Gender effect in survival after out-of-hospital cardiac arrest: A nationwide, population-based, case-control propensity score matched study based Korean national cardiac arrest registry.

OBJECTIVE: This study aimed to describe the relationship between sex and survival of patients with out-of-hospital cardiac arrest (OHCA) and further investigate the potential impact of female reproductive hormones on survival outcomes, by stratifying the patients into two age groups.
METHODS: This retrospective, national population-based observational, case-control study, included Korean OHCA data from January 1, 2009, to December 31, 2016. We used multiple logistic regression with propensity score-matched data. The primary outcome was survival-to-discharge.
RESULTS: Of the 94,160 patients with OHCA included, 34.2% were women. Before propensity score matching (PSM), the survival-to-discharge rate was 5.2% for females and 9.1% for males, in the entire group (OR 0.556, 95% CI [-0.526-0.588], P<0.001). In the reproductive age group (age 18-44 years), the survival-to-discharge rate was 14% for females and 15.6% for males (OR 0.879, 95% CI [0.765-1.012], P = 0,072) and in the post-menopause age group (age ≥ 55 years), the survival-to-discharge rate was 4.1% for females and 7% for males (OR 0.562, 95% CI [0.524-0.603], P<0.001). After PSM (28,577 patients of each sex), the survival-to-discharge rate was 5.4% for females and 5.4% for males (OR, 1.009 [0.938-1.085], P = 0.810). In the reproductive age group, the survival-to-discharge rate was 14.5% for females and 11.5% for males (OR 1.306, 95% CI [1.079-1.580], P = 0.006) and in the post-menopause age group, the survival-to-discharge rate was 4.2% for females and 4.6% for males (OR 0.904, 95% CI [0.828-0.986], P = 0.022). After adjustment for confounders, women of reproductive age were more likely to survive at hospital discharge. However, there was no statistically significant difference in neurological outcome (OR 1.238, 95% CI [0.979-1.566], P = 0.074).
CONCLUSIONS: Females of reproductive age had a better chance of survival when matched for confounding factors. Further studies using sex hormones are needed to improve the survival rate of patients with OHCA.

Introduction

Out-of-hospital cardiac arrest (OHCA) is a major cause of mortality worldwide. Approximately 350,000 Americans suffer OHCAs annually, with the overall survival rate being 12% in 2016 [1]; further, there have been approximately 29,800 OHCAs in Korea in 2016, with an overall survival rate of 7.6% [2].

Several investigators believe that there are sex-specific differences in survival outcomes in patients with OHCA. Reports regarding sex-based differences in outcomes are conflicting, with some studies showing comparable survival between both sexes [3, 4], and other studies showing comparable but better survival in females of reproductive age [5-8]. Certain studies have suggested that this difference is due to the protective effects of endogenous estrogen in females [9, 10]. Animal studies have shown that estrogen administration may improve cardiac arrest outcomes [11, 12]. Contrarily, some studies have reported that the OHCA survival rate among females in the reproductive age, was similar to that in males [13, 14]. Further research is required to explain these conflicting results.

A previous study [9] has reported differences in the baseline characteristics of women and men with OHCA. Compared with women, men were younger, were more likely to have witnessed OHCA, and had a higher frequency of bystander cardiopulmonary resuscitation (CPR) and initial shockable rhythm. In the present study, the basic differences in baseline characteristics between men and women were eliminated by propensity score matching, in order to determine the role of sex hormones in survival after OHCA. Furthermore, instead of sex hormone levels, the groups were divided into reproductive and non-reproductive age groups [9]. To date, no study has been conducted using a nationwide propensity score-matched data, to evaluate sex-specific survival after OHCA.

Our objective was to use a nationwide Korean population-based research database of OHCA, to describe the relationship between sex and survival in patients with OHCA, and further stratify them into two age groups [6, 7] for evaluation of the potential impact of female reproductive hormones on survival outcomes, using the propensity score matching (PSM) method to control covariates that produce selection bias.

Materials and methods

Study design and setting

This nationwide population-based observational study included 94,160 adult patients aged >17 years. In South Korea, 51.8 million people (2015 census) reside in an area of approximately 100,000 km2. The Korean emergency medical services (EMS) are a single-tier, government-provided system headed by the National Emergency Management Agency, which provides advanced cardiac life support (ACLS) and basic life support ambulance services throughout the 16 provincial headquarters.

