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Abstract
Objective Prehospital rule-out of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) in low-risk patient with a point-of-care troponin measurement reduces healthcare costs with similar safety to standard transfer to the hospital. Risk stratification is performed identical for men and women, despite important differences in clinical presentation, risk factors and age between men and women with NSTE-ACS. Our aim was to compare safety and healthcare costs between men and women in prehospital identified low-risk patients with suspected NSTE-ACS.
Methods In the Acute Rule-out of non-ST-segment elevation acute coronary syndrome in the (pre)hospital setting by HEART (History, ECG, Age, Risk factors and Troponin) score assessment and a single poInt of CAre troponin randomised trial, the HEAR (History, ECG, Age and Risk factors) score was assessed by ambulance paramedics in suspected NSTE-ACS patients. Low-risk patients (HEAR score ≤3) were included. In this substudy, men and women were compared. Primary endpoint was 30-day major adverse cardiac events (MACE), secondary endpoints were 30-day healthcare costs and the scores for the HEAR score components.
Results A total of 863 patients were included, of which 495 (57.4%) were women. Follow-up was completed in all patients. In the total population, MACE occurred in 6.8% of the men and 1.6% of the women (risk ratio (RR) 4.2 (95% CI 1.9 to 9.2, p<0.001)). In patients with ruled-out ACS (97% of the total population), MACE occurred in 1.4% of the men and in 0.2% of the women (RR 7.0 (95% CI 2.0 to 14.2, p<0.001). Mean healthcare costs were €504.55 (95% CI €242.22 to €766.87, p<0.001) higher in men, mainly related to MACE.
Conclusions In a prehospital population of low-risk suspected NSTE-ACS patients, 30-day incidence of MACE and MACE-related healthcare costs were significantly higher in men than in women.
Trial registration number NCT05466591.
- acute coronary syndrome
- gender
- risk stratification
Data availability statement
Data are available upon reasonable request. Data will be made available one year after publication of the manuscript with the final results. Data requests should be submitted to the corresponding author.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Men and women with acute coronary syndrome (ACS) have important differences in clinical presentation, risk factors and age.
The History, ECG, Age, Risk factors and Troponin (HEART) score was designed for risk stratification in the total population of chest pain patients, with identical application in men and women.
Although the incidence of ACS is higher in men, the discriminatory accuracy of the HEART score is similar in men and women.
WHAT THIS STUDY ADDS
In patients who are identified as low-risk patients by ambulance paramedics, the risk of 30-day major adverse cardiac events is significantly higher in men than in women.
In patients who are identified as low-risk patients by ambulance paramedics, 30-day healthcare costs are significantly higher in men.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Future research should investigate a modified HEART score which includes sex.
Future research should investigate the difference in risk between prehospital men and women in all risk categories.
Introduction
Important differences in clinical presentation and presence of cardiovascular risk factors between men and women with acute coronary syndrome (ACS) are known.1 Compared with men, women with an ACS are generally older, have more risk factors (hypertension, dyslipidaemia and diabetes mellitus) and present with a larger number of additional non-specific symptoms (eg, neck pain, fatigue, dyspnoea or nausea) or without chest pain.1 Moreover, women with an ACS are less likely than men to have diagnostic ECG changes or elevated troponin levels on admission.1 However, the early diagnostic process for patients with chest pain is identical in men and women, according to contemporary guidelines that were established from data over-representing the male population.1–3 The early diagnostic process often includes risk stratification tools such as the HEART (History, ECG, Age, Risk factors and Troponin) score.4 5 The HEART score is a widely validated tool for risk stratification for patients with suspected non-ST-segment elevation acute coronary syndrome (NSTE-ACS) at the emergency department (ED).4 Despite the differences between men and women in all five aspects of the HEART score, the HEART score is applied the same in both sexes. Meanwhile, previous validation studies of the HEART score at the ED have already shown that the male sex is an independent predictor of major adverse cardiac events (MACE).6 7 Moreover, women with a low HEART score tend to be less hospitalised and undergo less stress testing than men with the same score.8 However, the discriminatory accuracy of the HEART score for the occurrence of MACE has been shown not to differ between men and women.9 Yet, it remains unknown whether there is a difference in risk of MACE and healthcare costs between low-risk men and women who are deemed eligible for prehospital rule-out of NSTE-ACS. Therefore, this study aims to compare the incidence of MACE between men and women in a population of prehospital identified low-risk patients with suspected NSTE-ACS. Moreover, this study aims to compare the healthcare costs at 30 days and the scores for the individual components of the HEART score between prehospital low-risk men and women.
