Executive Summary　― Acute Coronary Syndrome in the Japan Resuscitation Council Guidelines for Resuscitation 2020 ―

Introduction

This is a summary of the key issues and systematic reviews (SysRev) in the chapter on acute coronary syndrome (ACS) in the Japan Resuscitation Council: JRC Guidelines for Resuscitation 2020.¹ The JRC Guidelines 2020 are a comprehensive revision of the guidelines for cardiopulmonary resuscitation (CPR), emergency cardiovascular care (ECC) and resuscitation science.² The guidelines also make reference to adult (basic and advanced life support), pediatric, neonatal and maternal resuscitation, ACS, neuro-resuscitation, and first aid, as well as education, implementation, and teams (EIT). The ACS guidelines have been developed for CPR and ECC providers to focus on the guideline recommendations that are most significant, or those that will result in changes in practice, and to provide the rationale for recommendations. These recommendations are focused on the prehospital and emergency department (ED) phases of care. In-hospital care has been addressed by the Guidelines for the management of ACS published in 2018 by the Japanese Circulation Society (JCS).³

Because this review is a summary, it briefly references the supporting published studies. For more detailed information and references, please refer to the JRC Guidelines for resuscitation 2020, published in March 2021.²

Evidence Evaluation Process

There is no chapter on ACS in the 2020 International Consensus on CPR and ECC Science with Treatment Recommendations (CoSTR),⁴ developed by the International Liaison Committee on Resuscitation (ILCOR). Resuscitation guidelines around the world are based on CoSTR and have been revised and published every 5 years since 2010, as have the JRC guidelines after accession to ILCOR through the Resuscitation Council of Asia (RCA) in 2007. However, due to circumstances, CoSTR discontinued its contribution to the ACS guidelines after 2015. The JRC, after discussions with the RCA, decided to continue developing the ACS part of the JRC Guidelines in 2020, because many cardiologists recognize the importance of the management of ACS. It is the greatest cause of out-of-hospital cardiac arrest and cardiogenic shock, and prehospital emergency care of ACS is still inadequate in Asia.

Because CoSTR has implemented the Grading of Recommendation Assessment, Development and Evaluation (GRADE) method,^5–7 which has become a global standard of clinical guideline development and is used for the classification of evidence and strength of recommendations, we have similarly used these recommendations according to the GRADE method by creating our own Clinical Questions (CQs) and conducting SysRev. The GRADE system is also used to assess the certainty of evidence and strength of recommendations. The strength of recommendations is based not only on the certainty of the evidence, but also on a series of factors such as the risk–benefit balance, values, and preferences of patients and professionals, and the use of resources or costs. The Grading notation, which combines the strength of recommendation (Table 1) and the certainty of evidence (Table 2), is appended at the end of the recommendations and suggestions.

Table 1. Strength of Recommendation in GRADE Approach^5,6

Grade	Strength of recommendation	Definition
1	Strong	Benefits clearly outweigh risks and burden, or vice versa. Usually stated as “we recommend that” or “It is recommended that”
2	Weak	Benefits closely balanced with risks and burdens. Usually stated as “we suggest that” or “ It is suggested that”

Table 2. Certainty of Evidence in GRADE Approach^5,6

Grade	Certainty of evidence	Definition
A	High	The authors have a lot of confidence that the true effect is close to the estimated effect
B	Moderate	The authors believe that the true effect is probably close to the estimated effect
C	Low	The true effect may be substantially different from the estimated effect
D	Very low	The true effect is probably markedly different from the estimated effect

The JRC has paid careful attention to avoid conflicts of interest (COI) in order to create this ACS chapter of the JRC Guidelines for Resuscitation 2020 (see “ Disclosures / Management of Potential COI ”).

Abbreviations

Abbreviations are shown in Table 3.

Table 3. Abbreviations

Abbreviations	Definition
ACCF/AHA	American College of Cardiology Foundation/American Heart Association
ACS	Acute coronary syndrome
AMI	Acute myocardial infarction
C	Comparator
CI	Confidence interval
CoSTR	International Consensus on Science with Treatment Recommendations
CPR	Cardiopulmonary resuscitation
CQ	Clinical Question
cTn	Cardiac troponin
DIDO	Door-in to Door-out
ECC	Emergency cardiovascular care
ECG	Electrocardiogram
ED	Emergency department
EIT	Education, implementation, and teams
EMS	Emergency Medical Services
GRADE	the Grading of Recommendation Assessment, Development and Evaluation
hs-cTn	High-sensitivity cardiac troponin
hs-cTnI	High-sensitivity cardiac troponin I
hs-cTnT	High-sensitivity cardiac troponin T
I	Intervention
ILCOR	International Liaison Committee on Resuscitation
JCS	Japanese Circulation Society
JRC	Japan Resuscitation Council
NSTE-ACS	Non-ST elevation ACS
NSTEMI	Non-ST elevation myocardial infarction
O	Outcomes
OR	Odds ratio
P	Patients
PCI	Percutaneous coronary intervention
RCA	Resuscitation Council of Asia
RCT	Randomized control trial
RR	Risk ratio
S	Study design
SpO2	Saturation of percutaneous oxygen
STEMI	ST elevation myocardial infarction
SysRev	Systematic reviews
T	Time frame
UCG	Ultrasonic echocardiography

Summary of Topics in the ACS Guidelines

Topics in the recommendations for ACS of the JRC Resuscitation Guidelines 2020 with SysRev include the following:

1) Diagnostic interventions in ST-elevation myocardial infarction (STEMI)

　• In the prehospital setting

　• In the non-percutaneous coronary intervention (PCI)-capable facilities

2) Prehospital therapeutic interventions in ACS

3) Triage using myocardial biomarkers in the ED

4) Decisions of reperfusion methods in STEMI

I. Diagnostic Interventions in STEMI

This section of diagnostic interventions focuses on the value of the prehospital electrocardiogram (ECG) in recognizing STEMI and STEMI patients who visited a non-percutaneous coronary intervention (PCI)-capable hospital.

