Coronary Angiography in Patients With Out-of-Hospital Cardiac Arrest Without ST-Segment Elevation on Electrocardiograms: A Comprehensive Review

Abstract

Out-of-hospital cardiac arrest (OHCA) is among the most common causes of death in the United States. Early coronary angiography (CAG) and percutaneous coronary intervention (PCI) have been associated with improved long-term outcomes in patients with ST-segment elevation (STE) on prearrest or postarrest electrocardiograms. However, data on the utility of catheterization and PCI for improving outcomes after OHCA in patients without STE on electrocardiograms are heterogeneous, with variable results. Although older data have suggested that there is a benefit, recent randomized controlled trials have demonstrated that performing early CAG in patients with OHCA without STE on electrocardiograms may not improve outcomes. In recognition that neurologic devastation and multiorgan failure are common in these patients, physicians face the challenge of selecting appropriate patients for cardiac catheterization and PCI. This review aims to summarize the current data on this topic, with the goal to guide decision making regarding the timing and appropriateness of CAG in patients with OHCA without STE on electrocardiograms, utilizing an evidence-based approach to streamline the patient selection process.

Graphical abstract

Highlights

• •Use of early coronary angiography in cardiac arrest without ST elevation is uncertain.
• •Recently, strong data with randomized trials and meta-analyses have come to light.
• •Early angiography has similar early & late outcomes as delayed selective approach.
• •Hence, it is critical to refine selection process of patients for catheterization.

Introduction

Out-of-hospital cardiac arrest (OHCA) is one of the leading causes of death worldwide.¹ It has been estimated that ∼395,000 adults experience OHCA in the United States annually, with a survival rate of 6% to 10%, leading to >350,000 deaths per year.^2,3 Despite continuous advancements in resuscitation science and postarrest management, the overall prognosis remains very poor. Even among patients who achieve return of spontaneous circulation (ROSC) and are admitted to a hospital, mortality remains very high, with the rate of survival to discharge with good neurologic function ranging from 0.8% to 20%, with wide geographic variation.⁴ Coronary artery disease (CAD) is discovered in up to 70% of patients with OHCA after ROSC.⁵ Hence, it has been suggested that immediate coronary angiography (CAG) and percutaneous coronary intervention (PCI) should be considered in all patients after OHCA. Current guidelines strongly recommend emergency CAG for all successfully resuscitated patients with OHCA with ST-segment elevation (STE) on prearrest or postarrest electrocardiograms (ECGs)6, 7, 8, 9 and an estimated reasonable neurologic prognosis. However, the potential benefit of immediate CAG in patients without STE on post-ROSC ECGs is less certain, because the studies on this topic are heterogeneous in their design and results. As a consequence, forming a recommendation on if and when to perform CAG for such patients is challenging; yet, this area remains of utmost importance given the complex decision making and heavy resource utilization that these patients often demand.

Accordingly, the current review aims to provide a concise summary of the existing evidence of the role of CAG in patients with OHCA without STE on pre- or post-ROSC ECGs. Existing observational studies, randomized controlled trials (RCTs), and meta-analyses as of July 2022 have been summarized and reviewed. An evidence-based, conceptual framework for the management of patients with OHCA has been presented.

Rationale for performing CAG in patients with OHCA

Cardiac catheterization has long been considered an essential diagnostic test for all patients following cardiac arrest to rule out acute coronary syndrome (ACS) as an antecedent cause. This thought process changed with the recognition that although CAD is often discovered as an incidental finding, it is not the cause of cardiac arrest in the majority of patients with OHCA without a shockable rhythm (ventricular tachycardia or ventricular fibrillation) and those without STE on pre- or post-ROSC ECGs. Patients with OHCA with an initial shockable rhythm and STE on post-ROSC ECGs have a prevalence of >85% for acute coronary occlusion, and 70% to 95% demonstrate significant CAD (defined as at least 1 stenosis of >70%) using diagnostic angiography (Figure 1).10, 11, 12 Similarly, for patients with OHCA with a shockable rhythm who are not able to achieve ROSC because of refractory ventricular tachycardia or fibrillation, the prevalence of significant CAD is 80% to 85% and that of acute coronary lesions is 60% to 65%.13, 14, 15 Conversely, among patients with OHCA with an initial shockable rhythm without STE on ECGs, the prevalence of acute coronary occlusion is much lower, at 5% to 30%, whereas that of significant CAD is 25% to 60%.^12,16, 17, 18 Unlike the prevalence of CAD in patients with a shockable rhythm, the prevalence of CAD in patients with an unshockable rhythm is not well defined^19,20; based on limited data, it has been estimated that in patients without STE on post-ROSC ECGs, the prevalence of significant CAD is ∼50% and that of a culprit lesion is ∼7%.²¹

Figure 1.

Prevalence of acute coronary occlusion and significant coronary artery disease in successfully resuscitated patients with out-of-hospital cardiac arrest. Significant coronary artery disease defined as >70% stenosis in at least 1 major epicardial coronary vessel. ACS, acute coronary syndrome; CAD, coronary artery disease; OHCA, out-of-hospital cardiac arrest; ROSC, return of spontaneous circulation; STE, ST-segment elevation.

