key: cord-1020157-e1ot1fqt
authors: Kunkel, Katherine J.; Lemor, Alejandro; Mahmood, Shazil; Villablanca, Pedro; Ramakrishna, Harish
title: 2021 Update in the Diagnosis and Management of Acute Coronary Syndromes For the Perioperative Clinician
date: 2021-07-22
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2021.07.032
sha: 8d632476a3d29a9f41f41baec8e0bc698604d1ea
doc_id: 1020157
cord_uid: e1ot1fqt

In this review, recent key publications related to acute coronary syndrome (ACS) are summarized and placed into context of contemporary practice. Landmark trials examining vascular access in STEMI (ST elevation myocardial infarction), the management of multivessel disease, acute myocardial infarction and cardiac arrest are discussed. An update in pharmacology for ACS provides updates in major trials relating to P2Y12 inhibitor initiation, de-escalation, and use in special populations. Additional updates in the use of lipid lowering agents and adjunctive medications in ACS are reviewed. Finally, cardiac pathology related to COVID-19 as well as the impact of the COVID-19 global pandemic on the care of patients with acute coronary syndrome is summarized.

Despite advances in the management of heart disease, cardiovascular disease remains a leading cause of death. Patients with acute coronary syndrome represent one of the highest risk groups in this cohort. Advances in the diagnosis and management of acute coronary syndrome (ACS) has shaped the way that these patients are identified, and treatment strategies have evolved. In this review, we discuss the most impactful publications related to acute coronary syndrome in 2020 and place them in the context of this evolving field. The year 2020 was also historic as the global spread of the COVID-19 predominated clinical medicine and biomedical research. In this review, we also discuss the impact that the COVID-19 pandemic has had on the management of patients with ACS as well as the cardiac manifestations of COVID-19.

The long-term epidemiology of coronary heart disease has been studied in multiple longitudinal cohort studies. The fifty year follow up of the European Seven Countries Study was published in 2020. 1 This study followed 6,500 men who were 40-59 years old at the time of enrollment and demonstrates changes in the prevalence of risk factors over time, notably demonstrating reductions in smoking and serum cholesterol levels as well as increases in average blood pressure. As the frequency of risk factors decreased over the study period, hazard rate for mortality decreased.

Similarly temporal trends in hospitalizations for acute MI have shown marked reductions over time, with a large cohort from Kaiser Permanente demonstrating a 48% reduction in hospitalizations for STEMI and NSTEMI between 2000 and 2014. 2 Analysis of AMI 4 hospitalization trends by race reveals that Caucasian patients have had a disproportionate reduction in hospitalizations for AMI compared to Hispanic and Black patients during this period. These findings shed light on persistent racial disparities in cardiovascular disease awareness, treatment, and risk factor optimization. Analysis of the same cohort demonstrated similar disparities when patients were stratified by gender, with the rate of reduction in hospitalization lower among women than men. 3 Despite higher rates of primary prevention, women with AMI are less likely to undergo revascularization and receive treatment for secondary prevention than men. 4 Identification of groups with lagging improvements in outcomes is a key step in achieving equitable healthcare outcomes.

Further risk factor elucidation in 2020 was notable for new insights into the role of malnutrition and smoking in acute coronary syndromes. In a retrospective study in northern Spain, researchers evaluated the nutritional status of patients discharged with a diagnosis of acute coronary syndrome. 5 Using validated tools to determine nutritional status, 8% of patients were found to have moderate to severe malnutrition. While the worst nutrition scores were associated with low body mass index (BMI), 8-36% of malnourished patients had a BMI 25 kg/m 2 depending on the nutritional index used. Poor nutritional status was associated with a two fold increase in the risk for all-cause death. These findings highlight the importance of identifying and intervening on this modifiable risk factor.

Smoking tobacco, an important risk factor for ACS, was examined in a large pooled analysis of primary PCI patients. Increased rates of STEMI among smokers has been well established. Previous studies have observed a favorable prognosis after STEMI among smokers, 5 with the "smoker's paradox" phenomenon posited to be related to ischemic preconditioning and perhaps reduced infarct size among smokers. Redfors and colleagues analyzed data from ten randomized controlled trials in which patients underwent primary PCI for STEMI and infarct size was subsequently characterized by cardiac MRI or SPECT. 6 Smokers were on average ten years younger nonsmokers at the time of STEMI and after adjustment for age and other risk factors, had a higher risk of death or heart failure hospitalization as well as reinfarction compared to nonsmokers. These findings suggest that the "smoker's paradox" is more likely to be related to the younger age and lower comorbidity burden at the time of STEMI in smokers rather than any protective effect of tobacco use.

Following the publication of the Fourth Universal Definition of Myocardial Infarction in 2018, the classification of acute and chronic myocardial injury has increased among patients with elevated troponin biomarkers. 7 The myocardial injury group has previously been shown to have increased mortality. Validation studies of the newly published Fourth Universal Definition have shown reclassification rates up to 30% compared to classification based on the Third Universal Definition of MI. 8 The majority of reclassified patients were reclassified to acute or chronic myocardial injury. This group had significantly higher rates of cardiovascular events compared to non-reclassified patients. Another study of patients aged 50 and younger compared patients with type 1 MI, type 2 MI, or myocardial injury based on the Fourth Universal Definition. 9 Increased mortality in the type 2 MI and myocardial injury groups was striking, with nearly half of patients with type 2 MI and one third of patients with myocardial injury dying within 10 years. 6 While the Fourth Universal Definition has improved identification of patients at high risk for subsequent cardiovascular events, particularly among those classified as myocardial injury, significant controversy continues in the application of these definitions to clinical trials.

