom. Ivica Premužić Meštrović and Mario Ivanuša are solely responsible for the translation and this reprint.

Andreas Baumbach, Christos V. Bourantas, Patrick W. Serruys, William Wijns

## Preamble Percutaneous coronary intervention (PCI) research focuses on the optimization of treatment strategies, the development of novel equipment and pharmacotherapies for improved results, and on risk stratification and identification of high-risk patients that will benefit from emerging therapies targeting atherosclerotic evolution. Over the last year, important clinical studies have been reported that examined the efficacy of different treatment strategies and stent platforms in patients with obstructive coronary artery disease (CAD) and guidelines have been published to provide recommendations about the management of these patients. The aim of this article is to summarize the findings of the pivotal studies published in 2019 and discuss their impact on clinical practice. Revascularization in patients with cardiac arrest or acute coronary syndromes Coronary Angiography after Cardiac Arrest (COACT) is a landmark study that changed the management of patients admitted with a cardiac arrest who had successful resuscitation and no ST elevation myocardial infarction (STEMI). (1) In this prospective multicentre trial, 552 patients admitted with an out of hospital cardiac arrest with an initial shockable rhythm who did not have an obvious non-cardiac cause of arrest were randomized to immediate coronary angiography and if needed coronary revascularization or delayed coronary angiography after neurological recovery. An acute thrombotic occlusion was noted only in 3.4% of the patients in the immediate angiography and in 7.6% of the patient in the delayed angiography group. Survival rate at discharge (65.2% vs. 68.7%) and at 90-day follow-up (64.5% vs. 67.2%) was not different between randomization groups. In addition, there was no difference for the incidence of the composite endpoint survival with good cerebral performance or mild or moderate disability (62.9% vs. 64.4%). These findings contradict previous observational studies that penalized a delayed invasive assessment of the coronary artery anatomy and justify both approaches in this setting. Conversely, the Complete vs. Culprit-Only Revascularization Strategies to Treat Multivessel Disease after Early PCI for STEMI (COMPLETE) study confirmed the value of an aggressive revascularization strategy in patients admitted with a STEMI. (2) In this study, 4041 patients who had multivessel CAD were randomized in a 1:1 ratio to complete revascularization vs. culprit-lesion-only PCI. At 3-year follow-up, the incidence of the composite endpoint cardiovascular death or myocardial infarction (MI) was lower in patients undergoing complete revascularization as compared to the patients that had PCI only in the culprit vessel (7.8% vs. 10.5%; P = 0.004); of note, the benefit of complete revascularization was similar in patients who had an in-hospital second procedure compared to a procedure following readmission within 45 days post-discharge; however, this comparison was not randomized, as the choice for timing of the second procedure was left to operator’s discretion. The prognostic value of complete revascularization in patients with non-STEMI has not been fully investigated yet. ## Chronic coronary syndromes ## Revascularization vs. medical therapy Despite the robust evidence supporting the prognostic implications of complete revascularization in patients admitted with a STEMI, studies examining the value of PCI in improving outcomes in patients with a chronic coronary syndrome show mixed results. A retrospective analysis including 16 029 patients who had positron emission computed tomography myocardial perfusion imaging demonstrated that an early surgical or percutaneous revascularization was associated with improved prognosis in patients with an ischaemic burden >5–10%. (3) These findings, however, were not confirmed in a post hoc analysis of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial that included 1379 patients who had stress perfusion imaging and quantitative coronary angiography. (4) At 7.9 years of follow-up, the extent of CAD—defined by the number of the diseased vessels—and not the severity of ischaemia was a predictor of survival. Percutaneous coronary intervention in this cohort did not improve outcomes over optimal medical therapy; more importantly, there was no interaction between the extent of ischaemia or CAD and the treatment strategy (i.e. conservative vs. PCI). In line with these findings, the International Study Of Comparative Health Effectiveness With Medical And Invasive Approaches (ISCHEMIA study) that included 5179 patients, with moderate or severe ischaemia in non-invasive imaging, who were randomized to optimal medical therapy or optimal medical therapy plus PCI demonstrated no differences in outcomes between groups at 3.3 years of follow-up for the composite endpoint of cardiovascular death, MI, admission for unstable angina, heart failure symptoms, or resuscitated cardiac arrest (15.5% vs. 13.8%, P = 0.34). (5) In this study, PCI was associated with an improvement in the quality of life, a reduction in the angina symptoms and a lower incidence of spontaneous MI [hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.53–0.83; P 22. (7) These recommendations are in line with the findings of the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) Follow-On study that included 1900 diabetic patients with multivessel disease that were randomized to surgical or percutaneous revascularization and reported a higher mortality rate at 8 years of follow-up in the PCI arm compared to the surgical revascularization group (24.3% vs. 18.3%, P = 0.010). (8) Conversely, the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) Extended Survival study that included 1689 patients with LMS or three-vessel disease did not demonstrate differences in the all-cause mortality between patients allocated to PCI and those treated surgically at 10 years of follow-up (27% vs. 24%, P = 0.092). There was, however, a treatment effect by subgroup interaction according to the presence or absence of three-vessel disease; mortality was increased in the PCI group compared to the coronary artery bypass graft (CABG) arm (HR 1.41, 95% CI 1.10–1.80), while there was no differences between the two groups in patients with LMS disease (HR 0.90, 95% CI 0.68–1.20); conversely, there was no difference in outcomes for the two treatment strategies in diabetic and non-diabetic patients (P-for interaction 0.660). (9) A limitation of both studies is the fact that the patients in the PCI arm were treated with a 1st generation drug-eluting stent (DES) that is not currently used in contemporary practice, and the fact that they both reported only all-cause mortality instead of patient-orientated cardiovascular endpoints. The Evaluation of XIENCE vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) study overcame these limitations; in this study, 1905 patients with LMS disease and SYNTAX score ≤32 were randomized to PCI with a 2nd generation DES or CABG. (10) In the PCI arm, intravascular ultrasound (IVUS) imaging was used in 77.2% of the cases. (11) At 5-year follow-up, there were no differences between groups for the combined endpoint of all-cause death, MI, or stroke (22.0% in the PCI arm vs. 19.2% in the CABG group; P = 0.13). The event rate at 30-day follow-up was lower in the PCI arm (4.9% vs. 8.0%), there was no difference between groups for the period 30 days to 1 year (4.1% vs. 3.8%), while for the period 1–5 years of follow-up a higher event rate was reported in patients undergoing PCI (15.1% vs. 9.7%). Patients randomized to CABG were more likely to suffer a cerebrovascular event (5.2% vs. 3.3%), while those treated with PCI had increased all-cause mortality (13.0% vs. 9.9%) and more often ischaemia driven revascularization (16.9% vs. 10.0%). Similarly to what it has been reported in the SYNTAX study, there was no difference in the outcomes between the two treatment strategies in diabetic and non-diabetic patients at 3- and 5-year follow-up. (10, 12) ## Percutaneous coronary intervention of bifurcation stenoses In 2019, the 3-year follow-up data of the DKCRUSH V study were published; similar to what has been reported at 1-year follow-up, double kiss-crush technique was associated with a lower incidence of target lesion revascularization (TLR, 5.0% vs. 10.3%, P = 0.029) target vessel MI (1.7% vs. 5.8%, P = 0.017), and definite or probable stent thrombosis (0.4% vs. 4.1%, P = 0.006) compared to provisional T-stenting. (13) Double kiss-crush technique, however, is a challenging procedure and requires skills and expertise; therefore, considering that the findings of the DKCRUSH V study may not be reproduced by centres with less experienced operators, the recently published 14th consensus document from the European Bifurcation Club advocates the use of provisional T-stenting technique for the treatment of bifurcations lesions and proposes a two stent strategy only in lesions with a complex anatomy, when