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Cardiovascular medicine
Protocol
Improving the accUracy of Referrals to the emerGency departmEnt of patieNts with chesT pain using the modified HEART score in Emergency Medical Transport (URGENT 2.0): protocol for a multicentre randomised controlled trial
  1. Lisa D S Frenk1,
  2. Braim M Rahel2,
  3. Cees B de Vos3,
  4. Frits H M van Osch4,5,
  5. Fabiana G Prestigiacomo2,
  6. Marcel J W Janssen6,
  7. Robert T A Willemsen7,
  8. Arnoud W van 't Hof8,9,10,
  9. Joan G Meeder2
  1. 1 Department of Cardiology, VieCuri Medical Centre, Venlo, Netherlands
  2. 2 Cardiology, VieCuri Medical Centre, Venlo, Limburg, Netherlands
  3. 3 Department of Cardiology, Laurentius Hospital, Roermond, Netherlands
  4. 4 Clinical Epidemiology, VieCuri Medical Centre, Venlo, Netherlands
  5. 5 Epidemiology, GROW Research Institute for Oncology and Reproduction, Maastricht University, Maastricht, Limburg, Netherlands
  6. 6 Clinical Chemistry, VieCuri Medical Centre, Venlo, Netherlands
  7. 7 Department of Family Medicine, Maastricht University, Maastricht, Netherlands
  8. 8 Cardiology, Maastricht University Medical Centre+, Maastricht, Limburg, Netherlands
  9. 9 Cardiology, Zuyderland Medical Centre Heerlen, Heerlen, Limburg, Netherlands
  10. 10 Cardiovascular Research Institute Maastricht (CARIM), Maastricht Universitair Medisch Centrum+ Hart+Vaat Centrum, Maastricht, Netherlands
  1. Correspondence to Ms Lisa D S Frenk; lfrenk{at}viecuri.nl

Abstract

Introduction Ischaemic heart disease is the single most common cause of death worldwide. Traditionally, distinguishing patients with cardiac ischaemia from patients with less alarming disease, in prehospital triage of chest pain, is challenging for both general practitioners and ambulance paramedics. Less than 20% of patients with chest pain, transferred to the emergency department (ED), have an acute coronary syndrome (ACS) and the transportation and analysis at the ED of non-ACS patients result in substantial healthcare costs and a great patient burden. Advanced risk stratification, with the help of cardiac troponin measurements, seems crucial to improve prehospital diagnostic accuracy.

Methods and analysis The URGENT 2.0 trial is a randomised controlled trial in which the primary objective is to reduce the referral of non-cardiac chest pain (NCCP) patients, using a modified HEART score including a high-sensitivity capillary point-of-care high-sensitivity cardiac troponin I measurement. Patients are included by ambulance paramedics and 1:1 randomised for (1) regular care (control group) or (2) modified HEART score analysis (intervention group) and non-referral in case of a low modified HEART score (0–3). In total, 852 patients will be included. Follow-up will be performed at 30 days, 6 months and 12 months. Both referral rates of NCCP patients and the occurrence of major adverse cardiac events are defined as primary outcome measures.

Ethics and dissemination The medical ethics committee Zuyderland-Zuyd Hogeschool (Netherlands) has approved this trial (reference numbers NL71820.096.19 and METCZ20190139). Written informed consent will be obtained from all participating patients. The results of this trial will be disseminated in one main paper and in additional papers with subgroup analyses.

Trial registration ClinicalTrials.gov, NCT04904107.

  • Randomised Controlled Trial
  • Coronary heart disease
  • Ischaemic heart disease
  • Safety
  • Adult cardiology
  • Clinical Trial
http://creativecommons.org/licenses/by-nc/4.0/

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https://doi.org/10.1136/bmjopen-2024-084139

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    STRENGTHS AND LIMITATIONS OF THIS STUDY

    • URGENT 2.0 is a randomised controlled trial in a large sample with few exclusion criteria which evaluates the use of the modified HEART score in a prehospital setting including high-sensitivity point-of-care (POC) troponin I testing.

    • URGENT 2.0 is a multicentre trial including patients with chest pain in mid- and northern Limburg (the Netherlands, Viecuri Medical Center Venlo and Laurentius Hospital Roermond).

    • Patients with an onset of chest pain<2 hours are excluded, because POC high-sensitivity cardiac troponin I measurement within this time window may be false negative due to time-dependent troponin release.

    • Adequate modified HEART score training for ambulance paramedics is required before the start of the study to prevent incorrect modified HEART score calculation.

