High rate of critical coronary stenosis in comatose patients with Non-ST-elevation out-of-hospital cardiac arrest (NSTE-OHCA) undergoing therapeutic hypothermia-Experience from the HAnnover COoling REgistry (HACORE).

BACKGROUND: Myocardial infarction is the most frequent cause for out-of-hospital cardiac arrest (OHCA) in adults. Patients with ST-segment elevations (STE) following return of spontaneous circulation (ROSC) are regularly admitted to the catheterisation laboratory for urgent coronary angiography. Whether patients without obvious STE (NSTE) should receive coronary angiography as part of a standardised diagnostic work-up following OHCA is still debated.
METHODS: We analysed a cohort of 517 subsequent OHCA patients admitted at our institution who received a standardised diagnostic work-up including coronary angiography and therapeutic hypothermia. Patients were 63±14 years old, 76% were male. Overall, 180 (35%) had ST-elevation in the post-ROSC ECG, 317 (61%) had shockable rhythm (ventricular fibrillation or tachycardia) at first ECG. ROSC was achieved after 26±21 minutes.
RESULTS: Critical coronary stenosis requiring PCI was present in 83% of shockable and 87% of non-shockable STE-OHCA and in 48% of shockable and 22% of non-shockable NSTE-OHCA patients. In-hospital survival was 61% in shockable and 55% in non-shockable STE-OHCA and 60% in shockable and 28% in non-shockable NSTE-OHCA.
CONCLUSION: Standardised admission diagnostics in OHCA patients undergoing therapeutic hypothermia with a strict admission protocol incorporating ECG and coronary catheterisation shows a high rate of relevant coronary stenosis in STE-OHCA irrespective of the initial rhythm and in NSTE-OHCA with initial shockable rhythm. Based on the unfavourable outcome and low PCI rate observed in NSTE-OHCA patients with a primary non-shockable ECG rhythm it might be reasonable to restrict routine early coronary angiography to patients with primary shockable rhythms and/or ST-segment elevations after ROSC.

Introduction

After out-of-hospital cardiac arrest (OHCA) cardio-pulmonary resuscitation (CPR) is provided to get return of spontaneous circulation (ROSC) as quickly as possible [1] and to prevent cerebral reperfusion injury [2]. The majority of cardiac arrest cases is attributed to cardiac causes with acute myocardial infarction and arrhythmias in patients with underlying heart disease being the most frequent ones [1]. In the landmark TTM-trial, a large proportion of patients with presumed cardiac cause of arrest died early due to evolving haemodynamic instability and coronary angiography had not been performed routinely [3]. Urgent coronary angiography is well recommended for patients with ST-segment elevations in their post-ROSC electrocardiogram (ECG), but there is no clear evidence for OHCA patients without ST-segment elevation (non-STE = NSTE) [1]. While urgent coronary angiography is highly recommended for NSTE-myocardial infarction patients with subsequent cardiac arrest [4,5], it is difficult to diagnose NSTE-myocardial infarction in patients with a primary presentation as OHCA, because elevated biomarkers such as troponin following CPR are not specific to proof myocardial infarction as the cause of cardiac arrest.

It remains unclear whether all NSTE-OHCA patients with a presumed cardiac cause for arrest should undergo routine coronary angiography as part of a standardised diagnostic work-up. We intend to provide an uninterrupted phase of intensive care including therapeutic hypothermia following ICU admission by performing potentially relevant diagnostic procedures early before ICU admission. The recent randomised COACT trial testing the concept of immediate angiography in patients with an initial shockable rhythm but absence of ST-segment elevations showed no survival benefit by early invasive assessment [6].

We previously adopted a strategy in our hospital of interdisciplinary screening in the emergency room including endotracheal airway management and early assessment of ventricular function by transthoracic echo [7]. All patients without evident non-cardiac cause for arrest undergo cardiac catheterisation and percutaneous coronary intervention (PCI) if needed, intravascular cooling, and placement of active hemodynamic assist devices if patients are in shock [8,9]. At latest after cardiac catheterization, all OHCA patients receive a cerebral and thoracic computed tomography as a routine workup before admission to our cardiology intensive care unit (ICU) harbouring the cardiac arrest centre, where therapeutic hypothermia and continuous neuromonitoring are initiated immediately upon arrival in all OHCA patients [10].

Here we report the rate of PCI and resulting in-hospital survival based on the presence of a shockable vs non-shockable rhythm during first post-arrest ECG in combination with the presence or absence of ST-segment elevations in ECGs documented either by ambulance or in the emergency room with the intention of using those early ECG markers as potential guidance for further diagnostic approaches.

Methods

Study design

The HAnnover COoling REgistry (HACORE) is prospective observational and in accordance with the Declaration of Helsinki and approved by the ethics committee (#3567–2017) at Hannover Medical School. The ethics committee approved the analysis as reported in the present manuscript. Written informed consent was obtained from legal guardians during the unconscious period and re-consented by survivors after gaining consciousness. HACORE includes anonymized data from all OHCA patients treated at our cardiac arrest centre with a standardized protocol including therapeutic hypothermia. Here, all patients receiving therapeutic hypothermia following OHCA were analysed with regard to their presenting ECG patterns and coronary angiography results.

Patient population

Consecutive comatose OHCA patients (n = 517) with presumed cardiac cause of arrest who received therapeutic hypothermia between January 1st 2011 and June 30st 2019 served as cases. All patients were admitted to the ICU at the Department of Cardiology and Angiology at Hannover Medical School and treated according to an institutional protocol ensuring a standardized approach including early diagnostics by computed tomography and coronary angiography as well as early haemodynamic stabilization in case of cardiogenic shock using microaxial pumps and/or extracorporeal life support [7]. Microaxial pumps were used primarily in isolated left-ventricular failure whereas ECMO was used in refractory arrest or biventricular failure. All OHCA patients with presumed cardiac cause of arrest are mandatorily treated by this protocol in order to provide optimal guideline-recommended therapy and, therefore, receive therapeutic hypothermia [7-9,11-13].