Multiple large clinical trials comparing revascularization strategies have used varying definitions of periprocedural MI including the Third and Fourth Universal definitions as well as the SCAI definition. As periprocedural MI is a commonly included component of the composite primary endpoint, nuances between different definitions has large repercussions on the outcomes of pivotal clinical trials. As investigators learn more about the clinical significance of periprocedural MI, the definition and role of this endpoint in clinical trials remains controversial. [10] [11] [12] The Fourth Universal Definition also codified the adoption of hs-troponin assays in the diagnostic algorithms for myocardial infarction and injury. Adoption of hs-troponin resulted in increased diagnosis of type 1 MI, type 2 MI, and myocardial injury by 11%, 22%, and 36% respectively. 13 Despite an increased number of patients diagnosed with myocardial infarction and injury, similar increases were not observed in treatment or improved outcomes.

An additional application of hs-troponin is the potential role of this biomarker to rule out MI in patients presenting to the emergency department with chest pain. In analysis from the APACE study, an international multicenter study aimed at early diagnosis of MI, a single hstroponin C measurement with a cut off value of <3 ng/l had a negative predictive value of 100%, and a cut off of >60 ng/l had a 77% positive predictive value. 14 Application of hs-troponin in the diagnostic algorithm of suspected MI was able to rule out 55% of patients, with ruled out patients having an event rate of 0% at 30 days and 1.6% at two years.

Among patients ruled in for NSTEACS, coronary CTA has become another diagnostic modality under investigation to identify those who would most benefit from invasive coronary angiography. In the VERDICT trial, patients with NSTEACS were randomized to very early or standard invasive coronary angiography. 15 Clinically blinded coronary CTA was performed in both groups to determine the accuracy of coronary CTA in ruling out stenoses <50% compared to invasive coronary angiography. In this study, the negative predictive value of CTA was 91%, suggesting that among patients with NSTEACS, coronary CTA may be appropriate to identify the group of patients who are less likely to derive benefit from invasive imaging.

The relationship of bleeding with recurrent thrombotic events and mortality in patients with ACS has been well established. The implications of post discharge bleeding was further elucidated Marquis-Gravel et al in a large post hoc analysis of data from four randomized trials comprising over 45,000 patients. 16 Among patients with non-CABG related GUSTO moderate, severe, or life threatening bleeding landmarked to seven days after presentation, mortality was higher particularly in the 30 days following discharge. Increased mortality in association with bleeding was similar among groups managed medically versus those who underwent PCI. While the application of these findings to individualized patient care decisions remains nuanced, these findings provide important insight into post-ACS bleeding among patients managed medically for ACS. 17 The importance vascular access selection in acute coronary syndromes has been extensively studied over the last decade. Multiple trials have examined role of femoral versus radial arterial access in primary PCI. Previous randomized control trials have largely shown 8 reduced bleeding and lower mortality in patients with radial access compared to femoral access in the setting of STEMI. 18-20 The SAFARI-STEMI trial, published in 2020, brings these findings into question. 21 In this open-label randomized trial, nearly 2300 patients at five Canadian centers were randomized to radial versus femoral access in primary PCI with a primary end point of 30 day all-cause mortality. The trial was stopped prematurely due to futility, with no difference in mortality or bleeding observed between the radial versus femoral groups. The low overall bleeding and mortality rates reflect a less sick cohort of patients than studied in previous trials as well as the adoption of multiple bleeding mitigation strategies including high rates of bivalirudin use, low rates of GP IIB/IIIA inhibitors, and high rates of femoral closure device use. These differences between the SAFARI-STEMI trial and historical studies make it difficult to rule out small differences between access site groups in contemporary practice. Overall, controversy remains regarding default femoral or radial access in STEMI, While this study is unlikely to lead to any significant changes in guidelines, it is encouraging to see that that with contemporary pharmacology and bleeding mitigation strategies, mortality and bleeding can be comparable regardless of access sites among highly experienced operators. 22

The superiority of primary PCI over fibrinolysis in the acute management of STEMI was established by a series of key trials in the late 1990s and early 2000s. This year, the 16 year follow up data was published from the DANAMI-2 trial which randomized nearly 1600 patients to fibrinolysis versus primary PCI in Denmark. Consistent with previously published 30 day and three year outcomes, 16 year follow up demonstrated a persistent benefit among patients treated with primary PCI compared to fibrinolytics, with lower composite primary outcome of death or rehospitalization for MI as well as lower cardiac mortality compared to patients treated with fibrinolysis. 23 These findings were also seen in the subgroup of patients who required transfer to a different facility for primary PCI.

Ten year data examining patient outcomes in STEMI with primary PCI with bare metal stents versus everolimus eluting stents from the EXAMINATION trial was presented. 24 Patients in the everolimus eluting stent arm had lower rates of the primary composite endpoint of allcause mortality, recurrent MI, or revascularization which was driven by lower rates of all-cause mortality (4.4% absolute risk reduction). Additionally, target lesion revascularization was higher among patients randomized to bare metal stents. These long-term findings are reassuring as they support the current practice of near universal adoption of drug eluting stents in ACS.

Adjunctive therapies in primary PCI in STEMI have similarly evolved over time. The role of intracoronary fibrinolytics in STEMI was studied by McCartney et al in an effort to determine if low dose alteplase after PTCA could reduce microvascular obstruction as measured by cardiac MRI. 25 The authors postulated that degrading fibrin bound thrombotic debris in the microcirculation could result in reduced microvascular obstruction. Unfortunately, the authors found the converse, with increased microvascular obstruction among patients treated with alteplase in a dose dependent fashion. These findings were postulated to be due to hemorrhagic transformation and vascular injury in the setting of ischemia and were particularly striking among patients with 4-6 hours of ischemia compared to those with less ischemic time. These findings continue to reduce the role of intracoronary lytics as the potential for harm is further appreciated.

A further contribution to our understanding of the role of PCI in NSTE-ACS came from Kaura and colleagues who examined outcomes in patients aged 80 and older. 26 This group has been largely excluded from prospective trials examining the role of PCI versus medical therapy in ACS. In this propensity matched observational data from the United Kingdom, researchers found that patients treated with PCI had markedly lower five-year mortality (hazard ratio 0. 66) and heart failure admissions compared to matched patients who were treated medically. Despite advanced age, these patients showed clinically significant improvement in both quality of life and mortality outcomes. These findings support the invasive management of NSTE-ACS in elderly patients when clinically appropriate.

