Differential Survival for Men and Women from Out-of-hospital Cardiac Arrest Varies by Age: Results from the OPALS Study

The effect of sex on survival in out-of-hospital cardiac arrest (OHCA) is controversial. Some studies report more favorable outcomes in women, while others suggest the opposite, citing disparities in care. Whether sex predicts differential age-specific survival is still uncertain. The objective was to study the sex-associated variation in survival to hospital discharge in OHCA patients as well as the relationship between age and sex for predicting survival. The Ontario Prehospital Advanced Life Support (OPALS) registry, collected in a large study of rapid defibrillation and advanced life support programs, is Utstein-compliant and has data on OHCA patients (1994 to 2002) from 20 communities in Ontario, Canada. All adult OHCAs not witnessed by emergency medical services (EMS) and treated during one of the three main OPALS phases were included. Clinically significant variables were chosen a priori (age, sex, witnessed arrest, initial cardiopulmonary resuscitation [CPR], shockable rhythm, EMS response interval, and OPALS study phase) and entered into a multivariable logistic regression model with survival to hospital discharge as the outcome, with sex and age as the primary risk factors. Fractional polynomials were used to explore the relationship between age and survival by sex. A total of 11,479 (out of 20,695) OPALS cases met inclusion criteria and 10,862 (94.6%) had complete data for regression analysis. As a group, women were older than men (median age = 74 years vs. 69 years, p < 0.01), had fewer witnessed arrests (43% vs. 49%; p < 0.01), had fewer initial ventricular fibrillation/ventricular tachycardia rhythms (24% vs. 42%; p < 0.01), had a lower rate of bystander CPR (12% vs. 17%; p < 0.01), and had lower survival (1.7% vs. 3.2%; p < 0.01). Survival to hospital admission and return of spontaneous circulation did not differ between women and men (p > 0.05). The relationship between age, sex, and survival to hospital discharge could not be analyzed in a single regression model, as age did not have a linear relationship with survival for men, but did for women. Thus, age was kept as a continuous variable for women but was transformed for men using fractional polynomials [ln(age) + age3]. In sex-stratified regression models, the adjusted probability of survival for women decreased as age increased (adjusted odds ratio = 0.88, 95% confidence interval = 0.81 to 0.96, per 5-year increase in age) while for men, the probability of survival initially increased with age until age 65 years and then decreased with increasing age. Women had a higher probability of survival until age 47 years, after which men maintained a higher probability of survival. Overall OHCA survival for women was lower than for men in the OPALS study. Factors related to the sex differences in survival (rates of bystander CPR and shockable rhythms) may be modifiable. The probability of survival differed across age for men and women in a nonlinear fashion. This differential influence of age on survival for men and women should be considered in future studies evaluating survival by sex in OHCA population. El efecto del género en la supervivencia de la parada cardiaca extrahospitalaria (PCEH) es controvertido. Algunos estudios documentan resultados más favorables en las mujeres, mientras que otros sugieren lo contrario, citando disparidades en la atención. Está todavía poco claro si el género predice una diferente supervivencia en función de la edad. Estudiar la variación asociada al género en la supervivencia al alta hospitalaria en los pacientes con una PCEH así como la relación entre la edad y el género para predecir la supervivencia. El registro Ontario Prehospital Advanced Life Support (OPALS) es un gran estudio que recoge los resultados de programas de desfibrilación rápida y de soporte vital avanzado de acuerdo al método Utstein y tiene datos de los pacientes con PCEH (1994 a 2002) de 20 comunidades de Ontario, en Canadá. Se incluyeron todos los adultos con PCEH no presenciada por los servicios de emergencias extrahospitalaria (SEM) y tratados durante una de las tres principales fases del OPALS. Las variables clínicamente significativas se eligieron a priori (edad, sexo, parada presenciada, resucitación cardiopulmonar (RCP) inicial, ritmo desfibrilable, intervalo de respuesta del SEM, y fase del estudio OPALS) y se introdujeron en un modelo de regresión logística multivarible con la supervivencia al alta hospitalaria como resultado, y con el sexo y la edad como los factores de riesgo principales. Se utilizaron polinomios fraccionarios para explorar la relación entre la edad y la supervivencia en función del género. Un total de 11.479 de los 20.695 casos OPALS cumplieron los criterios de inclusión y 10.862 (94,6%) tuvieron todos los datos para el análisis de regresión. Como grupo, las mujeres fueron de mayor edad que los varones (mediana de edad 74 vs. 69 años, p < 0,01), tuvieron menos paradas presenciadas (43% vs. 49%; p < 0,01), tuvieron menores ritmos de taquicardia/fibrilación ventricular iniciales (24% vs. 42%; p < 0,01), tuvieron menor frecuencia de RCP por testigos (12% vs. 17%; p < 0,01) y menor supervivencia (1,7% vs. 3,2%; p < 0,01). La supervivencia hasta el ingreso en el hospital y el retorno a la circulación espontánea no difirió entre las mujeres y los varones (p>0,05). La relación entre la edad, el sexo y la supervivencia hasta el alta hospitalaria no pudo analizarse en un modelo de regresión simple, debido a que la edad no tenía un relación lineal con la supervivencia para los varones pero si