Acute Chest Pain

Diagnostic accuracy and pre-hospital use of anticoagulants and platelet aggregation inhibitors

Background: Acute chest pain (aCP) can be a symptom of life-threatening diseases such as acute coronary or aortic syndrome, but often has a non-cardiac cause. The recommendations regarding pre-hospital drug treatment of patients with aCP are ambiguous.

Methods: A retrospective cohort study was conducted of 822 patients with aCP who were attended by emergency physicians. The cause of aCP was classified as follows: acute coronary syndrome without ST-segment elevation (NSTE-ACS), acute aortic syndrome, hypertensive crisis, cardiac arrhythmias, musculoskeletal, or other. The suspected and discharge diagnoses were compared, and the pre-hospital administration of acetylsalicylic acid (ASA) and unfractionated heparin (UFH) was analyzed. Furthermore, the parameters that improved diagnostic accuracy were investigated. 

Results: The positive predictive value of the diagnosis assigned by the emergency physician (EP diagnosis) was 39.7%. NSTE-ACS was the most commonly suspected cause of aCP (74.7%), but was confirmed after hospital admission in only 26.3% of patients. ASA was administered in 51%, UFH in 55%, and both substances in 46.4% of cases. A large proportion of patients received anticoagulants in the pre-hospital setting although the discharge diagnosis was not NSTE-ACS: ASA 62.9%, UFH 66.0%, both substances 56.5%.

Conclusions: ASA and UFH are often given to EP-accompanied patients with aCP despite the low accuracy of diagnosis in the pre-hospital setting. Pre-hospital measurement of high-sensitivity troponin T (hs Trop-T) might improve discrimination between NSTE-ACS and other causes of aCP. This is important, as the current guidelines contain no clear recommendations for pre-hospital drug treatment in NSTE-ACS.

Acute chest pain (aCP) accounts for 16.4% of all deployments of emergency physicians (1) and is among the most common reasons for presentation to emergency departments (2). aCP is sensitive for detecting potentially life-threatening diseases such as acute coronary syndrome without ST-segment elevation (NSTE-ACS) (3) and acute aortic syndrome (AAS) (4). However, aCP is not sufficiently specific to exclude less dangerous, non-cardiac causes, and less than 1% of persons with aCP in the emergency department need an acute intervention (5). This diagnostic discrimination is even more challenging in the pre-hospital setting. The German emergency medical service system is based on board-certified emergency physicians (EP) of various specialties. aCP is a typical reason for call-out of an EP, who generally meets the paramedics at the scene. The guideline-based recommendations for preclinical medical therapy are ambiguous. The aims of the present study were as follows:

• To investigate diagnostic accuracy of EP diagnoses in aCP
• To assess the pre-hospital use of anticoagulants and platelet aggregation inhibitors in aCP patients
• To correlate these findings with the definite aCP etiology

Patients and methods

In this retrospective cohort study, we analyzed the data of patients with aCP who were brought to the Chest Pain Unit (CPU) of Cologne University Hospital accompanied by an EP between July 2018 and December 2020. Patients in whom ST-elevation myocardial infarction (STEMI) was identified in the pre-hospital setting and those who were not treated by an EP before admission were excluded. The study was performed in accordance with the ethical standards of the Declaration of Helsinki and was approved by the ethics committee of the University of Cologne (reference no. 21–1143). The study was performed in accordance with the ethical standards of the Declaration of Helsinki.

Parameters and classification

The following parameters were recorded: age, sex, known cardiovascular risk factors, and selected long-term medication with platelet aggregation inhibitors such as acetylsalicylic acid (ASA) or adenosine diphosphate (ADP)-receptor antagonists, vitamin K antagonists (VKA), or direct oral anticoagulants (DOAC). Furthermore, vital signs, electrocardiogram (ECG) alterations, and selected laboratory parameters at hospital arrival were documented. Pre-hospital treatment with ASA and/or unfractionated heparin (UFH) administered by the EP was recorded. The causes of aCP cause were divided into the following categories: NSTE-ACS, AAS, hypertensive crisis (HC), cardiac arrhythmias (CA), musculoskeletal, and other (i.e., pain of gastrointestinal, pulmonary, neurological, or psychiatric origin) (6). Assignment to these subgroups was made on the basis of the EP protocol or the CPU discharge letter respectively and was thus at the discretion of the EP (pre-hospital diagnosis) or the treating physician at the CPU (discharge diagnosis). In line with the current guidelines (7), cases of chronic coronary syndrome (CCS) were classified as NSTE-ACS in the event of a positive result.