access to the side branch is challenging, or when there is ostial disease in the side branches extending >5 mm form the carina and/or increased calcification. (14) In the case of a two stent strategy, the European Bifurcation Club recommends the use of culotte or TAP technique and when the crush technique is considered it proposes the use of the double kiss-crush. ## Treatment of chronic total occlusions In 2019, the EuroCTO Club published a consensus document that summarizes the current evidence (**Figure 1**), discusses the indications for chronic total occlusion (CTO) revascularization, presents the advances in CTO equipment, and provides recommendations about training in CTO PCI. (15) In line with the ESC guidelines on myocardial revascularization and taking into account the findings of randomized controlled studies, the EuroCTO Club recommends CTO recanalization in the presence of symptoms despite optimal medical therapy; in asymptomatic patients, ischaemic burden assessment is recommended and CTO revascularization is advised if there is evidence of increased ischaemic burden (≥10% of the left ventricular mass). These recommendation are in line with the findings of the recently reported Drug-Eluting Stent Implantation vs. Optimal Medical Treatment in Patients With Chronic Total Occlusion (DECISION-CTO) trial. (16) In this study, 815 patients with a CTO were randomized in 1:1 ratio to complete revascularization or to the treatment of the obstructive non-CTO lesions whenever these were present. Only one-fourth of the patients included in the two groups had a single-vessel disease. At 4-year follow-up, there was no difference between the two groups for the combined endpoint of death, MI, stroke, or revascularization (22.4% vs. 22.3%, P = 0.86) or patients’ quality of life. These findings indicate that in case of multivessel disease revascularization of the non-CTO lesion and re-evaluation of the extent of ischaemia and patient symptoms should be considered before advocating recanalization of a CTO. Limitations of the study—the largest of its kind—included the high crossover rate (19.6%) from the non-CTO PCI group to the CTO-PCI group within the first days from randomization as well the fact that it was underpowered for the primary endpoint as patient recruitment was early terminated because of a slow enrolment rate. FIGURE 1. Please see the original article (Eur Heart J. 2020 Jan 14;41(3):394-405.). ## Small vessel and in-stent restenosis Percutaneous coronary intervention in small vessels has been associated with a higher incidence of major adverse cardiovascular events (MACE) and TLR due to in-stent restenosis. In 2019, a pre-specified sub-analysis of the Biodegradable Polymer and Durable Polymer Drug-eluting Stents in an All Comers Population (BIO-RESORT) study was published that compared outcomes following PCI in small vessels (aPrimary efficacy endpoint: target lesion revascularization. bPrimary safety endpoint: the composite of death, myocardial infarction, or target lesion thrombosis. cNet composite endpoint: the composite of death, myocardial infarction, target lesion thrombosis, or target lesion revascularization. dNet composite endpoint: the composite of death, myocardial infarction, target lesion thrombosis, or target vessel revascularization. *This content is covered by the terms of the CC BY-NC 4.0 Open Access agreement.* ## Existing and emerging interventional devices ## Drug-eluting stents and bioresorbable scaffolds The ESC Guidelines on myocardial revascularization recommends the use of 2nd generation DES in daily clinical practice. (7) The extended follow-up of the Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST-Elevation Myocardial Infarction (COMFORTABLE-AMI) study and the nested intravascular imaging analysis published this year has provided further evidence about the superiority of DES over bare-metal stents in patients admitted with a STEMI. At 5-year follow-up, Biolimus stent implantation was associated with a lower incidence of target vessel MI (2.2% vs. 5.0, P = 0.02) and ischaemia driven TLR (4.4% vs. 10.4%, P for non-inferiority 2 and an excellent stent expansion of 102.8 ± 30.6%. (28) Recently, Wilson et al. (29) showed that IVL therapy is associated with ventricular ectopics and asynchronous pacing. In this study, no malignant arrhythmias were reported; the ongoing DISRUPT CAD III study is expected to provide further evidence about the safety and efficacy of IVL in the treatment of calcified lesions (NCT03595176). ## Adjunctive pharmacotherapy The type and the duration of antiplatelet therapy in patients undergoing PCI is an area of intensive research. The Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention (TWILIGHT) study was designed to examine the optimal duration of dual antiplatelet therapy (DAPT) following PCI in high bleeding risk patients. (30) The study randomized 7119 patients to DAPT therapy for 3 months and then treatment with ticagrelor monotherapy or DAPT for 12 months. Short duration DAPT was associated with a lower incidence of bleeding [rate of Bleeding Academic Research Consortium (BARC) type 2, 3, and 5 bleeding: 4.0% in the short duration DAPT group vs. 7.1% in the group receiving DAPT for 12 months, P 50% on quantitative coronary angiography. (49) The study was prematurely stopped after enrolling 77% of the patients because of a slow recruitment (n = 306). The authors reported a higher incidence of non-culprit lesion revascularization in the angiography group (88% vs. 22%). At 1-year follow-up, there were no differences between groups for the primary endpoint of cardiac death, MI, coronary revascularization, or re-admission because of heart failure (14% vs. 14%, P = 0.85). A limitation of the CROSS-AMI study was the fact that it was underpowered to assess differences between groups. Therefore, further research is needed to examine the value of non-invasive imaging in guiding revascularization in patients with an ACS. ## Vulnerable plaque and patient detection The event rate of patients undergoing revascularization and especially of those admitted with an ACS is high- at short-term follow-up. (50) The identification of high-risk patients has recently attracted attention as novel pharmacotherapies have been introduced that appear able to modify atherosclerotic plaque and inhibit disease progression. However, these new therapies have significant limitations as they are associated with increased cost or side effects. Accurate risk stratification and identification of high-risk individuals is expected to allow a personalized therapy and aggressive treatment of these patients with novel medications that appear to improve outcomes in vulnerable populations. (51) Large scale prospective intravascular imaging studies of coronary atherosclerosis have highlighted the value of IVUS in detecting vulnerable plaques that are likely to progress and cause events and in stratifying more accurately cardiovascular risk. In 2019, the Lipid-Rich Plaque (LRP) and the CLIMA studies were reported which for the first time assessed the efficacy of near-infrared spectroscopy (NIRS)-IVUS and of OCT in detecting vulnerable plaques. (52, 53) The LRP registry included 1563 patients with suspected CAD that had coronary angiography and possible ad hoc PCI. NIRS-IVUS imaging was performed in the non-culprit vessels in at least two major coronary arteries with length >50 mm. At 2-year follow-up, patients with increased lipid burden (4 mm lipid core burden index, maxLCBI4mm > 400) had a higher incidence of non-culprit MACE than those with lipid-free plaques (13% vs. 6%, P 4mm >400 was independent predictor of MACE at 2-year follow-up. The LRP study provided evidence for the prognostic implications of plaque composition but it failed to investigate the synergetic value of NIRS and IVUS in predicting events as IVUS analysis was not complete but restricted to the 4 mm segment with the maxLCBI. The CLIMA study was a prospective multicentre registry that investigated the prognostic implications of OCT-derived plaque characteristic in 1003 patients who had coronary angiography for clinical purposes and OCT imaging of the untreated proximal left anterior descending coronary artery. (53) In this study, a minimum lumen area 2, a lipid arc >180°, a fibrous cap thickness <75 µm, and the presence of macrophages accumulations were independent predictors of the combined endpoint cardiac death and target segment MI. Patients having lesions with all the above plaque features had a higher event rate than the other patients (18.9% vs. 3.0%, P < 0.001). ## Advances in coronary imaging Summarizing the results of these studies and taking into consideration the findings of previous reports it appears that plaque characteristics provides useful prognostic information at a lesion and patient level; but they have a limited accuracy in predicting events. Over the last years, several methodologies have been introduced to enhance the efficacy of the existing modalities in assessing plaque characteristics and an effort has been made to develop hybrid-multimodality intravascular imaging catheters that will allow a