Patient treatment

Patients after primarily successful cardio-pulmonary resuscitation were first screened and stabilized in the emergency room. After initial assessment, all STE-OHCA patients were taken to the catheterisation laboratory. If non-cardiac causes such as asphyxia, stroke, intracranial bleeding, strangulation, drowning, pulmonary embolism or aortic dissection were suspected in NSTE-OHCA during initial assessment, patients received computed tomography first. If none of those suspicions were raised, NSTE-OHCA patients were treated like STE-OHCA and underwent coronary angiography first. In concomitant cardiogenic shock, active haemodynamic support with an Impella micro-axial pump was initiated as standard procedure in the catheterisation laboratory.

Clinical follow-up

Patients were followed up for the time period of their hospital stay.

Statistical analysis

Numbers are given as n (%), means ± standard deviation (SD) for quantification, or median and interquartile ranges (IQR) in the tables. Statistical analysis was performed with ANOVA and Mann-Whitney test as nonparametric test followed by a Bonferroni test for multiple comparisons. Chi-square test was applied to compare patient characteristics. Cumulative mortality was estimated by Kaplan-Meier method and compared by the log-rank test. Data were analysed using SPSS Statistics 24 (IBM SPSS Statistics 24). A two-sided P-value of < 0.05 was considered statistically significant.

While the primary analysis focused on the presence and absence of shockable rhythms and on the presence or absence of ST-segment elevation, a second step of the analysis was focused on the subgroup of patients in our registry, who matched the inclusion and exclusion criteria of the COACT trial, which investigated the effect of immediate compared to delayed coronary angiography in NSTE-OHCA [6].

Results

Patient characteristics

The overall OHCA patient population receiving therapeutic hypothermia consisted of 517 consecutive patients. ROSC had been achieved after 26±21 minutes. The majority of patients (61%) had a primarily shockable rhythm defined as either ventricular tachycardia or ventricular fibrillation. In 28 patients (5%), extracorporeal CPR had to be initiated upon arrival using vaECMO [11]. In 44 (9%) patients, coronary angiography was not performed due to identification of a non-cardiac cause of arrest during primary assessment. Critical coronary stenosis requiring PCI was present in 151 (84%) STE-OHCA and in 118 (40%) NSTE-OHCA patients (Table 1). Overall, 116 (23%) OHCA patients required mechanical support for cardiogenic shock, with 37 (32% of patients with circulatory support) being supported by vaECMO plus Impella [8].

Table 1

Baseline characteristics.

	STE-OHCA		NSTE-OHCA		p value	Shockable rhythm		Non-shockable rhythm		p value
Number (%)	180	(35)	337	(65)		317	(61)	200	(39)
Age–years	61±12		65 ±15		0.001	61±14		67±14		<0.001
Male sex, n (%)	147	(82)	247	(73)	0.040	256	(81)	138	(69)	0.030
In-hospital survival (%)	119	(66)	167	(50)	<0.001	208	(66)	78	(39)	<0.001
Cardiovascular risk factors
Hypertension (%)	94	(52)	191	(57)	0.350	175	(55)	110	(55)	1.000
Diabetes (%)	30	(17)	86	(26)	0.049	58	(18)	58	(29)	0.005
Hyperlipidaemia (%)	72	(40)	104	(31)	0.041	110	(35)	66	(33)	0.704
Family history for CAD (%)	15	(8)	25	(7)	0.730	34	(11)	6	(3)	0.001
Smoking (%)	78	(43)	87	(26)	<0.001	118	(37)	47	(24)	0.010
Previous comorbidities
CAD (%)	37	(21)	94	(28)	0.070	77	(24)	54	(27)	0.534
PCI (%)	20	(11)	39	(12)	1.000	37	(12)	22	(11)	0.887
CABG (%)	7	(4)	46	(14)	<0.001	32	(10)	21	(11)	0.883
PAD (%)	11	(6)	31	(9)	0.240	20	(6)	22	(11)	0.069
TIA/stroke (%)	13	(7)	42	(12)	0.070	26	(8)	29	(15)	0.028
CKD (%)	13	(7)	52	(16)	0.080	34	(11)	31	(16)	0.134
chronic RRT (%)	1	(1)	5	(1)	0.600	2	(1)	4	(2)	0.212
Atrial fibrillation (%)	14	(8)	87	(26)	<0.001	62	(20)	39	(20)	1.000
Pacemaker (%)	3	(2)	13	(4)	0.200	11	(3)	5	(3)	0.611
ICD (%)	2	(1)	4	(1)	0.300	2	(1)	4	(2)	0.119
COPD/ Asthma (%)	11	(6)	45	(13)	0.010	23	(7)	33	(17)	0.010
Characteristics of cardiac arrest
Witnessed arrest (%)	150	(83)	259	(77)	0.090	267	(84)	142	(71)	<0.001
Bystander CPR (%)	128	(71)	214	(64)	0.100	227	(72)	115	(58)	0.010
Shockable Rhythm (%)	149	(83)	168	(50)	<0.001	-	-	-	-	-
ST-segment elevation (%)	-	-	-	-	-	149	(47)	31	(16)	<0.001
ROSC, min	28±21		26±21		0.250	27±21		25±21		0.230
Ongoing CPR at admission (%)	21	(12)	39	(12)	1.000	31	(10)	29	(15)	0.120
eCPR (%)	15	(8)	13	(4)	0.410	18	(6)	10	(5)	0.843
Impella (%)	49	(27)	46	(16)	<0.001	72	(23)	23	(14)	0.020
va ECMO (%)	29	(16)	29	(10)	0.010	38	(12)	20	(12)	0.568
Renal replacement therapy (%)	44	(24)	104	(35)	0.127	84	(27)	64	(40)	0.194
Baseline laboratory values
Lactate, mmol/l	7.72±4.87		8.22±4.39		0.250	7.34±4.49		9.18±4.47		<0.001
pH	7.16±0.19		7.14±0.18		0.270	7.18±0.16		7.09±0.1.9		<0.001
Creatinine, μmol/l	108±48		142±120		<0.001	111±54		161±145		<0.001
Urea nitrogen, mmol/l	6.99±1.98		7.81±3.73		0.480	6.66±2.53		8.93±3.98		0.022
Creatinkinase, U/l	108±48		142±120		0.580	518±1328		446±1026		0.522
hs-Troponine T, μg/l	790±2619		652±5004		0.740	574±2202		903±6397		0.414
NT-proBNP, ng/l	806±2180		937±2873		0.700	706±1742		1138±3507		0.225
Haemoglobin, g/dl	13.57±1.99		12.70±2.74		0.004	13.55±1.88		12.31±3.04		<0.001
Leukocytes, *1000/μl	14.93±6.55		15.03±7.85		0.920	14.79±7.63		15.24±7.22		0.630
NSE- day 3, μg/l	34 [21–76]		29 [19–52]		0.630	27 [20–46]		39 [20–117]		0.027
S-100b- day 3, μg/l	0.111 [0.76–0.208]		0.129 [0.076–0.243]		0.690	0.109 [0.069–0.181]		0.183 [0.101–0.349]		0.571