Among patients who achieve ROSC and are discovered to have coronary artery stenoses of >50%, the diagnosis of type 1 myocardial infarction (MI) can be challenging. Many survivors of OHCA have elevated levels of cardiac troponin; however, this may be due to type 2 MI in the setting of hypoperfusion secondary to shock, even in cases secondary to a noncardiac etiology. The features that predict acute coronary occlusion as the etiology of OHCA are the presence of cardiovascular risk factors at baseline, chest pain preceding the arrest, an initial shockable rhythm, and STE on postresuscitation ECGs.^22,23

Potential downsides of early CAG

Although CAG may allow one to identify and treat ongoing cardiac ischemia, performing it emergently in patients following OHCA may pose logistic challenges and expose the patient to further risk. Early CAG requires patient mobilization often during a time of hemodynamic instability, results in exposure to contrast agents, and carries procedural risks, including bleeding, stroke, and other complications.^24,25 Prioritizing CAG as the primary focus may delay other critical and potentially life-saving interventions and slow the identification of the possible etiology when a coronary lesion is not the event trigger.²⁶

Current trends

The offering and timing of CAG in patients with OHCA varies significantly among institutions. In a study from the International Cardiac Arrest Registry, which represents 44 centers in the United States and Europe, 66% of patients with OHCA with a shockable rhythm and no STE on post-ROSC ECGs underwent CAG, with PCI performed in 37.7% of those who underwent CAG.²⁷ According to a meta-analysis by Verma et al,²⁸ 85 CAG and 24 PCI procedures are conducted per 100 patients with OHCA without STE on post-ROSC ECGs. Most of the existing observational studies found that an early CAG strategy is employed in 35% to 65% of patients with OHCA without STE on post-ROSC ECGs.29, 30, 31, 32, 33

The studies evaluating the benefit of early CAG in such patients with OHCA are mixed. Although many of the early observational studies have suggested a possible benefit, more recent high-quality cohort studies and RCTs have indicated that the benefit of early CAG in all comers is unlikely and that a selective approach to CAG in appropriate patients is warranted.

Review of the existing data

Observational data

Several observational studies evaluating the optimal timing of CAG in patients with OHCA without STE on post-ROSC ECGs are summarized in Table 1.34, 35, 36, 37, 38, 39, 40, 41, 42 These are difficult to interpret given their conflicting outcomes, different patient populations, heterogeneous designs, potential biases, and confounding results.

Table 1.

Summary of key observational studies evaluating the role of coronary angiography in patients with out-of-hospital cardiac arrest without ST-segment elevation on electrocardiogram^a

Reference, year	Design	No. of patients	Definition of early CAG	Definition of nonearly CAG	Primary end point	Favors early angiography
Bro-Jeppesen et al,34 2012	Nonrandomized, prospective	244	Within 12 h of cardiac arrest	After 12 h of cardiac arrest, within 30 d	30-d and 1-y survival rates	No
Hollenbeck et al,29 2014	Retrospective cohort	269	Either immediately upon hospital admission or during hypothermia treatment	After completing hypothermia protocol and assessment for neurologic recovery (at least 24 h after admission)	Survival to hospital discharge	Yes
Reynolds et al,35 2014	Retrospective cohort	191	Occurring directly from the ED, ICU, or referring facility	Late or none	Good outcome, defined as discharge to home or acute rehabilitation facility	Yes
Vyas et al,36 2015	Nonrandomized prospective registry	4029	Within 1 d of cardiac arrest	After 24 h of cardiac arrest	Survival to discharge	Yes
Kleissner et al,30 2015	Nonrandomized prospective registry	99	<2 h from hospital admission	Decision to perform delayed CAG or to not perform CAG at all was made only after completion of hypothermia protocol and reassessment of neurologic status	In-hospital and 6-mo mortality as well as neurologic performance	No
Dankiewicz et al,31 2015	Post hoc analysis of RCT	544	Performed on admission to OR in <6 h of cardiac arrest	>6 h of cardiac arrest or not	Mortality at the end of the trial	No
Kern et al,12 2015	Retrospective and prospective cohort study	548	Within 2 h of arrival at a PCI-capable hospital	>2 h of arrival at a PCI-capable hospital	Survival to hospital discharge	Yes
Geri et al,37 2015	Prospective cohort	1404	<6 h after collapse	No patient underwent delayed CAG	30-d and 10-y survival rates	Yes
Garcia et al,11 2016	Nonrandomized prospective registry	203	<6 h of arrival at the ED	>6 h of arrival at the ED	Survival to hospital discharge with favorable neurologic outcomes	Yes
Staudacher et al,38 2018	Retrospective cohort	287	≤3 h	>3 h after hospital admission	All-cause mortality at 30 d	No
Elfwén et al,32 2018	Nonrandomized prospective registry	799	<24 h	>24 h but within 4 wk (during same hospitalization)	Survival at 30 d, 1 y, and 3 y	Yes
Jentzer et al,39 2018	Prospective registry	599	<24 h of ROSC	>24 h of ROSC	Survival to hospital discharge	Yes
Kim et al,33 2019	Retrospective registry	227	Immediate: ≤2 h after ROSC or presentation to the ED	Early: 2-24 h after ROSC or presentation to the ED	Good neurologic outcomes at 1 mo, defined as a CPC score of 1-2	No
Song et al,40 2021	Prospective observational cohort study	678	≤24 h	>24 h or not performed	Good neurologic outcome at 6 mo, with a CPC score of 1-2	Yes
Vedamurthy et al,41 2021	Retrospective cohort	158	Within 24 h of presentation to the ER	>24 h after presenting to the ER or not	In-hospital mortality rates and final inpatient CPC	When risk adjusted and divided on the basis of CAHP score: No
Lim et al,42 2021	Prospective registry	976	Within 1 d of ROSC	After 1 d of ROSC	30-d survival and neurologic outcome	Yes