    Introduction

    Chest pain is a common symptom in acute care, and for most patients, either a general practitioner (during office hours), a general practitioner cooperative (GPC, during out-of-office-hours) or ambulance service is contacted, among patients contacting acute care.1 2 In out-of-office hours, 60.7% of the U1 ambulance responses (ambulance response for patients suspected of immediate life-threatening conditions) are forwarded from the GPC because of acute chest pain.3 Only 8.2% of the patients contacting the GPC with chest pain are solely investigated and treated by the GPC without ambulance care interference.3 69.4% of chest pain patients directly contacting the ambulance services are transported to the emergency department (ED) but eventually are not admitted to the hospital.3

    Acute coronary syndrome (ACS) with its inherent high risk is only 1 of over 40 diagnoses possibly causing chest pain.1 Patients with ACS should be referred promptly to the hospital to reduce mortality and morbidity.4 However, mortality in patients with non-cardiac chest pain (NCCP) is low.5 Referring NCCP patients to the ED induces great burden on the ED and has a psychological impact on patients and their family.6 This results in high healthcare utilisation and frequent readmissions, with high healthcare and societal costs.7–11 Moreover, patients unnecessarily referred to the hospital have an increased risk of adverse events due to extra testing.12

    The HEART score was developed in 2008 and has been validated to stratify the risk of short-term adverse cardiac events in patients with chest pain at the ED.13 The FamouS Triage trial showed that ruling out myocardial infarction in chest pain patients without ST-segment elevation in a prehospital setting is safe as well.14 The FamouS Triage study group integrated high-sensitivity cardiac troponin T results (hs-cTnT) into the HEART score, measured from venous blood drawn in the ambulance, and therefore defined it as the ‘modified HEART score’.14 The modified HEART score is an acronym for history, ECG, age, risk factors and troponin at arrival.13 The components can be rated 0, 1 or 2 points each and result in a total score between 0 and 10. Patients with a HEART score of 0–3 are considered to be at low risk for ACS.13 Both negative predictive value and positive predictive value of the modified HEART score for ACS and major adverse cardiac events (MACE), respectively, are high within 6 weeks after presentation.13

    Cardiac troponin (a component of the modified HEART score) is a biomarker specific for cardiac injury and can therefore be used to distinguish between a cardiac and non-cardiac diagnosis. Point-of-care (POC) troponin testing, defined as laboratory testing near the patient with rapid availability of results, has attracted much interest in the ED setting and seems feasible.15 Allowing ambulance paramedics to use POC devices to measure a troponin level and assess a modified HEART score before transport of patients to the ED may result in both earlier diagnosis of ACS and safe exclusion of ACS in NCCP patients.16

    A clinical prehospital study implementing venous POC hs-cTnI analysis revealed promising results.17 In a prehospital setting, venous blood drawing might not be easily available. However, POC testing of troponine is not yet implemented. Therefore, we performed a validation study to evaluate the analytical performance of the POC system using different sample types including capillary blood, in comparison with standard laboratory venous hs-cTnI testing, proving POC hs-cTnI testing in capillary blood at the (cardiac) ED to be feasible and reliable.18 A study on implementing capillary POC hs-cTnI analysis in the modified HEART score in a prehospital setting has not been performed yet. The URGENT 2.0 study aims to improve the prehospital triage of chest pain patients and to assess the diagnostic accuracy of the modified HEART score (including capillary POC hs-cTnI analysis) in ambulance care.

    Methods and analysis

    Study design and population

    The URGENT 2.0 trial is a multicentre randomised controlled trial which will be conducted in two hospitals and ambulance services (17 vehicles in total) in the Netherlands (Viecuri Medical Center Venlo and Laurentius Hospital Roermond). In these regions, patients experiencing acute chest pain have several possible routes to seek medical care: contact the emergency medical services (ambulance) immediately, contact their general practitioner (GP) or the regional out-of-hours GP cooperatives. Based on the urgency assessment, an ambulance is deployed. These ambulance services are affiliated with the hospital region and therefore work together. Patients with acute chest pain will be assessed for eligibility and informed about the study by the ambulance paramedic (table 1). Eligible patients will be enrolled in the study after providing written informed consent and will be randomised 1:1 to the intervention group or control group. The randomization sequence is based on a blocked computer-generated randomization list created in Microsoft Excel. Control group patients will receive standard ambulance care as usual and thus will be transferred to the ED in case ACS is suspected. Patients in the intervention group will be screened with the modified HEART score including capillary high-sensitivity POC troponin I measurement. Patient inclusion started on 4 July 2021, and the study is planned to end on 1 January 2026.

