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Original research article
Incidence and outcomes of unstable angina compared with non-ST-elevation myocardial infarction
  1. Christian Puelacher1,2,
  2. Mathias Gugala2,
  3. Philip D Adamson3,
  4. Anoop Shah4,
  5. Andrew R Chapman5,
  6. Atul Anand3,
  7. Zaid Sabti2,
  8. Jasper Boeddinghaus2,
  9. Thomas Nestelberger2,
  10. Raphael Twerenbold2,
  11. Karin Wildi2,
  12. Patrick Badertscher2,
  13. Maria Rubini Gimenez2,6,
  14. Samyut Shrestha1,2,
  15. Lorraine Sazgary1,2,
  16. Deborah Mueller2,
  17. Lukas Schumacher2,
  18. Nikola Kozhuharov2,
  19. Dayana Flores2,
  20. Jeanne du Fay de Lavallaz2,
  21. Oscar Miro7,
  22. Francisco Javier Martín-Sánchez8,
  23. Beata Morawiec9,
  24. Gregor Fahrni10,
  25. Stefan Osswald10,
  26. Tobias Reichlin10,11,
  27. Nicholas L Mills12,
  28. Christian Mueller2
  1. 1 Department of Internal Medicine, University Hospital Basel, Basel, Switzerland
  2. 2 Cardiovascular Research Institute Basel, Department of Cardiology, University Hospital Basel, University Basel, Basel, Switzerland
  3. 3 Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
  4. 4 BHF/University Centre for Cardiovascular Science, Royal Infirmary of Edinburgh, Edinburgh, UK
  5. 5 BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
  6. 6 Parc de Salut Mar-IMIM-UPF, Parc de Salut, Spain
  7. 7 Emergency Department, Hospital Clinic, Barcelona, Spain
  8. 8 Emergency Department, Hospital San Carlos de Madrid, Madrid, Spain
  9. 9 2nd Department of Cardiology, Medical University of Silesia, Zabrze, Poland
  10. 10 Department of Cardiology, University Hospital Basel, Basel, Switzerland
  11. 11 Department of Cardiology, Inselspital Bern University Hospital, University of Bern, Bern, Switzerland
  12. 12 BHF Centre for Cardiovascular Sciences, The University of Edinburgh, Edinburgh, UK
  1. Correspondence to Professor Christian Mueller, Department of Cardiology, University Hospital Basel, Basel 4031, Switzerland; Christian.Mueller{at}usb.ch

Abstract

Objective Assess the relative incidence and compare characteristics and outcome of unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI).

Design Two independent prospective multicentre diagnostic studies (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE] and High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome [High-STEACS]) enrolling patients with acute chest discomfort presenting to the emergency department. Central adjudication of the final diagnosis was done by two independent cardiologists using all clinical information including serial measurements of high-sensitivity cardiac troponin (hs-cTn). All-cause death and future non-fatal MI were assessed at 30 days and 1 year.

Results 8992 patients were enrolled at 11 centres. UA was adjudicated in 8.9%(95% CI 8.0 to 9.7) and 2.8% (95% CI 2.3 to 3.3) patients in APACE and High-STEACS, respectively, and NSTEMI in 15.1% (95% CI 14.0 to 16.2) and 13.4% (95% CI 12.4 to 14.3). Coronary artery disease was pre-existing in 73% and 76% of patients with UA. At 30 days, all-cause mortality in UA was substantially lower as compared with NSTEMI (0.5% vs 3.7%, p=0.002 in APACE, 0.7% vs 7.4%, p=0.004 in High-STEACS). Similarly, at 1 year in UA all-cause mortality was 3.3% (95% CI 1.2 to 5.3) vs 10.4% (95% CI 7.9 to 12.9) in APACE, and 5.1% (95% CI 0.7 to 9.5) vs 22.9% (95% CI 19.3 to 26.4) in High-STEACS, and similar to non-cardiac chest pain (NCCP). In contrast, future non-fatal MI in APACE was comparable in UA and NSTEMI (11.2%, 95% CI 7.8 to 14.6 and 7.9%, 95% CI 5.7 to 10.2), and higher than in NCCP (0.6%, 95% CI 0.2 to 1.0).