Methods
Study design
The ARTICA (Acute Rule-out of non-ST-segment elevation acute coronary syndrome in the (pre)hospital setting by HEART score assessment and a single poInt of CAre troponin) trial was the first randomised trial on prehospital rule-out of NSTE-ACS in low-risk patients using a point-of-care (POC) troponin measurement.10 11 The design of the ARTICA trial has been published previously.10 Patients with a History, ECG, Age and Risk factors (HEAR) score (HEART score without the Troponin component) of ≤3 were randomised to either the prehospital rule-out strategy or the ED rule-out strategy. In the prehospital rule-out strategy, a POC troponin measurement was performed. POC troponin T was measured using the Roche Cobas h232 (Roche Diagnostics, Basel, Switzerland), which has detection limits of 40–2000 ng/L. The care for the patient was transferred to the general practitioner if troponin was low (<40 ng/L). If troponin was elevated (≥40 ng/L), the patient was transported to the ED. Patients in the ED rule-out strategy were directly transported to the ED for evaluation according to standard practice. The aim of the ARTICA trial was to assess the safety (incidence of MACE, consisting of ACS, unplanned revascularisation and death) and healthcare costs at 30 days of prehospital rule-out of NSTE-ACS with a single POC troponin in low-risk patients. The aim of the current study was to compare men and women regarding the incidence of MACE, healthcare costs at 30 days and the components of the HEAR score in prehospital identified low-risk patients.
Study population
The study population consisted of prehospital patients suspected of having an NSTE-ACS with an onset of symptoms ≥2 hours before ambulance presentation, who were identified as low-risk patients (HEAR score ≤3) by ambulance paramedics. Patients were not eligible for participation if they were suspected of another diagnosis requiring ED presentation (eg, aortic dissection or pulmonary embolism) or if they were unable to provide written informed consent.10
Identification of low-risk patients
The ambulance paramedics identified low-risk patients by assessment of the HEAR score. Figure 1 shows the HEAR score. Patients with a HEAR score of ≤3 were considered low-risk patients. A detailed description of the HEAR score assessment has been published previously.10 12
The HEAR (History, ECG, Age and Risk factors) score. BMI, body mass index; LBBB, left bundle branch block; PM, pacemaker.
Outcomes
The primary outcome of this study was the occurrence of MACE at 30 days. MACE consisted of one or more of the following events: ACS, unplanned revascularisation and all-cause death. All events were blindly adjudicated by an independent Clinical Events Committee. Secondary outcomes were healthcare costs at 30 days and the HEAR score and its individual components. Healthcare costs consisted of all costs related to healthcare consumption (eg, general practitioner consultation, diagnostic tests and hospital visits). The cost-prices were determined according to the 2018 reference list of the Dutch National Institute and standard 2018 list prices.13
Follow-up
Follow-up was performed for all patients after 30 days by contacting the patients by telephone and email. If patients visited a hospital, the hospital was contacted to collect all data on procedures and events. In case of non-response of a patient, the general practitioner and hospital were contacted.
Statistical analysis
Statistical analysis was performed using SPSS statistics, V.27 (IBM, Armonk, New York, USA), and the software package Stata V.16 (StataCorp, College Station, Texas, USA). Continuous variables were summarised as means±SD or medians (IQRs). Categorical data were summarised by frequencies and percentages. Categorical variables were reported as (relative) frequencies and compared using the χ2 test or Fisher’s exact test, whichever was most appropriate. Medians (IQR) were compared between groups with the Mann-Whitney U test. Baseline characteristics were compared between men and women. Incidences of MACE were compared between all men and women, as well as the men and women for whom an ACS was ruled-out at first presentation. Risk ratios (RRs) were estimated, along with their 95% CIs, for MACE and its components in men versus women in the total population and in the ruled-out ACS population. Age-adjusted RR was estimated for MACE in men versus women in the total population, along with their 95% CI, by specifying a generalised linear model with a binomial distribution and log link. For the healthcare costs, means±SD were calculated, as well as mean differences and 95% CI. Healthcare costs were compared between men and women in the total population, as well as the subgroup of patients without MACE. The HEAR scores and its components were expressed as medians (IQR) and compared between all men and women, as well as the men and women in the subgroup of patients without MACE.