para las mujeres. Así, la edad se mantuvo como una variable continua para las mujeres pero se transformó para los varones mediante los polinomios fraccionales [ln(edad) + edad3]. En los modelos de regresión estratificados por el género, la probabilidad ajustada de la supervivencia para las mujeres disminuyó según se incrementó la edad (razón de ventajas ajustada = 0,88; [IC95% = 0,81 a 0,96] por cada incremento de 5 años de edad) mientas que para los varones la probabilidad de supervivencia inicial se incrementó con la edad hasta los 65 años de edad y después decreció con el incremento de la edad. Las mujeres tuvieron una mayor probabilidad de sobrevivir hasta los 47 años tras la cual los varones mantuvieron una mayor probabilidad de supervivencia. La supervivencia global para las mujeres fue menor que para los varones en el estudio OPALS. Los factores relacionados con las diferencias de género en la supervivencia (porcentajes de RCP por testigos y ritmos desfibrilables) pueden ser modificables. La probabilidad de supervivencia difirió con la edad entre los varones y las mujeres, y lo hizo de un forma no lineal. Esta influencia diferencial de la edad en la supervivencia para los varones y las mujeres debería ser considerada en futuros estudios que evalúen la supervivencia según el género en la población que sufre una PCEH. Each year, there are approximately 359,400 out-of-hospital cardiac arrests (OHCAs) assessed by emergency medical services (EMS) in the United States.1, 2 Despite considerable advancement in medical care, survival rates for these patients have remained relatively static at 7.6% over the past three decades.3 This is surprising as 85% of these arrests are attributed to coronary artery disease (CAD), and mortality from CAD in contrast has almost halved during the same period.4 Such data call for a closer look at factors that have been shown to predict survival from OHCA. Key factors include arrest witnessed by a bystander, arrest witnessed by EMS, provision of bystander cardiopulmonary resuscitation (CPR), shockable rhythm at EMS arrival, and return of spontaneous circulation (ROSC) in the field.5 The last two measures have the biggest effect on survival, suggesting a need for timely EMS interventions and community preparedness to provide out-of-hospital life support measures. Even in EMS systems with short transport times and consistent implementation of evidence-based prehospital care, the survival rates for OHCA come up to only about 20%.6 Understanding additional predictors, challenges, and mechanisms for improving survival are therefore essential in optimizing outcomes. Patient sex has been shown to influence OHCA survival. Men have a threefold higher incidence of OHCA than women, especially in middle age.7 Further, almost all studies examining sex show a survival-to-admission advantage in women.8-12 However, data on survival to hospital discharge are conflicting. A majority show either no survival advantage9, 12-18 or higher survival in men,8, 10, 19-24 while others indicate that women fare better.18, 25, 26 Studies that report worse survival in women often attribute it to worse prehospital factors. Women are less likely to have witnessed arrests, bystander CPR, EMS CPR, and intravenous (IV) medications.11, 27 There is also controversy with respect to survival advantage for women for shockable or other rhythms.28, 29 Six studies to date have evaluated the age–sex interaction. Four show a survival advantage in younger women.8, 23, 26, 30 However, the same interaction has not been tested across the age spectrum for men. We evaluated these controversies by studying the association between sex and survival to hospital discharge in a large multicenter multiphase population study conducted from 1991 to 2002 in OHCA patients. We chose the Ontario Prehospital Advanced Life Support (OPALS) as a well-documented robust database that represents the largest population-based prehospital study to date on cardiac resuscitation. While more contemporaneous registries are available, the OPALS registry is unique in providing pertinent information from population-based measures.2, 31 OPALS has a clear advantage of having a relatively homogenous population, large geographic area, homogeneous EMS care, and a large sample size to detect even a relatively small sex difference in mortality that can nevertheless have large public health implications. In addition, the specific role of sex on survival was not evaluated in the original OPALS study, and the registry remains a robust source for answering important questions related to sex and OHCA, especially as a hypothesis-generating tool. Our study objectives were to compare overall survival between men and women and to assess the influence of age on survival for men and women. This was a secondary analysis of the OPALS study data. Between 1994 and 2002, the Ontario Ministry of Health funded OPALS as a multiphase “before–after” trial of optimized rapid defibrillation and full advanced life support programs.32 The OPALS study was approved by the Ontario Ministry of Health Emergency Health Services Research Advisory Committee and the Ottawa Hospital Research Ethics Board. The requirement for informed consent was waived. Secondary analysis of this deidentified data set was designated as not human subjects research by the University of Arizona Institutional Review Board. The OPALS population consisted of all people at least 16 years of age who had OHCA and for whom resuscitation was attempted by emergency responders. Phase 1 represented the baseline survival status in the community with availability of an ambulance automated defibrillation (basic life support