Statistical analysis

The distribution of quantitative variables was summarized as mean ± standard deviation (SD) and that of qualitative variables as absolute and relative frequencies. The association of preclinical characteristics with diagnostic groups was evaluated by cross-tabulation (for categorical data) or analysis of variance based on ranks (for quantitative data). Pairwise comparisons of groups were based on the chi-square test or the Mann–Whitney U-test, respectively. Comparison of suspected or discharge diagnosis and pre-existing/administered medication was accomplished using the McNemar test. Any p values smaller than 0.05 were considered to indicate statistical significance, at least in an exploratory manner, since no adjustment for multiplicity was performed. All statistical calculations were carried out using SPSS Statistics (IBM Corp.).

Results

A total of 822 patients with a mean age of 65 ± 17 years (64% men) were included in the study. Of these patients, 548 (66.6%) had ≤ 1 risk factor, 99 patients (12%) had 2–3 risk factors, and 175 patients (21.3%) had > 3 risk factors for coronary heart disease (CHD). A history of CHD was present in 368 patients (45%). The preexisting drug treatment comprised ASA in 303 patients (36.9%), ADP in 120 patients (14.6%), VKA in 46 patients (5.6%), and DOAC in 142 patients (17.3%). The baseline characteristics are listed in full in Table 1.

Table 1

The characteristics of patients with acute chest pain by diagnostic subgroup (a–f*)

Pre-hospital drug treatment

In the studied cohort of patients with aCP, 419 patients (51%) were given ASA, 453 patients (55%) received UFH, and 381 patients (46.4%) were treated with both substances in the pre-hospital setting (Table 2). For patients with the suspected diagnosis of NSTE-ACS, the proportions were higher: ASA, 395 patients (64.4%); UFH, 427 patients (69.5%); both substances, 361 patients (58.8%). All in all, a large proportion of patients received drug treatment although their discharge diagnosis was not NSTE-ACS: ASA, 266 patients (62.9%); UFH, 279 patients (66.0%); both substances, 239 patients (56.5%). In cases where the EP suspected a cause other than NSTE-ACS, 24 patients (11.5%) were given ASA, 26 (12.5%) received UFH, and 20 (9.6%) were treated with both substances. Invasive coronary angiography was performed in 287 patients (34.9%), of whom 155 (18.9%) received a percutaneous coronary intervention (PCI).

Table 2

Preclinical medical treatment with either ASA or UFH by suspected cause of aCP and discharge diagnosis

Comparison of long-term medication and the drug treatment given by the EP revealed an influence of the pre-existing medication on the decision by the EP whether or not to administer an extra loading dose. Pre-existing treatment with ASA or ADP reduced the number of patients who received an additional loading dose of ASA (both p < 0.001). Likewise, prior treatment with either VKA or DOAC led to less frequent administration of an extra loading dose of UFH (both p < 0.001; eTable 1).

eTable

Pre-hospital medication with either ASA or UFH compared with regard to pre-existing long-term treatment focusing on platelet aggregation inhibitors (ASA, ADP) and anticoagulants (UFH, VKA, DOAC)

Diagnostic accuracy

NSTE-ACS was the leading suspected cause of aCP in the pre-hospital setting (614 patients, 74.7%) followed by other causes (96 patients, 11.7%), arrhythmias (53 patients, 6.4%), HC (25 patients, 3.1%), AAS (24 patients, 2.9%) and lastly musculoskeletal aCP (10 patients, 1.2%) (Figure). In contrast to the pre-hospital diagnosis, musculoskeletal aCP was the most common diagnosis at discharge (223 patients, 27.1%). Only 217 patients (26.3%) were diagnosed with NSTE-ACS at discharge. In 23 patients (10.6%), CCS was detected retrospectively. Nineteen persons (2.3%) were discharged with the final diagnosis of NSTE-ACS although another cause of aCP had initially been suspected (Figure). Comparison of suspected diagnosis and discharge diagnosis revealed an overall positive predictive value (PPV) of 39.7% (Table 3). Analysis of subgroups showed that the PPV was lowest in suspected AAS (7 of 24 persons, 29.2%), followed by suspected NSTE-ACS (198 of 614 persons, 32.2%). However, the PPV was high in HC (20 of 25 persons, 80%), musculoskeletal aCP (8 of 10 persons, 80%), and CA (42 of 53 persons, 79.2%). Pre-hospital diagnosis of NSTE-ACS had the greatest sensitivity (91.2%), a high negative predictive value (NPV) of 91%, and the lowest specificity (31.2%). For the remaining diagnostic categories, the sensitivity and specificity were 28.2% and 93.0%, respectively, for other causes, 58.3% and 97.9% for AAS, 17.5% and 99.3% for HC, 3.6% and 99.7% for musculoskeletal aCP, and 56.0% and 98.5% for CA.