Results
Between March 2019 and May 2022, 866 patients were included in the ARTICA trial. Informed consent was withdrawn by three patients and follow-up at 30 days was complete in all patients, resulting in 863 patients available for analysis. The study population consisted of 368 (42.6%) men and 495 (57.4%) women. Baseline characteristics are depicted in table 1.
Baseline characteristics
Incidence of MACE
MACE at 30 days occurred in 33 (3.8%) patients, including MACE at index presentation. In 836 (96.9%) patients, an ACS was ruled out (either at home or at the ED) at index presentation. In this subgroup of ruled-out ACS patients, MACE at 30 days occurred in six (0.7%) patients. Table 2 shows the incidences of MACE and its components at 30 days in both sexes in the total randomised population and in the ruled-out ACS population. In the total population, MACE at 30 days occurred in 25 (6.8%) men and 8 (1.6%) women, with an RR of 4.2 (95% CI 1.9 to 9.2, p<0.001). Age-adjusted RR was 4.4 (95% CI 2.0 to 9.7, p<0.001). In the ruled-out ACS population (836 patients), MACE at 30 days occurred in five (1.4%) men and one (0.2%) woman, with an RR of 7.0 (95% CI 0.8 to 59.8, p=0.04).
MACE at 30 days
Healthcare costs
Mean healthcare costs (±SD) were €1653.13 (±€1956.66). Figure 2 shows the healthcare costs in men and women in the total population and in the subgroup of patients without MACE. In the total population, mean healthcare costs were significantly higher in men, with €1942.50 (±€2708.71) in men versus €1437.99 (±€1058.74) in women. Mean difference was €504.55 (95% CI €242.22 to €766.87, p<0.001). Table 3 shows the healthcare resource use in men and women in the total population. In the prehospital rule-out strategy, mean healthcare costs were €1690.79 (±€2856.58) in men and €1090.98 (±€1038.09) in women, with a mean difference of €599.81 (95% CI €212.76 to €986.85, p=0.002). In the ED rule-out strategy, mean healthcare costs were €2202.63 (±€2528.57) in men and €1783.59 (±€963.45) in women, with a mean difference of €419.03 (95% CI €73.58 to €764.49, p=0.02). In the subgroup of patients without MACE (n=830), mean healthcare costs showed no significant difference between men and women, with €1371.11 (±€725.57) in men and €1347.51 (±€733.25) in women. Mean difference was €23.60 (95% CI €−77.42 to €125.62, p=0.65). In the subgroup of patients without MACE in the prehospital rule-out strategy (n=417), mean healthcare costs were €1053.52 (±€769.36) in men and €996.50 (±€620.81) in women, with a mean difference of €57.02 (95% CI €−77.02 to €191.07, p=0.40). In the subgroup of patients without MACE in the ED rule-out strategy (n=413), mean healthcare costs were €1698.10 (±€500.14) in men and €1697.09 (±€667.51) in women, with a mean difference of €1.01 (95% CI €−117.96 to €119.97, p=0.99).
Healthcare costs in men and women. (A) Healthcare costs in men and women in the total population. (B) Healthcare costs in men and women in the subgroup of patients without MACE. MACE, major adverse cardiac event.
Healthcare resource use at 30 days
HEAR score
Median HEAR score (IQR) was 3 (2–3), median History score (IQR) was 0 (0–1), median ECG score (IQR) was 0 (0–0), median Age score (IQR) was 1 (1–1) and median Risk factors score (IQR) was 1 (0–1). Table 4 shows the HEAR score and its components in men and women in the total population and in the subgroup of patients without MACE.
HEAR score and its components
Discussion
Principal findings
This study shows that in a population of suspected NSTE-ACS patients who were identified as low-risk patients by ambulance paramedics, incidence of MACE and healthcare costs at 30 days were significantly higher in men than in women.