The ambulance crew is trained to administer CPR and apply automatic external defibrillation at the scene and during transport; in limited cases, the ACLS-trained crew can also perform ACLS on-site under the direction of a physician. This includes administering intravenous fluids, inserting an endotracheal tube, and administering certain medications such as epinephrine and atropine, with the directions of a physician. Emergency medical technicians (EMTs) are not permitted to pronounce death, and they cannot stop CPR in the field unless return of spontaneous circulation (ROSC) occurs. Therefore, all OHCA patients who are treated by EMS personnel, are transported to the hospital emergency department (ED). There are situations in which CPR for cardiac arrest is not initiated at the scene or during ambulance transport. If the patient meets the eligibility criteria for withdrawal of resuscitation, then the EMTs are not permitted to start CPR. The criteria include prolonged arrest, decapitation or decomposition of the body, onset of rigor mortis, and livor mortis. The ED physicians can decide whether to continue or discontinue CPR, even in the setting of the EMS crew performing CPR during transport.

This study was approved by the institutional review boards of the participating institutions (IRB number: 2021-05-005), and the need for informed consent was waved.

Data collection and process

This study used a nationwide, population-based, EMS-assessed OHCA database covering the entire country [15, 16]. The database was built from ambulance-run sheets. Review of the run sheets was followed by a review of the subsequent hospitalization records for each patient. Database construction began in 2006, and the database is maintained at present (2020) with support from the Korean Centers for Disease Control and Prevention and the National Emergency Management Agency.

If apply for the use of raw data on the Korea Centers for Disease Control and Prevention site, OHCA data can be used with the consent of the official. The database comprises geographical and sociodemographic data, location of the cardiac arrest, elapsed time variables associated with resuscitation efforts (response time and transport time), content of treatments, and destination hospitals. A Korean Centers for Disease Control and Prevention expert who is trained in medical record review is responsible for reviewing the hospital records. The review form has been modeled on the Utstein-style report form and was customized for this study setting [3].

Selection and description of participants

All patients included in this study were adults with OHCA, >17 years, and with presumed cardiac etiology. OHCA cases from January 1, 2009, to December 31, 2016, were reviewed. Patients having arrests due to trauma, drowning, asphyxia, hanging, or other obvious non-cardiac causes were excluded. Exclusion criteria were based on the definition of the Utstein taxonomy. The characteristics included in the dataset were as follows: patient’s sex and age, place of arrest (home vs. outside of home), presence of bystander witnesses, maneuver of bystander CPR, initially identified cardiac rhythm (shockable vs. non-shockable), use of prehospital defibrillation, presence of ROSC, result of ED treatment, result of hospital treatment, and neurological status at discharge. Neurological status was defined using the Cerebral Performance Category (CPC) scale scores (1, good cerebral performance; 2, moderate cerebral disability; 3, severe cerebral disability; 4, coma or vegetative state; and 5, death) [17].

Outcome measure

Survival-to-hospital discharge (discharged alive/remained in-hospital 30 days post-arrest) was the primary outcome. Secondary outcomes were ROSC at the scene or in the ED, survival-to-hospital admission, and survival with good neurological status with an overall post-arrest CPC scale score of 1 or 2.

Statistical analysis

Continuous variables are presented as mean and standard deviation. Categorical variables are presented as numbers and percentages. Patients were divided into two groups (male and female). To compare the two groups, Student’s t-test was used for continuous variables and the chi-square test was used for categorical variables. To eliminate the effect of confounding variables that influence outcome variables, when analyzing basic characteristics, the PSM method was used to collect data in both groups. Women patients were matched 1:1 with male patients according to the propensity score, using exact matching. To assess bias reduction in the PSM method, absolute standardized differences were calculated, with a value of >20%, indicating a significant imbalance in the baseline covariate. Using matched data, differences between male and female outcome variables were analyzed again. If significant variables were found on comparing the matched data of both sexes, then multivariate logistic regression analysis was performed with these significant variables. In Korea, the mean age for natural menopause in women is approximately 49 years [18]. Although there are other age group definitions defined for reproductive age, studies have consistently used the age range of 18–44 years as measurement of reproductive age [19]. We also analyzed two subgroups, aged 18–44 years and ≥55 years (excluding the peri-menopausal group aged 45–54 years), to assess the association between estrogen exposure and survival [7, 13, 20].

All statistical analyses were performed using R software (version 3.6.2 0 (R Foundation for Statistical Computing, Vienna, Austria). P-values were based on a two-sided significance level of 0.05.