with defibrillator [BLS-D]) program. It was based on retrospective data for the most recent 36 months prior to implementation of phase 2. Phase 2 evaluated the incremental benefit of rapid defibrillation (defined as arriving at scene with defibrillator within 8 minutes for 90% of cases) on 12-month survival. Phase 3 assessed the effect of full advanced cardiac life support (ACLS) measures including endotracheal intubation and IV drug on survival. In this were to interventions a that of of and of in the The and full of the OPALS study has been were across the that in the OPALS study. The communities of variable to people in Each community had a ambulance that the study with information using a with It ambulance call initial rhythm and survival This analysis was survival to hospital This was by of hospital or an of the The analysis younger than years of age, who were of patients with and others with that had in which a phase was to the were from the analysis to from and on survival. We also patients arrests were witnessed by EMS, as this is often from the OHCA population and could have other factors survival. and variables were between men and women. In addition, variation in survival by age was evaluated by survival in men and women, across the of We used multivariable logistic regression with community within hospital as as well as hospital and community as to explore the effect of on the relationship between variable and risk factors. We used a ratio to for significant to A of or less was considered significant for including as in logistic regression The study variable was survival to hospital and the primary risk factors assessed for relationship with the were age and sex. variables assessed for with the and the primary risk either as of survival or as for the relationship between survival and age and sex, were witnessed arrest, initial rhythm at EMS arrival, provision of bystander CPR, EMS to interval, OPALS study and of the logistic regression models, assessed the relationship between sex and age and the survival to hospital We used fractional regression to the for age as a continuous variable for a linear relationship with survival in the age for and 36 Fractional regression that no for age as a continuous variable for OHCA model age was as an continuous variable for However, for a fractional for age + model and a linear relationship between age and survival in the a for continuous that age fractional for but not for a single model with sex as a variable could not be and all logistic regression were by sex. All of the variables were in the of of OHCA, The ratio for of variables hospital and were p = for the model and p = for the used logistic regression for all of OHCA was only for approximately of study subjects in phase and fewer than of patients in phase 1 or primary analysis did not include of OHCA We conducted a analysis for subjects in phase 3 who did have OHCA by a multivariable analysis with and OHCA the model for the overall to the of of OHCA for the relationship between age and sex and survival. A of or in the regression for either age in either the or models, OHCA was to a model OHCA was considered significant model and were assessed with the the the and the of model to and that could were used to the and adjusted of survival for men and women with 95% confidence on these the odds for survival of survival = probability of probability of for sex. We also adjusted for survival for all by sex, for all variables in the logistic regression We also the linear of model to for survival for age for with a fractional age All were using of the total cases in the OPALS registry, 11,479 met the inclusion and 10,862 (94.6%) cases with complete data used for logistic regression analysis 1 for study inclusion for the study population were by sex Women of the were older than men, had fewer witnessed arrests and fewer initial shockable and had lower bystander CPR (p < 0.01). The to EMS arrival, rates of and rates of survival to hospital admission did not by sex. patients in phase rates of intubation did not but IV was less in women to men. Women had lower survival than men (1.7% vs. 3.2%; = 95% = to survival was lower for women the that are with witnessed cardiac arrest vs. = 95% = to shockable rhythm vs. = 95% = to vs. = 95% = to and survival to hospital admission vs. = 95% = to 2 the logistic regression for and The adjusted for witnessed arrest was higher in than vs. and the was for shockable rhythm = vs. the for bystander CPR and EMS to scene interval did not by sex. However, the odds of survival for study phases 2 and 3 were higher for to phase while for study phase 3 had a higher for survival to phase 1 and phase 2. compare the relationship between age and survival for the of survival age are shown in 2. Overall of the probability of survival age are for and adjusted However, these differ by sex. In the probability of survival with increasing age. men, the probability of survival across age, increasing from to 65 years of age and show a higher probability of survival to men until approximately age 47 years, and then have lower to men The odds by age to assess age survival by sex is to the for survival for men and women across all The adjusted of survival for a who is 5 years older than is = 0.81 to the odds of survival with increasing age for women. In the for men 65 years younger men years is = to or an increase in the odds of survival with increasing age. This a age 65 the for survival for men years men 65 years was = to or a in the odds of survival. after age 65 years, the odds of survival for men and women. conducted a analysis for patients in phase 3 to OHCA the relationship between age, sex, and