key: cord-0761162-5sig3lqk
authors: Yildiz, Mehmet; Wade, Spencer R.; Henry, Timothy D.
title: STEMI care 2021: Addressing the knowledge gaps
date: 2021-08-25
journal: Am Heart J Plus
DOI: 10.1016/j.ahjo.2021.100044
sha: 2be05a72f99047169b595b4788bb8620e92f796b
doc_id: 761162
cord_uid: 5sig3lqk

Tremendous progress has been made in the treatment of ST-segment elevation myocardial infarction (STEMI), the most severe and time-sensitive acute coronary syndrome. Primary percutaneous coronary intervention (PCI) is the preferred method of reperfusion, which has stimulated the development of regional STEMI systems of care with standardized protocols designed to optimize care. However, challenges remain for patients with cardiogenic shock, out-of-hospital cardiac arrest, an expected delay to reperfusion (>120 min), in-hospital STEMI, and more recently, those with Covid-19 infection. Ultimately, the goal is to provide timely reperfusion with primary PCI coupled with the optimal antiplatelet and anticoagulant therapies. We review the challenges and provide insights into the remaining knowledge gaps for contemporary STEMI care.

long-term survival benefits [7] , [25] . The Society for Cardiovascular Angiography and Interventions (SCAI) CS classification schema may help select high-risk CS patients requiring transfer for more specialized centers with mechanical circulatory support [26] , [27] . The recent scientific statement by AHA recommends the management of CS patients may include: (1) Transport of the patient identified in the field by EMS directly to the CS center by bypassing non-CS centers; (2) STEMI patients should be transferred to the nearest PCI center for rapid revascularization and stabilization; (3) early communication with the CS center team; and (4) a consider mobile units from the CS center to be deployed to the referral hospital to stabilize the patient until the transfer can be made [22] .

Despite limited randomized trials with a lack of survival benefit, mechanical circulatory support (MCS) has been increasingly used in CS [7] , [22] [23] [24] [25] [26] , [28] . The recent scientific statement by AHA proposed that STEMI patients complicated by CS (SACI shock stages from C to E) may benefit from MCS devices in case of persistent hemodynamic instability. However, it should not delay revascularization [7] , [22] .

STEMI patients with OHCA are another high-risk population with a 10-fold increase in mortality compared to non-cardiac arrest STEMI [8] . Initial shockable rhythm and being awake after the initial resuscitation have more favorable outcomes than non-shockable rhythm and being comatose [8] , [29] , [30] . When coupled with revascularization, therapeutic hypothermia (TH) improves survival and neurological outcomes since every hour delay in cooling increases in-hospital mortality by 20%. Therefore, both ACCF/AHA and ESC guidelines consider TH a class I recommendation with immediate coronary angiography and PCI for STEMI patients with OHCA [15] , [31] .

In particular, STEMI patients with both CS and CA are the highest risk population with mortality of 44% compared to 19% in CA alone or 23% in CS alone [24] . Therefore, the SCAI CS classification considers CA an important modifier which has been confirmed by recent validation studies [27] .

Following the initial resuscitation, most patients will remain comatose or hypothermic, which challenges administering oral antiplatelet agents. In that respect, cangrelor, an intravenous P2Y 12 receptor antagonist, is an alternative agent with rapid onset and offset effects [7] .

While primary PCI is the preferred treatment approach, many STEMI patients transferred from non-PCI centers do not meet the guideline-recommended time of 120 minutes [6] , [18] . The safety and efficacy of pharmacoinvasive reperfusion with half-dose fibrinolytic therapy combined with transfer from remote rural hospitals (>60 miles away from PCI center) for primary PCI were demonstrated in the Level 1 MI program at the Minneapolis Heart Institute [4] , [17] , [32] . Compared with 600 patients presenting directly to the PCI center, 660 patients transferred from remote hospitals who received pharmacoinvasive therapy had similar 30-day mortality rates despite nearly an hour longer time to treatment (5.5% vs. 5.6%; P = 0.94) [17] .

There results were consistent with multiple randomized clinical trials [32] .

The primary concern with fibrinolytic therapy is the risk of intracranial hemorrhages documented by the Strategic Reperfusion Early After Myocardial Infarction (STREAM) trial [33] . In STREAM, the rates of major cardiovascular events at 30 days were similar among STEMI patients who received fibrinolytic therapy (half-dose for patients aged 75 years or older) compared with primary PCI. However, there were more intracranial hemorrhages in the fibrinolytic therapy group than the primary PCI group (1. Myocardial Infarction Treated with Pharmacological Thrombolysis (TREAT) trial [34] . In TREAT, patients aged < 75 years with STEMI, administration of ticagrelor after fibrinolytic therapy did not reduce the frequency of cardiovascular events compared to clopidogrel (6.7%

[129/1913] vs. 7.3% [137/1886]). Thus, STEMI patients with an expected delay >120 minutes can be treated safely and effectively using a pharmacoinvasive approach with half-dose fibrinolytic therapy, aspirin, and clopidogrel.