    View this table:
    Table 1

    Inclusion and exclusion criteria

    Intervention

    In the intervention group, the modified HEART score will be calculated upon arrival at the location of the patient by the ambulance out of the hospital (table 2). Ambulance paramedics are allowed to send the ECG by secured e-mail and contact the cardiologist to discuss the patient briefly in case of doubt.

    View this table:
    Table 2

    URGENT 2.0 modified HEART score

    Troponin testing will be performed by using the Atellica VTLi Patient-side Immunoassay Analyzer for hs-cTnI testing developed by Siemens Healthineers. The bedside system requires 30 µL of capillary blood, venous whole blood or plasma.19 For the URGENT 2.0 trial, capillary blood is drawn by a fingerstick and analysed. The droplet of blood is applied to a cartridge using a capillary transfer device. The total test time, from sample application to the test result, is approximately 8 min.19 The limit of detection is 1.6 ng/L, and the limit of quantitation is 8.9 ng/L (at 10% coefficient of variation (CV)) and 3.7 ng/L (at 20% CV).19 The 99th percentile in a normal reference population overall, for men and women are 23, 27 and 18 ng/L, respectively.19 A hs-cTnI level≤3.8 ng/L, being substantially lower than the 99th percentile in a normal reference population, is used as a cut-off in this study to exclude ACS.20 The POC hs-cTnI test is also used by the POB HELP study group.21

    Patients with a modified HEART score of >3 will be referred to the cardiac ED with suspected ACS and receive standard care including central laboratory hs-cTnT testing. In case of a low modified HEART score (modified HEART 0–3), patients will not be referred to the cardiac ED. In these cases, depending on the further evaluation by the ambulance paramedic, the patient will be referred to the general ED or GP or treated at home. In these patients at low risk for ACS, a venous hs-cTnT test (Roche Cobas) is obtained at the cardiac ED at least 4 hours and up to 24 hours after initial blood testing. The interpretation of this extra safety net to confirm the rule out of ACS (figure 1) is as follows:

    • In case of a positive hs-cTnT result (≥14 ng/L), the patient will be admitted to the cardiac ED and receive regular treatment, including ECG, rhythm monitoring, blood tests, depending on suspicion, additional examination and matching treatment.

    • In case of a negative hs-cTnT (<14 ng/L) result, the patient will be discharged.

    Figure 1
    Figure 1

    Flowchart URGENT 2.0 trial. ACS, acute coronary syndrome; ED, emergency department; EMT, emergency medical transport; GP, general practitioner; hs-cTnT, high-sensitivity cardiac troponin T; NTS, Dutch Triage Standard; OOH GPC, out-of-office hours general practitioner cooperative; STE-ACS, ST-segment elevated acute coronary syndrome.

    Outcomes

    The URGENT 2.0 study has two primary endpoints. The first primary endpoint is to assess the reduction of NCCP patients referred to the cardiac ED (efficacy), by performing the modified HEART score (including POC hs hs-cTnI measurement) compared with regularly referred chest pain patients (control group). A 10% reduction of referral of NCCP patients is pursued.

    The second (co-)primary endpoint is to determine the safety of this prehospital strategy by assessing the incidence of MACE at 30 days, 6 months and 12 months. MACE is defined as a combined end point of all-cause death, ACS, unplanned percutaneous coronary intervention and unplanned coronary artery bypass grafting.

    Secondary endpoints are the cost-effectiveness of the modified HEART score, the analytical performance of POC hs-cTnI assessment versus hs-cTnT at the cardiac ED and the evaluation of prehospital time elapsed in the intervention group versus control group.

    Finally, subgroup analyses for the primary endpoints will be performed for sex, diabetes mellitus, type of referral (GP vs triage nurse GPC vs self-referral) and symptom duration.

    Sample size calculation

    A large sample size is required to adequately power both the efficacy and safety endpoint and for the eventual implementation of the modified HEART score in the prehospital setting.

    A baseline registry performed at our hospital in 2015 showed that 74.5% of the patients who contacted the GPC were unnecessarily referred to the ED with suspected ACS.22 For the sample size calculation based on the primary endpoint, we used the clinical calculator (https://clincalc.com/stats/samplesize.aspx). Aiming at a power of 80% and a two-tailed type I error of 5%, 328 patients need to be enrolled within this study in each study group (the intervention and control group) in order to be able to demonstrate a reduction of 10% in unnecessarily referred patients.