CAG, coronary angiography; CAHP, cardiac arrest hospital prognosis; CPC, cerebral performance category; ED, emergency department; ER, emergency room; ICU, intensive care unit; OR, operating room; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; ROSC, return of spontaneous circulation.

^aMajor observational studies evaluating the role of early versus nonearly coronary angiography in patients with out-of-hospital cardiac arrest without ST-segment elevation on an electrocardiogram performed after return of spontaneous circulation.

RCTs

Guideline recommendations to date have mainly been derived from observational studies and expert consensus. Fortunately, in the last few years, there has been rigorous growth in the level of evidence because of newly published RCTs in this area. Most of the RCTs focused on short-term outcomes, which is appropriate because mortality primarily occurs during the first 2 to 3 months after an arrest, and if patients survive with a good neurologic status, long-term outcomes are generally favorable.^43,44 Table 245, 46, 47, 48, 49 depicts a summary of published and ongoing RCTs, summarizing the highest-quality evidence in this area.

Table 2.

Summary of key randomized controlled trials evaluating the role of coronary angiography in patients with out-of-hospital cardiac arrest without ST-segment elevation on electrocardiogram^a

Reference, year, study title	Clinical trial identifier, location	No. of patients	Definition of early CAG	Definition of nonearly CAG	Primary end point	Key results on the primary end point	Favors early angiography
Lemkes et al,16 2019 COACT	NTR4973, Netherlands	552	<2 h after randomization	After neurologic recovery	Survival at 90 d	OR, 0.89; 95% CI, 0.62-1.27; P = .51	No
Desch et al,45 2021 TOMAHAWK	NCT02750462, Germany	530	As soon as possible after hospital admission	>24 h after cardiac arrest or not at all	Death due to any cause at 30 d	HR, 1.28; 95% CI, 1.00-1.63; P = .06	No
Kern et al,46 2020 PEARL	NCT02387398, USA, Slovenia, and Australia	99	<120 min of admission	>6 h from admission or not at all	Safety and efficacy of early CAG	55.1% vs 46.0%; P = .64	No
Hauw-Berlemount et al,47 2022 EMERGE	NCT02876458, France	279	Transferred directly to the catheterization laboratory	Admitted to the intensive care unit, and CAG planned 48-96 h after admission	180-d survival rate, with no or minimal neurologic sequelae; CPC score of 1 or 2	HR, 0.87; 95% CI, 0.65-1.15; P = .324	No
COUPE	NCT02641626, Spain	166	As soon as possible after randomization	After extubation if the patient has a good neurologic prognosis	Composite of in-hospital survival and 6-mo survival free of severe dependence (CPC score of 1 or 2)	Yet to be published
DISCO	NCT02309151, Sweden	1006b	<120 min from randomization	Should preferably not be performed until 3 d after the cardiac arrest	30-d survival	Yet to be published
Lavi S, Cardiac Catheterization in Cardiac Arrest	NCT02587494, Canada	75b	Within 12 h of ROSC	After completion of mild therapeutic hypothermia or apyrexia for >24 h after ROSC	Composite of death and poor neurologic outcomes (CPC score of 1 or 2) at 30 d	Yet to be published
ARREST	NCT03872960, United Kingdom	804	To be treated same as ST-segment elevation after ROSC. Patient to be transferred to the cath lab.	Triage for cath lab to be delayed until at least 72 hours after arrest	30-d all cause mortality	Yet to be published

ARREST, A Randomised Trial of Expedited Transfer to a Cardiac Arrest Centre for Non-ST Elevation Out-of-hospital Cardiac Arrest; CAG, coronary angiography; CI, confidence interval; COACT, Coronary Angiography After Cardiac Arrest; COUPE, Coronariography in Out of Hospital Cardiac Arrest; CPC, cerebral performance category; DISCO, Direct or Subacute Coronary Angiography in Out-of-hospital Cardiac Arrest; EMERGE, Emergency vs Delayed Coronary Angiogram in Survivors of Out-of-Hospital Cardiac Arrest; HR, hazard ratio; OHCA, out-of-hospital cardiac arrest, OR, odds ratio; PEARL, Randomized Pilot Clinical Trial of Early Coronary Angiography vs No Early Coronary Angiography for Postcardiac Arrest Patients Without ST-Segment Elevation; ROSC, return of spontaneous circulation; TOMAHAWK, Immediate Unselected Coronary Angiography vs Delayed Triage in Survivors of Out-of-Hospital Cardiac Arrest Without ST-Segment Elevation.