Over the last decade, a growing body of evidence has supported revascularization of nonculprit lesions in the setting of STEMI ( Figure 1 ). [27] [28] [29] [30] The COMPLETE trial, published in late 2019, randomized over four thousand non-shock patients with multivessel coronary disease presenting with STEMI to complete revascularization versus culprit lesion only intervention. 31 The COMPLETE trial demonstrated that in patients with STEMI and multivessel disease, complete revascularization was superior to culprit-only PCI, with reduced rates of death or MI as well as reduced cardiovascular death, MI, or ischemia driven revascularization in the complete revascularization group.

Two meta-analyses of over seven thousand patients in ten randomized trials of nonculprit PCI in STEMI were published in 2020. 32, 33 Both demonstrate reduced cardiovascular mortality and subsequent MI without increased risk of vascular complications, bleeding, or acute kidney injury in the complete revascularization groups compared to the culprit-only groups.

In a subgroup analysis of the COMPLETE trial, severe stenoses, defined as QCA lesions of  60% , were found to be associated with the co-primary endpoints of the trial. 34 The findings that cardiovascular death and myocardial infarction were reduced to a greater extent in the group of lesions meeting criteria for severe stenosis by QCA provides insights on the mechanism of recurrent spontaneous myocardial infarction after STEMI. While procedural MI predominates the etiology of coronary events in the first 30 days after PCI for ACS, over 80% of recurrent ACS beyond 30 days are spontaneous rather than stent thrombosis or procedure related MI. 35 Controversy has remained regarding which types of lesions are most likely to be future culprits, with conflicting data as to the importance of mild to moderate lesions versus more severe stenoses. Based on this subgroup analysis, recurrent spontaneous MI was associated with severe stenosis, providing some biologic insight as to the mechanism for reduced cardiovascular mortality and myocardial infarction observed in the COMPLETE trial. While caution must be exercised in interpreting subgroup analyses, these conclusions provide insights as to the direction for future studies. 36 Further analyses examining the types of non-infarct related lesions most likely to result in spontaneous MI following STEMI were conducted on data from the COMPARE-ACUTE trial. 37 In this substudy, non-infarction related arteries were interrogated by FFR following successful primary PCI. The investigators were blinded to the FFR results, and all non-infarction related lesions were treated medially. In this 24-month natural history study, lesions with lower FFR (e.g., more physiologically significant lesions) were more likely to have major adverse cardiac events, myocardial infarction, and target vessel revascularization.

Overall, the preponderance of data supports revascularization of non-infarction related angiographically severe lesions following STEMI in patients who do not present with cardiogenic shock. Less robust evidence is available for patients with multivessel coronary disease presenting with non-ST elevation myocardial infarction. A retrospective analysis by Kim et al compared three year outcomes among patients with multivessel coronary disease presenting with NSTEMI who underwent culprit only, single staged, or multi-staged complete revascularization. 38 The authors found higher rates of all cause death, non-fatal MI, or repeat revascularization among the group of patients who underwent culprit only revascularization compared to those who underwent complete revascularization. No significant difference was seen between the complete revascularization groups whether the non-infarction related lesions were treated in the index procedure or staged. While retrospective analyses have significant limitations, these findings are certainly hypothesis generating as the role of complete revascularization following acute coronary syndrome is further elucidated.

Despite advances in the management of acute myocardial infarction, patients presenting with MI and out of hospital cardiac arrest continue to have high rates of mortality. Several key publications in 2020 have further defined the role of immediate angiography in out of hospital VT/VF arrest survivors, characterized patients with myocardial infarction most likely to present with cardiac arrest, and identified optimal treatments strategies for this group (Figure 2 ). Immediate coronary angiography and percutaneous coronary intervention is recommended by both American and European guideline documents in patients presenting with out of hospital cardiac arrest found to have STEMI following return of spontaneous circulation. 39, 40 In resuscitated cardiac arrest patients with an initial shockable rhythm who do not have a STEMI on EKG following resuscitation, coronary angiography has historically been recommended without high quality evidence supporting this practice. The COACT trial randomized cardiac arrest survivors presenting with an initial rhythm of VT/VF and no STEMI 13 of EKG to immediate coronary angiography versus delayed coronary angiography following neurologic recovery. 41 In 2019, the 90 day results were published which showed no difference in survival or any secondary endpoints between the immediate angiography and the delayed angiography groups. One year follow up of the COACT trial was published in 2020. 42 The findings at one year were consistent with the 90 day outcomes, with no differences in several key endpoints including survival, myocardial infarction, revascularization, ICD shocks, quality of life, and heart failure hospitalization between the immediate versus delayed angiography groups.

This data suggests that it is safe to defer angiography in this group of patients until neurologic recovery without any adverse short-or long-term consequences.

Among patients undergoing urgent PCI for AMI, Kosugi et al identified characteristics of patients most likely to present with out of hospital cardiac arrest. 43 In this study, the authors retrospectively analyzed 480 patients at a single center in Japan who underwent PCI for AMI.

Patients who underwent angiography for AMI and presented with out of hospital cardiac arrest were compared to patients with AMI not complicated by cardiac arrest. In this selected group of patients, cardiac arrest survivors had a considerably lower in-hospital survival compared to those who presented without cardiac arrest (62% vs 96%). The authors found that younger age, no use of calcium channel blockers, worse renal function, higher peak CK-MB, culprit lesion as the left main coronary artery, and presence of a chronic total occlusion were associated with AMI presenting with out of hospital cardiac arrest. Smaller infarction size, good renal function, VT/VF as the presenting rhythm, and no need for ECMO were predictors of in-hospital survival among those presenting with out of hospital cardiac arrest.