CAD–coronary artery disease; CABG–coronary artery bypass graft; CKD–chronic kidney disease; COPD–chronic obstructive pulmonary disease; CPR–cardiopulmonary resuscitation; eCPR–ECMO-CPR; ECMO–extracorporeal membrane oxygenation; ICD–implantable cardioverter-defibrillator; PAD–peripheral artery disease; PCI–percutaneous coronary intervention; ROSC–return of spontaneous circulation; RRT–renal replacement therapy; TIA–transient ischemic attack.

The role of ST-segment elevations after ROSC

Patients with STE-OHCA were younger, less comorbid, had a higher rate of shockable rhythm at first rhythm evaluation, and better renal function (Table 1). As expected, STE-OHCA patients were more likely to require PCI during coronary angiography, had less extensive coronary artery disease predominantly located in the LAD, and required mechanical circulatory support more often than NSTE-OHCA patients (Table 2). STE-OHCA patients had a higher in-hospital survival rate than NSTE-OHCA patients. Comparing PCI and non-PCI group within the NSTE-OHCA cohort, only witnessed arrest and primary shockable rhythm were identified by univariate analysis (S1 Table).

Table 2

Intrahospital parameters and findings of coronary angiography according to ECG findings and initial rhythm.

	STE-OHCA		NSTE-OHCA		p value	Shockable rhythm		Non-shockable rhythm		p value
Coronary angiography (%)	180	(100)	293	(87)	<0.001	312	(98)	161	(81)	<0.001
CAD (%)					<0.001					<0.001
1-vessel (%)	60	(33)	43	(15)		77	(25)	26	(16)
2-vessel (%)	59	(33)	37	(13)		72	(23)	24	(15)
3-vessel (%)	43	(24)	79	(27)		83	(27)	39	(24)
CABG (%)	3	(2)	16	(5)		15	(5)	4	(2)
no sign. CAD (%)	15	(8)	118	(40)		65	(21)	68	(42)
no PCI (%)	29	(16)	175	(60)		108	(35)	96	(60)
PCI (%)	151	(84)	118	(40)	<0.001	204	(65)	65	(40)	<0.001
Number of vessels (%)					<0.001					<0.001
Single (%)	116	(77)	89	(75)		159	(78)	46	(71)
Multiple (%)	30	(20)	25	(21)		38	(19)	17	(26)
missed PCI (%)	5	(3)	4	(3)		7	(3)	2	(3)
Culprit lesion (%)					<0.001					<0.001
LAD (%)	83	(55)	51	(43)		104	(51)	30	(46)
LCX (%)	29	(19)	33	(28)		47	(23)	15	(23)
RCA (%)	36	(24)	27	(23)		48	(24)	15	(23)
LMCA (%)	3	(2)	6	(5)		4	(2)	5	(8)
CABG (%)	0	(0)	1	(1)		1	(0)	0	(0)

CAD–coronary artery disease; CABG–coronary artery bypass graft; LAD–left anterior descending coronary artery; LCX–left circumflex coronary artery; LMCA–left main coronary artery; PCI–percutaneous coronary intervention; RCA–right coronary artery.

When applying the inclusion and exclusion criteria from the COACT trial to our population (only OHCA with initially shockable rhythm remaining unconscious after ROSC without STE, shock or an obvious non-coronary cause of arrest [6]) we found that only a minority of 102 out of 337 (30%) of our daily-practice NSTE-OHCA patients would have fit the trials’ criteria. These very selected patients had an in-hospital mortality rate of 31% in our registry comparable to the reported 35% in the angiography group within that trial (OR 0.86 95%-CI 0.53–1.39) [6].

The role of a shockable rhythm at first ECG

Patients with shockable rhythms were younger, had fewer history of cerebrovascular or obstructive pulmonary disease, higher rates of witnessed arrest, lower lactate levels on admission, better renal function, and lower NSE levels at day 3 compared to patients with non-shockable rhythms (Table 1). Patients with shockable rhythms were more likely to undergo coronary angiography and to require PCI, had more extensive coronary artery disease, and required mechanical circulatory support more often than patients with non-shockable rhythms. They had a higher in-hospital survival rate than patients with non-shockable rhythms (Table 2). Comparing PCI and non-PCI group within the non-shockable OHCA cohort, only a higher troponin level on admission was identified by univariate analysis (S1 Table).

Influence of combined ECG patterns on PCI rate and in-hospital survival

Critical coronary stenosis requiring PCI was present in 83% of shockable and 87% of non-shockable STE-OHCA and in 48% of shockable and 22% of non-shockable NSTE-OHCA patients (Fig 1).

Fig 1

PCI rates in the HAnnover COoling REgistry (HACORE).

Rate of flow-limiting coronary stenosis in patients following out-of-hospital cardiac arrest (OHCA) is shown depending on the presence of ST-segment-elevations (STE-OHCA) or their absence (NSTE-OHCA) and with respect to the first documented ECG rhythm, shockable (blue) or non-shockable (red).

In-hospital survival was 61% in shockable and 55% in non-shockable STE-OHCA and 60% in shockable and 28% in non-shockable NSTE-OHCA (Fig 2), respectively. The difference on survival between NSTE-OHCA patients with primarily shockable rhythm receiving PCI (56%) and those not requiring PCI (64%), however, was minor (p = 0.35).

