The Direct and Indirect Effects of COVID-19 on Acute Coronary Syndromes

KeywordsKey points

The COVID-19 pandemic has resulted in wide-ranging direct and indirect consequences for patients with ACS.

A sudden, unexpected decline in hospitalizations for ACS and an increase in out-of-hospital deaths coincided with the onset of the COVID-19 pandemic.

ACS in patients with COVID-19 is associated with excess rates of adverse events, particularly when medical intervention is delayed.

During the COVID-19 pandemic, many patients with ACS have been required to undergo alternative diagnostic and therapeutic strategies due to reorganization of health care resources.

Studies to further elucidate the complex relationship between SARS-CoV-2 infection and myocardial injury or infarction are required.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the most significant infectious disease outbreak and public health emergency for a century. Declared a pandemic by the World Health Organization in March 2020, coronavirus disease 2019 (COVID-19) has infected millions and caused excess mortality and morbidity across the world. Health care systems have been required to restructure and adapt to an entirely novel disease entity, while providing routine and emergency care for existing illness.

Patients with acute coronary syndrome (ACS) provide one such example in which these challenges intersected (Fig. 1). The diagnosis and treatment of acute myocardial infarction (MI) has attracted much scientific attention during the COVID-19 pandemic by virtue of several critical issues:1.An internationally observed reduction in hospital admission rates for ACSMafham M.M. Spata E. Goldacre R. et al.COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England.,De Filippo O. D'Ascenzo F. Angelini F. et al.Reduced rate of hospital admissions for ACS during Covid-19 outbreak in Northern Italy.2.SARS-CoV-2 infection is associated with myocardial injury,Bonow R.O. Fonarow G.C. O'Gara P.T. et al.Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality. accentuated predominantly in patients with underlying cardiometabolic risk factorsRichardson S. Hirsch J.S. Narasimhan M. et al.Presenting characteristics, Comorbidities, and outcomes Among 5700 patients hospitalized with COVID-19 in the New York city area.3.There are perceived diagnostic challenges with discrimination between COVID-19–related and non–COVID-19–related myocardial injury and infarctionSandoval Y. Januzzi Jr., J.L. Jaffe A.S. Cardiac troponin for Assessment of myocardial injury in COVID-19: JACC review Topic of the Week.4.Health care system reorganization limited the availability of ACS diagnostic tools and therapeutic strategiesBall S. Banerjee A. Berry C. et al.Monitoring indirect impact of COVID-19 pandemic on services for cardiovascular diseases in the UK.Figure thumbnail gr1

Fig. 1The direct and indirect effects of the COVID-19 pandemic on patient with acute coronary syndromes.

The present article addresses these challenges and discusses findings of the International COVID-ACS and UK-ReVasc registries, studies unique in their scope and investigation of the direct and indirect effects of the COVID-19 pandemic on patients with ACS.