Incidence of MACE and risk stratification
In the total population, the risk of MACE at 30 days was 4.2 times as high in men as in women (6.8% vs 1.6%, RR 4.2 (95% CI 1.9 to 9.2, p<0.001)). After adjustment for age, the RR rose to 4.4 (95% CI 2.0 to 9.7, p<0.001). In the patients for whom an ACS was ruled out (at home by POC troponin measurement or at the ED), which was true for 836 (96.9%) patients, the risk of MACE at 30 days was 7.0 times as high in men as in women (1.4% vs 0.2%, RR 7.0 (95% CI 0.8 to 59.8, p<0.001)). In validation studies of the HEART score for risk stratification for chest pain patients presenting to the ED, the male gender has already been shown to be an independent predictor of MACE.6 7 Moreover, a study on sex disparities in the ED management of patients with suspected NSTE-ACS has shown that women with low HEART scores were less hospitalised and underwent less stress testing than men.8 Three studies, two from the Netherlands and one from the USA, in which the HEART score was also assessed in the prehospital setting in combination with a POC troponin measurement, have shown that incidences of MACE were also higher in men than in women in prehospital identified low-risk populations.14–16 Despite the differences in MACE incidence between men and women, the HEART score was designed for risk stratification in the total population with identical application in men and women, which has been widely validated and accepted.4 Although risk stratification by HEART score assessment has been shown to be safe in the total population, using the HEART score to rule out an NSTE-ACS seems to be less safe in men than in women. However, a previous retrospective study on sex-based differences in the performance of the HEART score has shown that the HEART score distinguishes between patients with and without MACE equally well among men and women.9 17 Moreover, the discriminatory accuracy of the HEART score to identify the low-risk, intermediate-risk and high-risk patients also did not significantly differ between men and women.9 However, the baseline risk of MACE is higher in men than in women, while the sensitivity and specificity of the HEART score are equal in men and women, resulting in a lower negative predictive value (NPV) in men.9 This lower NPV is reflected by the higher incidence of MACE in low-risk men in our study, as well as the validation studies.6 7 Another potential explanation for the risk difference among low-risk men and low-risk women could be that the HEART score uses the age and risk factors to identify low-risk patients, whereas women who do have an ACS are generally older and have more risk factors than men. Using the HEART score to identify a low-risk population is likely to result in a population with relatively young patients without many risk factors. Since men who have an ACS are younger and have less risk factors than women with an ACS, the low-risk population as identified by the HEART score might automatically contain men who are at higher risk of ACS than women. Hence, we think the diagnostic value of a modified HEART score which includes sex should be investigated in future research. A modified HEART score, in which the Risk factors component was replaced by a Sex component (2 points for men and 0 points for women), along with different cut-off values for the Age component, has already been shown to outperform the overall performance of the HEART score.16 Several other options could be considered: sex-specific cut-offs for the low-risk category, adding a ‘Sex’ category to the HEART score or adding the male sex to the ‘Risk factors’ category.
HEART score assessment in women
Although women in the low-risk category have lower incidences of MACE than men, we think caution is warranted for potential underestimation of the risk when assessing the HEAR score in women, for several reasons. First, classification of the History component depends on the presence or absence of typical elements, while women with an ACS present with a larger number of additional non-specific symptoms or without chest pain.1 Second, women with an ACS are less likely to have diagnostic ECG changes or elevated troponin levels on admission.1 Third, in young (≤45 years) patients with an ACS, the female sex is an independent predictor of 30-day mortality, even after adjusting for use of guideline-recommended medications and reperfusion therapy.18 Fourth, female-specific risk factors such as pre-eclampsia, hypertension in pregnancy and gestational diabetes are not included in the HEART score, neither are other under-recognised risk conditions that appear to contribute to cardiovascular disease in women (eg, depression).1 3 19 Therefore, future research could also investigate the value of adding female-specific risk factors and other under-recognised risk conditions to the HEART score.