Results

Characteristics of study subjects

Total 214,954 patients of OHCA were identified in this study from January 1, 2009, to December 31, 2016. Patients with arrests due to trauma or of unknown origin (n = 57,153), no resuscitation attempted by EMS (n = 47,752), arrests of non-cardiac etiology (n = 10,181), under 18 years of age (n = 5,308) and having no age records (n = 400) were excluded from the study. Finally, 94,160 patients were included. There were 8,465 patients between 18 and 44 years and 72,119 patients in the age group of 55 years and above (Fig 1).

Fig 1

Inclusion and exclusion flow chart.

We had excluded patient step by step from top to above.

Patient matching was achieved in 61.1% (57,514 of 94,160) of all patients, 44.9% (3,798 of 8,465) in those aged 18–44 years, and 67.6% (48,756 of 72,119) in those aged over 55 years (Fig 2).

Fig 2

Inclusion after propensity score matching.

Main results

This study found that women (N = 32,345) had much less OHCA than men (N = 61,915), were older than men and their OHCA occurred more at home than outside of home. They were less likely, to experience a witnessed arrest, have an initial shockable rhythm, receive bystander CPR, and prehospital defibrillation (Table 1).

Table 1

Characteristics of patients with out-of-hospital arrest by sex (total number = 94,160).

Variables	Male (N = 61,915)	Female (N = 32,245)	P-value	Standardized difference
Age (mean ± SD)	63.6 ± 14.8	71.7 ± 15.2	<0.001	3.63664
Place of arrest			<0.001	−0.12886
Home residence	32,749 (60.8)	19,142 (67)
Outside of home	21,108 (39.2)	9,435 (33)
Witnessed arrest	32,825 (53)	16,278 (50.5)	<0.001	−0.05072
Bystander CPR	9,543 (15.4)	4,340 (13.5)	<0.001	−0.05561
Initial shockable rhythm	7,811 (12.6)	1,917 (5.9)	<0.001	−0.23142
Prehospital defibrillation	11,118 (18)	3,032 (9.4)	<0.001	−0.25087
ROSC at scene or ED	4,719 (7.6)	1,490 (4.6)	<0.001
Survival-to-admission	15,631 (25.2)	6,733 (20.9)	<0.001
Survival-to-discharge	5,609 (9.1)	1,692 (5.2)	<0.001
CPC 1 or 2	3,259 (5.3)	784 (2.4)	<0.001

SD, standard deviation; CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation; ED, emergency department; CPC, cerebral performance category

In the subgroup aged 18–44 years, women were younger, more likely to experience OHCA at home, less likely to be witnessed, have an initial shockable rhythm, and receive bystander CPR and prehospital defibrillation, than men. In the age group of 55 years and above, women were older, more likely to experience OHCA at home, less likely to be witnessed, have an initial shockable rhythm, and receive bystander CPR and prehospital defibrillation, than men (Table 2).

Table 2

Characteristics of patients with out-of-hospital arrest by age group and sex.

Variables	18–44 years (Total number = 8,465)				≥ 55 years (Total number = 72,119)
	Male (N = 6,332)	Female (N = 2,133)	P-value	Standardized difference	Male (N = 44,626)	Female (N = 27,493)	P-value	Standardized difference
Age (mean ± SD)	36.3 ± 6.9	35.2 ± 7.4	<0.001	−2.10271	70.8 ± 9.5	76.6 ± 9.6	<0.001	6.38088
Place of arrest			<0.001	−0.24259			<0.001	−0.08971
Home residence	3,175 (58)	1,322 (69.6)			24,254 (62.2)	16,211 (66.5)
Outside of home	2,295 (42)	577 (30.4)			14,737 (37.8)	8,167 (33.5)
Witnessed arrest	3,540 (55.9)	1,097 (51.4)	<0.001	−0.08986	23,274 (52.2)	13,486 (50.4)	<0.001	−0.03584
Bystander CPR	1,199 (18.9)	362 (17)	0.043	−0.05119	6,527 (14.6)	3,598 (13.1)	<0.001	−0.04455
Initial shockable rhythm	1,299 (20.5)	247 (11.6)	<0.001	−0.24525	4,526 (10.1)	1,396 (5.1)	<0.001	−0.19187
Prehospital defibrillation	1,721 (27.2)	360 (16.9)	<0.001	−0.25051	6,642 (14.9)	2,256 (8.2)	<0.001	−0.21012
ROSC at scene or ED	787 (12.4)	248 (11.6)	0.328		2,694 (6)	1,001 (3.6)	<0.001
Survival-to-admission	2,012 (31.8)	795 (37.3)	<0.001		10,136 (22.7)	5,031 (18.3)	<0.001
Survival-to-discharge	987 (15.6)	298 (14)	0.072		3,131 (7)	1,119 (4.1)	<0.001
CPC 1 or 2	681 (10.8)	185 (8.7)	0.006		1,572 (3.5)	430 (1.6)	<0.001