COVID-19 and the cardiovascular system: a changing landscapeIt rapidly became apparent that the SARS-CoV-2 virus would have wide-reaching consequences for patients with cardiovascular disease, because such risk factor profiles were recognized to portend an increased risk of hospitalization and mortality after infection.Zhou F. Yu T. Du R. et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Yet perhaps more unexpected was the sudden and unheralded decline in cases of heart attack observed at the outset of the COVID-19 pandemic. For example, in one of the first such reports, De Filippo and colleagues documented a 25% reduction in hospital admissions for all ACS in Northern Italy.De Filippo O. D'Ascenzo F. Angelini F. et al.Reduced rate of hospital admissions for ACS during Covid-19 outbreak in Northern Italy. These data that have since been replicated in larger and more robust analyses that also show preponderance for greater decreases in non–ST-elevation acute coronary syndrome (NSTE-ACS) presentations.Mafham M.M. Spata E. Goldacre R. et al.COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England.,Garcia S. Albaghdadi M.S. Meraj P.M. et al.Reduction in ST-segment elevation cardiac Catheterization Laboratory Activations in the United States during COVID-19 pandemic. Moreover, increases in out-of-hospital cardiac arrest and death at home when compared with prepandemic periods were described, suggesting that many patients were forgoing medical attention.Rashid M. Gale C.P. Curzen N. et al.Impact of COVID19 pandemic on the incidence and management of out of hospital cardiac arrest in patients presenting with acute myocardial infarction in England.,Wu J. Mamas M.A. Mohamed M.O. et al.Place and causes of acute cardiovascular mortality during the COVID-19 pandemic.Where did all the heart attacks go? Viral respiratory infections are well recognized to increase the risk of acute MI,Kwong J.C. Schwartz K.L. Campitelli M.A. Acute myocardial infarction after Laboratory-Confirmed Influenza infection. so why was this not reflected in greater hospital attendances during the initial waves of the pandemic? Proposed theories comprised: (1) a desire from patients to self-manage symptoms at home (perhaps compounded by societal pressures to quarantine), (2) a reduction in activity levels that may provoke MI, or (3) a fear of COVID-19 contagion in health care settings.Where have all the heart attacks gone?.Against the backdrop of falling heart attack case rates, a story of the complex interplay between SARS-CoV-2 infection and cardiovascular disease developed, fueled by rapid dissemination of knowledge via social media platforms.Aggarwal N.R. Alasnag M. Mamas M.A. Social media in the era of COVID-19. Case series described spontaneous and excess microthrombi and macrothrombi development in multiple vascular beds,Klok F.A. Kruip M. van der Meer N.J.M. et al.Incidence of thrombotic complications in critically ill ICU patients with COVID-19. myocarditis masquerading as ST-elevation myocardial infarction (STEMI),Doyen D. Moceri P. Ducreux D. et al.Myocarditis in a patient with COVID-19: a cause of raised troponin and ECG changes. and elevated rates of myocardial injury in patients with COVID-19 infection.Shi S. Qin M. Shen B. et al.Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.However, the exact degree and frequency of acute myocardial injury in patients with COVID-19, and its relationship with the cardiovascular system, has been difficult to accurately define. In perhaps the most robust study to investigate its prevalence, Lala and colleagues reported acute myocardial injury by means of cardiac troponin elevation in 36% of 2736 patients hospitalized with COVID-19.Lala A. Johnson K.W. Januzzi J.L. et al.Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection. Elevated levels correlated with disease severity, as troponin concentrations 3 times the upper reference limit were associated with a 3-fold increased risk of mortality.Lala A. Johnson K.W. Januzzi J.L. et al.Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection. Multiple hypotheses have been presented for the direct impact of SARS-CoV-2 on the cardiovascular system, ranging from supply-demand mismatch-mediated ischemia, intravascular thrombosis and endotheliitis, systemic hypoxia, or direct viral insult and injury—each a result of a systemic inflammatory cascade as the SARS-CoV-2 viral spike protein binds to angiotensin-converting enzyme 2 receptors.,COVID-19 is, in the end, an endothelial disease. Indeed, discrimination between COVID-19–related and non–COVID-19–related myocardial injury has been intensely debated and acknowledged to present significant diagnostic and therapeutic uncertainty for frontline clinicians.Giustino G. Pinney S.P. Lala A. et al.Coronavirus and cardiovascular disease, myocardial injury, and arrhythmia: JACC focus Seminar.An important group comprises those patients who present with ACS while concurrently infected with COVID-19. Such cases were documented in early observations to experience greater rates of adverse outcomes.Stefanini G.G. Montorfano M. Trabattoni D. et al.ST-elevation myocardial infarction in patients with COVID-19: clinical and angiographic outcomes. The worse clinical courses may be explained by:

It became clear that descriptive and mechanistic observational studies were required to better understand this multifaceted disease process.