^aRandomized controlled trials evaluating the role of early versus nonearly coronary angiography in patients with out-of-hospital cardiac arrest without ST-segment elevation on an electrocardiogram performed after return of spontaneous circulation.

^bEstimated enrollment.

Given the importance of these RCTs in clinical decision making, the important highlights are summarized below:

• •The Coronary Angiography after Cardiac Arrest (COACT) trial was the first RCT investigating the difference in outcomes between immediate and delayed CAG in patients with OHCA with an initial shockable rhythm and without STE on ECGs. The trial randomized 552 patients to undergo immediate CAG, defined as CAG performed within 2 hours after randomization, versus delayed CAG, defined as CAG after neurologic recovery. COACT found no difference in survival at 90 days, regardless of whether the patients underwent early versus delayed CAG. At 90 days, 64.5% of patients from the immediate CAG group and 67.2% from the delayed CAG group were alive (odds ratio for death, 0.89; 95% CI, 0.62-1.27; P = .51). Further, despite the early CAG group receiving therapeutic hypothermia earlier, there was no difference in the Cerebral Performance Category (CPC) score between the 2 groups at 90 days. To test the hypothesis of whether immediate PCI improves outcomes, a prespecified, exploratory analysis was used to measure the differences in survival; MI; revascularization; implantable cardiac defibrillator shock; quality of life; hospitalization for heart failure; and the composite of death, MI, and revascularization after 1 year. No significant differences were observed for any of the mentioned outcomes,⁴³ regardless of whether the early versus delayed CAG strategy was used. It is to be noted that the COACT trial only included patients with a shockable rhythm, which constituted only 60% of patients with OHCA without STE.
• •The Immediate Unselected Coronary Angiography vs Delayed Triage in Survivors of Out-of-Hospital Cardiac Arrest Without ST-Segment Elevation (TOMAHAWK) trial⁴⁵ is a recently published multicenter, international RCT on this topic. Unlike COACT, TOMAHAWK included patients with OHCA and no STE on ECGs, with either a shockable or nonshockable rhythm. Similar to COACT, TOMAHAWK compared the mortality and neurologic deficit at 30 days in patients randomized to a strategy of either immediate or delayed CAG. The trial analyzed 530 randomized patients who had been successfully resuscitated after OHCA to undergo CAG as soon as possible after hospital admission or delayed CAG, with transfer to the intensive care unit with the intention to proceed to CAG only after a minimum delay of at least 24 hours, except in limited prespecified situations such as development of cardiogenic shock. The prevalence of CAD in the immediate CAG group was 60.7%, and the prevalence of CAD in the delayed CAG group was 72.1%. A coronary culprit lesion was found to be the causative trigger event in 40% of the participants. At 30 days, 54% of patients in the immediate CAG group and 46% in the delayed CAG group died (hazard ratio, 1.28; 95% CI, 1.00-1.63; P = .06). Interestingly, the composite outcome of death and severe neurologic deficit followed similar trends and occurred more frequently in the immediate CAG group than in the delayed CAG group, with a relative risk of 1.16 (95% CI, 1.00-1.34). The authors postulated that this could have been due to delays in the diagnosis of other noncoronary underlying triggers for OHCA in the immediate CAG group. With these results, the TOMAHAWK trial supported the findings of the COACT trial and found that immediate CAG had no benefit over delayed or selective CAG.
• •The Emergency vs Delayed Coronary Angiogram in Survivors of Out-of-Hospital Cardiac Arrest (EMERGE) trial⁴⁷ is the most recently published multicenter RCT. Unlike the previous trials, it investigated a longer-term outcome, 180-day survival rate with a CPC score of ≤2 for emergent versus delayed CAG in patients with OHCA without STE on post-ROSC ECGs. A total of 279 patients who experienced OHCA, with ROSC, with no obvious noncardiac cause of cardiac arrest and no STE on post-ROSC ECGs were randomized to undergo either emergency angiography, with direct transfer to the catheterization laboratory, or delayed CAG, with admission to the intensive care unit and CAG planned within 48 to 96 hours after admission. Of 141 patients randomized into the emergency CAG group, 126 (89.4%) patients underwent CAG. Of 138 patients in the delayed CAG group, 74 (53.6%) patients underwent CAG. It is important to note that the main reason for not performing CAG in the delayed group was early death. No significant CAD was found in 45.2% of the patients who underwent emergency CAG and 55.4% of the patients who underwent delayed CAG. PCI was performed in 38 (30.2%) patients in the emergency CAG group compared with 17 (23%) patients in the delayed CAG group. No difference was found in the 180-day survival rate among patients with a CPC score of ≤2 in the emergency CAG group (34.1%) versus that among patients with a CPC score of ≤2 in the delayed CAG group (30.7%), with a hazard ratio of 0.87 (95% CI, 0.65-1.15; P = .32). Furthermore, there was no difference in the overall survival at 180 days between the emergency CAG (36.2%) and delayed CAG groups (33.3%), with a hazard ratio of 0.86 (95% CI, 0.64-1.15; P = .31). Although the EMERGE trial was underpowered, similar to COACT and TOMAHAWK, it did not support the early CAG strategy.
• •The Randomized Pilot Clinical Trial of Early Coronary Angiography vs No Early Coronary Angiography for Postcardiac Arrest Patients Without ST-Segment Elevation (PEARL) trial pilot (n = 99) trial also randomized patients with OHCA with a shockable or nonshockable rhythm without STE on post-ROSC ECGs to undergo either early angiography, ie, ≤120 minutes from arrival at a PCI-capable facility, or nonearly CAG. Although the study was terminated prematurely, it showed similar results of no benefit with early CAG.⁴⁶
• •The direct or subacute coronary angiography in out-of-hospital cardiac arrest (DISCO) pilot study (n = 79) trial found that performing immediate CAG in patients with OHCA without STE on ECGs is feasible and safe.⁴⁹ A secondary analysis of the DISCO pilot trial found no difference in the left ventricular ejection fraction at 24 hours, peak troponin T levels, lactate clearance, and N-terminal pro-b-type natriuretic peptide at 72 hours between the immediate and deferred CAG groups.⁵⁰ The outcomes of immediate versus deferred CAG groups are yet to be published in the DISCO trial.