    The sample size calculation for the safety endpoint is based on demonstrating that the proportion of MACE in the intervention group is non-inferior to that in the control group. Preliminary results of the second phase of the FAMOUS Triage trial showed a 15.7% (13.1–18.6) MACE rate.23 We used the expected incidence of 15.7% as the point estimate (meaning no difference between the control group and the intervention group). Phase 3 of the FAMOUS Triage trial is a non-inferiority trial, controlled before–after multicentre study with a sequential design with the aim to assess feasibility and safety of prehospital risk assessment by paramedics using the HEART score.24 Based on the study design paper of this trial, we set the non-inferiority margin at 7.5%. For the sample size calculation, we used the clinical calculator (see https://www.sealedenvelope.com/power/binary-noninferior/).

    If there is truly no difference between the standard and experimental treatment (15.7% in both groups), then 808 patients are required to be 90% sure that the upper limit of a one-sided 95% CI (or equivalently a 90% two-sided CI) will exclude a difference in favour of the standard group of more than 7.5%.

    To correct for loss to follow-up, we will include 426 patients in the intervention group and 426 patients in the control group, adding up to a total study population of 852 patients.

    Statistical analysis

    Data will be analysed according to the intention-to-treat principle and will be presented quantitatively as well as qualitatively. The categorical data will be presented as number of patients and percentages. Continuous data will be presented as means and SD in case of normally distributed data. In case of skewed data, the data will be presented as medians and ranges. All analyses will be adjusted for inclusion of multiple centres in URGENT 2.0 by using multilevel modelling applying a random effect. A p value of less than 0.05 is considered significant. Possible confounders that are not controlled for after randomisation will be adjusted by a multivariable logistic or linear regression model.

    The primary objective of this study is to evaluate the reduction of NCCP patients admitted to the cardiac ED by performing the modified HEART score in comparison to our control group. We estimate a minimal reduction of 10% in NCCP patients and will evaluate this by calculating the 95% CI of the observed proportion in the study sample. These data will be presented as number of patients and percentages. Differences between proportions will be tested using a χ2 test and multivariable logistic regression models. Additionally, we will repeat the above-mentioned analysis with a modified HEART score of 0–4 instead of 0–3 considered as low.

    The mortality, MACE and ACS diagnosis rate (at baseline) will be given in the number of patients and percentages. Event rates in the two groups will be estimated with the use of a Kaplan–Meier method. The HR and two-sided 95% CI will be calculated by a Cox proportional hazards model for the mortality and MACE rate. For evaluating and comparing the percentage of ACS diagnosis (at baseline) in both study groups, a logistic regression analysis will be performed. A non-inferiority analysis will be performed to assess whether the observed OR or HR for the mortality rate, MACE rate and ACS rate does not exceed the prespecified 7.5% non-inferiority margin.

    To compare the accuracy of referral, the Pearson χ2 test or Fisher’s exact test will be used when applicable. A p value of less than 0.05 is considered significant.

    An interim analysis will be performed after the inclusion of 500 subjects. The critical p value and 95% CI will be adjusted according to the Pocock boundary for one interim analysis (p=0.0294).

    Follow-up

    Follow-up will be performed by review of all medical records after 30 days, 6 months and 12 months.

    Patient and public involvement

    None are involved.

    Ethics and dissemination

    The study will be conducted following the Declaration of Helsinki. The medical ethics committee Zuyderland-Zuyd has approved the protocol (reference numbers NL71820.096.19 and METCZ20190139). Viecuri Medical Centre and Siemens Healthineers are the sponsors of the study. Written informed consent will be obtained from all participating patients (online supplemental material). In order to ensure the safety of this trial, a Data Safety and Monitoring Board has been established and the study will be monitored by the Clinical Trial Center Maastricht according to Good Clinical Practice.25

    Supplemental material

    The trial is registered at ClinicalTrials.gov, NCT04904107. Results of the study will be shared with professional healthcare workers, participants and the general public. The primary outcomes of the study will be presented in one main paper in a scientific peer-reviewed journal. Secondary outcomes will be shared in separate papers. Findings will be shared at conferences through oral and poster presentations.

    Ethics statements

    Patient consent for publication

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    Footnotes

    • Contributors LF, BR, JM and RTAW have written the protocol of the study. AvtH, FvO, MJWJ and CdV substantially revised the protocol. LF, BR, JM and RTAW have written this manuscript. FGP contributed to writing the revised version of the paper. All authors read and substantially revised the manuscript. All authors gave final approval of the published version. JM acted as guarantor.

    • Funding This work is supported by the STZ Innovation challenge 2021/2022 (see Feestelijke uitreiking prijzen STZ-innovatiechallenge-STZ) and the research department of Viecuri Medical Centre (grant number E.21.32.002-3). The Atellica VTLi immunoassay analysers used for the POC hs-cTnI measurements in this study are provided by Siemens Healthineers.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • 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.