SD, standard deviation; CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation; ED, emergency department; CPC, cerebral performance category

After matching male and female patients, we were able to analyze 28,577 pairs of patients over 18 years of age, 1,899 pairs of patients aged between 18 and 44 years, and 24,378 pairs of patients over 55 years of age. After matching data for the group of patients over 18 years of age, a comparison between the sexes showed differences in the age, place of arrest, and initial shockable rhythm variables. The outcome variables showed no difference between men and women (Table 3).

Table 3

Characteristics of patients with out-of-hospital arrest by sex after propensity score matching (total number = 57,514).

Variables	Male (N = 28,577)	Female (N = 28,577)	P-value	Standardized difference
Age (mean ± SD)	70.5 ± 14.2	71.8 ± 15.2	<0.001	0.58629
Place of arrest			<0.001	0.05125
Home residence	19824 (69.4)	19142 (67)
Outside of home	8753 (30.6)	9435 (33)
Witnessed arrest	14632 (51.2)	14547 (50.9)	0.477	−0.00595
Bystander CPR	4099 (14.3)	4061 (14.2)	0.65	−0.00381
Initial shockable rhythm	1580 (5.5)	1699 (5.9)	0.032	0.01791
Prehospital defibrillation	2584 (9)	2693 (9.4)	0.115	0.01317
ROSC at scene or ED	1189 (4.2)	1276 (4.5)	0.073
Survival-to-admission	5782 (20.2)	5951 (20.8)	0.08
Survival-to-discharge	1553 (5.4)	1540 (5.4)	0.810
CPC 1 or 2	688 (2.3)	713 (2.5)	0.22

SD, standard deviation; CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation; ED, emergency department; CPC, cerebral performance category

The matched data for the 18–44 age group of patients, showed no statistically significant variables, on comparison between men and women. The outcome variables showed that women were more likely to have ROSC at the scene or in the ED and had a better rate of survival to admission and discharge. No significant difference in good post-arrest CPC scale score was found between men and women. In patients aged 55 years and older, women were older than men and were more likely to have a cardiac arrest at home and an initial shockable rhythm. Women were less likely to survive admission and discharge (Table 4).

Table 4

Characteristics of patients with out-of-hospital arrest by age group and sex after propensity score matching.

Variables	18–44 years (Total number = 3,798)				≥ 55 years (Total number = 48,756)
	Male (N = 1,899)	Female (N = 1,899)	P-value	Standardized difference	Male (N = 24,378)	Female (N = 24,378)	P-value	Standardized difference
Age (mean ± SD)	35.3 ± 7.3	35.2 ± 7.4	0.68	−0.18251	75.3 ± 8.6	76.7 ± 9.6	<0.001	1.70111
Place of arrest				0.01032			<0.001	0.03472
Home residence	1,331 (70.1)	1,322 (69.6)	0.75		16,608 (68.1)	16,211 (66.5)
Outside of home	568 (29.9)	577 (30.4)			7,770 (31.9)	8,167 (33.5)
Witnessed arrest	973 (51.2)	980 (51.6)	0.82	0.00737	12,443 (51)	12,388 (50.8)	0.618	−0.00451
Bystander CPR	319 (16.8)	336 (17.7)	0.465	0.02369	3,420 (14)	3,378 (13.9)	0.583	−0.00497
Initial shockable rhythm	219 (11.5)	222 (11.7)	0.879	0.00493	1,139 (4.7)	1,239 (5.1)	0.036	0.01904
Prehospital defibrillation	322 (17)	324 (17.1)	0.931	0.00281	1,924 (7.9)	2,004 (8.2)	0.183	0.01205
ROSC at scene or ED	152 (8)	214 (11.3)	0.001		894 (3.7)	854 (3.5)	0.33
Survival-to-admission	498 (26.2)	710 (37.4)	<0.001		4,611 (18.9)	4,437 (18.2)	0.043
Survival-to-discharge	218 (11.5)	275 (14.5)	0.006		1,115 (4.6)	1,012 (4.2)	0.022
CPC 1 or 2	138 (7.3)	168 (8.8)	0.074		409 (1.7)	391 (1.6)	0.521

SD, standard deviation; CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation; ED, emergency department; CPC, cerebral performance category

Since there were differences between both the sexes in the matched data, multivariate logistic regression analysis was performed to eliminate the confounding effect. The subgroup of patients aged 18–44 years showed no differences between men and women; therefore, there was no need to perform multiple logistic regression analysis. After adjustment for other confounders (age, place of arrest, and initial shockable rhythm), women had a higher rate of survival to admission for patients over 18 years than men. For patients aged > 55 years, women showed no differences in outcomes (Table 5).