complete assessment of plaque morphology and biology. In 2019, the first in man application of the combined IVUS-OCT catheter has been presented. (54) In addition, this year the first in man application of a polarization sensitive OCT imaging system was presented; this modality is expected to enable better plaque characterization and more detailed evaluation of its components. (55) Finally, two reports have recently examined the efficacy of attenuation compensation technique, a post-processing methodology that appears able to enhance OCT imaging depth and enable more accurate evaluation of plaque burden in heavily diseased segments. (56, 57) These reports highlighted the potential of this approach in assessing plaque area in heavily diseased native vessels but also demonstrated significant limitations of this technique, because of imaging artefacts, in stented segments. Cumulative evidence has highlighted the implications of the local haemodynamic forces on atherosclerotic disease progression and destabilization. In 2019, an analysis of the Integrated Biomarkers Imaging Study 4 (IBIS-4) has shown that the shear stress distribution estimated using computational fluid dynamic analysis adds value in predicting atherosclerotic disease progression and changes in plaque morphology, while a meta-analysis of the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study has shown that estimation of plaque stress by processing virtual histology-IVUS images enables more accurate identification of lesions that will cause events in future. (58, 59) Acknowledging the importance of the local haemodynamic forces on atherosclerotic disease progression in native and stented segments expert recommendations have been recently published in a consensus document which describes the existing methodologies and their value for research and possibly clinical practice in the future. (60) ## Conclusions Published research in 2019 examining the efficacy of different treatment strategies, of emerging or existing devices and of the value of coronary physiology or intravascular imaging in PCI planning has enriched our understanding and modified the treatment of patients with obstructive CAD (**Figure 5**). Patients suffering from a STEMI should be treated aggressively aiming for complete revascularization. Conversely, an initially conservative management in patients with an out of hospital cardiac arrest without clinical evidence of ongoing acute ischaemia seems to be equally effective as an early invasive approach. Robust evidence highlights the short- and long-term efficacy of DES, while advances in coronary physiology and the development of image-based methodologies for the computation of FFR are expected to broaden its use in guiding revascularization. Cumulative data underscore the prognostic benefit of intravascular imaging in guiding PCI and in assessing lesion pathology, while advances in intravascular imaging and computational modelling are anticipated to allow better prediction of vulnerable lesions and of patients at risk that will benefit from emerging therapies targeting plaque evolution. These developments are expected to improve procedural results and long-term outcomes in patients with CAD through personalized pharmaco-invasive strategies. FIGURE 5. *Take home figure* Summary of the important clinical studies published in the field in 2019 that will have an impact on the clinical practice. AF, atrial fibrillation; BRS, bioresorbable scaffold; CTO, chronic total occlusion; DES, drug-eluting stent; ISR, in stent restenosis; IVUS, intravascular ultrasound; OFR, optical coherence tomography-based fractional flow reserve software; STEMI, st elevation myocardial infarction; VFFR, vessel fractional flow reserve software. ## Acknowledgments Reproduced from: Baumbach A, Bourantas CV, Serruys PW, Wijns W. The year in cardiology: coronary interventions. Eur Heart J. 2020 Jan 14;41(3):394-405. https://doi.org/10.1093/eurheartj/ehz947, by permission of Oxford University Press on behalf of the European Society of Cardiology. ® The Authors(s) 2020. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com The opinions expressed in the Journal item reproduced as this reprint 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. The mention of trade names, commercial products or organizations, and the inclusion of advertisements in this reprint do not imply endorsement by the Journal, the editors, the editorial board, Oxford University Press or the organization to which the authors affiliated. The editors and publishers have taken all reasonable precautions to verify drugs 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 this reprint 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 or in this reprint. Please inform the editors of any errors. Oxford University Press, OPL., and the European Society of Cardiology are not responsible or in any way liable for the accuracy of the translated reprint, for any errors, omissions, or inaccuracies, or for any consequences arising therefrom. Saša Pavasović and Mario Ivanuša are solely responsible for the translation and this reprint.

Adrian P. Banning, Filippo Crea, Thomas F. Lücher

## Preamble The management of acute coronary syndromes (ACS) has made enormous progress over the last five decades due to the introduction of defibrillation, beta blockers, thrombolytics, aspirin, primary percutaneous transluminal intervention (PCI), P2Y12 inhibitors, statins, radial access, and eventually PCSK9 inhibitors, among others. (1) However, in spite of all these remedies, there is a remaining acute mortality risk, in particular, in those presenting in cardiogenic shock or after resuscitation and an accruing number of major cardiovascular events (MACE) over the following years. (2) Thus, there is an unmet need in the management of ACS. In 2019, there were a number of important papers published in the European Heart Journal and other journals that deepened our knowledge about the spectrum of ACS and their management. Today patients presenting with acute chest pain and changes in the electrocardiogram (ECG) or biomarkers may have ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) caused by atheroma, coronary dissection, (3) takotsubo syndrome, (4, 5) MINOCA (Myocardial infarction with Non-Obstructed Coronary Arteries (6)), or myocarditis. (7) ## Genetics ## Whole-genome sequencing and early acute myocardial infarction The relative prevalence and importance of monogenic mutations related to familial hyper-cholesterolaemia (FH) and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction (MI) remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual. Khera et al. (8) performed whole-genome sequencing in 2081 patients hospitalized for early-onset AMI to assess the prevalence and clinical importance of FH mutations and a high polygenic score. They observed an FH mutation in 1.7% of patients and a high polygenic score in 17% of patients, each of which was associated with a greater than three-fold increased odds of early-onset AMI. Beyond clinical risk stratification, the polygenic score may additionally foster insights into the mechanistic underpinnings of AMI. Indeed, this risk associated with a high polygenic score is not the result of a discrete underlying mechanism but rather a quantitative blend of numerous risk pathways. ## Pathophysiology ## Plaque rupture and healing assessed by optical coherence tomography The mechanisms and the pathologic substrate of plaque erosion and plaque fissure are different. Indeed, plaques complicated by erosion tend to be matrix-rich, lipid-poor, and usually lack prominent macrophage collections, unlike plaques that rupture, which characteristically have thin fibrous caps, large lipid pools, and abundant foam cells. (9) In a prospective study in 211 patients with STEMI who underwent pre-intervention optical coherence tomography (OCT) examination for the culprit lesion, Tan et al. (10) found that trimethylamine N-oxide (TMAO) levels, a gut microbiota-dependent metabolite derived from dietary phosphatidylcholine and choline, were significantly and independently higher in patients with plaque fissure than in those with plaque erosion. The area under the receiver operating characteristic curve for distinguishing plaque rupture from plaque erosion was 0.89. Thus, plasma TMAO has the potential to serve as a novel biomarker for plaque rupture in patients with STEMI and indeed is a prognostic marker in these patients (see below). This might be relevant because risk stratification and management are probably different for plaque fissure and erosion. Healed plaque ruptures or erosions may be considered as a signature of an aborted ACS. However, the role of plaque healing in the natural history of ischaemic heart disease (IHD) is largely unknown. OCT has been validated for the detection of healed coronary plaques against histology and therefore, offers the opportunity of assessing their clinical relevance. Vergallo et al. (11) assessed plaque healing in two groups of patients at the extremes of the clinical presentations of IHD: (**a**) patients with recurring ACS, defined as history of at