Acute coronary syndrome and concomitant COVID-19: The International COVID-ACS registryThe International COVID-ACS Registry was designed to evaluate the characteristics and outcomes of ACS patients with concurrent COVID-19 infection.Kite T.A. Ludman P.F. Gale C.P. et al.International prospective registry of acute coronary syndromes in patients with COVID-19. As it became clear that this population represented a unique challenge,Bangalore S. Sharma A. Slotwiner A. et al.ST-Segment elevation in patients with Covid-19 - a case series. the study was established in March 2020 to elucidate potential mechanisms that may account for the adverse outcomes observed.The International COVID-ACS Registry has provided a pragmatic means of investigator-initiated data collection via an online web-hosted portal. Lead investigators were cognisant of increased clinical demands, redeployed research personnel, and redistributed funding streams during this period. The criteria for study inclusion were as follows: (1) COVID-19 positive (or high index suspicion according to clinical status and chest imaging findingsSimpson S. Kay F.U. Abbara S. et al.Radiological society of North America Expert Consensus Statement on reporting chest CT findings related to COVID-19. Endorsed by the society of Thoracic Radiology, the American College of Radiology, and RSNA - secondary Publication.) and (2) invasive coronary angiography undertaken for suspected ACS.A consortium of international investigators collected data from 144 STEMI and 121 NSTE-ACS patients with concomitant COVID-19 infection. The key findings of the study were consistent regardless of ACS subtype (Table 1).Kite T.A. Ludman P.F. Gale C.P. et al.International prospective registry of acute coronary syndromes in patients with COVID-19. Compared with pre-COVID-19 control cohorts taken from the UK-based British Cardiovascular Intervention Society (BCIS) National PCI Audit,British Cardiovascular Intervention Society database: insights into interventional cardiology in the United Kingdom. and English data from the Myocardial Ischaemia National Audit Project (MINAP) databases,Wilkinson C. Weston C. Timmis A. et al.The myocardial Ischaemia national Audit Project (MINAP). COVID-19 positive ACS patients had:1.

A greater burden of comorbidity

2.

Longer delays seeking medical attention, and, in the case of STEMI, less frequently received timely reperfusion therapy

3.

Higher rates of intensive care unit admission for ventilatory and/or hemodynamic support

4.

Greater adverse in-hospital clinical events, including a more than doubling of cardiogenic shock

5.

A 4-fold increase of in-hospital mortality

Table 1Summary of key findings from the International COVID-ACS registry

Adapted from Kite TA, Ludman PF, Gale CP, et al. International Prospective Registry of Acute Coronary Syndromes in Patients With COVID-19. J Am Coll Cardiol. 2021;77(20):2466-2476.

Pre-COVID-19 STEMI controls were taken from the British Cardiovascular Intervention Society 2018 to 2019 National Audit database. Pre-COVID-19 NSTE-ACS controls were taken from the Myocardial Ischaemia National Audit Project 2019 database.

Abbreviations: IQR, interquartile range; NA, data not available; NSTE-ACS, non–ST-elevation acute coronary syndrome; SD, standard deviation; STEMI, ST-elevation myocardial infarction.

These results have been replicated in similar observational studies that have described in-hospital mortality rates of 23% to 33% in COVID-19 positive STEMI patients, and the predilection for SARS-CoV-2 infection in ACS patients with greater baseline comorbidities and of minority ethnic background (Table 2).Garcia S. Dehghani P. Grines C. et al.Initial findings from the North American COVID-19 myocardial infarction registry.,Rashid M. Wu J. Timmis A. et al.Outcomes of COVID-19-positive acute coronary syndrome patients: a multisource electronic healthcare records study from England. Furthermore, elevated rates of unfavorable presenting characteristics such as out-of-hospital cardiac arrest, heart failure, and cardiogenic shock in COVID-19–positive STEMI patients have consistently been described in the literature.Kite T.A. Ludman P.F. Gale C.P. et al.International prospective registry of acute coronary syndromes in patients with COVID-19.,Garcia S. Dehghani P. Grines C. et al.Initial findings from the North American COVID-19 myocardial infarction registry.Rashid M. Wu J. Timmis A. et al.Outcomes of COVID-19-positive acute coronary syndrome patients: a multisource electronic healthcare records study from England.Rodriguez-Leor O. Cid Alvarez A.B. Perez de Prado A. et al.In-hospital outcomes of COVID-19 ST-elevation myocardial infarction patients.