Optimal post arrest care has continued to evolve in 2020. The ideal blood pressure goal in post arrest patients with AMI has been controversial; low blood pressure may result in end 14 organ hypoperfusion leading to worse neurological outcomes and larger infarction sizes while higher blood pressure targets may require higher doses of pressors and lead to more dangerous atrial and ventricular arrhythmias. A patient level pooled analysis of two randomized controlled trials in post arrest patients with AMI evaluated optimal blood pressure targets. 44 Patients were randomized to a lower or higher target blood pressure (MAP of 65 mmHg versus 80-100 mmHg). Despite higher doses of inotropes and pressors, the higher MAP group did not have higher rates of arrhythmias and infarction size was smaller. There was no difference in 180-day survival between the two groups. While this analysis failed to demonstrate differences in patient centered outcomes, lack of increased arrhythmias at higher doses of pressors provides reassurance that the strategy of higher MAP targets is safe.

Finally, analyses of the SWEDEHEART registry attempted to improve identification of patients at the highest risk of cardiac arrest in the 90 days following hospital discharge for AMI. 44 The authors found that out of hospital cardiac arrest was relatively rare in the 120,000 patients included in the analysis, with a <0.3% incidence of subsequent cardiac arrest. In an effort to better identify the post MI patients at highest risk of out of hospital cardiac arrest in the 90 days after discharge, the authors analyzed clinical variables to stratify risk, creating a risk score incorporating six parameters (male sex, diabetes, poor renal function, Killip class II or worse heart failure, new onset atrial fibrillation/flutter, and impaired LVEF). While this risk score performed better than depressed LVEF alone, patients in the highest risk group only had a 2% risk of out of hospital cardiac arrest. Further research is required to identify the post MI group at the highest risk of out of hospital cardiac arrest which while rare is devastating.

Antiplatelet therapy is a pharmacologic cornerstone of the management of ACS. In particular, P2Y12 inhibitors have been the subject of scrutiny as the optimal agent, timing of initiation, and duration of therapy continue to be defined. Several key studies published in 2020 have helped to further elucidate the optimal strategies for initiation and cessation of P2Y12 inhibitors as well as their roles in special populations.

Timely P2Y12 inhibitor initiation in STEMI has been recommended by US and European guideline documents. Despite emphasis on early P2Y12 inhibitor administration, data demonstrating improved clinical outcomes with prehospital P2Y12 inhibitor administration is lacking. 45 A hypothesized reason for this lack of benefit is the prolonged time required for gastric transit and absorption. One method that has been explored to address this barrier is crushing P2Y12 inhibitors prior to administration. Vlachojannis and colleagues conducted a randomized trial of over 700 STEMI patients in the Netherlands investigating the clinical effect of crushed prasugrel. 46 Eligible patients who presented within six hours of symptom onset and were scheduled for primary PCI were randomized to a 60 mg loading dose of prasugrel administered as crushed or integral tablets. The authors were unable to demonstrate any differences between the two groups with respect to the co-primary endpoints of TIMI 3 flow in the infarct-related artery on initial angiography or resolution of ST elevation one hour after primary PCI. As the rates of stent thrombosis and mortality in STEMI have dramatically decreased due to improvements in stent engineering, PCI techniques, and STEMI systems of care, it has become increasingly difficult to demonstrate significant outcome differences with 16 new agents or strategies in the setting of STEMI. In this study, the average time from randomization to angiography was just over 20 minutes. Oral agents, regardless of administration method, are unlikely to be able to demonstrate a significant difference in such a compressed timeframe.

In order to address the delay in onset of action with current oral agents, the novel P2Y12 inhibitor selatogrel has been developed. This agent is administered subcutaneously and has been shown in pharmacodynamic studies to have a rapid onset of action. In a phase II clinical trial, 47 patients presenting with acute MI were randomized to a single dose of selatogrel of 8 or 16 mg followed by ticagrelor. 47 At 30 minutes, 91% of low dose and 96% of high dose patients had effective platelet inhibition which was sustained at 60 minutes. No major side effects or bleeding complications were noted. These initial findings are promising as the agent of choice in the preprocedural management of STEMI continues to be iterated upon, and the phase III trial of selatogrel is planned. 48 Timing of P2Y12 inhibitor initiation in NSTEMI has similarly been a historical area of controversy. The largest study questioning routine pre-treatment with P2Y12 inhibitor administration in NSTEACS was the ACCOAST trial which found that patients pre-treated with prasugrel had no benefit in ischemic endpoints and had higher rates of serious bleeding. 49 The DUBIUS study, published in 2020, is an open label randomized controlled trial of over 1,400 patients with NSTEMI. Patients were randomized to ticagrelor administration upstream (pretreatment) versus downstream (at the time of angiography). 50 The study was terminated prematurely due to futility at interim analysis, with no difference in the primary composite efficacy and safety endpoints. These findings, in concert with previously published work, show that routine P2Y12 pretreatment in NSTEMI is at best not helpful and at worst harmful with increased bleeding events. 51 Following the publication of PLATO and TRITON-TIMI 38, the P2Y12 inhibitor of choice in patients with NSTEACS has been prasugrel or ticagrelor. 52, 53 Limited data has supported the choice of one of these agents over the other. Post hoc analysis of the unstable angina and NSTEMI groups of the ISAR-REACT 5 trial compared patients randomized to ticagrelor versus prasugrel. 54 The authors found prasugrel to be superior in reducing the one year composite endpoint of death, MI, and stroke without increasing the risk of serious bleeding. This post hoc analysis is hypothesis generating and is limited by the initial open label trial design, however the findings are reassuring that no differences in bleeding are observed when directly comparing prasugrel and ticagrelor in patients with NSTEACS. 55 

As the significance of bleeding events has become widely appreciated, P2Y12 inhibitor de-escalation and cessation has been an area of considerable interest in ongoing clinical trials.