least three AMIs or at least four ACS with at least one AMI; (**b**) patients with long-standing chronic coronary syndromes, defined as a minimum 3-year history of stable angina in the absence of previous ACS. In the first group, non-culprit plaques only were assessed. They found that patients with recurrent ACS had a distinct atherosclerotic phenotype compared with those with chronic coronary syndrome and longstanding angina, including a much lower prevalence of healed coronary plaques, suggesting that plaque healing may play a role in leading the natural history of patients with IHD. In another OCT study, Fracassi et al. (12) assessed plaque healing in the culprit stenosis, among 376 patients with ACS and found plaque healing in more than one-quarter. Such patients more frequently were diabetic or hyperlipidaemic; furthermore, healed plaques frequently showed OCT features of local and systemic inflammation. This suggests that the combination of risk factors and local in addition to systemic inflammation may outweigh the protective mechanism of plaque healing and predispose those plaques to develop occlusive thrombus. Thus, a better knowledge of the mechanisms promoting plaque healing might provide new therapeutic targets to reduce ACS burden in addition to optimal risk factor control. ## Mechanisms of coronary microvascular obstruction The rapid re-opening and stenting of occluded epicardial coronary arteries via emergency PCI have revolutionized STEMI treatment. Despite technical refinements and the introduction of numerous antiplatelet and anticoagulant drugs, more than one-third of patients demonstrate coronary microvascular obstruction (CMVO) which deny the benefit of an apparently successful PCI. The mechanisms of CMVO are still largely unknown, while its prevention and treatment remain an unmet need. Herring et al. (13) found that STEMI patients with the highest neuropeptide Y levels in the coronary sinus had significantly lower coronary flow reserve, and higher index of microvascular resistance measured with a coronary flow wire, both markers of CMVO. After 2 days, they also had significantly higher levels of myocardial oedema and microvascular obstruction (MVO) on magnetic resonance imaging (MRI), and significantly lower ejection fractions and ventricular dilatation 6 months later. Interestingly, neuropeptide Y (NPY) (100–250 nM) caused significant vasoconstriction of rat microvascular coronary arteries via increasing vascular smooth muscle calcium waves, and increased coronary vascular resistance and infarct size in Langendorff hearts. These effects were blocked by the Y1 receptor antagonist BIBO3304. Immunohistochemistry of the human coronary microvasculature confirmed the presence of vascular smooth muscle Y1 receptors. Thus, antagonism NPY might be an attractive future therapeutic target in the prevention of CMVO (**Figure 1**). FIGURE 1. Neuropeptide-Y following primary percutaneous coronary intervention for ST-elevation myocardial infarction causes vasoconstriction of the coronary microvasculature and is associated with a high index of microcirculatory resistance and low coronary flow reserve, leading to microvascular obstruction, oedema, and eventually a lower ejection fraction and ventricular dilatation. Redrawn with permission from Ref. (13) ## New insight into post-myocardial infarction remodelling The immune response to AMI involves two equally important, consecutive phases: the inflammatory phase and the reparatory phase. During the inflammatory phase, neutrophils and inflammatory Ly6Chi monocytes are recruited into the ischaemic myocardium. Subsequently, the Ly6Chi monocytes give rise to reparatory Ly6Clo macrophages, with an important role in cardiac recovery. A balance between the two phases is crucial for recovery of cardiac function and patient prognosis. An excessive inflammatory response to AMI amplifies myocardial injury, leading to larger infarcts and loss of function. However, clinical trials testing anti-inflammatory strategies in AMI have so far led to non-significant or even deleterious effects. Ideally, an efficient therapy should inhibit the damaging effects of excessive inflammation, while leaving the repair mechanisms intact. Alarmins are a group of heterogeneous molecules released from dying cells and activated leucocytes that signal tissue damage and trigger an innate immune response. S100A9 and its dimerization partner S100A8, also called myeloid-related proteins 8 and 14, are proinflammatory alarmins that are readily produced and stored in large amounts in neutrophils and are increased at the site of acute coronary occlusion. (14) Marinković et al. (15) studied 524 patients with ACS and found that high plasma S100A8/A9 at the time of ACS was associated with lower left ventricular ejection fraction (LVEF) at 1 year and increased hospitalization for heart failure during follow-up. Moreover, in wild-type C57BL/6 mice with AMI induced by permanent coronary artery ligation, treatment with the S100A9 blocker ABR-238901 during the inflammatory phase of the immune response inhibited haematopoietic stem cell proliferation and myeloid cell egression from the bone marrow. The treatment reduced the numbers of neutrophils and monocytes/macrophages in the myocardium, promoted an anti-inflammatory environment, and significantly improved cardiac function compared with controls. To mimic the clinical scenario, they further confirmed the effects of the treatment in a mouse model of ischaemia and reperfusion. Compared with untreated mice, 3-day ABR-238901 treatment significantly improved LVEF. Thus, S100A9 blockade might represent a feasible strategy to improve prognosis in ACS patients. Tang et al. (16) investigated the effects of gut microbiota on cardiac repair after AMI. C57BL/6J mice were treated with antibiotics 7 days before AMI to deplete mouse gut microbiota. Antibiotic-treated mice displayed drastic, dose-dependent mortality after AMI associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. The physiological status and survival of mice were significantly improved after faecal reconstitution or dietary supplementation with short-chain fatty acids that are altered after antibiotic treatment; this benefits appeared to be mediated by immunomodulatory effects. In addition, supplementing antibiotic-treated mice with a Lactobacillus probiotic before AMI restored yielded cardioprotective effects. Thus, this study uncovers the adverse effects of antibiotics on survival after MI and addresses a promising therapeutic strategy that involves modulation of gut microbiota composition through probiotic supplementation (**Figure 2**). FIGURE 2. Please see the original article (Eur Heart J. 2020 Feb 14;41(7):821-832.) ## Mechanisms of takotsubo syndrome In 55 patients with takotsubo syndrome, Scally et al. (17) found myocardial macrophage inflammatory infiltrates as assessed by MRI as well as changes in the distribution of monocyte subsets and an increase in systemic pro-inflammatory cytokines. Many of these changes persisted for at least 5 months suggesting a low-grade chronic inflammatory state. Obviously, whether inflammation is a cause or a consequence of the acute takotsubo event remains to be shown. Moreover, whether inflammation is maladaptive and implicated in the persistence in the long-term consequences of this condition is uncertain. Nevertheless, inflammation might play a role in the complex pathogenesis of this syndrome. Most importantly, novel investigations using functional MRI of the brain suggest that an altered limbic and central autonomic signal processing plays a crucial role in takotsubo and may explain the inappropriately excessive reaction of the sympathetic nervous system to stressful triggers. Thus, takotsubo is indeed by a brain disease and the heart may just represent the target organ. (18) ## Diagnosis ## Troponins Boeddinghaus et al. (19) prospectively enrolled patients presenting with symptoms suggestive of AMI in three large diagnostic studies in order to assess the validity of the 0/h-algorithms according to age (99.3% in all age-strata, while triage efficacy decreased with increasing age with sensitivity dropping from 93% to 55%. Slightly higher cut-off concentrations optimized for older patients maintained very high safety of rule-out and increased specificity. Findings were confirmed in two validation cohorts and also for hsTnI. While safety of the ESC 0/1 h-algorithms remained very high, increasing age significantly reduced overall efficacy and the accuracy of rule-in. Thus, alternative slightly higher cut-off concentrations may be considered for older patients, although the problem remains for other confounders like chronic kidney disease, chronic heart failure, atrial fibrillation, and others that also need to be incorporated. Twerenbold et al. (20) confirmed the excellent applicability, short time to emergency department discharge, and low rate of 30-day MACE associated with the routine clinical use of the ESC 0/1-h-algorithm for the management of patients presenting with acute chest discomfort to the emergency department in a real-world setting. Finally, important