Table 2Key characteristics and outcomes of COVID-19–positive ACS registry studies

Abbreviations: ACS, acute coronary syndrome; BCIS, British Cardiovascular Intervention Society; MINAP, Myocardial Ischaemia National Audit Project; NACMI, North American COVID-19 Myocardial Infarction; NSTE-ACS, non–ST-elevation acute coronary syndrome; OHCA, out-of-hospital cardiac arrest; STEMI, ST-elevation myocardial infarction.

The principal mechanistic finding of the International COVID-ACS Registry was that time taken for patients to render the hospital was prolonged when compared with pre-COVID controls, and that this was associated with poorer clinical outcomes (symptom onset to admission: COVID-STEMI vs controls: median 339.0 minutes vs 173.0 minutes; P P = .012). In addition, a lengthening of door-to-balloon time in the STEMI subgroup was also observed (COVID-STEMI vs controls: median 83.0 minutes vs 37.0 minutes; P De Luca G. Verdoia M. Cercek M. et al.Impact of COVID-19 pandemic on mechanical reperfusion for patients with STEMI.,Xiang D. Xiang X. Zhang W. et al.Management and outcomes of patients with STEMI during the COVID-19 pandemic in China. thereby suggesting that pathways and well-established systems of care struggled to adapt to the obligatory organizational changes, screening of patients, and preparation of personnel in the catheter laboratory. Such insights in STEMI patients, irrespective of COVID-19 status, provide valuable information and add credence to early hypotheses that deferment in seeking and receiving medical care may, in part, explain the excess mortality rates observed. Public health communications that requested the public “stay at home,” alongside a perceived fear of COVID-19 contagion, appear to have impacted patterns of health care–seeking behavior.Studies to date have often focused on COVID-19–positive patients with STEMI. The unique scope of the International COVID-ACS registry also afforded insights into patients with NSTE-ACS who underwent an invasive strategy. A striking observation existed that magnitude increases of cardiogenic shock and in-hospital mortality compared with prepandemic controls were similar across both COVID-19–positive ACS subgroups (see Table 1). It is well-established that superior outcomes after STEMI are driven by a time-critical concept dependent on expeditious mechanical reperfusion of an occluded coronary artery. For NSTE-ACS, however, the underlying pathophysiology differs and the association with time from symptom onset to angiography (with or without revascularization) is not nearly as strong when compared with STEMI.Ting H.H. Chen A.Y. Roe M.T. et al.Delay from symptom onset to hospital presentation for patients with non-ST-segment elevation myocardial infarction. Although limited by a small number of events in the NSTE-ACS group, acceptance that a median time difference of approximately 2 hours until attendance at hospital between COVID-19–positive NSTE-ACS and pre–COVID-19 control patients would result in such marked differences in outcome is initially problematic. Although confounding factors could be at play, in a cohort of patients who carry a greater comorbidity burden (especially those with concomitant COVID-19 in the COVID-ACS registry),McManus D.D. Gore J. Yarzebski J. et al.Recent trends in the incidence, treatment, and outcomes of patients with STEMI and NSTEMI. the direct effect of COVID-19 infection could be playing a greater part in this ACS subgroup. Worse outcomes in COVID-19–positive NSTE-ACS patients have been associated with excess thrombogenicity, comparable to reports in COVID-19 positive STEMI cases.Choudry F.A. Hamshere S.M. Rathod K.S. et al.High thrombus burden in patients with COVID-19 presenting with ST-elevation myocardial infarction. This concept surely warrants further investigation.Matsushita K. Hess S. Marchandot B. et al.Clinical features of patients with acute coronary syndrome during the COVID-19 pandemic.Percutaneous coronary intervention in patients typically treated with coronary artery bypass grafting: the UK-ReVasc registryBeyond the direct effects of SARS-CoV-2 infection on the global population, the COVID-19 pandemic continues to indirectly impact on mortality and morbidity. Specifically, health care system reorganization, together with changes in patient and clinician behavior, have resulted in restricted access to previously established care pathways, with suggestions that this has led to an increase in deaths from cardiovascular disease.Wadhera R.K. Shen C. Gondi S. et al.Cardiovascular deaths during the COVID-19 pandemic in the United States.In particular, reduced availability of intensive care unit support for procedures such as coronary artery bypass grafting (CABG) and valvular surgery resulted in an up to 80% reduction in cardiac surgical activity during the first wave of the COVID-19 pandemic.Mohamed Abdel Shafi A. Hewage S. Harky A. The impact of COVID-19 on the provision of cardiac surgical services. In the United Kingdom, National Health Service resources were largely reconfigured to only provide care for emergency cases, with clinicians requested to defer treatment for all other patients in preparation for the expected surge of patients with COVID-19 who would require hospitalization and ventilatory support.Next steps on NHS response to COVID-19: Letter from Sir Simon Stevens and Amanda Pritchard.The UK-ReVasc Registry was therefore established as a prospective multicenter registry to investigate the characteristics and outcomes of patients with patterns of coronary artery disease (CAD) that in ordinary circumstances would have been deemed most suitable for CABG surgery,Kite T.A. Ladwiniec A. Owens C.G. et al.Outcomes following PCI in CABG candidates during the COVID-19 pandemic: the prospective multicentre UK-ReVasc registry. but who were instead treated with percutaneous coronary intervention (PCI) because of pandemic-enforced constraints on surgical activity and access to ventilators.Harky A. Harrington D. Nawaytou O. et al.COVID-19 and cardiac surgery: the perspective from United Kingdom.