1) In the prehospital setting:

　• Prehospital 12-lead ECG acquisition with hospital notification

　• Prehospital ECG interpretation by non-physicians

　　- Paramedics’ ECG STEMI interpretation

　　- Computer-assisted ECG STEMI interpretation

　• Prehospital STEMI activation of the catheterization laboratory

2) In non-PCI-capable facilities:

　• Door-in to door-out (DIDO) time in non-PCI-capable facilities

1. 12-Lead ECG in the Prehospital Setting

We, the ACS Task Force, focused our attention on the prehospital 12-lead ECG for recognition of STEMI patients. Signs and symptoms alone may not be sufficiently sensitive to diagnose acute myocardial infarction (AMI) or ischemia in the prehospital or ED setting, but a 12-lead ECG can rapidly provide evidence of acute ST elevation and is essential for the initial triage and initiation of the management of patients with possible ACS, also in prehospital settings. Prehospital 12-lead ECG acquisition and interpretation is critical for early recognition of STEMI and other high-risk ACS patients.

For STEMI patients, the goal is to achieve reperfusion within 120 min of the onset of symptoms. The first step is to educate patients to call an ambulance as soon as possible after the onset. Emergency medical services (EMS) who have first contact with the patient also aim to perform PCI within 90 min of contact. To achieve this goal, it is essential that paramedics record a 12-lead ECG and convey their findings or transmit the ECG. Accurate recognition and pre-notification to the hospital can minimize in-hospital treatment delays, thus improving patient outcomes. These also can reduce the time required for the two processes, from the onset of MI to reperfusion therapy: the selection of hospital by the EMS and the evaluation in the ED after arrival at the hospital (Figure 1).

Figure 1.

Reperfusion strategy. EMS, emergency medical service.

1.1 Prehospital 12-Lead ECG Acquisition With Hospital Notification

The JRC Resuscitation Guidelines 2010, as with several other guidelines, suggested obtaining a prehospital 12-lead ECG and notifying the destination hospital.⁸ The JRC Resuscitation Guidelines 2015 emphatically suggested that this could help reduce mortality and door-to-balloon time compared with no prehospital ECG in patients with STEMI.⁹ However, a prehospital 12-lead ECG is not currently widely available in Japan, but recently, several small observational studies of prehospital 12-lead ECG acquisition in patients with ACS were conducted in Japan.^10–12 To promote the acquisition of prehospital 12-lead ECGs in Japan, we believe that more high-quality evidence from Japan is required.

Therefore, the ACS Task Force performed a SysRev to investigate the impact of prehospital 12-lead ECG acquisition and destination hospital notification on early mortality and door-to-balloon time in patients with suspected STEMI, including Japanese studies.

CQ: Does prehospital 12-lead ECG transmission or notification improve STEMI outcomes?

P (patients): adult patients with suspected STEMI that occurred outside of a hospital

I (intervention): prehospital 12-lead ECG acquisition and destination hospital notification

C (comparator): no ECG acquisition or no notification

O (outcomes): critical outcome, defined as short-term mortality (30-day mortality or in-hospital mortality) from any cause, and important outcome, defined as door-to-balloon time

S (study design): randomized control trials (RCTs) or observational studies

T (time frame): all studies published before March 31, 2020

Treatment Recommendations

For adult patients with suspected STEMI, we recommend recording a prehospital 12-lead ECG and notifying the hospital (strong recommendation, low-certainty evidence, Grade 1C).

Summary of Evidence

In the SysRev and the JRC Resuscitation Guidelines 2020, 18 observational studies were analyzed.¹³ For the critical outcome of short-term mortality from any cause, 15 observational studies with 29,365 patients were identified. Among these patients, 833 of 15,621 (5.3%) in the group with prehospital 12-lead ECG acquisition and hospital notification died, compared with 1,123 of 13,744 (8.2%) in the control group. Short-term mortality was significantly lower in the group with prehospital 12-lead ECG acquisition and destination hospital notification than in the control group (odds ratio [OR] 0.72; 95% confidence interval [CI] 0.61–0.85; P<0.0001). There were 22 fewer deaths per 1,000 patients (95% CI from 30 fewer to 11 more) in the group with prehospital 12-lead ECG acquisition and destination hospital notification than in the control group. For the important outcome of door-to-balloon time, 10 studies with 2,947 patients were identified. The group with prehospital 12-lead ECG acquisition and destination hospital notification had significantly shorter door-to-balloon time than the control group (26.2 min shorter; 95% CI from 33.5 to 19.0 min shorter; P<0.0001).

1.2 Prehospital ECG Interpretation by Non-Physicians

There are 4 ways to interpret a prehospital 12-lead ECG: by physicians, by non-physician healthcare professional, by computer, or by sending it to an off-site physician or other experienced healthcare professional. Early hospital notification of those who record the 12-lead ECG in the prehospital setting, whether they are physicians or non-physician healthcare professionals, decreases the time to reperfusion and morbidity and mortality (described above). However, diagnostic accuracy is a crucial element for the adoption of non-physician interpretation of ECGs in clinical practice. The expansion of ECG programs to EMS systems has been hindered by worries that non-physicians’ interpretation of ECGs could result in either overdiagnosis with an associated overuse of resources or underdiagnosis with an associated delay in treatment. Computer-based ECG interpretation raises similar issues.

The diagnostic accuracy of STEMI identification on prehospital ECGs by paramedics or computers was given priority by the ACS Task Force because neither of these topics had been fully elucidated and no meta-analysis was done in CoSTR 2015. In formulating the recommendations, we made an effort to strike a balance between minimizing the time that STEMI patients are left without treatment as a result of false negatives and preventing the potential wastage of medical resources due to incorrectly activating the healthcare system as a result of false positives. That is, we were more concerned with minimizing delays in treatment for STEMI patients than with wasting medical resources.

a) Paramedics ECG STEMI Interpretation

CQ: Can prehospital 12-lead ECG interpretation by paramedics diagnose STEMI?