Several possible factors contributed to the differences between the results of the RCTs and those of early observational studies (Figure 2). First, the definition of early CAG in most of the observational studies varied significantly, ranging from 0 to 24 hours. Second, in most observational studies, the decision to undergo early versus delayed or no CAG was based on clinical presentation and clinicians’ judgments; younger patients with fewer comorbidities and those who were expected to have better neurologic and overall outcomes were likely to undergo early CAG compared with the rest, which raises the possibility of a selection bias. Third, many of the early observational studies included patients with OHCA with and without STE as a single cohort, when, in fact, they are very different patient populations,51, 52, 53, 54 and this limits the external validity of these studies to apply to patients with OHCA without STE.^12,34,52,55, 56, 57, 58 RCTs eliminate these biases and are inherently more statistically sound and valid than observational studies by virtue of their design.

Figure 2.

High-level evidence for the timing of coronary angiography in patients with out-of-hospital cardiac arrest without ST-segment elevation on an electrocardiogram. As depicted, no randomized controlled trial published to date has shown that immediate coronary angiography is superior to delayed coronary angiography.

Meta-analyses

To evaluate the evidence in totality, Table 3^28,51,59, 60, 61, 62, 63 presents the key findings of the meta-analyses published in the last 5 years. It is apparent that older meta-analyses had concluded the early CAG approach to be superior to the delayed CAG approach; however, these studies mostly included observational data and acknowledged the “low quality” or “very low quality” of available evidence because of the inherent nature of these observational studies. The more recent meta-analyses included the RCTs summarized in Table 245-49 and, as a result, indicated no benefit of early CAG over delayed CAG. Another reason for the discrepancy could have been that the older meta-analyses included studies that grouped patients with OHCA with and without STE as a single cohort, as mentioned above. Because the benefit of immediate CAG is well established for patients with OHCA with STE, this jeopardizes the external validity of their results to patients with OHCA without STE.

Table 3.

Summary of key meta-analyses evaluating the role of coronary angiography in patients with out-of-hospital cardiac arrest without ST-segment elevation on electrocardiogram^a

Reference, year	Included studies	Primary outcome	Secondary outcome	Key results on the primary end point	Favors early angiography
Khan et al,59 2017	8 studies: 7 observational and 1 RCT	Short- (at discharge) and long-term (at 6-14 mo of follow-up) mortality	Good neurologic outcome (CPC score of 1 or 2) at discharge and follow-up	Short-term: OR, 0.46; 95% CI, 0.36-0.56; P < .001 Long-term: OR, 0.59; 95% CI, 0.44-0.74; P < .001	Yes
Welsford et al,51 2018	23 studies: 22 observational and 1 post hoc analysis of RCT	Survival and good neurologic outcome: Short-term (discharge OR, 30 d) Intermediate-term (3-11 mo) Long-term (1-5 y)		Survival short-term: RR, 1.52; 95% CI, 1.32-1.74; P <.00001 Survival long-term: RR, 1.56; 95% CI, 1.14-2.14; P = .006	Yes
Barbarawi et al,60 2019	11 studies: 8 observational, 1 post hoc analysis, and 2 RCTs	Long-term mortality	Short-term mortality CPC score of 1-2 at the longest follow-up period	Immediate vs no CAG: OR, 0.21; 95% CI, 0.05-0.82 Delayed vs no CAG: OR, 0.11; 95% CI, 0.03-0.43	No
Subahi et al,61 2020	3 RCTs	All-cause mortality	NA	HR, 1.0; 95% CI, 0.7-1.4	No
Yang et al,62 2020	10 studies: 8 observational and 2 RCTs	Survival: At hospital discharge (OR, 1.78; 95% CI ,  1.51-2.11; P  <  .0001) Middle-to-long-term follow-up (6-14 mo) (OR, 1.21; 95% CI ,  0.93-1.57; P  =  .15) Neurologic outcomes, with a CPC score of 1 to 2: At discharge (OR, 1.66; 95% CI ,  1.37-2.02; P  <  .00001) Middle-term follow-up (1-3 mo) (OR ,  0.74; 95% CI ,  0.59-0.97)			Yes
Verma et al,28 2020	11 studies: 7 observational, 1 post hoc analysis, and3 RCTs	30-d mortality	Neurologic status and the rate of PCI following cardiac arrest	RR, 0.86; 95% CI, 0.71-1.04; P = .12	No
Abusnina et al,63 2022	6 RCTs	Mortality at 30 d	Neurologic status with a CPC score ≤2 Rate of PCI following CAG	RR, 1.06; 95% CI, 0.94-1.20; P = .32	No