The TWILIGHT trial randomized 9,000 patients who were identified as high risk for bleeding or ischemic complications to DAPT with ticagrelor and aspirin versus ticagrelor monotherapy after successful completing three months of DAPT. 56 The investigators found a lower risk of serious bleeding in the ticagrelor monotherapy group with no increase in ischemic outcomes. Several subgroup analyses of the TWILIGHT have subsequently been published. In a prespecified subgroup analysis of patients undergoing complex PCI as defined by coronary anatomy and extensive/complex stenting techniques, patients in the ticagrelor monotherapy group continued to show benefit compared to those treated with DAPT despite theoretically higher risk of stent thrombosis in more complex stenting. 57 In patients presenting with acute coronary syndrome, subgroup analysis of patients in the TWILIGHT trial also showed benefit with ticagrelor monotherapy over DAPT, with the benefit of reduced bleeding events more pronounced among patients with acute coronary syndrome than those with stable ischemic heart disease. 58 Similar results were observed in the TICO study which was designed similarly to TWILIGHT with the exception of limiting enrollment to patients who underwent stenting for ACS. 59 After tolerating DAPT with aspirin and ticagrelor for three months, patients were randomized to ticagrelor monotherapy versus DAPT for the next nine months. Similar to TWILIGHT, the authors found reduced composite bleeding, cardiovascular, and cerebrovascular events in the ticagrelor monotherapy group driven by a reduction in major bleeding (hazard ratio 0.56 for major bleeding).

Prasugrel was studied in a similar fashion in the HOST-REDUCE-POLYTECH-ACS trial which randomized 2,300 patients who underwent stenting for ACS to DAPT with full dose prasugrel and aspirin versus low dose prasugrel and aspirin after completing three months of DAPT. 60 Consistent with TWILIGHT and TICO, patients who were treated with low dose prasugrel and aspirin had lower net adverse clinical events at one year driven by a reduction in the risk of bleeding. Overall, the available data supports early de-escalation of P2Y12 inhibitor intensity, particularly among patients at high risk for bleeding complications.

Special consideration for the P2Y12 inhibitor use in the elderly must take into account unique risk factors in this age group including increased risk of bleeding, risk of ischemic events, and co-treatment with anticoagulation. Analysis from the SWEDEHEART Registry compared patients aged 80 or older who were prescribed DAPT with clopidogrel versus ticagrelor at hospital discharge for a diagnosis of myocardial infarction. 61 After inverse probability weighting of Cox regression models to adjust for differences in patient and therapy characteristics, the authors found no difference in ischemic outcomes with clopidogrel versus ticagrelor. Ticagrelor use was associated with a significantly higher risk of death and bleeding. This hypothesis put forth by this registry data was tested in the POPular AGE trial which randomized 1000 patients over the age of 70 presenting with NSTEACS to loading and maintenance doses of clopidogrel versus ticagrelor for one year of treatment. 62 Several key findings are notable from this trial. Premature cessation of ticagrelor was very common, with 47% patients in the ticagrelor stopping treatment due to bleeding or shortness of breath.

Bleeding was also frequent in all subjects, but was significantly more common in the ticagrelor group, with 24% of patients experiencing PLATO major or minor bleeding compared to 18% in clopidogrel group. The composite clinical benefit outcome was non-inferior for clopidogrel versus ticagrelor. Overall, this study highlights the high frequency of bleeding in elderly patients treated with P2Y12 inhibitors and demonstrates reduced bleeding with similar ischemic endpoints with clopidogrel versus more potent P2Y12 inhibitors.

An additional group that merits special consideration are those with known cytochrome p-450 polymorphisms that confer reduced clopidogrel metabolism. Patients with loss of function mutations of the CYP2C19 gene have reduced concentrations of the active metabolites of clopidogrel, increased platelet reactivity, and increased risk of subsequent ischemic events. 63 Despite these findings, evidence of improved clinical outcomes when antiplatelet therapy is tailored to individual genetics is lacking. 64 The findings of the TAILOR-PCI randomized trial 20 were consistent with the lack of benefit in gene tailored antiplatelet therapy seen in previous studies. In this trial, 5,300 patients who underwent PCI were randomized to standard therapy with clopidogrel versus genotype-guided therapy with ticagrelor substituted for clopidogrel in patients with CYP2C19 loss of function mutations. 65 There was no differences in composite efficacy or bleeding endpoints in the standard versus genotype-guided therapy groups. These findings underline previous work which has shown that while genotyping can identify higher risk individuals, no effective interventions have been identified to ameliorate this risk.

The role of lipids in atherogenesis is foundational in the pathogenesis of coronary artery disease. Identifying and targeting lipid metabolites has further elucidated the mechanistic role of lipid lowering therapies. The importance of VLDL was demonstrated in analysis from the Copenhagen General Population Study. 66 This observational study found that elevated VLDL cholesterol explained half of the MI risk from elevated apoB containing lipoproteins whereas VLDL triglycerides did not account for risk. This is theorized to be due to increased direct uptake of VLDL into macrophages which then morphologically become foam cells, a key component of atherosclerotic lesions. These findings inform future directions for study to reduce MI risk by identifying novel lipid targets.

The most recent major advance in anti-lipid therapy has been the development and approval of evolocumab and alirocumab, monoclonal PCSK-9 inhibitors. In the landmark FOURIER and ODYSSEY trials, these agents where shown to significantly reduce LDL levels and adverse cardiovascular outcomes. 67, 68 A pre-specified analysis from the ODYSSEY trial evaluated the effect of alirocumab-induced changes in Lp(a) and LDL-C on MACE. 69 The authors found that both baseline levels and relative reductions of Lp(a) and LDL-C were independently associated with a reduction in MACE. While providing mechanistic insight into the effect of alirocumab, these findings suggest that Lp(a) may have additional value as an independent treatment target after ACS.

The role of plaque burden and composition in ACS has continued to inform future directions for research. In a large CTA dataset, investigators found that after stratifying patients by calcified plaque burden, the degree of stenosis did not predict future cardiovascular events. 70 That is to say patients with a similar amount of plaque had similar risk for subsequent MI whether the plaque was diffuse, e.g. non-obstructive, versus focal, e.g. obstructive. These findings suggest that plaque burden rather than the degree of stenosis may predict future risk.