Patients that develop STEMI while in the hospital represent another high-risk population. These patients tend to have prolonged time to treatment because they often present with atypical symptoms. In addition, there is frequently a delay in obtaining an ECG and activation of the STEMI system. Mortality rates may be up to 10-fold higher for in-hospital STEMI patients (31%-42%) than those presented via EMS or independently [9] , [35] . In particular, patients who develop STEMI on non-cardiovascular units (e.g., post-anesthesia care, intensive care, or neurologic intensive care units) have significantly higher mortality [35] . Thus, implementing quality improvement programs for in-hospital STEMI is essential to decrease delays and streamline care to improve treatment and outcomes.

Covid-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), resulted in a devastating worldwide pandemic. The heart is a critical target for SARS-CoV-2 by direct (viral J o u r n a l P r e -p r o o f entry into cardiomyocytes) and indirect (pro-inflammatory response, pro-thrombotic state, demand ischemia, cardiac stress, or plaque rupture) mechanisms [36] , [37] . Destabilization of pre-existing atherosclerotic plaque may predispose to STEMI in Covid-19 infection [38] . Troponin is elevated in 15-30% of Covid-19 patients admitted to the hospital and is predictive of higher in-hospital mortality [38] .

SARS-CoV-2 spreads mainly via droplets or aerosols from person to person through close contact. Thus, federal and local agencies implemented several measures to mitigate the pandemic, such as stay-at-home orders, social isolation, and deferral of elective procedures. Additional measures implemented by individual healthcare systems include shifting medical resources to patients with Covid-19 infection, canceling in-person appointments, and initiating new triage protocols [39] [40] [41] . These interventions and patient fears contributed to unintended consequences and resulted in a decrease in STEMI and other acute coronary syndrome admissions and an increase in late STEMI complications and OHCA [10] , [42] , [43] . Overall, STEMI incidences declined remarkably during the Covid-19 pandemic by 38% in the US, 26% in China, and 18.9%

in Europe [10] , [42] , [43] Early reperfusion is critical in STEMI treatment. However, the ISACS-STEMI Covid-19 registry, established in Europe, reported a significant increase in total ischemic and door-to-balloon times during the Covid-19 pandemic [43] . Although some healthcare systems and experts endorsed fibrinolytic therapy early in the Covid-19 pandemic in order to minimize the risk of virus spread and avoid any delay in reperfusion [44] , [45] , it became clear that Covid-19 patients with ST-segment elevation frequently had no clear culprit. Also, CCL staff could safely and quickly deal with STEMI in Covid-19. Therefore, primary PCI remains the reperfusion method of choice for Covid-19 patients [11] .

In the light of the delays to presentation, the incidence of STEMI complications such as OHCA or mechanical complications (e.g., ventricular septal defect, free wall rupture, papillary muscle rupture, or left ventricular thrombus) have increased considerably compared to the pre-Covid-19 era [46] , [47] . Furthermore, in-hospital mortality rates increased by 41% in Europe and 21% in China [42] , [43] .

In addition to the abovementioned challenges on STEMI systems of care, Covid-19 patients that present with STEMI are a very high-risk population. Initial reports during the early phase of the pandemic revealed heterogeneous findings but were limited by small sample sizes and lack of control groups. A systemic review of case reports and case series reported a relatively higher incidence of non-obstructive lesions (17%) in STEMI patients with concurrent Covid-19 infection. In-hospital mortality was also relatively high (30%), without a significant difference between obstructive and non-obstructive lesions [48] . The recently published NACMI registry, established in North America with a collaboration of multinational societies, provided a more comprehensive view [49] . STEMI patients with concurrent Covid-19 infection (n=230) were more likely to be diabetic and ethnic minorities. They were more likely to present with atypical symptoms such as dyspnea (54%) and with high-risk features such as CS (18%) and cardiac arrest (11%). Only 78% underwent coronary angiography. Among those patients, the majority (71%) received primary PCI, while 20% were treated medically. Consistent with previous reports, many patients (23%) had no culprit lesion, which may reflect microthrombi, takotsubo syndrome, spontaneous coronary artery dissection, or myocarditis. STEMI patients with concurrent Covid-19 infection had an increased risk for in-hospital mortality compared with control STEMI patients from the pre-Covid-19 era (33% vs. 4%, P <0.001) [49] .