CAG, coronary angiography, CPC, cerebral performance category; HR, hazard ratio; NA, not applicable; OR, odds ratio; RCT, randomized controlled trial; ROSC, return of spontaneous circulation; RR, risk ratio.

^aSummary of key meta-analyses evaluating the role of early versus nonearly coronary angiography in patients with out-of-hospital cardiac arrest without ST-segment elevation on an electrocardiogram performed after return of spontaneous circulation.

The meta-analysis by Barbarawi et al⁶⁰ was the first to find no difference in mortality between early and delayed CAG groups. The patients were divided into 3 treatment groups: immediate, delayed, and no CAG. Eleven studies were included, and it was concluded that there is no difference in mortality between the early and delayed groups. In a more clinically relevant analysis, Verma et al²⁸ minimized the selection bias that may have affected their predecessors by including patients not offered angiography in the delayed CAG group. Because the clinical question for physicians is often whether to offer early or delayed angiography (if at all), this study design most reflects the dilemma that clinicians face at the time of patient care. Verma et al²⁸ included 11 studies, and a random-effects analysis showed no difference in 30-day mortality (relative risk, 0.86; 95% CI, 0.71-1.04; P = .12), neurologic status (relative risk, 1.08; 95% CI, 0.94-1.24; P = .28), and the rate of PCI (relative risk, 1.22; 95% CI, 0.94-1.59; P = .13) between the 2 groups. Additionally, factors such as the presence of type 2 diabetes mellitus, chronic renal failure, previous PCI, and elevated lactate levels predicted mortality more than the decision of whether to undergo the CAG procedure itself. A sensitivity analysis showed no small study or publication bias. Furthermore, Subahi et al⁶¹ performed a similar meta-analysis, which included 3 RCTs, and found no significant difference in mortality between immediate and delayed CAG or noninvasive groups (hazard ratio, 1.0; 95% CI, 0.7-1.4).

Hauw-Berlemont et al⁴⁷ performed a meta-analysis of the 4 major RCTs, the COACT, PEARL, TOMAHAWK, and EMERGE trials. A combined analysis of 1446 patients was included along with the results of the EMERGE trial, and it showed no benefit of an early CAG approach compared with a nonearly CAG approach (risk ratio, 1.04; 95% CI, 0.92-1.18) in patients with OHCA without STE on post-ROSC ECGs.

Current guidelines

A concise summary of the current guidelines on this topic is provided in Table 4.^6,8,9 It is important to note that these guidelines were authored prior to the publication of the COACT, TOMAHAWK, and EMERGE trials as well as subsequent meta-analyses and, thus, are heavily weighted toward the observational studies mentioned in Table 1.34, 35, 36, 37, 38, 39, 40, 41, 42

• •The 2020 International Liaison Committee on Resuscitation Consensus of Science, American Heart Association, guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care⁶⁴ recommend that CAG be performed emergently for all patients with a suspected cardiac cause of OHCA and STE on ECGs. It also suggests that emergency CAG is reasonable in select comatose patients, such as those who are electrically or hemodynamically unstable and have a suspected cardiac cause of arrest even without STE on ECGs.
• •The 2019 Society for Cardiovascular Angiography & Interventions expert consensus document⁶ recommends deferring cardiac catheterization for patients with OHCA and a nonshockable rhythm. For patients with OHCA and a shockable rhythm, the consensus recommends an invasive strategy only in select patients who are found to have STE on post-ROSC ECGs. This selection is defined by the absence of unfavorable factors determining the likelihood of neurologic recovery, such as high Cardiac Arrest Hospital Prognosis scores, no bystander CPR, time to ROSC >30 minutes, lactate level >7 mmol/L, arterial pH <7.2, age >85 years, and the presence of end-stage renal disease. For patients with the absence of STE on post-ROSC ECGs, the consensus recommends deferring CAG in hemodynamically stable patients and transferring them to the intensive care unit for targeted temperature management, postresuscitative care, clinical reassessment, and the assessment of neurologic recovery.
• •The 2017 European Society of Cardiology guidelines for the management of acute MI in patients presenting with STE⁸ recommends urgent CAG (within 2 hours) in survivors of OHCA with STE on ECGs, including unresponsive survivors. In the absence of STE on post-ROSC ECGs, urgent CAG is recommended for patients with a high suspicion of ongoing myocardial ischemia (such as the presence of chest pain before the arrest, a history of established CAD, and abnormal or uncertain ECG results). The European Society of Cardiology guidelines also strongly recommend considering unfavorable factors for the likelihood of neurologic recovery in the decision making process—such as unwitnessed cardiac arrest; late arrival of a prehospital team, without lay basic life support for >10 minutes; the presence of an initial nonshockable rhythm; or >20 minutes of advanced life support, without ROSC—as arguments against an invasive strategy.