Fig 2

In-hospital survival in the HAnnover COoling REgistry (HACORE).

In-hospital survival in patients following out-of-hospital cardiac arrest (OHCA) is shown depending on the presence of ST-segment-elevations (STE-OHCA) or their absence (NSTE-OHCA) and with respect to the first documented ECG rhythm, shockable (blue) or non-shockable (red).

Discussion

In HACORE, applying a standardized interdisciplinary approach to OHCA patients including routine computed tomography, therapeutic hypothermia and coronary angiography in patients with suspected cardiac cause of arrest [7], we found a high rate of critical coronary stenosis in NSTE-OHCA patients, in particular if NSTE-OHCA patients had a shockable presenting rhythm. More specifically, survival in NSTE-OHCA patients with relevant coronary stenosis receiving early PCI was similar to that observed in STE-OHCA patients and good neurological outcome was observed predominantly in patients with a shockable presenting irrespective of presence or absence of ST-elevations.

Our surprisingly high rate of 16% of STE-OHCA patients not requiring PCI might be related to the effort in the emergency ambulance service of acquiring the ECG rapidly. A recent study conducted at three different cardiac arrest centres in Europe reported a rate of false-positive ECGs regarding ST-segment elevations within the first 7 minutes of almost 20% [14]. As we tried to get ECGs written as soon as possible after ROSC, this might have affected our sensitivity in the STE-OHCA group to predict the necessity of PCI.

When reviewing the literature regarding appropriateness of coronary angiography in NSTE-OHCA, in general approximately 30% of patients were reported to have critical coronary stenosis requiring revascularisation [15-17]. In some registries, even OHCA patients with ECGs free of any sign suggesting myocardial ischaemia had impaired coronary flow in 19–33% [17,18]. In an analysis from the Minnesota Resuscitation Consortium, urgent coronary angiography in OHCA patients with primarily shockable rhythm irrespective of ST-elevations was associated with improved outcome. Adjusting for covariates, direct access to the cath lab improved survival with good neurological outcome with an odds ratio of 1.99 (1.07–3.72, p = 0.03), and more specifically NSTE-OHCA patients had an absolute 13% higher survival when treated by protocol with direct cath lab access (adjusted odds ratio 2.77; 1.31–5.85, p = 0.01) [19]. Similarly, we identified the presence of a shockable rhythm as a good indicator for PCI irrespective of ST-segment elevation. PCI in NSTE-OHCA patients was associated with improved outcome [16,19], whereas survival rates in STE-OHCA compared to NSTE-OHCA appeared to be higher in general [17]. Accordingly, we observed a similar survival rate in NSTE-OHCA patients with primary shockable rhythm, which was highly suggestive for a coronary cause of cardiac arrest, as we observed in the group with STE-OHCA. The comparable mortality in NSTE-OHCA patients receiving PCI might be attributable to the rapid access to the cath lab in a standardised patient management as there are no significant delays compared to the access times in STE-OHCA patients. Similarly, in the Minnesota project, early access to coronary angiography with achievement of revascularisation was associated with a three-fold higher probability of survival with a favourable neurological outcome [19]. In a previous retrospective analysis in two large US hospitals, early coronary angiography without PCI was associated with better outcome than not performing coronary angiography in OHCA patients [20]. A meta-analysis of available low-volume data on early coronary angiography in NSTE-OHCA patients supported the use of early coronary angiography in those patients [21]. However, more recently in the prospective, randomised, controlled COACT trial, immediate coronary angiography in NSTE-OHCA patients did not provide a benefit regarding survival of NSTE-OHCA patients [6]. By definition, that trial included only NSTE-OHCA patients if they had shockable rhythms at first ECG and had been haemodynamically stable following ROSC. Furthermore, 65% of the control group received a coronary angiogram on average 5 days after arrest [6]. Of note, only less than one out of three patients in our every-day practice fitted the trials inclusion/ exclusion criteria.

The major reason for not fitting the COACT trials criteria in HACORE was cardiogenic shock following ROSC. We observed cardiogenic shock in 246 out of 337 NSTE-OHCA patients (73%), but PCI was only required in 39% of NSTE-OHCA patients with shock indicating a substantial amount of patients with non-coronary causes of arrest. Nevertheless, survival within the NSTE-OHCA shock group was 42%. Considering that these patients did not have ST-elevations, had all been resuscitated, and were all in shock, a 42% survival rate might represent a reasonable outcome. Many contemporary shock trials in patients with acute myocardial infarction report a mortality rate of 40–50%, whereby the rate of OHCA in those trials was only about 50–60% [22,23]. Even in the very early years of coronary angioplasty there were two predictors of survival: first, successful coronary angioplasty (OR 5.2, p = 0.04), and second absence of need for inotropic drugs (OR 3.6, p = 0.03) [24]. These early findings already strengthen another very important component of early coronary angiography in modern times, the option of access to mechanical circulatory support devices. When analysing all cardiogenic shock patients at our institution we recognized that about two out of three shock patients had OHCA prior to hospital admission [9]. Their chance for survival seemed to be influenced by the availability of early haemodynamic support.

While the COACT trial suggested that early coronary angiography does not provide benefit in NSTE-OHCA patients [6], we realised that our NSTE-OHCA patients included a large group of patients in cardiogenic shock, which is not reflected in that trial. In HACORE, the smaller group of COACT-like patients had a similar in-hospital mortality rate of 31% compared to 35% in the trial.

When putting our data on ECG patterns and angiography results into perspective with previously published observations [15-19,24] and assess the neurological outcome in our patients, it seems not to be the absence or presence of ST-elevations that is predictive for good outcome, but rather the primary rhythm that is (Fig 3). Therefore, a standardised approach for all STE-OHCA patients and NSTE-OHCA patients with an initial shockable rhythm appears to be useful, if there is no clear evidence for a non-coronary cause of arrest.

Fig 3

Rate of coronary stenosis requiring revascularisation, in-hospital survival and good neurological outcome (Cerebral Performance Category (CPC) ≤2) in the HAnnover COoling REgistry (HACORE).