concepts for institutional transition to hs-cTn methodology providing recommendations useful for education before implementation have been reported in an Expert Panel chaired published by Januzzi et al. (21) ## Implantable cardiac alert system Symptoms remain a poor prompt for ACS. In a multicentre, randomized trial of an implantable cardiac monitor that alerted 907 high-risk ACS patients with rapidly progressive ST-segment deviation randomized to a control (alarms deactivated) or treatment group for 6 months, after which alarms were activated in all subjects. (22) Safety revealed a 96.7% freedom from system-related complications. The primary efficacy endpoint of cardiac or unexplained death, new Q-wave MI, and detection to presentation time >2 h following a confirmed occlusive event within 7 days was numerically, but not statistically reduced among patients with activated alarms group. When the observation window was extended to 50, 70, and 90 days in a prespecified analysis to include the majority of confirmed occlusive events in the control group, and an exploratory dual-baseline ECG analysis was used to reduce noise, a significant reduction in the primary endpoint was observed. Moreover, alarms significantly decreased detection to arrival time at a medical facility. This device may be beneficial among high-risk subjects in potentially identifying asymptomatic events. ## Risk stratification ## Biomarkers Among 4257 patients of the VISTA-16 trial, initial and subsequent increases in high-sensitivity C-reactive protein (hsCRP) levels during 16 weeks after ACS were associated with a greater risk of the combined MACE endpoint, cardiovascular (CV) death, and all-cause death despite established background therapies. (23) Further studies will be required to determine whether initial and serial hsCRP measurements can help guide the use of targeted anti-inflammatory therapies after ACS or whether more specific inflammatory markers will be needed to this end. Four new biomarkers have been investigated in different trials in the setting of ACS: (**a**) galectin-3, implicated in fibrosis (24); (**b**) impaired endogenous fibrinolysis (25); (**c**) trimethyllysine and TMAO, gut-microbiota derived metabolite (26); (**d**) serum cholesterol efflux capacity. (27) All these biomarkers were found to be independently associated with MACE at follow-up. Again, further studies will be required to establish whether these markers identify patient subsets who need personalized forms of treatment. Finally, Lindholm et al. (28) assessed the association between cystatin-C, growth differentiation factor-15 (GDF-15), hsCRP, hs-TnT and TnI, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and specific causes of mortality among 17 095 ACS patients of the PLATO trial. They found that NT-proBNP and GDF-15 were strong markers associated with all-cause death based on their associations with death due to heart failure as well as due to arrhythmia and sudden cardiac death. Growth differentiation factor-15 had the strongest associations with death due to other vascular or non-vascular causes and possibly with death due to bleeding. It remains to establish how to these important prognostic information can guide treatment. ## Cardiac magnetic resonance and entropy Entropy is a new late gadolinium-enhanced MRI-derived parameter to evaluate tissue inhomogeneity, independent of signal intensity thresholds. Androulakis et al. (29) enrolled 154 consecutive post-AMI patients undergoing late gadolinium-enhanced MRI prior to implantable cardioverter-defibrillator (ICD) implantation. When entropy involved the entire left ventricle (LV), this was associated with mortality. After adjusting for multivessel disease, acute revascularization, and ejection fraction, entropy of the scar was independently associated with the presence of ventricular arrhythmias. The association between LV entropy and mortality may reflect adverse and irreversible, inhomogeneous remodelling of the post-infarct LV and/or possibly fatal arrhythmias. Further studies are warranted to establish whether this new marker can allow a better identification of candidates for ICD after AMI. ## Treatment Ticagrelor compared to prasugrel were studied in the ISAR-REACT 5 study (**Figure 3**). (30) Patients with ACS and a proposed interventional strategy were randomized and the primary composite endpoint was death, MI, or stroke. In these patients with or without STEMI, prasugrel therapy was superior to ticagrelor with no difference in bleeding. These important comparative data are likely to change clinical practice. FIGURE 3. Please see the original article (Eur Heart J. 2020 Feb 14;41(7):821-832.) ## Timing of treatment The optimal timing of administration of dual antiplatelet therapy (DAPT) in STEMI patients was investigated by the Swedish Coronary Angiography and Angioplasty Registry. (31) Patients were stratified between either post- or pre-procedure treatment with P2Y12 receptor antagonists. Of the 44’804 patients 58% had been on clopidogrel, 35% on ticagrelor, and 5% on prasugrel. There was no survival benefit from pre-treatment or any impact on infarct-related artery patency, stent thrombosis, or bleeding. These data are surprising as a potential impact on early stent thrombosis, in particular, might have been anticipated. Existing Guidelines (32) recommend catheter-lab administration of antiplatelet drugs and these data are supportive of that strategy, although Abtan and Steg (33) argue that we should continue to give P2Y12 receptor antagonists as early as possible in probable STEMI patients as there is a strong biological plausibility of likely benefit with no obvious likely detriment. Whether patients with patients with transient ST-elevation (patients who present initially with ST-elevation on the electrocardiogram but, subsequently, show complete normalization of the ST-segment and relief of symptoms before reperfusion therapy) require immediate revascularization was studied in a trial (34) of 142 patients who were randomized to immediate (mean 0.3 h) or delayed angiography (mean 22.7 h). The outcome was infarct size by MRI at Day 4. The observed infarcts were generally small and there was no clear benefit from the immediate strategy, although 4/71 patients required urgent intervention because of further symptoms and ST elevation whilst waiting. Consequently, these data can probably be interpreted as allowing decisions about timing of revascularization in patients with transient STEMI, to be guided by the availability of angiography and careful clinical assessment. The management of non-culprit lesions in STEMI patients has been extensively discussed over the last years. Small randomized trials have suggested a probable benefit from complete revascularization. The large COMPLETE trial randomized 4041 STEMI patients (**Figure 4**) to complete or partial revascularization. (35) Complete revascularization was superior to culprit-only as it reduced the risk of CV death or AMI. There was also benefit from complete revascularization in reducing ischaemic endpoints. Timing appeared to be less important and deferring any secondary revascularization procedure was safe. Thus, the advantage of complete revascularization will presumably be reflected in subsequent ESC Guidelines. FIGURE 4. Please see the original article (Eur Heart J. 2020 Feb 14;41(7):821-832.) ## Can we tailor treatment in acute coronary syndromes? There remains a desire to tailor drug therapy to the individual patients and perhaps the individual lesion. This strategy would allow pharmaceutical optimization of protection with minimization of side effects or bleeding risk. The CHAMPION PHOENIX trial (36) has suggested that complex coronary lesions can be characterized and that it is inadequate treatment of these ‘high risk’ lesions that leads to repeat revascularization or clinical events. Compared with a loading dose of clopidogrel, cangrelor reduced MACE occurring within 48 h after PCI in patients with ACS regardless of baseline lesion complexity. However, the absolute benefit: risk profile for cangrelor was greatest during PCI in complex coronary anatomy. In a substudy of the PROSPECT trial, (37) virtual histology and grey scale intravascular ultrasound (IVUS) was a predictor of a suboptimal final angiographic result reflected as a high residual Syntax Score after intervention. A detailed Expert consensus review has provided detail on characterization of acute coronary lesions using IVUS or OCT and suggested a triaged therapeutic approach. (38) Unfortunately measuring individuals’ responses to antiplatelet drugs has not shown clinical utility. Randomizing patients to measuring platelet function in the TROPICAL trial (39) showed no measurable clinical advantage. Within the trial, those patients with maximal platelet inhibition were predictably most prone to bleeding. ## Optimizing treatment in ST-segment elevation myocardial infarction About one-third of STEMI patients have suboptimal reperfusion after PCI and it is this group of patients that might experience heart failure and premature death. MRI can provide evidence of MVO and