Table 4.

Summary of guidelines on the role of coronary angiography in patients with out-of-hospital cardiac arrest^a

Guideline	Postresuscitation ECG with ST-segment elevation	Postresuscitation ECG without ST-segment elevation
2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation8	IB recommendation: primary PCI strategy recommended	IIa C: urgent angiography (and PCI if indicated) should be considered for patients with high suspicion
2019 SCAI expert consensus statement on out-of-hospital cardiac arrest6	For select comatose patients with OHCA: definite invasive strategy	Defer invasive strategy at initial encounter in hemodynamically stable comatose patients
2020 ILCOR Consensus on Science: American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care9	COR 1 (LOE B-NR): CAG should be performed emergently for all patients with a suspected cardiac cause of arrest	COR 2a (LOE B-NR): Emergency CAG is reasonable in select (such as electrically or hemodynamically unstable) comatose patients with a suspected cardiac cause of arrest

CAG, coronary angiography; COR, classification of recommendation; ECG, electrocardiogram; ESC, European Society of Cardiology; IB, Class I recommendation with level of evidence B; IIa C, Class IIa recommendation with level of evidence C; ILCOR, International Liaison Committee on Resuscitation; LOE, level of evidence; OHCA, out-of-hospital cardiac arrest; PCI, percutaneous coronary intervention; SCAI, Society for Cardiovascular Angiography and Interventions.

^aSummary of current guideline-based recommendations on the management of successfully resuscitated patients with out-of-hospital cardiac arrest.

We favor the guidelines for the management of patients with OHCA outlined by the American Heart Association and Society for Cardiovascular Angiography & Interventions over those proposed by the European Society of Cardiology. These guidelines are newer and based on more recent data, and they recommend performing CAG only in a subset of patients with OHCA without STE on ECG. They emphasize the assessment of the likelihood of a cardiac cause to be the etiology of arrest and the presence of unfavorable factors that predict a poor prognosis.

Patient selection for early CAG

Data from recent RCTs and meta-analyses advise against the practice of routinely performing CAG in all patients with OHCA. These data indicate that CAG may be futile in patients without myocardial ischemia as the cause of arrest, which may lead to delay in the management of underlying medical issues and subsequent harm. The benefit of CAG is associated with providing PCI, and, therefore, it is crucial to identify patients without STE who are likely to have ACS and favorable resuscitation features and those who would benefit from early CAG or PCI. Various studies have attempted to create models to identify such patients.

In 2015, the American College of Cardiology Interventional Council proposed 10 unfavorable resuscitation features for triaging comatose survivors of OHCA for emergency cardiac activation in the catheterization laboratory. These include the following: unwitnessed arrest, initial rhythm nonventricular fibrillation, no bystander CPR, >30 minutes from collapse to ROSC (time to ROSC), ongoing CPR, pH < 7.2, lactate level > 7 mmol/L, age > 85 years, end-stage renal disease, and noncardiac etiology.⁶⁵ Nonshockable rhythm has been associated with poor survival and neurologic recovery.^8,66 It has been suggested that the presence of multiple unfavorable features can predict a poor outcome in a patient questioning the utility of advanced cardiac interventions. An algorithm to identify patients in whom further treatment may not add meaningful value was proposed to help inform physicians’ decisions on whether to proceed with invasive management. However, there were several limitations of such recommendations. First, there was no ranking of such “unfavorable factors” in terms of their importance. Second, there was no set number of these factors that would render the decision to proceed with an intervention futile. Third, these factors and algorithm were not evaluated in a large patient cohort up until 2021. To address this, Harhash et al⁶⁷ validated these 10 factors and showed that the presence of ≥3 of these factors predict a survival rate of <40% in successfully resuscitated patients with OHCA. Further, the absence ≥6 of the unfavorable features predicted survival, thus making a reasonable case for such patients to not undergo an invasive procedure or have it at a later time, once their status improves. Age >85 years, >30 minutes of time to ROSC, and initial nonshockable rhythm were found to be the 3 most powerful predictors of adverse outcomes. It was also found that the presence of these 3 factors predicted a 95% possibility of a ≤10% rate of survival to discharge. Although the study included patients with and without STE, no difference was seen in the number of unfavorable features associated with a very poor outcome while stratifying the patients based on the presence or absence of STE.