The results observed in our real-life cohort in HACORE are supported by recommendations given by the European Association for Percutaneous Cardiovascular Interventions/ Stent for Life groups regarding invasive coronary angiography in OHCA patients, which recommend immediate coronary angiography in all STE-OHCA and in those NSTE-OHCA patients, who have no obvious non-coronary cause of arrest, no significant comorbidities, and an favourable arrest setting [25]. However, guidelines also recommended considering a stop prior to the cath lab in comatose OHCA survivors without ECG for ST-segment elevation on the post-resuscitation ECG to exclude non-coronary causes of arrest [26].

Similar to the analysis reported here, our previous analysis investigating all patients receiving extracorporeal CPR for ongoing arrest had demonstrated a non-shockable rhythm as a strong factor associated with non-survival [11]. The presence or absence of a shockable rhythm might indicate a potential different etiology of cardiac arrest. Shockable might be more likely to indicate an ischaemic cause, whereas non-shockable might be attributable to anoxic causes. Indeed, baseline characteristics do support such a hypothesis depicting a significantly higher number of chronic pulmonary diseases in patients with non-shockable rhythm and a higher proportion of ST-elevation in shockable rhythm. Patients with non-shockable rhythm had worse conditions of resuscitation indicated by less witnessed arrest and bystander CPR potentially contributing to higher admission lactate and NSE levels (as described in Table 1).

Limitations

Our registry was performed in a tertiary university hospital setting with a specific algorithm for treating and handling OHCA as well as shock patients. This might influence the results in the way that still comatose patients were aggressively stabilized and treatment was optimized to the local conditions. The data, however, should not be extrapolated to alert patients admitted after short cardiac arrest, who could have a different pattern of underlying disease. While the sample size of an observational single-centre study has to be considered as a limitation, nevertheless, more than 500 consecutively treated patients are reported.

Conclusion

Based on the unfavourable outcome and low PCI rate observed in NSTE-OHCA patients with a primary non-shockable ECG rhythm it might be reasonable to restrict routine early coronary angiography to patients with primary shockable rhythms and/or ST-segment elevations after ROSC.

Characteristics regarding PCI of NSTE-OHCA and non-shockable patients.

(DOCX)

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8 Feb 2021

PONE-D-21-01798

High Rate of Critical Coronary Stenosis in Patients with Non-ST-Elevation Out-of-Hospital Cardiac Arrest (NSTE-OHCA) – Experience from the HAnnover COoling REgistry (HACORE)

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- https://www.jacc.org/doi/full/10.1016/j.jcin.2018.06.022

The text that needs to be addressed involves sentences 1, 2, 8, 9, and 10 of the Introduction. Overlap also should be addressed in Paragraph 2, sentences 3 and 5 of the Discussion.

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear authors,

I believe that your paper is of potential intererst, however I have some concerns that should be addressed and I hope can improve the quality of your manuscript.

Introduction

- your study is focused on post-ROSC ECG and PCI, but you have focused your introduction more on brain and hypotermia. I suggest to re-balance your introduction.

- moreover, especially in the first part of the introduction, many sentence require a reference (e.g. line 58, line 62 and line 64-65).

Methods

- please, specify when you chose, in your hospital, to use ECMO rather than Impella

Results:

- line 163: please, change ECG in rhythm evaluation. ECG here is misleading

- line 168 and line 191: I believe that "when trying to identify potential discriminating factors" should be changed in a more simply "Comparing PCI and non-PCI group..."

- line 176 and line 194: please, specify which are the inclusion criteria of COACT-like and HYPERON-like patients to improve clarity for the readers. Moreover, you should pre-specify these sub-group analysis in the methods

Discussion:

- in general I believe that the discussion should be deeply revised for these reasons:

-- you study is interesting, however it is a observational study and not a RCT, so you have all the typical limitation of the observational studies, including selection bias and a limited sample size. Therefore I believe you cannot state (directly or indirectly) that your study can provide more useful results than a RCT as COACT. The same when comparing Minnesota study with COACT, Minnesota is observational, COACT RCT. I suggest to focus on those sub-groups of patients excluded from the COACT, for example the patients with shock.

-- please, considering all above, mitigate your conclusions

-- I believe that in the discussion you should focus also on the difference regarding survival between shockable and non-shockable (due to different etiology?)

-- you skipped in the discussion an issue that I believe it is very important. About 20% of the STE-patients were not treated with a PCI, this is consistent with previous data in literature and should be stressed. Moreover, considering recent data regarding the key role of timing from ROSC to first ECG acquisition to decrease the percentage of false-positive ECG (JAMA Netw Open. 2021;4(1):e2032875. doi:10.1001/jamanetworkopen.2020.32875), please consider to comment your results in light of this recent evidence

- line 254: "had had" is a typo

Limitations

- please, consider your limited sample size as a limitation. Moreover, your study is observational, therefore this should be recognized in the limitations

- your registry consider only patients in whom hypotermia is performed. This is an important limitation and selection bias and should be highlighted

Reviewer #2: The conclusions expressed in the abstract and in the full paper are slightly different. In the full paper the conclusion is that NSTEMI non-shockable rhythm do not deserve angiography (since just 22% had PCI), while in the abstract is stated that patients with NSTEMI shockable rhythm deserve immediate angiography (since the authors compare the STEMI shockable survival with NSTEMI shockable survival). So if the real conclusions are the ones expressed in the abstract, I think that some information are missing, in particular there is no data about survival in the subgroups NSTEMI shockable PCI vs NSTEMI shockable non PCI. The 60% of survival in NSTEMI shockable patients, which is similar to the STEMI shockable ones (61%), refers to all the NSTEMI shockable (no distinction between PCI vs no PCI), which may be crucial in recommending angiography in this population. Moreover, it's not clear the purpose in citing the HYPERION trial (lines 292-293) in which there is no mention about the link between PCI-rate and in-hospital mortality rate.

**********

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Reviewer #1: No

Reviewer #2: No

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9 Apr 2021

Response to Reviewer #1 Manuscript PONE-D-21-01798

We would like to thank the reviewer for his/her constructive criticism and valuable input. We hope that the changes made to the manuscript and the responses detailed below, satisfactorily address the concerns raised.