Figure

Sankey plot showing the changes from suspected diagnosis to discharge diagnosis in all 822 patients with aCP. AAS, Acute aortic syndrome; aCP, acute chest pain; CA, cardiac arrhythmia; HC, hypertensive crisis; NSTE-ACS, acute coronary syndrome without ST-segment elevation

Satisfactory discrimination of patients with NSTE-ACS from all other groups was not possible on the basis of pre-hospital variables. The initial pre-hospital systolic blood pressure was higher in HC than in other causes of aCP (185 ± 27 mm Hg vs. 40 ± 28 mm Hg, p < 0.05). The heart rate was higher in CA than in aCP of other causes (115 ± 52 vs. 82 ± 21 bpm, p < 0.05). Addition of the first available high-sensitivity troponin T (hs Trop-T) measurement allowed for discrimination of NSTE-ACS from all other causes of aCP (0.18 ± 0.43 vs. 0.03 ± 0.1 µg/L, p < 0.05; Table 1).

Discussion

This study demonstrates that the frequency of life-threatening causes of aCP is often overestimated in the pre-hospital setting, commonly resulting in non-indicated pre-hospital treatment with anticoagulants and platelet aggregation inhibitors.

The overall PPV for all aCP patients was 39.7%, driven mainly by the frequency of the suspected diagnoses NSTE-ACS and AAS. Various scoring systems for the risk assessment of persons with NSTE-ACS are available: while the Thrombolysis in Myocardial Infarction (TIMI [8]) and Global Registry of Acute Coronary Events (GRACE [9]) scores are used mainly to predict the outcome after confirmed NSTE-ACS, the HEART score (history, ECG, age, risk factors, troponin) has shown its potential for enabling early and safe discharge from the emergency department (10). The advent of reliable point-of-care troponin testing (11) could enable the EP to exclude NSTE-ACS in the pre-hospital setting. This concept has proven its value in a large observational cohort (12) and is currently being evaluated in a randomized study (13). Similarly, a score has been published that rules out AAS with sensitivity of 91% (14). Point-of-care testing (POCT) of troponin may prove useful in the future.

Improvement in the pre-hospital diagnostic accuracy of NSTE-ACS and AAS would reduce unnecessary transportation to tertiary centers after exclusion of these diagnoses. Moreover, secondary transportation following delayed diagnosis of NSTE-ACS would be avoided. This would be of benefit especially in rural areas where access to interventional treatments such as PCI is limited. Furthermore, it bears the potential to improve the pre-hospital use of anticoagulants and platelet aggregation inhibitors. As demonstrated in this study, a large proportion of patients are given ASA and UFH on suspicion of NSTE-ACS in the pre-hospital setting.

The current European Society of Cardiology (ESC) guidelines on NSTE-ACS emphasize the need for balancing the risks of ischemia and bleeding with regard to platelet aggregation inhibition and anticoagulation (15). Both ASA and UFH have a class 1A recommendation for use in patients with confirmed NSTE-ACS who are undergoing PCI. Even though the scientific foundation for this recommendation predates the advent of widely available diagnostic imaging and hs trop-T testing (16, 17), the importance of both substances in confirmed NSTE-ACS during PCI is not in question. However, neither the European (15) nor the American (18) guidelines provide specific advice to the pre-hospital use of anticoagulants and platelet aggregation inhibitors—this lack of evidence has been criticized before (19). In fact, according to a recent ESC position paper neither ASA nor UFH are advisable in the pre-hospital setting if the patient will not undergo acute PCI within < 2 h (19). There are practically no robust data on the pre-hospital use of ASA or UFH in NSTE-ACS (20).

The combination of low diagnostic accuracy coupled with broad use of ASA and UFH in patients with suspected NSTE-ACS gives rise to various problems. First, both ASA and UFH are regularly administered with no indication. The incidence of heparin-induced thrombocytopenia (HIT) in patients with ACS ranges from < 1% (21) to 9.5% (22), and HIT is associated with a less favorable outcome (23). Even a single dose of UFH can trigger severe HIT (24). Bleeding time can be significantly prolonged in certain patients after a single dose of ASA (25, 26), with potentially fatal complications (27). If the symptoms turn out to be caused by AAS rather than the initially suspected NSTE-ACS, pre-hospital treatment with ASA and UFH leads to a significant increase in fatal complications (28). On the other hand, experience has shown that UFH use is safe and possibly beneficial in patients with STEMI (29, 30).