Bascom et al⁶⁸ retrospectively analyzed 638 patients in the International Cardiac Arrest Registry to quantify the risk of death due to a circulatory etiology in patients with OHCA without STE on post-ROSC ECGs. A point was assigned for each associated factor in the model, yielding a CREST score (C, history of CAD; R, nonshockable rhythm; E, initial ejection fraction < 30%; S, circulatory shock at the time of presentation; and T, total ischemic time > 25 minutes) of 0 to 5, which was reasonably predictive of in-hospital circulatory death, with an area under the curve of 0.68. However, the CREST model did not include neurologic status, which is a very important predictor of mortality in patients with OHCA.

Interestingly, Baldi et al⁶⁹ retrospectively studied 370 patients to analyze the impact of time from achieving ROSC to obtaining ECG on the diagnostic accuracy of ECG for STEMI. It was found that false-positive STE was up to 3 times greater in ECGs that were performed within 7 minutes of achieving ROSC. The study suggested waiting for 8 minutes after ROSC to capture ECG to reduce false-positive STE and increase true-negative STE on post-ROSC ECGs.

The “Assess, Consult & Expect” approach

Given the complexity of managing patients with OCHA without STE on ECGs, the authors of this review developed a simple framework to guide patients’ care. The “Assess, Consult & Expect” (ACE) approach is outlined in the Central Illustration. With the ACE approach, the goal is to “ACE” the management of patients with OHCA.

Central Illustration.

“Assess, Consult& Expect” (ACE) approach for patients with out-of-hospital cardiac arrest without ST-segment elevation on electrocardiograms. The ACE approach may serve as a conceptual framework for the management of patients with out-of-hospital cardiac arrest (OHCA) and no ST-segment elevation (STE) on electrocardiograms. CAD, coronary artery disease; CAG, coronary angiography; ECG, electrocardiogram; LVEF, left ventricle ejection fraction; ROSC, return of spontaneous circulation.

Using the ACE approach, the provider should first assess the patient’s overall condition, cardiac and noncardiac status. A careful assessment of the unfavorable resuscitation features should be performed, including an assessment of the patient’s neurologic status, arterial pH, and lactate level. History should be gathered regarding existing comorbidities such as advanced cancer, dementia, functional status, and quality of life at baseline. With this background, the provider can then consult with colleagues, such as critical care intensivists and interventional cardiologists. The patient’s surrogate decision maker should be approached and presented with a tentative prognosis, and the goals of care should be discussed. Defining expectations—in terms of realistic results expected from PCI, mechanical circulatory support devices, and other interventions—is critically important.²⁷ The team should appropriately discuss what to “expect” from interventions such as CAG, PCI, and mechanical circulatory support devices (such as intra-aortic balloon pump, Impella, and extracorporeal membrane oxygenation) and weigh them against the associated risks of changing the overall patient outcome. The implementation of this 3-step approach can help reduce variability and promote consistency while selecting patients for CAG from a cohort of patients with OHCA without STE.

The ACE approach provides a stepwise holistic approach specifically for patients with OHCA and no evidence of STE on ECGs. It is different from prior algorithms in several ways.^6,65,70 First, in addition to considering unfavorable resuscitation-related factors, the ACE approach takes into consideration cardiac and noncardiac history to predict the likelihood of a cardiac etiology behind OHCA. Second, the ACE approach advocates for a multidisciplinary team, which involves an interventional cardiologist, intensivist, and, most importantly, the family, with the discussion of the goals of care and reaching a shared medical decision. Third, the ACE approach involves setting appropriate expectations and consideration of realistic outcomes with the use of different modalities and interventions such as temperature management, CAG, and mechanical circulatory support.

The clinical dilemma of the use of the CAG strategy in patients with OHCA without STE has been well answered by recent evidence, resulting in a paradigm shift in the management of these patients. Accordingly, we anticipate and recommend an upgrade of the current guidelines with regard to CAG and PCI for such patients as we await results from current trials that are underway. Whether a particular subgroup would benefit from an early CAG and PCI strategy is yet to be discovered. We recommend future studies to be directed toward better identifying such subgroups, improving neurologic prognostication of comatose patients, and recognizing interventions that improve outcomes in these patients. Until then, it is imperative for multidisciplinary teams to make decisions using relevant clinical data to provide individualized care.

Conclusions

Patients who experience OHCA without a shockable rhythm and without STE on post-ROSC ECGs are among the most challenging patients encountered by critical care and interventional cardiologists. With limited options, early CAG and PCI have long been embraced as interventions associated with improved outcomes. However, the results of recent RCTs and meta-analyses contradict these assumptions and indicate that the strategy of routine early CAG is not beneficial and, in fact, has similar short- and long-term outcomes as of the delayed or selective CAG strategy.

The challenge ahead of the critical care team of the next decade is to identify patients with OHCA without STE on ECGs who will benefit from CAG at all. The approach should integrate the likelihood of an acute coronary lesion to be the cause of OHCA as well as the patient’s on-presentation neurologic, cardiac, and systemic statuses and should involve a multidisciplinary team to work closely to determine which interventions are most likely to benefit the patient.