Frontiers of acute coronary syndromes: primary PCI time window, 15-year outcomes, bleeding and MINOCA

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. The spectrum of acute coronary syndromes (ACS) is expanding rapidly, paving the way for a more personalized management of these patients. What used to be a heart attack has become an ST-segment elevation myocardial infarction (STEMI) or a non-ST segment elevation myocardial infarction (NSTEMI).1 Then we learned that in young women of childbearing age the underlying cause of ACS may be spontaneous coronary dissection,2,3 whereas in postmenopausal women it may be Tako Tsubo syndrome.4,5 Finally, myocarditis may present as an ACS. Moreover, STEMI and NSTEMI may be caused not only by plaque rupture, but also by endothelial erosion6 which may not even require stenting.7 What’s more, some patients do have features of an ACS without obstructive coronary artery disease, the so-called MINOCA (myocardial infarction with non-obstructive coronary arteries).8,9 This fascinating development is further discussed in ‘The year in cardiology: acute coronary syndromes’ by Adrian Banning from the John Radcliffe Hospital in Oxford, UK and colleagues.10 They remind us that the management of ACS has made enormous progress over the last decades due to the introduction of defibrillation, beta-blockers, thrombolytics, aspirin, primary percutaneous transluminal intervention,11 P2Y12 inhibitors,12 statins,13 radial access,14 and eventually PCSK9 (Proprotein convertase subtilisin/kexin type 9) inhibitors,15 among others. However, in spite of all these remedies, there is a remaining acute mortality risk, in particular in those presenting in cardiogenic shock16 or after resuscitation, and an accruing number of major cardiovascular events (MACE) over the following years. There is therefore an unmet need in the management of ACS. A frequent complication of the modern management of ACS with primary percutaneous coronary intervention (PCI) is bleeding.17,18 In their Fast Track contribution entitled ‘Temporal trends in bleeding events in acute myocardial infarction: insights from the SWEDEHEART registry’, Moa Simonsson and colleagues from the Karolinska Institutet in Stockholm, Sweden describe the time trends of in-hospital and out-of-hospital bleeding parallel to the development of new treatments and to ischaemic outcomes over the last 20 years in a nationwide myocardial infarction population in 371 431 enrolled in the SWEDEHEART registry.19 In-hospital bleeding increased from 0.5% to a peak at 2% in 2005–2006 and thereafter slightly decreased to 1.3%. Out-of-hospital bleeding increased in a stepwise manner from 2.5% to 3.5% and eventually to 4.8% (Figure 1). The increase in both in-hospital and out-of-hospital bleeding was paralleled by an increasing use of primary PCI and antithrombotic treatment and potent dual antiplatelet therapy, while the decrease in in-hospital bleeding between 2007–2010 was paralleled by the implementation of bleeding avoidance strategies. In-hospital reinfarction decreased from 2.8% to 0.6% and out-of-hospital myocardial infarction from 12.6% to 7.1%. The composite of out-of-hospital myocardial infarction, cardiovascular death, and stroke decreased similarly from 18.4% to 9.1%. Thus, during the last 20 years, the introduction of primary PCI and intense antithrombotic regimens led to increased bleeding, but concomitantly ischaemic events were markedly reduced, and survival improved. These impressive findings are further discussed in an Editorial by Debabrata Mukherjee from Texas Tech University in El Paso, Texas, USA.20 Bleeding and ischaemic outcomes added: all patients. Upper: in-hospital bleeding + reinfarction + cardiovascular (CV) death; lower: out-of-hospital bleeding + myocardial infarction (MI) + stroke + CV death (from Simonsson M, Wallentin L, Alfredsson J, Erlinge D, Hellström Ängerud K, Hofmann R, Kellerth T, Lindhagen L, Ravn-Fischer A, Szummer K, Ueda P, Yndigegn T, Jernberg T. Temporal trends in bleeding events in acute myocardial infarction: insights from the SWEDEHEART registry. See pages 833–843). Primary PCI today is first-line therapy in patients presenting with STEMI.21 Indeed, the pioneering DANish Acute Myocardial Infarction 2 (DANAMI-2) trial found that interhospital transport to primary PCI was superior to fibrinolysis at the local hospital in patients with STEMI at 30 days.22 In their article ‘16-year follow-up of the Danish Acute Myocardial Infarction 2 (DANAMI-2) trial: primary percutaneous coronary intervention vs. fibrinolysis in ST-segment elevation myocardial infarction’, Michael Maeng and colleagues from the Aarhus University Hospital in Denmark investigated the 16-year cardiovascular outcomes.23 Initially, 1572 STEMI patients were randomized to primary PCI or fibrinolysis. Those undergoing primary PCI at referral hospitals were immediately referred to the nearest invasive centre. After 16 years, those treated with primary PCI had a sustained lower rate of MACE compared with patients treated with fibrinolysis, with a hazard ratio of 0.86, and among those transported for primary PCI, with a hazard ratio of 0.82 (Figure 2). No difference in all-cause mortality was found, but cardiac mortality was reduced by 4.4% in favour of primary PCI. Primary PCI postponed a main event by 12.3 months compared with fibrinolysis. Thus, the benefit of primary PCI over fibrinolysis was maintained at 16-year follow-up. This exciting confirmation of the values of revascularization is put into context in a thought-provoking Editorial by Borja Ibanez from Cientro National de Investigationes de Cardiologia in Madrid, Spain.24 Cumulative event curves of 16-year outcomes in the DANAMI-2 study. The composite endpoint includes all-cause death and rehospitalization for MI. Fib., fibrinolysis; pPCI, primary percutaneous coronary intervention (from Thrane PG, Kristensen SD, Olesen KKW, Mortensen