P: prehospital adult patients suspected of STEMI

I: interpretation of prehospital 12-lead ECG by paramedics

C: 12-lead ECG or clinical diagnosis of STEMI by a physician

O: diagnostic accuracy of STEMI, including false negatives, which can interrupt early diagnosis, and false positives, which can cause unnecessary catheterization laboratory activation

S: all human studies, regardless of whether randomized or non-randomized, prospective or retrospective, showing all 4 values (i.e., true-positive, false-positive, false-negative, and true-negative values)

T: all published literature until July 15, 2020

Treatment Recommendations

We suggest that non-physicians* may perform 12-lead ECG interpretation to recognize STEMI in adult patients with suspected STEMI in the prehospital setting (weak recommendation, very-low-certainty evidence, Grade 2D).

*Nurses or paramedics, emergency medical technicians

Summary of Evidence

In the SysRev and the JRC Resuscitation Guidelines 2020, 4 prospective cohort studies with 1,414 patients were analyzed.¹⁴ For prehospital patients with suspected STEMI, the diagnostic accuracy of paramedic prehospital ECG interpretations was favorable, with high pooled sensitivity of 95.5% (95% CI 82.5–99.0%) and specificity of 95.8% (95% CI 82.3–99.1%). The estimated number of false positives was 38 per 1,000 patients (95% CI 8–159), with an assumed baseline risk of 10% as the maximum false positives, and false negatives occurred in 13 per 1,000 patients (95% CI 3–53), with an assumed baseline risk of 30% as the maximum false negatives, which is considered acceptable.

b) Computer-Assisted ECG STEMI Interpretation

CQ: Can computer-assisted interpretation of 12-lead ECG diagnose STEMI?

P: prehospital adult patients suspected of STEMI

I: computer-assisted interpretation of prehospital 12-lead ECG

C: 12-lead ECG or clinical diagnosis of STEMI by a physician

O: diagnostic accuracy of STEMI, including false negatives, which can interrupt early diagnosis, and false positives, which can cause unnecessary catheterization laboratory activation

S: all human studies, regardless of whether randomized or non-randomized, prospective or retrospective, showing all 4 values (i.e., true-positive, false-positive, false-negative, and true-negative values)

T: all published literature until July 15, 2020

Treatment Recommendations

We suggest that computer-assisted ECG interpretation can be used as an adjunct* to diagnosing STEMI, given the high specificity of the computer algorithms evaluated, and not used alone to rule out STEMI (weak recommendation, very-low-certainty evidence, Grade 2D).

NOTE: The sensitivity and specificity of computer-assisted interpretation of 12-lead ECG differ according to the algorithm used, and it is important to evaluate each algorithm in the environment in which it is to be used. The computer-assisted interpretation of 12-lead ECG can be used as an adjunct or in combination with an interpretation by a physician or experienced non-physician healthcare professional. The computer-assisted interpretation should be used as stated above; the recognition of STEMI by computer-assisted interpretation can be individually validated, avoiding the exclusion of STEMI solely based on the results of computer-assisted interpretation.

Summary of Evidence

In the SysRev and the JRC Resuscitation Guidelines 2020, 6 retrospective cohort studies with 47,717 patients were analyzed.¹⁴ For prehospital patients with suspected STEMI, computer-assisted ECG interpretation showed a high pooled specificity of 95.4% (95% CI 87.3–98.4%) with an acceptable estimated number of false positives of 46 per 1,000 patients (95% CI 16–126), with an assumed baseline risk of 1% as the maximum false positive, but the pooled sensitivity of 85.4% (95% CI 74.1–92.3%) was relatively low.

Delays May Occur

The door-to-balloon time, a crucial performance indicator in STEMI management, has been reduced through numerous efforts. Because it includes the prehospital stage, where delays can be significant, total ischemic time, which is defined as the period from the onset of symptoms to reperfusion, is emerging as a more appropriate indicator. Delays may occur during the transfer of STEMI patients from non-PCI hospitals, evaluation in the ED or activation of the catheterization laboratory and the arrival of catheterization staff. The ACS Task Force has therefore examined the question of whether activating the catheterization laboratory after a prehospital ECG would be useful in reducing these delays and improving outcomes.

1.3 Prehospital STEMI Activation of the Catheterization Laboratory

CQ: Will STEMI patients have improved outcomes by preparing a cardiac catheterization room and convening a catheter team with prehospital notification?

P: adult patients with suspected STEMI outside of a hospital

I: prehospital activation of the catheterization laboratory and team

C: ED activation of the catheterization laboratory

O: short-term mortality (in-hospital or 30-day mortality) and long-term mortality (>6 months) as critical outcomes; door-to-balloon time as an important outcome

S: observational studies (no RCTs exist); studies without comparators, review articles, and those with pooled analyses were excluded

T: all literature published up to July 2, 2020

Treatment Recommendations

For adult patients who are interpreted as STEMI by a prehospital 12-lead ECG recorded by paramedics, we recommend preparing a cardiac catheterization room and convening a team with prehospital notification (strong recommendation, very-low-certainty evidence, Grade 1D).

Summary of Evidence

In the SysRev and the JRC Resuscitation Guidelines 2020, 11 observational studies were analyzed.¹⁵ For the critical outcome, 7 studies assessed short-term mortality (in-hospital or 30-day mortality); 1,541 patients were assigned to the prehospital activation (PH) group and 1,191 were assigned to the ED activation (ED) group. There were 26 fewer deaths per 1,000 patients (95% CI from 43 fewer to 19 more) in the PH group than in the ED group (OR 0.56; 95% CI 0.28–1.12; P=0.04). For the critical outcome, 3 studies assessed long-term mortality (>6 months); 713 patients were assigned to the PH group and 1,026 were assigned to the ED group. There were 54 fewer deaths per 1,000 patients (95% CI from 71 fewer to 33 fewer) in the PH group than in the ED group (OR 0.47; 95% CI 0.34–0.66; P=0.02). For the important outcome, 5 studies assessed door-to-balloon time; 959 patients were assigned to the PH group and 631 to the ED group. Door-to-balloon time was 33.1 min shorter (95% CI from 47.5 to 18.7 min shorter; P<0.0001) in the PH group than in the ED group.