Conclusions The relative incidence and mortality of UA is substantially lower than that of NSTEMI, while the rate of future non-fatal MI is similar.

  • unstable angina pectoris
  • acute coronary syndrome
  • mortality
  • myocardial infarction

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Introduction

The acute coronary syndrome (ACS) is a major cause of death and disability worldwide.1–3 Among the three phenotypes comprising the ACS, ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI) and unstable angina (UA), the latter two are considered by many to exist along a spectrum with shared patient characteristics, pathophysiology and outcome. They are accordingly grouped together with regard to management recommendations in current non-ST-elevation-ACS practice guidelines.1 2

Post hoc subgroup analyses from randomised controlled trials of early coronary revascularisation and dual-antiplatelet therapy have provided first hints regarding possible differences in the underlying pathophysiology between UA and NSTEMI. In particular, the benefit of both early revascularisation and intensified dual-antiplatelet therapy was substantial in NSTEMI, but non-existent in UA.4 5

High-sensitivity cardiac troponin (hs-cTn) assays precisely quantify even subtle amounts of cardiomyocyte injury and for the first time allow clinicians to reliably differentiate UA from NSTEMI and thereby better characterise patients with UA.6–12 Both UA and NSTEMI exhibit symptoms and signs of myocardial ischaemia at rest or minimal exercise, while only the latter fulfils the mandatory criteria of the universal definition of MI with a rise or fall in cardiac troponin and absolute levels >99th percentile reference limit.10

To better understand the underlying incidence, patient characteristics, pathophysiology and outcome of UA,13–16 we performed two large prospective study of patients with suspected ACS, central adjudication using hs-cTn and long-term follow-up.

Methods

Study design and population

Advantageous Predictors of ACS Evaluation (APACE) is an ongoing prospective international multicentre diagnostic study with 12 centres in Europe (NCT00470587).6 9 11 12 High-Sensitivity Troponin in the Evaluation of Patients With ACS (High-STEACS, NCT01852123) included patients enrolled in three hospitals in Scotland into the standard care arm of an ongoing stepped-wedge cluster randomised trial.17 Further detail is found in the online supplemental material.

Both studies were carried out according to the principles of the Declaration of Helsinki (see online supplemental material). Informed consent was obtained.

Primary end points

The relative incidence of UA in patients presenting to the emergency department (ED) with symptoms suggestive of ACS, as well as all-cause mortality and future non-fatal MI at 30 days and 1 year were the primary end points of this analysis.

Adjudication of final diagnosis

Adjudication of the final diagnosis was performed centrally for each study individually, in Basel6 9 11 and Edinburgh17 by two independent cardiologists. In situations of disagreement, cases were adjudicated in conjunction with a third cardiologist.

Adjudication of the final diagnosis was done using hs-cTn (hs-cTnT in APACE, hs-cTnI in High-STEACS) measured from study blood samples and by review of all available medical records (including patient history, physical examination, ECG, results of laboratory testing including local (hs)-cTn levels, radiologic testing, echocardiography, cardiac exercise test and coronary angiography) pertaining to the patient from the time of ED presentation to 90-day follow-up.