myocardial haemorrhage. (40) In the DANAMI-3 trial delayed presentation (41) as evidenced by prolonged door-to-wire-time predicted adverse clinical outcome, consistent with previous observations using intracoronary physiology measurements suggesting increased risk in these ‘late presenters’. (42) Enhanced and continued public information campaigns are required to optimize outcomes in high-risk STEMI patients along with novel adjunctive therapies. In this context, full dose intracoronary tenectaplase was inferior to abciximab in a small randomized trial (43) and using low dose intracoronary tenecteplase after reperfusion in the T-time trial also failed to reduce MVO measured using cardiac magnetic resonance imaging (CMRI). (44) Hypothesis generating results were presented by the Microvascular Reperfusion Utilizing Sonothrombolysis in Acute Myocardial Infarction (MRUSMI) investigators. (45) They randomized STEMI patients to either standard PCI or diagnostic ultrasound transducer guided, high mechanical index impulses during an ultrasound agent transfusion prior to and following PCI. The ultrasounds high mechanical index impulses create microbubble cavitation that induce shear forces, designed to dissolve intracoronary thrombi. The treatment cohort demonstrated higher recanalization (48% vs. 20%) and TIMI 3 flow rates (32% vs. 14%) within the infarcted vessel ST-segment resolution prior to primary PCI occurred more frequently. Furthermore, infarct size as assessed by MRI and TNT peak values was also reduced by the intervention. Optimizing reperfusion for patients with STEMI when there is lot of thrombus is challenging and these preliminary results hint at a possible alternate approach. Remote preconditioning in STEMI was studied in the CONDI-2/ERIC PPCI trial (46) which randomized 5401 patients to standard treatment (including a sham simulated remote ischaemic conditioning at UK sites) or remote ischaemic conditioning (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before primary PCI. Unfortunately, remote ischaemic conditioning did not improve clinical outcomes (cardiac death or hospitalization for heart failure) at 12 months. New approaches and therapies within this area are warranted if this experimentally well-documented concept should ever reach the clinical applicability. ## Outcomes ## Quality of treatment and outcomes In a cohort of 389 507 NSTEMI patients, optimal care, defined as the receipt of all eligible treatments, was inversely related to risk status (defined by the GRACE risk score), i.e. 25.6% in low, 18.6% in intermediate, and 11.5% in high-risk patients. At the end of 2.3 years of follow-up, the association between the use of all eligible guideline-indicated treatments and improved survival remained only significant for high-risk NSTEMI. (47) Thus, optimal use of guideline-indicated care for NSTEMI was associated with greater survival gains with increasing GRACE risk, but its use paradoxically decreased with increasing GRACE risk, thus leaving room for improvement. In the SWEDHEART registry, outcomes of patients presenting with NSTEMI followed over 20 years demonstrated a substantial improvement in long-term survival and reduction in the risk of MACE. (48) These improvements were associated with the gradual uptake and widespread use of PCI and long-term use of evidence-based medications, consistent with the anticipated effectiveness of their implementation as proposed in guidelines (**Figure 5**). FIGURE 5. (A and B) Kaplan–Meier estimates of the cumulative incidence of the first coprimary outcome (death from cardiovascular causes or new myocardial infarction) and the second coprimary outcome (death from cardiovascular causes, new myocardial infarction, or ischaemia-driven revascularization), respectively. Insets show the same data on an enlarged y axis. PCI, percutaneous coronary intervention. Reprinted with permission from Ref. (48) The value of a cardiac rehabilitation programme was compared in 839 patients who attended a planned programme at discharge after ACS or surgical revascularization, while 441 patients were discharged without it. (49) At multivariable Cox proportional hazard analysis, the cardiac rehabilitation programme was an independent predictor of lower occurrence of MACE (hazard ratio 0.55), while in a propensity-matched analysis patients attending the cardiac rehabilitation programme also experienced a lower total mortality (10% vs. 19%) and CV mortality (2% vs. 7%) compared to non-rehabilitated ones. Thus, the positive effects of ambulatory of cardiac rehabilitation are also notable in a real-world population. Finally, in a cohort study of 123 780 consecutive PCIs from the Pan-London PCI Registry the outcomes pre- and post-public reporting in the UK were compared. (50) After public reporting was introduced, patients were older and had more complex medical problems, while in-hospital MACE and MACCE and 30-day mortality rates were significantly lower. These results probably reflect continued improvements in PCI outcomes concomitant with the introduction of public reporting, but the lower reported complication rate could also reflect a change in the documentation of risk factors and a change in operator behaviour. Reassuring, additional data from the UK registry also confirm continued temporal improvement in outcomes in ACS and notably demonstrate no difference in outcome depending on the times of day that treatment occurred. Patients treated as emergencies at night had similar outcomes to those treated within ‘office hours’. ## Modes of death after non-ST-segment elevation myocardial infarction In 66 252 patients with NSTEMI enrolled in 14 TIMI trials, baseline characteristics and modes and timing of death were examined. Of the 2606 patients with known modes of death, 75.1% were r elated to MACE, 3.0% were related to a bleeding event (including intracranial haemorrhage), and 21.8% were related to a non-CV/non-bleeding event. (51) The most common modes of CV death were sudden death and recurrent AMI (36.4% and 23.4%, respectively). The proportion of CV deaths related to recurrent AMI was higher in the first 30 days than it was after 30 days following NSTEMI (30.6% vs. 18.7%), whereas the proportion of sudden death was lower in the first 30 days than after 30 days (21.6% vs. 46.2%). Thus, sudden death represented the largest proportion of CV deaths after 30 days. Further investigations aimed at defining management approaches to reduce sudden death following NSTEMI may be critical to reducing late mortality. ## Outcomes of in-hospital acute coronary syndromes In a cohort study of 1.3 million patients hospitalized in US Veterans Health Administration facilities, an incidence of in-hospital AMI of 4.27 per 1000 admissions and risk factors associated with in-hospital AMI such as history of IHD, elevated heart rate, low haemoglobin level, and elevated white blood cell count were reported. (52) Compared with matched controls, mortality was significantly higher for in-hospital AMI. Thus, in-hospital AMI is common and associated with common CV risk factors and markers of acute illness and with high mortality approaching 60% at 1 year. Further studies of in-hospital AMI may yield opportunities to reduce in-hospital AMI risk and improve patient outcomes. ## Outcomes of atypical acute coronary syndromes ## Spontaneous coronary artery dissection Spontaneous coronary artery dissection (SCAD) is an underdiagnosed and poorly understood condition and an important cause of AMI in young women. (3) In the Canadian multicentre, prospective, observational study of 750 patients, predisposing conditions included fibromuscular dysplasia in 31.1%, systemic inflammatory diseases in 4.7%, peripartum in 4.5%, and connective tissue disorders in 3.6% were noted. (53) Most were treated conservatively, while 14% underwent PCI and a few coronary artery bypass surgery. In-hospital composite MACE was 8.8%, but higher in peripartum SCAD (20.6% vs. 8.2%). Overall 30-day MACE was 8.8% with peripartum SCAD and connective tissue disease being independent predictors of 30-day MACE. ## Takotsubo syndrome Two different studies of the InterTak Registry including over 1500 patients with takotsubo syndrome found that both in-hospital cardiac arrest (4.9 of patients) (54) or the presence of an associated malignancy (16.6% of patients) (55) were associated with worse long-term outcome. Of note, patients with cardiac arrest were more likely to be younger, male, and have apical takotsubo, atrial fibrillation, neurologic comorbidities, physical triggers, longer corrected QT-interval, and lower LVEF, while those with malignancy were older and more likely to have physical triggers, but less likely to have emotional triggers. ## Myocardial infarction with non-obstructed coronary arteries The long-term outcome of MINOCA was investigated in a large US Registry of 286 780 AMI admissions of which 5.9% had MINOCA. (56) Following risk-adjustment, MINOCA patients had a 43% lower risk of MACE over 12 months compared to those with AMI and coronary artery disease. This pattern was similar for adjusted risks of the MACE components. Thus, MINOCA