2. In Non-PCI-Capable Facilities

Primary PCI for STEMI is now widely accepted, and the efficacy of timely PCI has been established. Shorter total ischemic time, defined as the time from the onset of chest pain to reperfusion, is associated with a more favorable prognosis. If a patient with STEMI arrives at a non-PCI-capable hospital, they must be rapidly transferred to a PCI-capable hospital to shorten the total ischemic time. The DIDO time, defined as the time from arrival at a non-PCI-capable hospital to leaving for a PCI-capable hospital, may affect the STEMI patient’s prognosis. However, the DIDO time is no longer addressed in the ACS guidelines after the 2013 ACCF/AHA STEMI guidelines,¹⁶ and a relevant meta-analysis is lacking. Therefore, the ACS Task Force has prioritized this topic.

2.1 DIDO Time in Non-PCI-Capable Facilities

CQ: Does a DIDO time within 30 min improve outcomes for STEMI patients?

P: STEMI patients who presented to non-PCI-capable hospitals and were transferred to a PCI-capable hospital

I: DIDO time ≤30 min

C: DIDO time >30 min

O: in-hospital or 30-day mortality

S: observational trials (no RCTs exist) published in English, excluding review papers

T: all literature published up to April 15, 2020

Treatment Recommendations

We suggest the DIDO time should be within 30 min for STEMI patients (weak recommendation, very-low-certainty evidence, Grade 2D).

Summary of Evidence

In the SysRev and the JRC Resuscitation Guidelines 2020, 2 retrospective cohort studies with 15,596 patients were analyzed.¹⁷ The primary endpoint of in-hospital or 30-day mortality occurred in 51 of 1,794 (2.8%) in the group with a DIDO time ≤30 min and in 831 of 13,802 (6.0%) with a DIDO time >30 min. There were 34 fewer deaths per 1,000 (95% CI from 41 fewer to 25 fewer) in the group with a DIDO time ≤30 min than in the group with a DIDO time >30 min (OR 0.45; 95% CI 0.34–0.60 P<0.00001).

II. Prehospital Therapeutic Interventions in ACS

This section onprehospital therapeutic interventions in ACS focuses on the value of supplementary oxygen and administration of aspirin and nitroglycerin by non-physician healthcare professionals.

• Supplementary oxygen in ACS

• Prehospital administration of aspirin and nitroglycerin by non-physician healthcare professionals in ACS

1. Supplementary Oxygen in ACS

The CoSTR 2015 found high-flow oxygen administration for AMI patients with saturation of percutaneous oxygen (SpO₂) >93% was harmful,¹⁸ but there were no adverse reports in the subsequent evidence.^19,20 The ACS Task Force prioritized this topic for review in the ACS chapter of the JRC Resuscitation Guidelines 2020.

CQ: For suspected or confirmed AMI patients with normal SpO₂ (≥90%) in a prehospital or ED setting, does not administering oxygen (ambient air) improve outcomes compared with routinely administering oxygen?

P: suspected or confirmed AMI patients with normal SpO₂ (≥90%) in a prehospital or ED setting

I: no oxygen administration (ambient air)

C: routine oxygen administration

O: critical outcome, defined as mortality (in-hospital, 6–12), cardiac shock, cardiac arrest, and recurrent MI; and important outcome, defined as infarct size, heart failure, arrhythmia; not important outcome, defined as chest symptoms

S: RCTs published in English

T: studies published before June 21, 2020

Treatment Recommendations

We suggest withholding oxygen compared with routine*¹ oxygen supplementation in normoxic patients*² with AMI*³ or suspected AMI (weak recommendation, very-low-certainty evidence, Grade 2D).

*¹Oxygen was administered at >6 L/min in the study, and the effects of administering a small amount of oxygen by nasal cannula is unknown.

*²Normoxic is defined as having a percutaneous oxygen saturation (SpO₂) ≥90%. This saturation criterion was chosen because the number of patients enrolled in DETO2X-AMI was the largest among the RCTs reported so far. Hypoxemia was defined as PaO₂ <60 mmHg, with SpO₂ <90% equivalent.

*³Patients with AMI exclude those with previous MI, severe chronic obstructive pulmonary disease, respiratory failure, cardiogenic shock, central cyanosis, dyspnea from any other cause.

NOTE: Oxygenation is necessary for tachypnea, orthopnea, and cardiogenic shock, even if SpO₂ is >90%.

Summary of Evidence

In the SysRev and the JRC Resuscitation Guidelines 2020, 7,322 patients from 9 studies derived from 4 RCTs were analyzed.²¹ For the critical outcome, deaths within 6–12 months of onset among 7,157 patients with suspected or confirmed AMI available from 3 studies occurred in 174 (4.9%) in the oxygen group and 181 (5.1%) in the ambient air group (risk ratio [RR] 1.04; 95% CI 0.84–1.28). In-hospital mortality among 7,227 patients with suspected or confirmed AMI, available from 3 studies occurred in 66 (1.8%) in the oxygen group and 57 (1.6%) in the ambient air group (RR 0.90; 95% CI 0.38–2.10). Similarly, experiencing recurrent MI in the oxygen and ambient air groups was 0.8% and 0.5%, respectively (RR 0.44; 95% CI 0.12–1.54), experiencing cardiac shock; 1.5% and 1.6%, respectively (RR 1.10; 95% CI 0.77–1.59), and experiencing cardiac arrest; 2.4% and 2.0%, respectively (RR 0.91; 95% CI 0.43–1.94). At this time, routine supplemental oxygen administration may not be beneficial or harmful, and high-flow oxygen may be unnecessary for normoxic patients in the acute phase of AMI.