Table 5

Adjusted logistic model with propensity score matching data.

Primary outcomes		≥ 18 years (Total number = 57,514)		≥ 55 years (Total number = 48,756)
	Variables	Odds ratio (95% CI)	P-value	Odds ratio (95% CI)	P-value
ROSC at scene or ED
Age (increasing 1 year)		0.976 (0.974–0.979)	<0.001	0.967 (0.962–0.972)	<0.001
Outside of home (vs. home residence)		2.019 (1.853–2.2)	<0.001	2.051 (1.856–2.267)	<0.001
Initial shockable rhythm (vs. non initial shockable rhythm)		10.093 (9.921–11.981)	<0.001	10.373 (9.263–11.617)	<0.001
Women (vs. men)		1.076 (0.988–1.172)	0.093	0.952 (0.862–1.052)	0.333
Survival-to-admission
Age (increasing 1 year)		0.978 (0.976–0.979)	<0.001	0.967 (0.965–0.97)	<0.001
Outside of home (vs. home residence)		1.796 (1.72–1.876)	<0.001	1.785 (1.701–1.873)	<0.001
Initial shockable rhythm (vs. non initial shockable rhythm)		3.868 (3.592–4.166)	<0.001	3.326 (3.05–3.626)	<0.001
Women (vs. men)		1.044 (1.001–1.089)	0.045	0.976 (0.932–1.023)	0.315
Survival-to-discharge
Age (increasing 1 year)		0.969 (0.967–0.972)	<0.001	0.953 (0.949–0.958)	<0.001
Outside of home (vs. home residence)		2.312(2.142–2.497)	<0.001	2.367 (2.162–2.591)	<0.001
Initial shockable rhythm (vs. non initial shockable rhythm)		8.159 (7.456–8.929)	<0.001	6.881 (6.154–7.693)	<0.001
Women (vs. men)		0.988 (0.915–1.067)	0.752	0.914 (0.835–1.001)	0.052
CPC 1 or 2
Age (increasing 1 year)		0.958 (0.955–0.961)	<0.001	0.930 (0.923–0.937)		<0.001
Outside of home (vs. home residence)		2.254 (2.006–2.532)	<0.001	2.604 (2.243–3.024)		<0.001
Initial shockable rhythm (vs. non initial shockable rhythm)		15.369 (13.664–17.287)	<0.001	13.882 (11.922–16.164)		<0.001
Women (vs. men)		1.082 (0.964–1.215)	0.182	0.963 (0.831–1.116)		0.620

CI, confidence interval; ROSC, return of spontaneous circulation; ED, emergency department; CPC, cerebral performance category

Discussion

In this large nationwide, population-based observational study, male patients generally had better survival outcomes. The incidence of OHCA in men was higher than that in women, which is consistent with another national registry [10, 20]. This could be explained by the higher prevalence of cardiovascular disease and lifestyle risk factors in men [21]. Many studies have shown that survival outcomes differ between the sexes, although the findings are somewhat contradictory [14, 22–25].

Before PSM, survival outcome in women was worse than men in OHCA. This could be explained by the poor prognostic characteristics of OHCA in women, such as older age, higher occurrence of arrest at home, lower witnessed arrest, bystander CPR, initial shockable rhythm, and prehospital defibrillation [9, 26]. A previous study suggested that OHCA was more likely to occur at home in female patients, who were admitted with a negative prognosis [27]. Female patients tended to have a low survival rate due to less prehospital resuscitation efforts and the social norms of a community in attempting chest compression or defibrillation in women [3]. Female patients tended to have a lower initial shockable rhythm (ventricular fibrillation or pulseless ventricular tachycardia) than male patients; moreover, the presence of ventricular fibrillation is known to show a better prognosis than that of asystole or pulseless electrical activity, according to the latest studies [27].