The registry reported on 215 patients (75% of whom presented with NSTE-ACS) from across the UK and found in-hospital major adverse cardiovascular events were no different when compared with a conventional pre–COVID-19 all-comer PCI population from the British Cardiovascular Intervention Society (BCIS) National Audit database, despite greater complexity of CAD and a more comorbid population in the UK-ReVasc Registry. Low rates of death, MI, stroke, and unplanned revascularization in the registry population persisted out to 30 days follow-up. When compared with isolated CABG data from the United Kingdom, in-hospital mortality was similar, although lower rates of major bleeding and shorter length of hospital stay were observed in the UK-ReVasc Registry group.

To the best of our knowledge, the UK-ReVasc Registry is the only prospective study that has collected data on this specific and novel patient cohort who were required to undergo an alternative mode of revascularization due to the impact of the COVID-19 pandemic. It affords examination of contemporary PCI techniques in a group of patients with high rates of multivessel disease (96%) and left main stem disease (52%), that according to international guidelines should primarily be reserved for CABG.Neumann F.J. Sousa-Uva M. Ahlsson A. et al.2018 ESC/EACTS Guidelines on myocardial revascularization.

Even so, only short-term outcomes have been reported and initial findings perhaps generate more questions than answers. In a population with anatomically complex CAD, does revascularization with contemporary PCI techniques provide comparable and durable longer-term results that are comparable to CABG surgery? Have calcium modification techniques and newer generation drug-eluting stents evolved such that historical revascularization trials require updating to best inform current practice? Longer-term follow-up is required, and ongoing, to inform these important discussions.

Discussion

As we enter the next stages of the COVID-19 pandemic, with decreasing rates of mortality driven by improved therapeutics and mass vaccination strategies, now seems an appropriate juncture to reflect on the impact of this unprecedented crisis. Focus must now shift away from COVID-19 itself and examine the consequences of the SARS-CoV-2 virus on other areas of health service delivery and care.

Cardiovascular disease remains the leading cause of morbidity and mortality globally and is associated with 17.8 million deaths annually.World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions. Patients with cardiovascular disease have been one of the hardest hit groups during the pandemic period, directly because of SARS-CoV-2 predilection to cause severe infection and death in people with such comorbidities, but also indirectly because of restricted availability and access to routine and urgent health care provision that is recognized to improve clinical outcomes.Ball S. Banerjee A. Berry C. et al.Monitoring indirect impact of COVID-19 pandemic on services for cardiovascular diseases in the UK. These 2 effects are well illustrated by the International COVID-ACS and UK-ReVasc registries.Kite T.A. Ludman P.F. Gale C.P. et al.International prospective registry of acute coronary syndromes in patients with COVID-19.,

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