survival. The inclusion of OHCA for women the regression for the continuous variable of age for women by and the inclusion of of OHCA the regression for the two transformed fractional age variables for men, and by and in the regression for age variables for and were of suggesting that of OHCA was not a significant for the relationship between age and survival for either or this study is the to show that survival in men from OHCA not have a linear relationship with age. men have relatively lower survival to older men until age 65 years, this in have a in survival as age. Our study is also the to show this differential effect by sex for the relationship between age and OHCA survival using fractional Our has significant for future OHCA that the age and sex This may be the that differ from of prior studies that not show a difference in survival by to be an but did not for it in model and did not the of age for men and women to it was linear in the The of effect of age on the relationship between sex and survival OHCA be to include age and sex as well as an interaction variable as in a logistic regression model with survival to hospital discharge as the A significant interaction (p < effect and survival to be in the of this as to age or sex in the This that the relationship between age and survival has the same for men and women. We that this of a logistic regression model was not met for study In the OPALS study, that while women had a linear relationship between survival and age in the men did men, survival increased from age to 65 years and then the of a linear relationship in the A fractional the linear between age and survival in the for men. The two age–sex could not be in one logistic regression model and analysis by sex. is to one could be that all logistic regression and differences in survival. Our suggest future that include age and sex as risk factors for survival from OHCA should the of age for in logistic regression models, for all cases and by sex. We fractional regression as a relatively and robust for age that significant advantage over as of continuous variables using from or a for Our study other important We that men of younger age to 47 have a lower probability of survival to hospital discharge from OHCA than women. This is higher of favorable of survival in men as witnessed cardiac arrests, bystander CPR, and shockable as well as from with to This until age 47 years and then men show an advantage in survival over women until age the of survival The higher mortality in men could be to the of sex and differential age-specific Men are at higher risk of CAD and to of which is by a higher for and than in also the and men to from CAD to call for for in men and about cardiac Some even suggest patients with CAD for as primary of cardiac using on the other are more likely to during 23, 26, 30 This advantage in a linear as Women have increased and disparities in it to women by and CAD also by the of and into the that to and that to the mechanisms are at in the that is by a cardiac the role of in the even a role for IV as a drug in of cardiac women are more likely to have with The higher of and coronary in women than in men have all been with 47 Our study also prior that an advantage in overall survival in women is lower than in 10, 19-24 This could be a majority of the cardiac arrests between the of 65 and years men have a survival advantage over women. women have fewer prehospital factors that survival arrest and shockable rhythms EMS In women to hospital admission at rates to men, but did not show survival to hospital This is at odds with cardiac arrests more women to women with have fewer and more robust ventricular than It is having a women worse in the population of Factors as of a higher of to more or older age at of cardiac arrest could be a role in women. is to these Our suggest the need for public health measures at increasing bystander CPR for women and for for women for defibrillator In contrast to other that women had lower survival to men cardiac arrests were by sex, that survival for women in phase 3 to phase 2 of the OPALS study men, survival increased only from phase 1 to phase 2 implementation of optimized Our for men the of the overall OPALS while for women show a benefit of the in contrast to the initial study are hypothesis-generating as the study was not to for differences in the study was not to survival by sex, it is that that could also survival could be for the original study evaluated the benefit of it is that these the implementation of the study and In addition, not have information important medical factors as the of by sex that could of the data from Ontario, from 1994 to 2002 lower overall survival for OHCA than data. This could to of and of differences recent interventions as CPR, and could influence survival. The effect of age on sex and survival should be in status was not as an outcome, to for a of sex and age. studies are that are to this and it between men and women across the age Survival for women was lower than for men in the Ontario Prehospital Advanced Life Support study. Some of the factors to the sex differences in survival as bystander cardiopulmonary resuscitation rate the rate of shockable rhythms) may be modifiable. The probability of survival differed across age for men and women in a nonlinear fashion. This that studies examining out-of-hospital cardiac arrest outcomes should the relationship between age and sex. age may need to be transformed using fractional for and logistic regression may need to be by sex to the relationship between age and out-of-hospital cardiac arrest survival.

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