In the comparison of reproductive age group (18–44 years old) of present study, there were many factors that men had a better effect on survival except being slightly older than women [20]. In other words, men had more OHCA in public places than women, and received more bystander CPR by witnesses. The initial cardiac rhythm was also subjected to more defibrillation caused by the shockable rhythm. Nevertheless, there was no difference between men and women in ROSC at scene or ED and survival-to-discharge, and survival-to-admission was higher for women. Although men have better survival factors, the failure to show better results than women seems to indicate that there are physiological differences between men and women. In menopausal women (over 55 years old), the results were similar to the all age group analyses.

After PSM, the confounding effect of three Utstein variables, that excluded the variables of age, place of arrest, and initial shockable rhythm, were eliminated for patients of all age and over 55 years groups. In the subgroup of patients aged between 18 and 44 years, all Utstein variables were matched without differences. In the all age and over 55 years groups, multiple logistic regression analyses were used to eliminate confounding effects, which were the unmatched variables. Women in the all age group (≥18 years) had a better rate of survival to admission in the final adjusted logistic model with PSM data. Hubert et al. [23] demonstrated the same results as ours, but Ng et al. [20] reported different results. In the final adjusted logistic model, the subgroup of patients over 55 years old, had no difference in survival outcomes, which was consistent with the findings of a previous study [23]. In the reproductive age group (18–44 years), in which all variables, except for good post-arrest CPC scale score variable, were matched, women had better rates of ROSC at the scene or in the ED, survival-to-admission, and survival-to-discharge. Previous studies have also shown similar results to ours [20, 23].

Physiological differences between male and female sex hormones have already been described to affect the survival rates in patients with OHCA, in the reproductive age group. Sex hormones not only have reproductive roles but are also cardioprotective and neuroprotective [28, 29]. Estrogen has a cardioprotective effect after a cardiac arrest and mediates hormonal responses in ischemia–reperfusion injuries in women of childbearing age [12, 30–32]. Although the mechanism of protection remains unclear, it appears to be related to reduced levels of lipoprotein (a) and inhibition of the oxidation of low-density lipoprotein. In animal models, estrogen was found to protect against OHCA by binding to the estrogen receptor on vascular cells and initiating the production of nitric oxide, which is required for the maintenance and repair of vascular endothelium and dilatation of vascular smooth muscle [33]. Estrogen reportedly slows down the progression of brain injury and diminishes the extent of cell death by suppressing apoptotic pathways [34]. In our study, however, no significant difference in neurological outcome of a good post-arrest CPC scale score, was observed between male and female patients. It is thought that further research will be needed on this point.

Limitations

This study has some limitations. First, the study could not exclude uncontrolled confounders such as sex hormone levels, due to the retrospective observational and non-randomized design. Another limitation is that there may be unmeasured confounders that could have affected the association between sex and outcome. Moreover, sex hormone levels such as those of estrogen and progesterone, were not measured in this study, and age groups were used as substitutes for hormonal levels in women.

Second, socioeconomic data were not included. This study was unable to identify the underlying socioeconomic implications of gender for OHCA results because it focused on pre-hospital factors, and socioeconomic data were not available. If differences in socioeconomic levels between men and women existed, then this would have been a confounding variable.

Third, we did not include underlying diseases such as hypertension and diabetes in patients with OHCA. Clearly, the presence or absence of an underlying disease can affect survival.

Finally, even in the PSM analysis, we are unable to exclude numerous unknown confounding factors that may mislead the sex-specific differences in outcomes after OHCA. Other limitations are common to epidemiological studies, including ascertainment bias and lack of data integrity and validity.

Conclusion

This Korean nationwide OHCA study showed that women in the reproductive age group had better survival outcome after OHCA, when matched for confounding factors (age, location, witness and bystander presence, initial cardiac rhythm, and prehospital defibrillation). However, neurological outcomes post arrest, did not differ between men and women. Menopausal women also showed no difference in survival and neurological outcomes. On the basis of the results of this study, further studies on sex hormones are required to improve the survival rate in patients with OHCA.

27 Aug 2021

PONE-D-21-23845

Gender effect in survival after out-of-hospital cardiac arrest: a nationwide, population-based, case-control propensity score matched study based Korean National Cardiac Arrest registry.

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Academic Editor

PLOS ONE

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5. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

- https://journals.lww.com/euro-emergencymed/Abstract/2021/01000/Effect_of_gender_on_out_of_hospital_cardiac_arrest.12.aspx

- https://ccforum.biomedcentral.com/articles/10.1186/s13054-019-2547-x

The text that needs to be addressed involves the Discussion and Limitations sections.

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."