Intracoronary imaging has furthered study of plaque burden and characteristics en vivo.

Using NIRS intravascular imaging, investigators in an international prospective cohort study imaged non-culprit segments in 1500 patients undergoing cardiac catheterization for suspected coronary artery disease. 71 Investigators were able to demonstrate the association of large lipid rich plaques with major cardiac events over the next two years at both a patient and plaque level.

The concept that high risk plaques can be identified and prophylactically intervened upon before progressing to acute coronary syndrome was explored in the PROSPECT ABSORB study. 72 In this pilot trial, patients who underwent successful PCI for STEMI or NSTEACS underwent three vessel intravascular imaging with IVUS and NIRS. Of the 902 patients enrolled, 182 had lesions eligible for randomization. Lesions that were <70% stenosed with  65% plaque burden were randomized to treatment with Absorb bioresorbable vascular scaffold (BVS) and guideline directed medical therapy versus medical therapy alone. The investigators found that PCI of angiographically mild lesions with large plaque burdens was safe and 22 associated with larger minimal lumen area on follow up angiography. There were similar rates of target lesion failure at 24 months. While underpowered to detect any differences in long term clinical outcomes, this trial provides reassuring safety data in preparation for a larger pivotal trial. Further study and refinement of identification of the highest risk plaques as well as robust outcome and safety data are required before the adoption of PCI with BVS is adopted. 73

IV morphine has historically been recommended to control pain in patients with ACS despite the absence of safety data. Given negative effects of opioids on gastrointestinal motility, IV morphine prior to PCI in the setting of ACS has been theorized to delay absorption of P2Y12

inhibitors which rely on gastric motility for transit to the intestine where absorption occurs.

Delayed absorption with lower circulating concentrations of P2Y12 inhibitors and their metabolites in the time period immediately surrounding PCI has been theorized to increase thrombotic events and lead to higher mortality in patients receiving IV morphine prior to PCI.

Previous data in this area has been conflicting, with some studies showing an impact on all-cause mortality and composite endpoints and other studies failing to show any difference in outcomes in those receiving IV morphine versus those who do not. 74, 75 A posthoc analysis from the EARLY ACS trial examined a group of patients pre-treated with clopidogrel prior to coronary angiography for NSTEACS and compared the group who received IV morphine to those who did not. 76 After propensity matching, the group treated with morphine had a higher rate of the composite endpoint of death, MI, recurrent ischemia requiring urgent revascularization, or thrombotic bailout at 96 hours (odds ratio 1.40). Periprocedural MI was also significantly increased in the morphine group, suggesting that stent thrombosis and 23 thrombotic complications may be driving these findings. These findings inform the evolving role of opioids in patients with ACS, particularly among patients pretreated with clopidogrel as pharmacologic studies have shown both delay in absorption as well as reduced levels of clopidogrel and its metabolites when co-administered with IV morphine. In patients receiving clopidogrel and IV opioids prior to PCI, intensive anti-platelet therapy with IV cangrelor, an IV GP IIB/IIIA inhibitor, or a reloading dose in six hours can be considered to reduce the risk of acute thrombotic events. 77 Following myocardial infarction, the use of NSAID medications has been shown to be associated with increased rates of cardiovascular events and bleeding. Despite recommendations to avoid NSAIDs in patients with a history of ischemic heart disease, rates of exposures to NSAIDs remain high due to the presence of other co-morbidities. 78 In a nationwide cohort study from Korea with data from over 100,000 patients who were diagnosed with their first myocardial infarction, NSAID use was significantly associated with cardiovascular events (hazard ratio 9.96) and bleeding events (hazard ratio 4.08). 79 Among the NSAIDs prescribed, celecoxib and meloxicam had the lowest adjusted rates cardiovascular events and bleeding, suggesting that these agents may be the NSAIDs of choice in patients with a history of MI in whom NSAIDs cannot be avoided.

Inflammation has been known to play an important role in the pathophysiology of acute coronary syndromes. After the pivotal CANTOS trial which demonstrated improved cardiovascular outcomes after treatment with an anti-inflammatory agent, interest has grown in the use of other immunomodulating agents in patients with coronary artery disease. 80 Multiple key publications in 2020 investigated colchicine for secondary prevention in this group. The

LoDoCo2 Trial randomized patients with angiographic or computed tomography evidence of 24 coronary disease to colchicine versus placebo. 81 In this group of stable patients who had no clinical events in the six months leading to enrollment, colchicine was associated with a reduction in the composite endpoint of cardiovascular death, spontaneous MI, ischemic stroke, or ischemia-driven revascularization (hazard ratio 0.69).

These results were concordant with the previously published COLCOT trial which randomized nearly 5,000 patients with recent myocardial infarction to colchicine versus placebo. 82 In COLCOT, treatment with low dose colchicine was similarly associated with a lower composite risk of cardiovascular death, cardiac arrest, myocardial infarction, stroke, or urgent coronary revascularization at two years. A subsequent analysis of time to treatment with colchicine in the COLCOT trial demonstrated that the benefit of colchicine was greatest in those who started treatment with colchicine within three days of myocardial infarction (hazard ratio of 0.52) compared to those who started treatment greater than eight days after revascularization (hazard ratio 0.82). 83 These positive findings were tempered with contradictory data from a smaller multicenter randomized controlled trial from Australia (the Austrialian COPS trial). 84 In a design similar to COLCOT, investigators randomized patients who presented with ACS with angiography showing coronary artery disease to one year of colchicine versus placebo prior to hospital discharge. No difference was found with respect to the primary composite endpoint and concerningly, a higher rate of non-cardiovascular mortality was observed in the colchicine group. The association of COVID-19 with myocardial injury and structural abnormalities was studied in a large multi-national study. 89 In this study, investigators compared the in-hospital morality of COVID-19 patients with myocardial injury who were found to have structural abnormalities on echocardiography such as regional wall motion abnormalities, LV systolic or diastolic dysfunction, RV dysfunction, or pericardial effusions to those with structurally normal hearts. In this cohort of 305 patients, 62% of COVID-19 patients were found to have myocardial injury demonstrated by elevated cardiac biomarkers. Of those with myocardial injury, two in three had evidence of structural abnormalities on imaging, the most common of which was right ventricular dysfunction. A worse prognosis was observed in those with structural abnormalities on echocardiography who had a 32% in hospital mortality compared to a 19% mortality in patients with biochemical evidence of myocardial injury with no significant structural abnormalities.