2. Prehospital Administration of Aspirin and Nitroglycerin by Non-Physician Healthcare Professionals

Aspirin and nitroglycerin have been recommended as initial drug therapy for ACS; however, no studies have examined whether prehospital administration of aspirin or nitroglycerin to patients with suspected ACS improves clinical outcomes compared with no administration. The effect of early administration of either one or both of the drugs is based on data from patients administered them after arrival at the ED, rather than prehospital. The 2010 and 2015 Japan JRC Resuscitation Guidelines state that there is insufficient evidence to support or refute the routine administration of aspirin and/or nitroglycerin to patients with suspected ACS in a prehospital setting.^8,9

Therefore, the ACS Task Force decided to conduct a new evidence search for areas listed with a non-GRADE evaluation in the JRC Resuscitation Guidelines 2015 in order to conduct a GRADE evaluation and include them in the new guidelines, the JRC Resuscitation Guidelines 2020.

CQ: Should patients with suspected ACS be administered aspirin by non-physician healthcare professionals in the prehospital setting?

P: adult patients with suspected ACS in the prehospital setting

I: prehospital administration of aspirin by non-physician healthcare professionals

C: no prehospital administration of aspirin by non-physician healthcare professionals

O: mortality, intracranial bleeding, reinfarction, revascularization, stroke, major hemorrhage, infarct size, and ECG resolution ≥50%

S: RCTs and non-randomized studies published in English

T: studies published before August 14, 2020

Treatment Recommendations

For patients with chest pain and suspected ACS (chest pain with ECG abnormality), we suggest the administration of aspirin in the prehospital setting by non-physician healthcare professionals under medical control instructions (weak recommendation, very-low-certainty evidence, Grade 2D).

Summary of Evidence

In the SysRev and the JRC Resuscitation Guidelines 2020, three observational studies were analyzed.²² For the critical outcome of 30-day mortality, which 3 observational studies assessed, 93 of 2,193 patients (4.2%) in the prehospital administration of aspirin group and 160 of 2,157 (7.4%) in the control group were observed. For the critical outcome of 1-year mortality, which one observational study assessed, 102 of 995 (10.3%) in the prehospital administration group and 143 of 731 (19.6%) in the control group were observed. The prehospital administration group had significantly lower 30-day and 1-year mortality than the control group (OR 0.59 [95% CI: 0.35–0.99; P<0.01] and 0.47 [95% CI: 0.36–0.62; P<0.01], respectively). Similarly, the critical outcome of reinfarction was observed in 14 of 338 patients (4.1%) in the prehospital administration group and 17 of 584 (2.9%) in the control group, and stroke, in 1 of 860 (0.1%) in the prehospital administration group and 3 of 842 (0.4%) in the control group. For the important outcome of major hemorrhage, in 43 of 860 patients (5.0%) in the prehospital administration group and 59 of 842 (7.0%) in the control group. For the critical outcome of reinfarction and stroke, and for the important outcome of major hemorrhage, there were no significant differences between the prehospital administration and control groups. There were no clinical papers assessing the outcome of intracranial bleeding, revascularization, infarct size, or ECG resolution ≥50%.

CQ: Should patients with suspected ACS be administered nitroglycerin by non-physician healthcare professionals in the prehospital setting?

P: adult patients with suspected ACS in the prehospital setting

I: prehospital administration of nitroglycerin by non-physician healthcare professionals

C: no prehospital administration of nitroglycerin by non-physician healthcare professionals

O: mortality

S: RCTs and non-randomized studies published in English

T: studies published before July 15, 2020

Treatment Recommendations

For patients with chest pain and suspected ACS (chest pain with ECG abnormality), we suggest the administration of nitroglycerin in the prehospital setting by non-physician healthcare professionals under medical control instructions (weak recommendation, very-low-certainty evidence, Grade 2D).

Summary of Evidence

In the SysRev and the JRC Resuscitation Guidelines 2020, only 1 observational study was analyzed.²² For the critical outcome of 30-day mortality, as well as the 1-year mortality, 52 of 1,142 patients (4.6%) in the prehospital administration of nitroglycerin group and 71 of 584 (12.2%) in the control group were observed, with 114 of 1,142 (10.0%) in the prehospital administration group and 131 of 584 (22.4%) in the control group. The prehospital administration group had significantly lower 30-day and 1-year mortality than the control group (OR 0.34 [95% CI: 0.24–0.50; P<0.01] and 0.38 [95% CI: 0.29–0.50; P<0.01], respectively).

To summarize the two SysRev, prehospital administration of aspirin and nitroglycerin by non-physician healthcare professionals is associated with lower 30-day and 1-year mortality rates for patients with AMI compared with administration after arrival at the hospital.

III. Triage Using Myocardial Biomarker, Cardiac Troponin (cTn), in the ED

cTn is a myocardial biomarker with established validity for the diagnosis of myocardial ischemia. A large body of evidence has accumulated, and the measurement of cTn is included in most international diagnostic criteria for AMI. The accuracy of high-sensitivity cTn (hs-cTn) measurement to exclude AMI in patients with chest pain in the absence of ST elevation on 12-lead ECG in the ED has been well studied. One of the most important missions of the ED is to identify patients whose ACS diagnosis can be safely ruled out and they be discharged. Therefore, an important indicator for assessing the value of a diagnostic test is the false-negative rate. A sufficiently low false-negative rate indicates that ACS can be safely ruled out.

The JRC Resuscitation Guidelines 2015⁹ suggested that a negative cTnI at presentation and 2 h later or a negative cTnI or cTnT at presentation and 3–6 h later can rule out AMI in low-risk patients. However, using these management protocols for non-STEMI (NSTEMI) can lead to prolonged ED stays for patients with chest pain, potentially increasing the burden on medical resources. To address this issue, the ACS Task Force reviewed the latest evidence.

1. High-Sensitivity cTn to Rule-In and Rule-Out NSTEMI

CQ: Should the 0-hour/1-hour algorithm with hs-cTn for diagnostic testing be used to diagnose AMI exclusion in patients with chest pain who visited the ED and did not have ST elevation?

P: patients presenting to the ED with symptoms suggestive of ACS

I: not applicable

C: not applicable

O: diagnostic accuracy of the 0/1-h algorithm for AMI (i.e., the pooled sensitivity, specificity, and positive and negative likelihood ratios).