Additional Editor Comments:

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Reviewers' comments:

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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: Partly

Reviewer #2: Yes

**********

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: Yes

Reviewer #2: No

**********

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Reviewer #1: No

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: The manuscript reported results from a propensity score matching analysis on differences in out of hospital cardiac arrest outcome according to the gender. Authors reported how in the reproductive age females have a better survival outcome than males. Meanwhile, in post-menopausal age group no differences in outcome were reported.

I have some comments for the authors:

- In the objectives of the study authors reported that they aim to analyse differences in the outcome on a gender basis, and considering subgroups of females’age. However in the abstract the results of the study were only partially reported. Particularly, results of th comparison among males and females in the post-menopausal subgroup are not reported.

- How can the authors explain the absence of significant differences in OHCA clinical presentation between males and females in reproductive age? I think that this point should be better addressed in the Discussion

- At the beginning of the discussion, authors mentioned the incidence of OHCA in their population but in the results’ session there was no reported any analysis on incidence of OHCA, thus this period should be removed from the Discussion.

- In general I found the Discussion a bit confusing, authors referred to previous studies that are in disagree with their findings but not provide a possible explanation of this disagreement

- Page 11: “Before PSM, several factors had low survival outcomes in women”. This sentence has no sense, please amend it.

Reviewer #2: Thank you for the opportunity to review your manuscript entitled "Gender effect in survival after out-of-hospital cardiac arrest: a nationwide, population-based, case-control propensity score matched study based Korean National Cardiac Arrest registry".

First of all, I would like to suggest you specify the total word count at the beginning of the manuscript and insert line numbers to make it easier to review and to correct any mistake.

Specific comments:

Abstract

-Please remove the comma between "OR" and the value. Moreover, you should write "95% CI" before the interval and at the end the p-value inside the brackets when you present your results.

Materials and Methods

-Interesting description of your EMS setting, thank you.

-Has this study an approval from the ethics committee? If yes, you should specify.

Results

-Consider rephrasing: "From January 1, 2009, to December 31, 2016 a total of 214,954 patients with OHCA were identified

from the OHCA database".

-The description of inclusion and exclusion flow chart is not very clear. Considering the numbers, it seems that no patient excluded from the study has more than one excluding criteria (i.e., under 18 years old with arrest due to trauma). Moreover, you should specify what you mean with "arrest of non-cardiac etiology", because also an arrest due to trauma has not cardiac etiology.

-Consider changing inclusion and exclusion flow chart (Fig.1): you should separate the chart about 18-44 years and >=55 years in the main flow chart you should only specify the number of female and male of the 94,160 patients included.

Discussion

-Consider changing every semicolon to punctuation in the paragraph "A previous study suggested that OHCA was more likely to occur at home in female patients (...) the presence of ventricular fibrillation is known to show a better prognosis than that of asystole or pulseless electrical activity, according to the latest studies".

-Add a punctuation at the end of the sentence "In menopausal women (over 55 years old), the results were similar to the all age group analyses".

**********

6. 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.

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Reviewer #1: No

Reviewer #2: No

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18 Sep 2021

The manuscript reported results from a propensity score matching analysis on differences in out of hospital cardiac arrest outcome according to the gender. Authors reported how in the reproductive age females have a better survival outcome than males. Meanwhile, in post-menopausal age group no differences in outcome were reported. I have some comments for the authors:

Dear reviewer.

Thank you for giving us the opportunity to submit a revised draft of the manuscript. We appreciate the effort you and you have devoted to providing your valuable feedback on the manuscript. We are thankful to you for your insightful comments on the paper. We have been able to incorporate changes to reflect the suggestions provided by you.

Here is a point-by-point response to your comments and concerns.

1. In the objectives of the study authors reported that they aim to analyse differences in the outcome on a gender basis, and considering subgroups of females’age. However in the abstract the results of the study were only partially reported. Particularly, results of th comparison among males and females in the post-menopausal subgroup are not reported.

Thank you for your advice. We had added result of analysis of comparison among males and females in the post-menopausal subgroup in the result of abstract section.

2. How can the authors explain the absence of significant differences in OHCA clinical presentation between males and females in reproductive age? I think that this point should be better addressed in the Discussion

We totally agree with you. We had added more discussion about this point in the third paragraph of discussion.

3. At the beginning of the discussion, authors mentioned the incidence of OHCA in their population but in the results’ session there was no reported any analysis on incidence of OHCA, thus this period should be removed from the Discussion.

The following contents were added at the beginning of the main results.