Another characteristic of COVID-19 is the high prevalence of thrombotic complications.

In a single-center study in the United Kingdom, patients with COVID-19 who presented with STEMI were found a higher thrombus burden than those with STEMI in the absence of COVID- 19 . 90 This observational study noted that patients with COVID-19 and STEMI showed higher risk of thrombotic complications including stent thrombosis, high thrombus grade, and larger areas of myocardial damage with a greater degree of left ventricular systolic dysfunction 90 .

While the pathophysiology of the pro-thrombotic state of COVID-19 is not completely understood, COVID-19 has been associated with higher rates on pre-hospital cardiac arrest, intensive care admission, and in-hospital mortality in patient with STEMI. 90 In addition to the direct effect of COVID-19 on cardiac pathology, important secondary effects due to stressors on healthcare systems adversely effected the care of patients with ACS.

Data collected from studies around the world showed a significant decline in the number of patients admitted to hospitals due to ACS in the spring of 2020. 91 This phenomenon was 27 attributed to messaging encouraging the public to remain at home in the early stages of the pandemic as well as public fear of contracting the virus at medical facilities and hospitals.

Reductions in ACS hospitalizations was observed globally. [92] [93] [94] [95] Delayed presentations and reduced admissions for primary percutaneous interventions (PCI) resulted in increased out of hospital deaths, worse outcomes with primary PCI, and increases in mechanical complications of MI. 86-88, 91, 96 Italy was one of the first countries to have the healthcare system overwhelmed by COVID-19. Italian hospitals reported a 48% overall reduction in admissions for ACS during the spring of 2020, with a 65% reduction in NSTEMI and 27% reduction in STEMI admissions. 97 STEMI outcomes also suffered, with time from first medical contact to PCI increased 32% and case fatality rates of 17% compared to a historic control of 10%. Similar trends with a 40% reduction in admissions for acute coronary syndrome were seen in Australia, the UK, and the United States. 93, 95, 98 Understanding the pathophysiology, management, and treatment of COVID-19 patients with ACS has been the result of global efforts. Primary PCI remains the standard of care in STEMI regardless of COVID-19 status. Similar management strategies are applied to early invasive management versus medical management of NSTEACS. 99 While much of the cardiac effects of COVID-19 remains to be learned, considerable progress has been made in identifying cardiac manifestations of COVID-19 as well as optimizing existing systems of care to provide effective care for cardiac patients during the global pandemic.

In the last year, there was considerable advancement in the care of patients with ACS.

Particular emphasis on the management of multivessel disease as well as advances in pharmacology continue to shift the field to safer, more selective use of therapies to improve both short-and long-term outcomes. The COVID-19 pandemic resulted in major disruptions to clinical care in the spring of 2020. Despite these challenges, lessons learned, and the application of clinical science continues to drive this evolving field forward. 

Coronary heart disease mortality trends during 50 years as explained by risk factor changes: The European cohorts of the Seven Countries Study

Trends in Acute Myocardial Infarction by Race and Ethnicity

Sex-Specific Trends in Acute Myocardial Infarction Within an Integrated Healthcare Network

Variations between women and men in risk factors, treatments, cardiovascular disease incidence, and death in 27 high-income, middleincome, and low-income countries (PURE): a prospective cohort study

Prevalence and Prognostic Significance of Malnutrition in Patients With Acute Coronary Syndrome

Effect of Smoking on Outcomes of Primary PCI in Patients With STEMI

Clinical application of the 4th Universal Definition of Myocardial Infarction

Cardiovascular Mortality After Type 1 and Type

Myocardial Infarction in Young Adults

Procedural Myocardial Infarction: Definitions Everywhere, But Not Any That May Fit

Implications of Alternative Definitions of

Peri-Procedural Myocardial Infarction After Coronary Revascularization

Impact of Peri-Procedural Myocardial Infarction on Outcomes After Revascularization

High-Sensitivity Cardiac Troponin and the Universal Definition of Myocardial Infarction

Early Diagnosis of Myocardial Infarction With Point-of-Care High-Sensitivity Cardiac Troponin I

Elevation Acute Coronary Syndrome

Post-Discharge Bleeding and Mortality Following Acute Coronary Syndromes With or Without PCI

Mortality From Bleeding Versus Myocardial Infarction: Loosening A Strand of the Antithrombotic Therapy "Gordian Knot

Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial

Radial versus femoral randomized investigation in ST-segment elevation acute coronary syndrome: the RIFLE-STEACS (Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome) study

Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial

Safety and Efficacy of Femoral Access vs Radial Access in ST-Segment Elevation Myocardial Infarction: The SAFARI-STEMI Randomized Clinical Trial

Comparing Percutaneous Coronary Intervention Access Sites for ST

Elevation Myocardial Infarction-Are Radial and Femoral Access Equally Safe?