Introduction

- your study is focused on post-ROSC ECG and PCI, but you have focused your introduction more on brain and hypothermia. I suggest to re-balance your introduction.

As suggested by the reviewer, we have rewritten the introduction now focusing primarily on post-ROSC-ECG and indication for PCI (lines 61-66).

- moreover, especially in the first part of the introduction, many sentence require a reference (e.g. line 58, line 62 and line 64-65).

The reference to recent AHA ACLS guidelines has been added early on. Most of the other requirements for references are not required anymore as the sentences under concern have been deleted as requested above.

Methods

- please, specify when you chose, in your hospital, to use ECMO rather than Impella

Microaxial pumps were used primarily in isolated left-ventricular failure whereas ECMO was used in refractory arrest or biventricular failure. This has now been added to the patient population section (lines 112-116).

Results:

- line 163: please, change ECG in rhythm evaluation. ECG here is misleading

The wording has been changed as suggested (line 166).

- line 168 and line 191: I believe that "when trying to identify potential discriminating factors" should be changed in a more simply "Comparing PCI and non-PCI group..."

The wording has been changed as suggested (lines 171).

- line 176 and line 194: please, specify which are the inclusion criteria of COACT-like and HYPERON-like patients to improve clarity for the readers. Moreover, you should pre-specify these sub-group analysis in the methods

In the revised version of the manuscript we focused on the COACT trial as it is a trial selectively addressing PCI in NSTE-OHCA patients and we have skipped the reference to the HYPERION trial as also suggested by reviewer #2. Inclusion and major exclusion criteria have been added at the suggested part of the text including the respective reference (lines 180-181). The respective sub-group analysis has now been pre-specified in the Methods section (lines 140-144).

Discussion:

- in general I believe that the discussion should be deeply revised for these reasons:

-- you study is interesting, however it is a observational study and not a RCT, so you have all the typical limitation of the observational studies, including selection bias and a limited sample size. Therefore I believe you cannot state (directly or indirectly) that your study can provide more useful results than a RCT as COACT.

We have changed the discussion section with regard to this matter. Our intention was not to imply that an observational study provides better results than a RCT. However, observational studies can provide useful information if they indicate that a RCT had been very selective. To this regard, the COACT criteria applied to less than one third of our observational cohort. In other words, every day’s clinical life is much more complex and patients differ largely from the cohort selectively investigated in the trial. Therefore, we believe it is warranted to raise some caution regarding extrapolation of study results into a much more heterogeneous and eventually sicker patient population in every day clinical routine. Following publication of COACT, there was an urge by colleagues that it might generally not be necessary to perform coronary angiography in resuscitated patients if they do not show ST-elevations. However, our registry shows that most patients in clinical routine were not represented by the trial population. Therefore, we tried to find some further indicator to guide patient flow regarding potential beneficiaries from coronary angiography. Following our experience, there is a higher rate of PCI in NSTE-OHCA patients with shockable rhythm; on the contrary, PCI rate and survival in non-shockable rhythms are very low. Therefore, combination of primary rhythm and absence of ST-segment elevations might be a useful indicator to guide patient flow.

The same when comparing Minnesota study with COACT, Minnesota is observational, COACT RCT. I suggest to focus on those sub-groups of patients excluded from the COACT, for example the patients with shock.

-- please, considering all above, mitigate your conclusions

We thank the reviewer for pointing out this important point. However, with all due respect to the reviewer, given the data in our registry it rather appears that the patients in COACT represent a subgroup of the patients being admitted in everyday clinical routine. We never intended to question the trial results; we rather observed a similar outcome in COACT-like patients in HACORE (lines 293-294). Nevertheless, the majority of our patients would have been excluded from the trial mainly due to presence of haemodynamic instability. Considering that these patients did not have STE, all had been resuscitated, and all were in shock, 42% survival is not too bad a result (lines 271-280).

-- I believe that in the discussion you should focus also on the difference regarding survival between shockable and non-shockable (due to different etiology?)

We agree with the reviewer that the presence or absence of a shockable rhythm might indicate a potential different etiology of cardiac arrest. Shockable might be more likely be indicative for an ischaemic cause, whereas non-shockable might be attributed to anoxic causes. Indeed, baseline characteristics do support such a hypothesis depicting a significantly higher number of chronic pulmonary disease in patients with non-shockable rhythm and a higher proportion of ST-elevation in shockable rhythm. Patients with non-shockable rhythm had worse conditions of resuscitation indicated by less witnessed arrest and bystander CPR potentially contributing to higher admission lactate and NSE levels (lines 312-321).

-- you skipped in the discussion an issue that I believe it is very important. About 20% of the STE-patients were not treated with a PCI, this is consistent with previous data in literature and should be stressed. Moreover, considering recent data regarding the key role of timing from ROSC to first ECG acquisition to decrease the percentage of false-positive ECG (JAMA Netw Open. 2021;4(1):e2032875. doi:10.1001/ jamanetworkopen.2020.32875), please consider to comment your results in light of this recent evidence

We agree with the reviewer on this important point, which has been added to the discussion section. Prior to the cited analysis we intended to perform a 12-channel ECG as rapidly as possible after ROSC (lines 229-235).

- line 254: "had had" is a typo

We apologize for that, the typo has been corrected; a past perfect does not seem to be necessary.

Limitations

- please, consider your limited sample size as a limitation. Moreover, your study is observational, therefore this should be recognized in the limitations

This has been done as requested (lines 327-329).

- your registry consider only patients in whom hypothermia is performed. This is an important limitation and selection bias and should be highlighted

With all due respect to the reviewer, we do not believe that strong adherence to guideline recommendations is an important limitation. Our protocol and registry ensure that there is a strict approach towards post-arrest patients in our centre. We just want to confirm to the reviewer that there are no comatose OHCA patients in our hospital with presumed cardiac cause of arrest who are treated by normothermia or no TTM at all. This aspect regarding the setting has been highlighted in detail in the introduction section (lines 82-84).

Response to Reviewer #2 Manuscript PONE-D-21-01798

We would like to thank the reviewer for his/her constructive criticism and valuable input. We hope that the changes made to the manuscript and the responses detailed below, satisfactorily address the concerns raised.