S: observational study

T: inception to March 31st, 2020

Treatment Recommendations

We suggest applying the 0/1-h algorithm with the measurement of hs-cTn to rule out AMI diagnosis in patients who complain of chest pain and do not have ST elevation on ECG in the ED (weak recommendation, very-low-certainty evidence, Grade 2D).

However, it is desirable to make clinical judgments that consider the patient’s background (age, renal function, etc.), 12-lead ECG and echocardiographic findings, rather than biomarkers alone.

Summary of Evidence

In the SysRev and the JRC Resuscitation Guidelines 2020, 7 studies, including a total of 16 databases, were analyzed.²³ Six observational databases with 7,235 patients were included in a meta-analysis of the diagnostic accuracy of the 0/1-h algorithm using hs-cTnI. The results revealed a pooled sensitivity of 99.3% (95% CI 98.5–99.7%) and a specificity of 90.1% (95% CI 80.7–95.2%). The false-positive rate was 89 per 1,000 patients (95% CI 43–174) when the prevalence of AMI was assumed to be 10%, assuming a maximum number of false positives. The false-negative rate, calculated using a prevalence of 30% and a maximum number of false negatives, was 2 per 1,000 (95% CI 1–4). A meta-analysis of the diagnostic accuracy including 10 observational databases with 9,188 patients showed that the pooled sensitivity and specificity of the ESC 0/1-h algorithm using hs-cTnT were 99.3% (95% CI 96.9–99.9%) and 91.7% (95% CI 83.5–96.1%), respectively. The false-positive rate was 75 per 1,000 patients (95% CI 35–148) with an assumed prevalence of 10% and a maximum number of false positives, and the false-negative rate was 2 per 1,000 (95% CI 0–9) with an assumed prevalence of 30% and a maximum number of false negatives.

IV. Decisions of Reperfusion Methods in STEMI

In this area, we follow the JRC Resuscitation Guidelines 2015, as no new studies were found. We suggest that reperfusion therapy for patients with STEMI should be performed with primary PCI and/or fibrinolysis depending on the elapsed time from onset and the delay time until PCI is performed. Within 2 h of onset, fibrinolysis therapy should be selected if the delay for primary PCI is between 60 and 160 min. Between 2 and 3 h of onset, either fibrinolysis therapy or primary PCI should be selected if the delay for primary PCI is between 60 and 120 min; between 3 and 12 h, primary PCI should be selected if the delay for primary PCI is ≤120 min. Fibrinolysis therapy is an option in cases of prolonged transport or of delaying PCI due to COVID-19 time management.

V. ACS Algorithm 2020 for Initial Evaluation and Treatment

We have revised the ACS algorithm in the JRC Guideline 2020 based on the results of the SysRev using the GRADE approach (Figure 2). Whether a victim with chest symptoms suggestive of ACS requests an ambulance or visits the ED, the basic concept is to rapidly diagnose ACS and treat it using oxygen, aspirin, nitroglycerin, and morphine. The 12-lead ECG plays a central role in the initial triage of patients, and it is more effective when the 12-lead ECG is transmitted in advance from the paramedics to the cardiologist. If the paramedic determines STEMI, the cardiologist will work with the paramedic before arriving at the hospital to promptly perform reperfusion therapy after arrival. If ST depression is observed, it is judged to be non-ST-elevation ACS (NSTE-ACS), and the patient can then be admitted to the cardiac care unit in cooperation with a cardiologist. It is often difficult to distinguish between unstable angina and NSTEMI during initial triage. Therefore, in both cases, it should be treated as NSTE-ACS for diagnosis and treatment at the time of initial medical care. These patients are at increased risk of developing short-term cardiac events (death, non-fatal MI, and emergency revascularization), and early PCI-based invasive treatment is often selected in addition to drug therapy. In patients with normal or difficult-to-determine ECG findings, risk stratification is possible by observing myocardial biomarkers such as hs-cTn and the 12-lead ECG over time according to the chest pain observation protocol of each institution (Figure 1). Reperfusion therapy is more effective when performed earlier after the onset of STEMI. Therefore, having a treatment strategy that shortens the time from onset to reperfusion is essential in the initial medical care of STEMI. In this revision of the ACS algorithm, if it is necessary to transfer to a facility where emergency PCI can be performed, we recommend that the time from arrival in the ED of the initial emergency medical institution to transportation to the PCI-capable facility be within 30 min. We also propose the use of hs-cTn as a myocardial biomarker for diagnosing MI. In addition, it is necessary to confirm any increase or decrease of cTn over time, rather than judging the hs-cTn alone by the result of one test.

Figure 2.

Acute coronary syndrome (ACS) algorithm for initial evaluation and treatment. DIDO, Door-in to Door-out; ED, emergency department; EMS, emergency medical service; MI, myocardial infarction; PCI, percutaneous coronary intervention; UCG, ultrasonic echocardiography.

VI. Future Directions to 2025 (Knowledge Gap)

First, these SysRevs included observational studies, except for the studies on supplemental oxygen. There is also rarely any evidence from Japan regarding these topics and it is difficult to directly apply data from overseas to Japan. However, we consider that our results should be taken seriously because critical outcomes for patients with ACS have been improved and we expect that future RCTs will strongly support our findings.

Second, recording a prehospital 12-lead ECG is not sufficiently practiced widely in Japan. There are also significant differences in the systems of different regions. It is necessary to have the recommendations of the guidelines reflected in the protocols of the Medical Control Councils in each region. Training is needed to develop the skills necessary to accurately record 12-lead ECGs, as the quality of the individual recording may affect the accuracy of interpretation. In addition to the transmission of the 12-lead ECG, we consider non-physician- and computer-assisted ECG interpretations as potential prehospital approaches for the early diagnosis of STEMI. When the optimal algorithm for 12-lead ECG interpretation is determined, together with a strong initial education program, a quality assurance program, and ongoing supervision, we expect that the recognition of STEMI with 12-lead ECG will be optimized by on-site interpretation by trained non-physician healthcare professionals with computer-assisted interpretation. The optimal solutions regarding when and how to implement notification by the EMS to activate the catheterization laboratory need to be considered among regions and facilities. It is expected that the method of notification of 12-lead ECG findings and its cost-effectiveness will be studied.