16-year follow-up of the Danish Acute

DANAMI-2) trial: primary percutaneous coronary intervention vs. fibrinolysis in ST-segment elevation myocardial infarction

Everolimus-Eluting Stent Versus Bare-Metal Stent in ST-Segment Elevation Myocardial Infarction: 10-Year Follow-Up of the Multicenter Randomized Controlled Examination Trial

Low-Dose Alteplase During Primary Percutaneous Coronary Intervention According to Ischemic Time

Invasive versus non-invasive management of older patients with non-ST elevation myocardial infarction (SENIOR-NSTEMI): a cohort study based on routine clinical data

Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial

Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial

Fractional Flow Reserve-Guided

Multivessel Angioplasty in Myocardial Infarction

Randomized trial of preventive angioplasty in myocardial infarction

Complete Revascularization with Multivessel PCI for

Multivessel Versus Culprit-Only Revascularization in STEMI and Multivessel Coronary Artery Disease: Meta-Analysis of Randomized Trials

Complete vs Culprit-Lesion-Only Revascularization for ST-Segment Elevation Myocardial Infarction: A Systematic Review and Meta-analysis

Nonculprit Lesion Severity and Outcome of Revascularization in Patients With STEMI and Multivessel Coronary Disease

Nonculprit Lesion Myocardial Infarction Following Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome

On the Credibility of Subgroup Analyses in the COMPLETE Trial

The Natural History of Nonculprit Lesions in STEMI: An FFR Substudy of the Compare-Acute Trial

Segment-Elevation Myocardial Infarction With Multivessel Coronary Artery Disease: Culprit-Only Versus One-Stage Versus Multistage Revascularization

ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)

ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the

Cardiac Arrest without ST-Segment Elevation

Coronary Angiography After Cardiac Arrest Without ST Segment Elevation: One-Year Outcomes of the COACT Randomized Clinical Trial

Clinical and Angiographic Features of Patients With Out-of-Hospital Cardiac Arrest and Acute Myocardial Infarction

Incidence and Predictors of Out-of-Hospital Cardiac Arrest Within 90 Days After Myocardial Infarction

Prehospital ticagrelor in ST-segment elevation myocardial infarction

Effect of Prehospital Crushed Prasugrel Tablets in Patients With ST-Segment-Elevation Myocardial Infarction Planned for Primary Percutaneous Coronary Intervention: The Randomized COMPARE CRUSH Trial

Subcutaneous Selatogrel Inhibits Platelet Aggregation in Patients With Acute Myocardial Infarction

Selatogrel for Acute Myocardial Infarction: The Promise and Challenges of Self-Medication

Pretreatment with prasugrel in non-STsegment elevation acute coronary syndromes

Timing of Oral P2Y12 Inhibitor Administration in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome

Non-ST-Segment Elevation Acute Coronary Syndrome: The Last Nail in the Coffin of Pre-Treatment

Ticagrelor versus clopidogrel in patients with acute coronary syndromes

Prasugrel versus clopidogrel in patients with acute coronary syndromes

Ticagrelor or Prasugrel in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes

Dual Antiplatelet Therapy Following PCI for NSTEMI: An Obvious Choice or a Calculated Decision?

Ticagrelor with or without Aspirin in High-Risk Patients after PCI

Ticagrelor With or Without Aspirin After Complex PCI

Ticagrelor alone vs. ticagrelor plus aspirin following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes: TWILIGHT-ACS

Effect of Ticagrelor Monotherapy vs Ticagrelor With Aspirin on Major Bleeding and Cardiovascular Events in Patients With Acute Coronary Syndrome: The TICO Randomized Clinical Trial

Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial

Comparison Between Ticagrelor and Clopidogrel in Elderly Patients With an Acute Coronary Syndrome: Insights From the SWEDEHEART Registry

Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome (POPular AGE): the randomised, open-label, non-inferiority trial

Cytochrome p-450 polymorphisms and response to clopidogrel

Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial

Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection vs Conventional Clopidogrel Therapy on Ischemic Outcomes After Percutaneous Coronary Intervention: The TAILOR-PCI Randomized Clinical Trial

VLDL Cholesterol Accounts for One-Half of the Risk of Myocardial Infarction Associated With apoB-Containing Lipoproteins

Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease

Alirocumab and Cardiovascular Outcomes after

Acute Coronary Syndrome

Cardiovascular Risk After Acute Coronary Syndrome

Impact of Plaque Burden Versus Stenosis on Ischemic Events in Patients With Coronary Atherosclerosis

Identification of patients and plaques vulnerable to future coronary events with near-infrared spectroscopy intravascular ultrasound imaging: a prospective, cohort study

Percutaneous Coronary Intervention for Vulnerable Coronary Atherosclerotic Plaque

Preemptive Stenting of the Vulnerable Plaque: Fixing a Dogma?

Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative

Correlates of pre-hospital morphine use in STelevation myocardial infarction patients and its association with in-hospital outcomes and longterm mortality: the FAST-MI (French Registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction) programme

Morphine and Cardiovascular Outcomes Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Undergoing Coronary Angiography

Opiates and Clopidogrel Efficacy: Lost in Transit?

Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study

Cardiovascular and Bleeding Risks Associated With Nonsteroidal Anti-Inflammatory Drugs After Myocardial Infarction

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Colchicine in Patients with Chronic Coronary Disease

Efficacy and Safety of Low-Dose Colchicine after

Time-to-treatment initiation of colchicine and cardiovascular outcomes after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT)

Colchicine in Patients With Acute Coronary Syndrome: The Australian COPS Randomized Clinical Trial

Effects of Acute Colchicine Administration Prior to Percutaneous Coronary Intervention: COLCHICINE-PCI Randomized Trial

Pandemic: A Global Perspective

Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic

SARS-CoV-2: a potential novel etiology of fulminant myocarditis

Characterization of Myocardial Injury in Patients With COVID-19

High Thrombus Burden in Patients With COVID-19 Presenting With ST-Segment Elevation Myocardial Infarction

Pandemic on Hospitalizations for Acute Coronary Syndromes: a Multinational Study

Estimating excess 1-year mortality associated with the COVID-19 pandemic according to underlying conditions and age: a population-based cohort study

Decline of acute coronary syndrome admissions in Austria since the outbreak of COVID-19: the pandemic response causes cardiac collateral damage

Reduced Rate of Hospital Admissions for ACS during Covid-19 Outbreak in Northern Italy

Reduction in ST-Segment Elevation Cardiac Catheterization Laboratory Activations in the United States During COVID-19 Pandemic

Impact of COVID-19 Pandemic on Mechanical Reperfusion for Patients With STEMI

Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era