It is unknown whether preclinical use of anticoagulants or platelet aggregation inhibitors is superior to administration following hospital confirmation of the diagnosis. Patients with non-STEMI are older and have more comorbidities and a higher bleeding risk than those with STEMI or unstable angina (31, 32). Importantly, the introduction of hs trop-T testing and the ESC’s 0/1 h algorithm has greatly improved the rule-in/rule-out of myocardial infarction. Particularly in densely populated areas, the time between notification of the emergency medical services and rule-in/rule-out of myocardial infarction can be as little as a few hours. It is unknown whether administration of ASA and/or UFH just a few hours earlier outweighs the potential complications, especially in view of the low pre-hospital diagnostic accuracy. In this context, it is important to remember that pretreatment of patients with NSTE-ACS using prasugrel (33) or ticagrelor (34) had no positive effect on hard outcomes and led to more bleeding complications.

Many persons with ACS regularly take a VKA or DOAC preparation. In the case of confirmed STEMI, a recent consensus paper from the German Cardiac Society recommends administration of an additional loading dose of UFH and ASA, regardless of the timing of the last intake of VKA or DOAC (35). We found in this study that pre-existing treatment with ASA/ADP or VKA/DOAC influences the pre-hospital administration of an additional dose of ASA or UFH in the presence of aCP. Although this finding may not be surprising overall, a closer look reveals heterogeneous behavior on the part of the EP: only 24% of patients on pre-existing VKA therapy but 54% of patients on pre-existing DOAC therapy were treated with an additional dose of UFH. It may well be that persons with aCP whose symptoms are indeed due to partial or complete coronary occlusion benefit from an additional loading dose. Robust data supporting this are lacking, however, and in the context of the relatively high incidence of aCP it remains open whether rare complications are overlooked.

This study has several limitations. We present retrospective findings from a single center in an urban area of Germany that cannot be extrapolated to a region or country with a differently structured emergency medical system. Furthermore, practical clinical conclusions can be drawn only from a prospective, ideally randomized study of hard outcomes such as major adverse cardiovascular events (MACE) or bleeding complications and the the incidence of HIT. The discharge diagnoses were taken from the CPU discharge letters without any detailed workup, so there is a lack of precision in the group “other causes” and “musculoskeletal cause” are very likely overestimated. However, the focus of this study was on patients with NSTE-ACS—a category that in the hospital is practically never overlooked or misdiagnosed owing to the use of fixed algorithms and high-sensitivity diagnostics. Finally, using the first available hs Trop-T measurement in the hospital overestimates the actual hs Trop-T concentration at the preclinical scene, although the short transportation times in an urban setting counter this effect.

In summary, we demonstrate that pre-hospital diagnosis of NSTE-ACS is challenging and often leads to overuse of ASA and UFH. The sparsity of data is reflected in the uncertainty displayed by EP, especially in the presence of pretreatment with VKA or DOAC. The relative incidence of the complications associated with this is probably very low; given the sheer number of NSTE-ACS patients and the widespread use of platelet aggregation inhibitors and anticoagulants in the pre-hospital setting worldwide, however, an impact of this overuse on the incidence of these complications cannot be excluded. Improving pre-hospital diagnostic accuracy is necessary to ease decision making for EP in aCP. Future studies should investigate whether preadmission treatment with ASA and UFH is beneficial or harmful in suspected NSTE-ACS.

Funding

This research did not receive any specific funding from public, commercial, or non-profit agencies.

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 20 September 2022, revised version accepted on 7 March 2023

Corresponding author:
PD Dr. med. Christoph Adler
Medizinische Fakultät und Uniklinik Köln
Klinik III für Innere Medizin
Universität zu Köln
Kerpener Str. 62, 50937 Köln, Germany

Cite this as:
Braumann S, Faber-Zameitat C, Macherey-Meyer S, Tichelbäcker T,
Meertens M, Heyne S, Nießen FS, Nies RJ, Nettersheim FS, Reuter H,
Pfister R, Hellmich M, Burst V, Baldus S, Lee S, Adler C:
Acute chest pain—diagnostic accuracy and pre-hospital use of anticoagulants and platelet aggregation inhibitors. Dtsch Arztebl Int 2023; 120: 317–23.
DOI: 10.3238/arztebl.m2023.0065

►Supplementary material

eTable:
www.aerzteblatt-international.de/m2023.0065

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