Third, in the prehospital initial treatment for ACS, the EMS implement only supplemental oxygen administration in Japan. Evidence on the presence or absence of oxygen administration is needed, and evidence for low-flow oxygen administration is also to be gathered. Prehospital administration of aspirin and nitroglycerin has been implemented under a doctor-car system and a doctor-helicopter system, so evidence for this treatment needs to be accumulated. In addition, it is necessary to establish a prehospital treatment system for ACS patients under an appropriate protocol by each regional Medical Control Council.

Acknowledgments

We thank Dr. Morio Aihara and staff at the Japan Council for Quality Health Care (Minds Tokyo GRADE Center) staff and for their help with the GRADE approach. We would also like to thank Mr. William Hassett and Mr. Chris Smith for English language editing.

Sources of Funding

Funding was provided by the JRC and the JCS of ECC Committee and by Ministry of Health, Labour and Welfare Grant Number JPMH2267492.

Disclosures / Management of Potential COI

The authors declare the relationships of the authors that may be perceived as actual or reasonably perceived COI as reported on the Disclosure Questionnaire, which all authors are required to complete and submit (Table 4). The COI to be described in this Disclosure Questionnaire include those related to the declarant himself/herself, his/her spouse, first-degree relatives, and persons living and making a living together. The period of the conflict is from April 2018 to December 2022, which covers the development of the guidelines to publication.

Table 4. Writing Group Disclosures

Writing Group member	Employment	Research granta,b	Other research supportg	Speakers’ bureau/ honorariad	Compensation/ rewarda; including Expert Witness, Consultant, or Advisory Board	Ownership interesta,c,f	Other financial supporte	Academic relevanceh
Migaku Kikuchi	Dokkyo Medical University	None	None	None	None	None	None
Yoshio Tahara	National Cerebral and Cardiovascular Center	Ministry of Health, Labour and Welfare (MHLW) Grant No. JPMH22674927	None	None	None	None	None	Kawakami, et al. Circ J 2016; 162410
Junichi Yamaguchi	Tokyo Women’s Medical University	None	Abbott Medical Japan, Boehringer- ingelheim, Otsuka Pharmaceutical, Endowed department (Abbott Medical Japan, Boston Scientific Japan, Japan Medtronic, Terumo)	Abbott Medical Japan, Amgen, Bayer, Daiichi Sankyo, Kowa	None	None	None
Takahiro Nakashima	University of Michigan	A Grant-in-Aid for Young Scientists (A) (20K17914) of the Japan Society for the Promotion of Science	None	None	None	None	The Uehara Memorial Foundation Overseas Research Fellowship
Osamu Nomura	Hirosaki University	Toyota Research Foundation	None	None	None	None	None
Akihito Tanaka	Nagoya University Graduate School of Medicine	None	None	None	None	None	None
Sunao Kojima	Sakurajyuji Yatsushiro Rehabilitation Hospital	None	Teijin Pharma, Bayer	Teijin Healthcare	None	None	None
Katsutaka Hashiba	Saiseikai Yokohama-shi Nanbu Hospital	None	None	None	None	None	None
Naoki Nakayama	Kanagawa Cardiovascular and Respiratory Center	None	None	None	None	None	None
Hiroyuki Hanada	Hirosaki University	None	Endowed department (Hirosaki city)	None	None	None	None
Toshiaki Mano	Kansai Rosai Hospital cardiovascular Center	Abbott Medical Japan, Japan Lifeline, Biosensors International	None	None	None	None	None
Takeshi Yamamoto	Nippon Medical School Hospital	None	None	Bayer	None	None	None
Kunihiro Matsuo	Fukuoka University Chikushi Hospital	None	None	None	None	None	None
Ichiro Takeuchi	Yokohama City University	None	None	None	None	None	None
Tetsuya Matoba	Kyushu University Faculty of Medical Sciences	None	Amgen	Bayer, MSD, Abbott Vascular Japan	None	None	None
Hiroshi Nonogi	Osaka Aoyama University	None	None	None	None	None	None	Kawakami, et al. Circ J 2016; 162410

This table presents relationships of the Writing Group members that may be perceived as actual or reasonably perceived conflicts of interest (COI) as reported on the Disclosure Questionnaire, which all members of the Writing Group were required to complete and submit.

The COI to be described in this Disclosure Questionnaire include those related to the declarant himself/herself, his/her spouse, first-degree relatives, and persons living and making a living together.

The period of the conflict is from April 2018 to December 2022, which covers the development of the guideline to publication.

It should be described if the person receives (a) ≥1,000,000 yen per year from one company/organization, (b) ≥1,000,000 yen per year from one company/organization to his/her department (group, field, or laboratory, etc.), (c) ≥1,000,000 yen per year per patent, (d) ≥500,000 yen per year from one company/organization for speakers’ bureau/honoraria, (e) ≥50,000 yen per year from one company/organization for travel expenses (not including those related to requested lectures), gifts, etc., or (f) owns ≥5% shares in the entity.

It should be also described if the person (g) belongs to an endowed department that has been offered by companies/organization, etc., or belongs to a department donated by a company/organization, etc.

For academic COI, the first author’s last name, the name of the journal, year, and page (first page) of the paper if the person (h) is the first author or co-author of a paper that was used as a significant basis for the development of this guidelines should be listed.

Authors’ Contributions

All authors involved in the process of developing these guidelines. All authors compiled recommendations derived from the SysRevs of meta-analyses, which were assigned in pairs, and all authors discussed the development of their recommendations. M.K. synthesized them into a manuscript, and Y.T., T. Matoba, and H.N. reviewed the manuscript. All authors had access to all data contained in these guidelines and reviewed and approved the final manuscript.

IRB Information

None.