has an unfavourable prognosis in elderly patients with one in five suffering a major adverse event over 12 months. ## Women vs. men The impact of gender was assessed in 13 451 NSTEMI and STEMI patients undergoing PCI in the Victorian Cardiac Outcomes Registry in Australia. (57) Women with STEMI had significant delays in presentation and revascularization with a higher 30-day mortality compared with men, while women with NSTEMI had no delay in presentation or revascularization, with mortality comparable to men. Thus, public awareness campaigns might be needed to address women’s recognition and early action for STEMI. In a Swiss population of 4360 patients with STEMI ischaemic time in women remained greater than that in men due to persistently greater patient delays. (58) In contrast to men, clinical signs of ongoing chest discomfort did not predict delays in women, suggesting that female STEMI patients were less likely to attribute symptoms to a condition requiring urgent treatment. In a Chinese population of 82 196 patients women hospitalized for ACS less frequently received acute treatments and strategies for secondary prevention than men. (59) The observed sex differences in in-hospital mortality were mainly due to worse clinical profiles and fewer evidence-based acute treatments provided to women with ACS. Finally, Vicent et al. (60) in an octogenarian Spanish population of 535 patients with STEMI found that female sex was independently associated with death and hospitalization at 6-month follow-up. ## Medicaid beneficiaries vs. privately insured individuals In 42 645 and 171 545 STEMIs receiving Medicaid or private insurance, respectively, (61) in unadjusted analyses, Medicaid beneficiaries had lower rates of coronary revascularization and higher rates of in-hospital mortality compared with privately insured individuals. Similar results were found in a propensity-matched cohorts. Further studies are needed to identify and understand the causes of the variation in STEMI outcomes by insurance status. ## Black vs. White patients In a US cohort of 6402 patients, self-identified black and white patients differed in several clinical and socioeconomic characteristics. (62) The higher the prevalence of characteristics associated with being black, the higher the 5-year mortality rate, but no differences were observed between black and white patients with similar characteristics. Thus, a greater prevalence of characteristics associated with black race, but not race itself, was associated with higher mortality risk after AMI. ## Conclusions Important data from large randomized trials have augmented the management of patients presenting with ACS. Importantly, recognition of the clinical spectrum of ACS has expanded in recent years and atypical forms, besides the classical STEMI and NSTEMI, such as takotsubo syndrome, coronary dissection, MINOCA, and myocarditis (**Figure 6**) have been increasingly recognized, characterized and their causes and mechanisms defined. The management of these novel forms of ACS is still not evidence-based, but significant progress has been made recently. Furthermore, disparities in the implementation of guideline-based therapies are increasingly addressed to the benefit of the patient population at large. FIGURE 6. *Take home figure* The spectrum of acute coronary syndromes encompasses plaque rupture and erosion (=Type 1 myocardial infarction), Type 2 myocardial infarction, epicardial and microvascular coronary spasm, coronary embolism, acute myocarditis, takotsubo syndrome, and coronary dissection. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. ## Acknowledgments Reproduced from: Banning AP, Crea F, Lüscher TF. The year in cardiology: acute coronary syndromes. Eur Heart J. 2020 Feb 14;41(7):821-832. https://doi.org/10.1093/eurheartj/ehz942, by permission of Oxford University Press on behalf of the European Society of Cardiology. ® The Authors(s) 2020. All rights reserved; no part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission of the Publishers. For Permissions, please email: journals.permissions@oup.com The opinions expressed in the Journal item reproduced as this reprint 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. The mention of trade names, commercial products or organizations, and the inclusion of advertisements in this reprint do not imply endorsement by the Journal, the editors, the editorial board, Oxford University Press or the organization to which the authors affiliated. The editors and publishers have taken all reasonable precautions to verify drugs 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 this reprint 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 or in this reprint. Please inform the editors of any errors. Oxford University Press, OPL., and the European Society of Cardiology are not responsible or in any way liable for the accuracy of the translated reprint, for any errors, omissions, or inaccuracies, or for any consequences arising therefrom. Nina Jakuš, Ivo Planinc and Mario Ivanuša are solely responsible for the translation and this reprint.

Zdravko Babić, Eduard Margetić, Davor Miličić

## Global experiences The COVID-19 virus pandemic represents a massive challenge to national healthcare systems. Given the characteristics of the virus, such as its virulence, i.e. its ability to spread infection in the asymptomatic phase, its rapid spread in enclosed environments, especially in healthcare institutions, and its pathogenicity, i.e. the high number of patients who require hospital treatment and the relatively high ratio of patients that require intensive care, critical care capacities in countries with large-scale epidemics of the virus have been almost completely occupied by patients with COVID-19 infection. Controlling the epidemic requires rigorous measures in the general population but even more aggressive measure within the healthcare system. Care for patients with indications for primary percutaneous coronary intervention (pPCI) can be facilitated by experiences from our colleagues in China as well as Italy and Slovenia as being countries in which the organization of the healthcare system is similar to ours. Zeng et al published a letter to the Editor in the Intensive Care Medicine journal describing the protocol for the treatment of acute coronary syndrome in patients positive for COVID-19 or suspected to have the virus (1). Fibrinolysis was reported to be the preferred reperfusion method in such patients with acute myocardial infarction ST elevation (STEMI) on the ECG, with percutaneous coronary intervention (PCI) used only in patients after failed fibrinolysis, and even then only in those with mild pneumonia or contraindications for fibrinolysis. In other words, the benefits of the interventional procedure must significantly outweigh the risk of spreading the infection. In non-ST-segment elevation myocardial infarction (NSTEMI), PCI is recommended after curing the pneumonia, i.e. the respiratory system infection caused by COVID-19. However, opinions of Western authors differ in comparison with Chinese authors. Welt et al commented on the recommendations of the Chinese authors in JACC from the perspective of a healthcare system with widely available pPCI and suggested a more liberal approach, i.e. they do not recommend giving up on providing optimal reperfusion strategy despite organizational issues (2). They suggest considering fibrinolysis as the therapy of choice in stable patients with active COVID-19 infection (without further elaboration), but they recommend individual assessment of the benefits of the procedure given the risk of exposing healthcare personnel to infection. They emphasize protection of healthcare workers during PCI procedures using protective gear that includes N95 masks, coveralls, and goggles or face shields. After the intervention is complete the cardiac catheterization lab should be thoroughly disinfected, especially considering that such labs are unfortunately almost always equipped only with normal ventilation systems without negative pressure capability. The authors suggest that early intubation should be performed in the ward/critical care before the PCI procedure, and if indicated to avoid procedures that generate aerosols in the laboratory. Direct communication with colleagues from the Ljubljana University Medical Centre showed their patients suspected to have COVID-19 were not denied pPCI. A swab was taken from these patients as soon as they arrived at the lab, pPCI was performed with all the protective measures against infection, and the patient remained in the “grey zone” (an isolated area, possibly as part of the lab, but with monitoring appropriate for coronary syndrome) until arrival of the test results. Patients who required mechanical circulatory support waited for the swab results in an isolated part of the intensive care unit. Further patient procedures depend on the swab results, and the decision is made as a team and individually for each patient based on available personnel and hospital capacity, while applying all the possible measures to protect hospital staff and other patients