As Covid-19 extends into the second year with different surge patterns worldwide, the to ticagrelor when used in conjunction with bivalirudin and drug-eluting stents [54] . However, prasugrel is less frequently used because of the black box warning for patients with previous stroke, despite evidence-based pharmacodynamics and clinical studies that it may be the most effective oral agent. The Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST-Elevation Myocardial Infarction to Open the Coronary Artery (ATLANTIC) trial supported prehospital ticagrelor use to reduce stent thrombosis compared with in-hospital administration in STEMI patients [55] . Several studies have suggested the potential for a drugdrug interaction between ticagrelor and opioids, which could result in reduced platelet inhibition and impaired ticagrelor absorption [56] , [57] . Overall, the ACCF/AHA guideline provides a class Ib recommendation for oral antiplatelet agents in STEMI management [15] .

Aspirin plus an oral P2Y 12 inhibitor (dual antiplatelet therapy [DAPT]) is the mainstay treatment following PCI. The optimal duration of DAPT after coronary artery stent implantation is still under debate, but current guidelines recommend 1-year DAPT for STEMI patients [15] , [31] .

The advances in stent technology have challenged the recommendations regarding the optimal duration of DAPT following PCI. Recent randomized studies suggested short-term DAPT with potentially discontinuing aspirin after 3 months. For instance, after completing 3-

Intervention (TWILIGHT) trial randomized patients into ticagrelor monotherapy versus 12month DAPT [58] . In TWILIGHT, there were significantly fewer bleeding complications with ticagrelor monotherapy than 12-month DAPT, but mortality risks were similar. However, the study excluded STEMI or CS patients. On the other hand, Ticagrelor Monotherapy After 3

Journal Pre-proof Syndrome (TICO) trial used a similar study design, however, included STEMI patients (36%).

TICO trial reported an absolute reduction in major bleeding and cardiovascular events with ticagrelor monotherapy at 1-year [59] .

Cangrelor is a reversible P2Y 12 receptor antagonist and administered as 30 µg/kg bolus followed by 4 µg/kg/min intravenous infusion. The half-life of cangrelor is 6 minutes in healthy volunteers, and no dose adjustment is required for renal failure patients [60] , [61] . inhibitor naïve ) as pre-treatment [64] , which may be potentially beneficial in STEMI patients with CS or OHCA [7] , [22] .

The third type of antiplatelet therapy targets the GPIIb/IIIa molecule, expressed on platelet cell surfaces, which leads to platelet aggregation through binding to fibrinogen in activated platelets.

Inhibitors of this molecule prevent fibrinogen binding to the receptor, thereby preventing platelet aggregation. Three GPIIb/IIIa inhibitors are currently approved for use in STEMI patients undergoing PCI: abciximab, eptifibatide, and tirofiban. These three inhibitors are reversible and administered intravenously as a bolus followed by an infusion of variable duration [65] . A recent study suggested that routine usage of GPIIb/IIIa inhibitors compared with selective usage was associated with lower all-cause, 1-year mortality (9.7% vs. 11.0%; P < 0.001) [66] . The overall use of GPIIb/IIIa inhibitors has declined primarily due to the higher bleeding risk. Currently, the ACCF/AHA guideline designates a grade IIA recommendation for all three GPIIb/IIIa inhibitors for STEMI patients [15] . The ESC guideline designates a class IIa recommendation for GPIIb/IIIa inhibitors for STEMI patients as a bailout therapy if there is evidence of noreflow or a thrombotic complication [31] .

1. Establishing regional STEMI systems of care by utilizing standardized STEMI protocols and predetermined transfer strategies is crucial to optimize STEMI care. The standardized protocols should include early recognition of STEMI patients with prehospital ECGs, triage quickly to the CCL, and pre-treatment with antithrombotic therapy.

2. CS and OHCA are the significant causes of death in STEMI and require special consideration and experience. The SCAI clinical expert consensus statement on CS classification is a valuable J o u r n a l P r e -p r o o f tool to stratify this population to determine which patients benefit from mechanical support.

Current guidelines strongly recommend the transfer of these patients to specialized centers with early revascularization and TH for patients with OHCA.

3. A pharmacoinvasive strategy should be considered for STEMI patients with an expected delay >120 minutes based on the distance from a PCI center and transfer availability.

4. In-hospital STEMI is often associated with delays in treatment time. Thus, quality and performance measures in hospital settings should be implemented to identify and prompt reperfusion early. *The binding site of cangrelor at the P2Y 12 receptor level is not clearly defined; nevertheless, cangrelor is associated with high levels of receptor occupancy, preventing ADP signaling. † Indicates times after loading dose and bolus administration for oral and intravenous agents, respectively. Times for oral agents refer to clinically stable subjects and may be prolonged in patients with ST-segment-elevation myocardial infarction or treated with opioids.

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