The conclusions expressed in the abstract and in the full paper are slightly different. In the full paper the conclusion is that NSTEMI non-shockable rhythm do not deserve angiography (since just 22% had PCI), while in the abstract is stated that patients with NSTEMI shockable rhythm deserve immediate angiography (since the authors compare the STEMI shockable survival with NSTEMI shockable survival). So if the real conclusions are the ones expressed in the abstract, I think that some information are missing, in particular there is no data about survival in the subgroups NSTEMI shockable PCI vs NSTEMI shockable non PCI. The 60% of survival in NSTEMI shockable patients, which is similar to the STEMI shockable ones (61%), refers to all the NSTEMI shockable (no distinction between PCI vs no PCI), which may be crucial in recommending angiography in this population.

We thank the reviewer for pointing out the differing wording which we have corrected in the revised version. However, there is one point in the wording which we would like to strengthen: we used the expression of NSTE-OHCA instead of NSTEMI, because it is very difficult and in many cases impossible after resuscitation to clarify by laboratory parameters alone (e.g. troponin) whether there is an myocardial infarction responsible for release of troponin and the “NSTEMI” is cause of arrest or whether the release of myocardial biomarkers is the consequence of arrest and resuscitation efforts. While patients with NSTEMI with subsequent arrest might have the chance to profit from coronary angiography it is very unlikely that patients with cardiac arrest not related to coronary ischaemia will have a benefit. We have elaborated that problem in the revised introduction section.

As requested, we modified the abstract to be in line with the final conclusion.

Moreover, it's not clear the purpose in citing the HYPERION trial (lines 293-294) in which there is no mention about the link between PCI-rate and in-hospital mortality rate

We agree with the reviewer that the focus of the HYPERION trial is on therapeutic hypothermia rather than on ECG and PCI and we have, therefore, removed the respective sentences.

Submitted filename: 20210309_Revision 1_HACORE ECG.docx

Click here for additional data file.

16 Apr 2021

PONE-D-21-01798R1

High rate of critical coronary stenosis in patients with Non-ST-elevation out-of-hospital cardiac arrest (NSTE-OHCA) – Experience from the HAnnover COoling REgistry (HACORE)

PLOS ONE

Dear Dr. Andreas Schäfer

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR:

Thank you very much for having addressed the majority of the  reviewers' comments.  However some uncovered issues still remain as highlighted by the reviewers.

The first is concerning your enrolling only patients who underwent to therapeutic hypothermia. I have no doubt that you apply therapeutic hypothermia  according to guidelines. However, by doing so you did not consider those patients resuscitated from an OHCA and not matching with the hypothermia indications after ROSC (e.g. the awake patients). So my advice for you is  either to acknowledge that as a limitation or to state clearly in the title that you are referring only to hypothermic patients. The second concerns is about the comparison in terms of survival between NSTE patients receiving or not a PCI . The p value required by reviewer#2 is of pivotal importance because some your statement are grounded on that.

==============================

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Academic Editor

PLOS ONE

Journal Requirements:

Additional Editor Comments (if provided):

Thank you very much for having addressed the majority of the reviewers' comments. However some uncovered issues still remain as highlighted by the reviewers.

The first is concerning your enrolling only patients who underwent to therapeutic hypothermia. I have no doubt that you apply therapeutic hypothermia according to guidelines. However, by doing so you did not consider those patients resuscitated from an OHCA and not matching with the hypothermia indications (e.g. not comatose patients). So my advice for you is either to acknowledge that as a limitation or to state clearly in the title that you are referring only to hypothermic patients. The second concerns is about the comparison in terms of survival between NSTE patients receiving or not a PCI . The p value required by reviewer#2 is of pivotal importance because some your statement are grounded on that.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Authors,

thank you so much for addressing the majority of my concerns.

I have few minor concerns:

- line 55: you stated that "arrhythmias" is a cause of OHCA of cardiac etiology. However, I believe that arrhythmias are the epiphenomen of an underlying heart disease. Or do you mean "primary arrhythmias" such as in LQTS, SdB and so on?

- line 58 and 61: "while urgent"... "while urgent", please rephrase

- line 69-70 "uninterrupted phase of therapeutic hypotermia following ICU admission": there are many demonstrations that coronary angiography can be performed during hypotermia, therefore the decision to perform coronary angiography before ICU admission cannot be based on this justification

Methods:

- line 106: as outlined in my previous revision, I believe that the fact that you included only patients who undergone to hypotermia has to be addressed as a limitation. In fact, following the guidelines, hypotermia is for unconscious patients after ROSC, therefore you excluded all the conscious patients after ROSC, and it is a limitation

Results:

- line 155: you state that 116 OHCA patients required mechanical supporto for cardiogenic shock (Table 1). However, in Table 1 if you add the patients with eCPR, those with Impella and those with vaECMO they are more than 116. Why?

Discussion

- line 226: change "during first rhythm control" in "shockable presenting rhythm"

- line 290-295: I'm aware that the COACT had selective inclusion criteria, but the trial was designed in that way and it is speculative to argue that someone wants to extrapolate the results of a trial (which has, by definition, inclusion and exclusion criteria) to the general population. It is like you argue to extrapolate the results of a trial about the use of Ticagrelor in STEMI patients to all the patients with cardiac ischemic disease.

- line 307-310: I believe that here you introduce a very important point that should be more highlighted, as the importance of a stop in Emergency Department to exclude non-cardiac cause, as reccomanded by 2015 ESC Guidelines on ventricular arrhythmias.

Reviewer #2: Why should routine early PCI be performed on patients with primary shockable rhythms during NSTE-OHCA if it is stated that the difference of survival between NSTE-OHCA patients with primarily shockable rhythm receiving PCI (56%) and those not requiring PCI (64%) was minor (p=??)? It seems that by performing PCI in these patients there is no survival benefit.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

20 Apr 2021

Response to Reviewer #1 Manuscript PONE-D-21-01798R1

We would like to thank the reviewer for his/her constructive criticism and valuable input. We hope that the changes made to the manuscript and the responses detailed below, satisfactorily address the concerns raised.

Dear Authors, thank you so much for addressing the majority of my concerns.