from infection. The current state of the Croatian Primary Percutaneous Coronary Interventions Network Heads of laboratories included in the Croatian Primary Percutaneous Coronary Interventions Network were polled by phone (3), showing that all cardiac catheterization labs outside Zagreb and central Croatia are continuing normal treatment for patients with acute coronary syndrome but with significant or complete reduction of the elective program. The situation is also similar at the Magdalena Clinic for Cardiovascular Diseases. Most labs have introduced and implemented the previously mentioned protocols recommended by foreign authors, but some colleagues have complained about the initial lack of specific protective gear for treating patients with COVID-19 and the lack of education on its use. In addition to the COVID-19 pandemic, the situation in cardiac catheterization labs in Zagreb was further complicated by the earthquake that took place on March 22, 2020. Due to having to place a number of physicians and nurses in isolation, the University Hospital Centre (UHC) Zagreb was forced to reduce its intervention program to directly hospitalized patients with NSTEMI for a period of two weeks, whereas pPCI was practically no longer conducted for STEMI patients until March 27, 2020, especially from the relevant counties. The situation has now changed and the UHC Zagreb has returned to the Croatian pPCI Network taking over both its own patients and the patients who gravitate to the University Hospital (UH) Dubrava. Given that the UH Dubrava has, along with the Zagreb University Hospital for Infectious Diseases, been strategically selected as the care center for patients COVID-19, according to current information the University Hospital is not able to provide PCI services for the time being. It is not currently clear whether the physicians and staff of the cardiac catheterization lab in that hospital will be engaged somewhere else in service of the Croatian pPCI Network or if they will be mobilized solely for treating patients with COVID-19. Given the circumstances, the Laboratory at the UHC “Sestre milosrdnice” has temporarily taken over emergency interventional treatment for all patients who gravitate towards the UHC Zagreb and UH Dubrava as well as the area covered by the UHC “Sestre milosrdnice” itself, both in Zagreb and other counties. Unfortunately, the earthquake of March 22 severely damaged the building that houses the Cardiac Catheterization Lab of the UHC “Sestre milosrdnice”. The lab was closed due to danger of building collapse after a preliminary building safety inspection on the day of the earthquake, but a conclusive building safety inspection on March 25 approved recommencement of work in the building and the center was returned to pre-earthquake levels of activity. Between March 22 and March 25 this year, all patients with STEMI and hemodynamically unstable NSTEMI for whom these three institutions were responsible as well as patients under the responsibility of the city of Zagreb and the Zagreb County were treated at the UH “Sveti Duh” under the 24/7 system, whereas the Cardiac Catheterization Laboratory at the UH “Merkur” took over patients with NSTEMI from the UHC “Sestre milosrdnice” as well as from other institutions with which it has established cooperation, but only during regular working hours. Since March 25 these two centers returned to regular activity regarding interventional treatment of acute coronary syndrome. Help in caring for patients with acute myocardial infarction under the 24/7 system was also offered by the Čakovec County Hospital (especially to the Varaždin County and Koprivnica-Križevci County) and the Magdalena Clinic, and the Agram Special Hospital also offered to help within its means. Further dynamic reorganization of activity and jurisdiction with be greatly dependent on the dynamics of the epidemic and its spread, the material resources and personnel required for its treatment, and on resolving the issues in the work of the cardiac catheterization labs of the aforementioned clinical institutions in Zagreb. We would like to note that professional societies like the Croatian Cardiac Society have an advisory role in such situations and that final decisions are made by the Ministry of Health of the Republic of Croatia and the directors of the relevant healthcare institutions. The cardiological community will receive timely notifications on all future changes in the functioning of the Croatian pPCI Network. ## Conclusion and recommendations for further activity The conclusions we can draw based on experiences with the COVID-19 pandemic so far are the necessity of rationally selecting patients for interventional cardiologic treatment, acquisition of all necessary protective gear and their proper use by cardiological teams working with infected or potentially infected patients, creating protocols for working with these patients in cardiac catheterization labs and after intervention, and forming both active and reserve cardiological teams that guarantee uninterrupted work in case of infection or suspected infection among members of the currently active team. Until further notice, we recommend that all patients with suspected COVID-19 infection are tested immediately and that they, along with patients positive for COVID-19, receive pPCI only in case of STEMI or hemodynamical instability in NSTEMI. The precondition for emergency interventions in such patients is adequate protection for the staff of the cardiac catheterization lab as well as other personnel that will be in contact with these patients. Until the test results for COVID-19 arrive, these patients should be closely monitored and treated in an isolated environment, and the whole staff in contact with the patient must be optimally protected. If the patient is positive for COVID-19, they are to be transferred to a COVID hospital, and if the patient is negative they should be transferred to intensive cardiac care at the appropriate hospital (**Figure 1**, **Figure 2**). FIGURE 1. Postupnik za hitnu perkutanu koronarnu intervenciju u bolesnika pozitivnih ili suspektnih na infekciju virusom COVID-19. *Klinička bolnica Dubrava za Zagreb i sjeverozapadnu Hrvatsku PCI – perkutana koronarna intervencija; KB – klinička bolnica; katlab – laboratorij za kateterizaciju; OHBP = objedinjeni hitni bolnički prijam. FIGURE 2. Protocol for emergency percutaneous intervention in patients positive or suspected of COVID-19 infection. *University Hospital Dubrava for Zagreb and northwestern Croatia PCI = percutaneous coronary intervention; UH = University Hospital; cath lab = cardiac catheterization lab; ER = emergency room. In case of STEMI and pPCI being impossible to perform under the conditions described above, fibrinolysis should be applied according to current guidelines (4) as an alternative to pPCI. Due to the risk of infection, it is likely that fibrinolysis will be the therapy of choice for most patients positive for COVID-19 but also for those in whom infection is suspected, especially if emergency PCI requires transport from the county hospital to a PCI center. In case of unsuccessful fibrinolysis, rescue PCI can be considered, after which the patient is generally transferred to a COVID hospital. Patients with suspected COVID-19 infection or those positive for the virus who are suffering from acute coronary syndrome and have indication for mechanical support should be treated in an isolated area of the coronary care unit or the cardiac catheterization lab, with appropriate protective measures for medical staff. If the test is positive, the patient should be transferred to a COVID hospital after introduction of mechanical support and should be treated in the current hospital if transport is not possible. Patients with NSTEMI should be treated in hospitals to which they belong according to territorial division. Indications for invasive procedures are to be established individually, based on risk and disease severity and in consultation with the responsible interventional center. Patients with established or suspected COVID-19 infection should be considered for invasive treatment only in case of hemodynamic instability or symptoms refractory to medication therapy. PCI and postinterventional care should be performed under the conditions and recommendations for STEMI that have been described above. Other patients with NSTEMI should be treated conservatively until they are negative for COVID-19. Finally, it should be emphasized that the decision on applying acute interventional treatment should be based on the condition of the patient, estimated benefit from PCI and infection risk, and the availability of appropriate protection for medical staff and other patients, and should be made individually for every patient and under full authority and responsibility of the interventional team responsible for their treatment. The coauthors would like to thank Marin Pavlov, the Secretary of the Working Group for Acute Coronary Syndrome of the Croatian Cardiac Society for his help in the writing of this text. Follow the article updates at www.kardio.hr