References

• 1.   Kojima S, Takeuchi I, Tanaka A, Nakashima T, Hashiba K, Hanada H, et al. Acute coronary syndrome. In: JRC guidelines for resuscitation 2020. Tokyo: Igaku Shoin, 2021; 279–313 [in Japanese].
• 2.   Japan Resuscitation Council. JRC guidelines for resuscitation 2020. Tokyo: Igaku Shoin, 2021 [in Japanese].
• 3.   Kimura K, Kimura T, Ishihara M, Nakagawa Y, Nakao K, Miyauchi K, et al. JCS 2018 guideline on diagnosis and treatment of acute coronary syndrome. Circ J 2019; 83: 1085–1196, doi:10.1253/circj.CJ-19-0133.
• 4.   Nolan JP, Maconochie I, Soar J, Olasveengen TM, Greif R, Wyckoff MH, et al. Executive summary: 2020 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation 2020; 142: S2–S27, doi:10.1161/CIR.0000000000000890.
• 5.   Aihara M. GRADE system for clinical practice guideline, 3rd edn. Tokyo: Chugai Igaku-sha, 2018 [in Japanese].
• 6.   Schünemann H, Brożek J, Guyatt G, Oxman A. GRADE Handbook. Updated October 2013. https://gdt.gradepro.org/app/handbook/handbook.html (accessed February 2023).
• 7.   Morley PT, Atkins DL, Finn JC, Maconochie I, Nolan JP, Rabi Y, et al. Evidence evaluation process and management of potential conflicts of interest: 2020 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation 2020; 142: S28–S40, doi:10.1161/CIR.0000000000000891.
• 8.   Japan Resuscitation Council. JRC guidelines for resuscitation 2010. Tokyo: Herusu Shuppan, 2011 [in Japanese].
• 9.   Japan Resuscitation Council. JRC guidelines for resuscitation 2015. Tokyo: Igaku Shoin, 2016 [in Japanese].
• 10.   Kawakami S, Tahara Y, Noguchi T, Yagi N, Kataoka Y, Asaumi Y, et al. Time to reperfusion in ST-segment elevation myocardial infarction patients with vs. without pre-hospital mobile telemedicine 12-lead electrocardiogram transmission. Circ J 2016; 80: 1624–1633.
• 11.   Kobayashi A, Misumida N, Aoi S, Steinberg E, Kearney K, Fox JT, et al. STEMI notification by EMS predicts shorter door-to-balloon time and smaller infarct size. Am J Emerg Med 2016; 34: 1610–1613.
• 12.   Yufu K, Shimomura T, Fujinami M, Nakashima T, Saito S, Ayabe R, et al. Impact of mobile cloud electrocardiography system on door-to-balloon time in patients with acute coronary syndrome in Oita Prefecture. Circ Rep 2019; 1: 241–247.
• 13.   Nakashima T, Hashiba K, Kikuchi M, Yamaguchi J, Kojima S, Hanada H, et al. Impact of prehospital 12-lead electrocardiography and destination hospital notification on mortality in patients with chest pain: A systematic review. Circ Rep 2022; 4: 187–193, doi:10.1253/circrep.CR-22-0003.
• 14.   Tanaka A, Matsuo K, Kikuchi M, Kojima S, Hanada H, Mano T, et al. Systematic review and meta-analysis of diagnostic accuracy to identify ST-segment elevation myocardial infarction on interpretations of prehospital electrocardiograms. Circ Rep 2022; 4: 289–297, doi:10.1253/circrep.CR-22-0002.
• 15.   Hashiba K, Nakashima T, Kikuchi M, Kojima S, Hanada H, Mano T, et al. Prehospital activation of the catheterization laboratory among patients with suspected ST-elevation myocardial infarction outside of a hospital: Systematic review and meta-analysis. Circ Rep 2022; 4: 393–398, doi:10.1253/circrep.CR-22-0034.
• 16.   O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 127: e362–e425, doi:10.1161/CIR.0b013e3182742cf6.
• 17.   Yamaguchi J, Matoba T, Kikuchi M, Minami Y, Kojima S, Hanada H, et al. Effects of door-in to door-out time on mortality among ST-segment elevation myocardial infarction patients transferred for primary percutaneous coronary intervention: Systematic review and meta-analysis. Circ Rep 2022; 4: 109–115, doi:10.1253/circrep.CR-21-0160.
• 18.   Stub D, Smith K, Bernard S, Nehme Z, Stephenson M, Bray JE, et al. Air versus oxygen in ST-segment-elevation myocardial infarction. Circulation 2015; 131: 2143–2150.
• 19.   Khoshnood A, Akbarzadeh M, Roijer A, Meurling C, Carlsson M, Bhiladvala P, et al. Effects of oxygen therapy on wall-motion score index in patients with ST elevation myocardial infarction-the randomized SOCCER trial. Echocardiography 2017; 34: 1130–1137.
• 20.   Hofmann R, James SK, Jernberg T, Lindahl B, Erlinge D, Witt N, et al. Oxygen therapy in suspected acute myocardial infarction. N Engl J Med 2017; 37: 1240–1249.
• 21.   Kojima S, Yamamoto T, Kikuchi M, Hanada H, Mano T, Nakashima T, et al. Supplemental oxygen and acute myocardial infarction: A systematic review and meta-analysis. Circ Rep 2022; 4: 335–344, doi:10.1253/circrep.CR-22-0031.
• 22.   Nakayama N, Yamamoto T, Kikuchi M, Hanada H, Mano T, Nakashima T, et al. Prehospital administration of aspirin and nitroglycerin for the patients with suspected acute coronary syndrome: A systematic review. Circ Rep 2022; 4: 449–457, doi:10.1253/circrep.CR-22-0060.
• 23.   Nomura O, Hashiba K, Kikuchi M, Kojima S, Hanada H, Mano T, et al. Performance of the 0-hour/1-hour algorithm for diagnosing myocardial infarction in patients with chest pain in the emergency department: A systematic review and meta-analysis. Circ Rep 2022; 4: 241–247, doi:10.1253/circrep.CR-22-0001.