I have few minor concerns:

- line 55: you stated that "arrhythmias" is a cause of OHCA of cardiac etiology. However, I believe that arrhythmias are the epiphenomen of an underlying heart disease. Or do you mean "primary arrhythmias" such as in LQTS, SdB and so on?

Indeed, arrhythmias are in most cases considered an epiphenomenon of underlying heart disease as stated by the reviewer. We have stated this now more clearly as suggested (page 3).

- line 58 and 61: "while urgent"... "while urgent", please rephrase

We have modified the first sentence in order to remove the similar start of subsequent sentences as suggested by the reviewer (page 3).

- line 69-70 "uninterrupted phase of therapeutic hypotermia following ICU admission": there are many demonstrations that coronary angiography can be performed during hypotermia, therefore the decision to perform coronary angiography before ICU admission cannot be based on this justification

We do agree with the reviewer that it is technically feasible to perform coronary angiography during hypothermia. Nevertheless, we wanted to express that we intend to provide consecutive intensive care in general without requiring patients to be transported to other departments for diagnostic procedures such as coronary angiography or computed tomography. As described in Table 1, quite a number of patients are either on renal replacement therapy and/or mechanical circulatory support and unnecessary transports are kept to a minimum. We hope that the revised wording is clearer to understand and not as misleading as the previous one (page 3-4).

Methods:

- line 106: as outlined in my previous revision, I believe that the fact that you included only patients who undergone to hypotermia has to be addressed as a limitation. In fact, following the guidelines, hypotermia is for unconscious patients after ROSC, therefore you excluded all the conscious patients after ROSC, and it is a limitation

We now clarified the fact that all patients were still comatose and receiving hypothermia in the title, the patient population, and the limitations section. (pages 1, 5 & 18).

Results:

- line 155: you state that 116 OHCA patients required mechanical support for cardiogenic shock (Table 1). However, in Table 1 if you add the patients with eCPR, those with Impella and those with vaECMO they are more than 116. Why?

The overall number of patients on mechanical support was 116 as stated in the text. E.g. all eCPR patients are also included in the vaECMO line and several patients received vaECMO plus Impella (n=37 in total), which attributes to the higher number when adding eCPR, Impella and vaECMO. This has now been explained in more detail (page 7).

Discussion

- line 226: change "during first rhythm control" in "shockable presenting rhythm"

This has been changed as suggested (page 13).

- line 290-295: I'm aware that the COACT had selective inclusion criteria, but the trial was designed in that way and it is speculative to argue that someone wants to extrapolate the results of a trial (which has, by definition, inclusion and exclusion criteria) to the general population. It is like you argue to extrapolate the results of a trial about the use of Ticagrelor in STEMI patients to all the patients with cardiac ischemic disease.

We have rephrased that paragraph and now exclude the speculative part just stating that the overall NSTE-OHCA cohort included a large proportion of shock patients (page 16).

- line 307-310: I believe that here you introduce a very important point that should be more highlighted, as the importance of a stop in Emergency Department to exclude non-cardiac cause, as recommended by 2015 ESC Guidelines on ventricular arrhythmias.

We thank the reviewer for this suggestion and have quoted the 2015 ESC guideline as suggested (page 17).

Response to Reviewer #2 Manuscript PONE-D-21-01798

We would like to thank the reviewer for his/her constructive criticism and valuable input. We hope that the changes made to the manuscript and the responses detailed below, satisfactorily address the concerns raised.

Why should routine early PCI be performed on patients with primary shockable rhythms during NSTE-OHCA if it is stated that the difference of survival between NSTE-OHCA patients with primarily shockable rhythm receiving PCI (56%) and those not requiring PCI (64%) was minor (p=??)? It seems that by performing PCI in these patients there is no survival benefit.

We acknowledge this important remark by the reviewer, but due to the observational and non-interventional registry design, we believe that we should not draw this conclusion. We would be allowed to conclude like that, if we had identified NSTE-OHCA patients with primarily shockable rhythms who had relevant coronary stenosis and had them randomized to PCI vs conservative treatment. In our manuscript (and the registry), however, we have the group with relevant coronary stenosis receiving PCI (coronary artery disease as most probable cause of arrest) and the group without coronary stenosis treated conservatively (underlying heart disease with arrhythmic cause of arrest). Therefore, neither can we state that performing PCI provides a benefit nor that “performing PCI in these patients is without survival benefit”. We just compare to very different groups of patients.

Our primary intention was to describe the pattern of underlying disease in a cohort that received routine angiography. To enhance the discussion about the impact on outcome, we have now added the data on good neurological outcome as assessed by cerebral performance category ≤2 in addition to hospital survival and discharge in Figure 3, which now illustrates even more that initial rhythm seems to be more important for outcome than ST-segment elevation. Still, we cannot state that NSTE-OHCA patients receiving PCI have better outcomes than those not receiving PCI. However, we can illustrate that it is not the absence or presence of ST-elevations that is predictive for outcome, but rather the primary rhythm that is. As these patients’ potential outcome is not as futile as many think, we want to encourage the discussion about providing similar care regarding treatment of cardiac ischaemia as it is provided in STE-OHCA patients. This has been added to the discussion on page 16.

Nevertheless, the requested p-value has been added to the sentence on page 13.

Submitted filename: 20210416_Revision 2_HACORE ECG.docx

Click here for additional data file.

22 Apr 2021

High rate of critical coronary stenosis in comatose patients with Non-ST-elevation out-of-hospital cardiac arrest (NSTE-OHCA) undergoing therapeutic hypothermia – Experience from the HAnnover COoling REgistry (HACORE)

PONE-D-21-01798R2

Dear Dr. Andreas Schäfer

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Additional Editor Comments (optional):

Thank you very much for having addressed also the remaining issues. Now the message you want to deliver with your paper is more clear.

Reviewers' comments:

26 Apr 2021

PONE-D-21-01798R2

High rate of critical coronary stenosis in comatose patients with Non-ST-elevation out-of-hospital cardiac arrest (NSTE-OHCA) undergoing therapeutic hypothermia – Experience from the HAnnover COoling REgistry (HACORE)

Dear Dr. Schäfer:

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