LS, Bøtker HE, Thuesen L, Hansen HS, Abildgaard U, Engstrøm T, Andersen HR, Maeng M. 16-year follow-up of the Danish Acute Myocardial Infarction 2 (DANAMI-2) trial: primary percutaneous coronary intervention vs. fibrinolysis in ST-segment elevation myocardial infarction. See pages 847–854). STEMI guidelines recommend primary PCI as the default reperfusion strategy when feasible within 120 min of a diagnostic ECG, while otherwise a pharmaco-invasive strategy is recommended.25 There is, however, a lack of direct evidence to support the guidelines, and, in real-world situations, primary PCI is often performed beyond recommended timelines. In their article ‘Five-year outcomes following timely primary percutaneous intervention, late primary percutaneous intervention, or a pharmaco-invasive strategy in ST-segment elevation myocardial infarction: the FAST-MI programme’ Nicolas Danchin from the Hopital Europeen Georges Pompidou in Paris, France and his colleagues assessed 5-year outcomes according to timing of primary PCI compared with a fibrinolysis with referral to a primary PCI centre.26 Among 4250 STEMI patients, 2942 with reperfusion therapy and onset-to-first call within 12 h were included. Outcomes at 5 years were compared according to type of reperfusion strategy and timing of primary PCI. Overall, 54% had timely primary PCI, while 28% had late primary PCI and 28% received fibrinolysis. Five-year survival was higher with a pharmaco-invasive strategy with 89.8% compared with late primary PCI with 79.5%, with an adjusted hazard ratio of 1.51, and similar to timely primary PCI (88.2%, adjusted hazard ratio 1.02). Concordant results were observed in propensity score-matched cohorts and for event-free survival. Thus, a substantial proportion of patients have primary PCI beyond recommended timelines and have poorer 5-year outcomes, compared with a pharmaco-invasive strategy. These stimulating results are put into context in an Editorial by Frans Van de Werf from the Catholic University Leuven in Belgium.27 Surprisingly, some patients presenting clinically as an ACS with chest pain, ECG changes, and necrosis markers do not show significant coronary obstruction at angiography.28 However, their outcome is still a matter of debate. In their article entitled ‘Myocardial infarction with non-obstructive coronary arteries as compared with myocardial infarction and obstructive coronary disease: outcomes in a Medicare population’, Rachel Patricia Dreyer and colleagues from the Yale-New Haven Hospital in Connecticut, USA investigate the long-term prognosis of MINOCA.9 Among 286 780 with ACS, 5.9% had MINOCA. In MINOCA patients, the 12-month rates of MACE (18.7% vs. 27.6%), mortality (12.3% vs. 16.7%), and re-hospitalization for ACS (1.3% vs. 6.1%) and heart failure (5.9% vs. 9.3%) were significantly lower compared with ACS caused by coronary obstruction, but were similar for re-hospitalization for stroke. Following risk adjustment, MINOCA patients had a 43% lower risk of MACE over 12 months compared with those with coronary obstruction. Thus, this study confirms an unfavourable prognosis in elderly patients with MINOCA, with one in five patients suffering MACE over 12 months. These clinically highly relevant findings are further discussed in a balanced Editorial by Giampaolo Niccoli, Filippo Crea, and Rocco Montone from the Catholic University of the Sacred Heart in Rome, Italy.29 Novel prognostic markers besides classical cardiovascular risk factors are crucial to increase precision in the risk assessment of ACS patients. Recently, a number of novel biomarkers providing incremental value have been described.30,31 Glucagon-like peptide 1 or GLP-1 is a gut incretin hormone inducing post-prandial insulin secretion. GLP-1 levels were recently found to be increased in patients with ACS. GLP-1 receptor agonists improve cardiovascular outcomes in patients with diabetes. In their article ‘Glucagon-like peptide 1 levels predict cardiovascular risk in patients with acute myocardial infarction’ Michael Lehrke and colleagues from the University Hospital Aachen in Germany assessed the predictive capacity of GLP-1 in ACS.32 In 918 patients presenting with ACS including 321 with STEMI and 597 with NSTEMI, GLP-1 and N-terminal pro brain natriuretic peptide (NT-proBNP) plasma levels and the Global Registry of Acute Coronary Events or GRACE score were assessed at the time of hospital admission. GLP-1 was associated with MACE with a hazard ratio of logarithmized GLP-1 values of 6.29. After multiple adjustments, the hazard ratio remained significant at 10.98. Time-dependent receiver operating characteristic (ROC) curve analyses illustrated that GLP-1 levels are a strong indicator for early events. Indeed, for events up to 30 days, GLP-1 was superior to high sensitivity troponin T, glomerular filtration rate, chronic kidney disease, high sensitivity C-reactive protein, and NT-proBNP. Adjustment of the GRACE risk estimate by addition of GLP-1 increased the area under the ROC curve over time in NSTEMI patients. These novel results are put into clinical context in an excellent Editorial by Leonardo Roever from the Federal University of Uberlândia in Brazil.33 This issue is complemented by two Discussion Forum contributions. In a first one entitled ‘Genetic instruments with too many strings: acknowledging pleiotropy and population structure in Mendelian randomization studies’, Jeremy A. Labrecque and colleagues from Erasmus MC in Rotterdam in the Netherlands comment on the recent publication ‘Genetically modulated educational attainment and coronary disease risk’ by Heribert Schunkert and colleagues from the Deutsches Herzzentrum in Munich in Germany.34,35 Schunkert et al. respond in a separate comment.36 The editors hope that this issue of the European Heart Journal will be of interest to its readers. With thanks to Amelia Meier-Batschelet for help with compilation of this article.