Healthcare costs
Mean healthcare costs at 30 days were significantly higher in men than in women (€1943±2709 vs €1438±1059), with a mean difference of €505 (95% CI €242 to €767, p<0.001). In men, significantly more ECGs were obtained, more second high-sensitivity troponin measurements were performed, more coronary angiographies and more percutaneous coronary interventions were performed than in women. Moreover, coronary artery bypass grafting is an expensive intervention (over €13.000 for the surgery, in the Netherlands) which was performed in two men and in zero women. The performance of the aforementioned tests and procedures is related to the presence of MACE, which was reflected in the comparison of the healthcare costs in men versus women in the subgroup of patients without MACE. Excluding the 33 patients with MACE from the analysis resulted in equal healthcare costs for men and women (€1371±726 vs €1348±733), with a mean difference of €24 (95% CI €−77 to €126, p=0.65). Therefore, the difference in healthcare costs between men and women in our study was caused by the higher incidence of MACE in men. As mentioned, another study has shown that women with low HEART scores were less hospitalised and underwent less stress testing than men.8 However, in our study, the numbers of hospitalisations and stress tests showed no significant differences between men and women.
Limitations
This study has some limitations. First, this substudy is a post-hoc analysis and the ARTICA trial was not powered for comparisons between men and women. However, we think the comparison of outcomes between men and women in this study population is relevant, because it is a representation of the patients that are selected for potential prehospital rule-out of ACS. Second, the growing awareness for non-specific symptoms in women may have caused the ambulance paramedics to not feel comfortable to assess the HEAR score in women with non-specific symptoms, out of fear for underestimation of the History component. Third, because of the study design of the ARTICA trial, the study population consists of patients who were transported to the ED and of patients who were not transported to the ED in case of a low POC troponin concentration. Therefore, healthcare costs in men and women as presented in the current study are not representative for the costs according to the current guidelines-recommended strategy (standard transfer to the ED), nor for the costs after implementation of a prehospital rule-out strategy. However, women were equally distributed between the ED rule-out strategy and the prehospital rule-out strategy of the ARTICA trial and the healthcare costs were significantly lower in women in both strategies.11 Fourth, our study consists of a selection of patients who were identified as low-risk patients by ambulance paramedics. A study in which all consecutive patients with a suspected NSTE-ACS are included might provide more insight in the differences in prehospital risk stratification between men and women.
Conclusion
In a population of patients with suspected NSTE-ACS who were identified as low-risk patients by ambulance paramedics, the incidence of MACE at 30 days and healthcare costs at 30 days were significantly higher in men than in women. In patients without MACE (96% of the total population), healthcare costs were equal between men and women.
Supplemental material
Data availability statement
Data are available upon reasonable request. Data will be made available one year after publication of the manuscript with the final results. Data requests should be submitted to the corresponding author.
Ethics statements
Patient consent for publication
Ethics approval
The study was conducted according to the principles of the Declaration of Helsinki and in accordance with the Medical Research Involving Human Subjects Act (WMO) and the statements of the Dutch Central Committee on Research Involving Human Subjects (CCMO). The ARTICA trial was approved by the Medical Ethics Committee Oost-Nederland, the Netherlands, on 27 November 2018 (NL66755.091.18). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
P van Grunsven, MD, PhD, medical lead ambulance region Gelderland-Zuid (2018–2020). M Verbakel, Dutch patient federation for cardiovascular patients, ‘Harteraad’.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @aarts_joris
Contributors CC conceived the idea. GWAA, CC, R-JvG, GEC, RRLvK, PD and NvR designed the study methodology. EMMA designed the economical and statistical analyses. GWAA, CC and NvR drafted the manuscript. GWAA, CC, EMMA, LR and NvR designed the statistical analysis plan. The first draft of the manuscript was written by GWAA, CC and NvR. GWAA is the guarantor. All authors reviewed and revised the final manuscript. All authors agreed with the final version of the manuscript.
Funding The ARTICA trial was supported by a grant from The Netherlands Organisation for Health Research and Development (ZonMw); 2018 grant number 852001942.
Competing interests CC reports a grant from ZonMw (The Netherlands Organisation for Health Research and Development) and consulting fees from AstraZeneca and Xenikos BV. RRLvK reports honoraria grants from Bayer and Novartis. PD reports grants from Philips, Abbott and AstraZeneca and consulting fees from Philips. NvR reports grants from Abbott, Philips, Medtronic and Biotronik and speaker fees from Microport, Abbott, Rainmed and Bayer.
Patient and public involvement statement A patient member of ‘Harteraad’, a patient advisory council for patients with cardiovascular disease, was involved during the development of the trial protocol and patient information. This patient representative was also involved during the conduct of the trial by providing advice to the ambulance professionals on how to perform informed consent and how to increase communication skills from a patient’s perspective.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.