�  This study found that women (N=32,345) had much less OHCA than men (N=61,915), were older than men and their OHCA occurred more at home than outside of home. They were less likely, to experience a witnessed arrest, have an initial shockable rhythm, receive bystander CPR, and prehospital defibrillation

4. In general I found the Discussion a bit confusing, authors referred to previous studies that are in disagree with their findings but not provide a possible explanation of this disagreement

In the previous study, we found that there were many opinions on the inconsistency of results. I think the discrepancy in previous studies was probably due to different analysis methods from other patient groups. Several statistical techniques were used to eliminate the limitations of the analysis presented in previous studies, such as confounding effects, as much as possible. First of all, selection bios were eliminated using the entire population data of Korea, and the PSM method was used to eliminate gender differences

5. Page 11: “Before PSM, several factors had low survival outcomes in women”. This sentence has no sense, please amend it.

Thank you for your comment. We had changed sentence as below.

Before PSM, survival outcome in women was worse than men in OHCA

Thank you for your kind comments and advice. Our manuscript has improved due to your thoughtful comments.

We look forward to hearing from you in due time regarding our submission.

Reviewer #2: Thank you for the opportunity to review your manuscript entitled "Gender effect in survival after out-of-hospital cardiac arrest: a nationwide, population-based, case-control propensity score matched study based Korean National Cardiac Arrest registry".

Dear reviewer.

Thank you for giving us the opportunity to submit a revised draft of the manuscript. We appreciate the effort you and you have devoted to providing your valuable feedback on the manuscript. We are thankful to you for your insightful comments on the paper. We have been able to incorporate changes to reflect the suggestions provided by you.

Here is a point-by-point response to your comments and concerns.

First of all, I would like to suggest you specify the total word count at the beginning of the manuscript and insert line numbers to make it easier to review and to correct any mistake.

Thank you

Specific comments:

Abstract

-Please remove the comma between "OR" and the value. Moreover, you should write "95% CI" before the interval and at the end the p-value inside the brackets when you present your results.

Materials and Methods

-Interesting description of your EMS setting, thank you.

Thank you for your kind compliment.

-Has this study an approval from the ethics committee? If yes, you should specify.

Thank you for your advice. This study was approved by the institutional review boards of the participating institutions (IRB number: 2021-05-005), and the need for informed consent was waved. We additionally mention this in front of method section as bellow

This study was approved by the institutional review boards of the participating institutions (IRB number: 2021-05-005), and the need for informed consent was waved.

Results

-Consider rephrasing: "From January 1, 2009, to December 31, 2016 a total of 214,954 patients with OHCA were identified

from the OHCA database".

Thank you for your advice, we had changed sentence as below

“Total 214,954 patients of OHCA were identified in this study from January 1, 2009, to December 31, 2016.”

-The description of inclusion and exclusion flow chart is not very clear. Considering the numbers, it seems that no patient excluded from the study has more than one excluding criteria (i.e., under 18 years old with arrest due to trauma). Moreover, you should specify what you mean with "arrest of non-cardiac etiology", because also an arrest due to trauma has not cardiac etiology.

Thank you for your advice. We had excluded patients step by step. Therefore, there might be some patients who had more than one exclusion criteria. However, these patients had been banned in the previous step already. For example, a patient under 18 years old with arrest due to trauma had excluded in exclusion of patient in arrest due to trauma. We had added these contents in figure 1 legend as below.

-Consider changing inclusion and exclusion flow chart (Fig.1): you should separate the chart about 18-44 years and >=55 years in the main flow chart you should only specify the number of female and male of the 94,160 patients included.

I totally agree with your point. We had changed figure 1 as following and clarify the separation of patients.

Submitted filename: Response to Reveiwer2.docx

Click here for additional data file.

4 Oct 2021

Gender effect in survival after out-of-hospital cardiac arrest: a nationwide, population-based, case-control propensity score matched study based Korean National Cardiac Arrest registry.

PONE-D-21-23845R1

Dear Dr. MYUNG CHUN KIM

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Simone Savastano

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you very much for having addressed all the comments of the reviewers.

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: All comments have been addressed

**********

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: Yes

**********

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: Yes

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: (No Response)

Reviewer #2: Thank you for addressing all the comments in a satisfying way, I really appreciate the changes. I have no further comments.

**********

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

3 May 2022

PONE-D-21-23845R1

Gender effect in survival after out-of-hospital cardiac arrest: a nationwide, population-based, case-control propensity score matched study based Korean National Cardiac Arrest registry.

Dear Dr. Kim:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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