STEMI, NSTEMI and UA angina were defined and hs-cTn levels were interpreted as recommended in the current guidelines.1–3 18 Specifically, NSTEMI was diagnosed when there was evidence of acute myocardial necrosis in association with a clinical setting consistent with myocardial ischaemia.1–3 10 Acute myocardial necrosis was inferred from the detection of a rise and/or fall in hs-cTn, with at least one measurement >99th percentile.1–3 10 If, in addition to the aforementioned criteria, there was significant new and persistent ST-segment elevations, STEMI was diagnosed.3

UA was diagnosed in patients with ischaemic symptoms at rest or minor exercise with no evidence of acute myocardial necrosis. hs-cTn concentrations are in the normal range or may be mildly elevated due to other chronic cause, for example, valvular heart disease or heart failure, but without dynamic changes (criteria for MI not met). The following criteria increased the likelihood, but were not mandatory, for the diagnosis of UA: typical angina pectoris at rest; worsening/deterioration of a previously stable angina; cardiac stress test showing myocardial ischaemia; coronary angiography revealing a diameter stenosis of at least 70%; fractional flow reserve documenting functional significance of a coronary lesion and sudden cardiac death or MI occurred during 60-day follow-up. Imaging evidence of coronary artery disease (CAD) or exercise-induced myocardial ischaemia in isolation was not sufficient for UA adjudication. For example, a patient with CAD and typical musculoskeletal chest pain, aggravated by palpation or inspiration, would have been adjudicated as suffering from non-cardiac chest pain (NCCP).

However, perhaps reflecting some imprecision in the current diagnostic guidelines, the significance of troponin in the adjudication of UA was considered differently in the APACE and High-STEACS cohorts. In the appropriate clinical context, patients in APACE could be judged to have UA in the presence of mild hs-cTn elevations >99th percentile without dynamic changes and the mild hs-cTn elevations related to other cardiac disease such as valvular heart disease or heart failure. In contrast, within the High-STEACS population, any measurement of hs-cTn >99th percentile precluded this diagnosis being made. To investigate the clinical significance of this diagnostic discrepancy, a post hoc analysis was performed aligning the definitions and splitting UA according to maximum hs-cTn <99th percentile or >99th percentile.

Furthermore, in APACE patients without an ACS were differentiated into NCCP and ‘cardiac, other’, while in High-STEACS no further differentiation was performed and all patients were classified as having ‘non-coronary chest pain’ (NCoCP),

Additional details regarding diagnostic adjudication including hs-cTn measurements are provided in the online supplemental material.

Statistical analysis

The primary aim of this analysis was to evaluate the relative incidence and compare baseline characteristics and outcomes of patients with UA, NSTEMI and NCCP among patients with suspected ACS presenting to and initially managed in the ED.

Relative incidence of each diagnosis within patients presenting to and initially managed in the ED was determined and 95% CI were calculated using the formula by Agresti and Coull.19 To evaluate outcome, Kaplan-Meier curves were used to estimate the 1-year mortality and future non-fatal MI rate separately, and comparison between UA and NSTEMI was done using the log-rank test. The analyses were repeated using the aligned definition of UA split according to the presence or absence of any hs-cTn concentration >99th percentile.

Furthermore, subgroup analyses to explore the clinical characteristics associated with both outcomes were performed.

As exploratory secondary analyses we quantified changes of hs-cTnT within 1 hour and 2 hours in patients with UA from APACE to detect and quantify acute cardiomyocyte injury irrespective of the peak concentrations achieved. This could potentially identify a subgroup of patients with dynamic changes in hs-cTnT in whom plasma concentrations remained <99th percentile of healthy individuals, the sine qua non for a diagnosis of MI.12 These changes have been observed in about 25% of patients when adjudication was performed using conventional less sensitive cTn assays.12

Multivariable Cox proportional hazards analysis was performed to determine the impact of UA in comparison to NSTEMI on the end points. For future non-fatal MI, competing risk analysis was performed. Further detail on modelling as well as subgroup analyses and angiographic characteristics of patients with UA are described in the online supplemental material.

All hypothesis testing was two-tailed and p values <0.05 were considered to be statistically significant. All statistical analyses were performed using SPSS for Windows V.22.0 (SPSS, Chicago, Illinois, USA) and R (V.3.3.0, ‘survival’, ‘survminer’, ‘cmprsk’).

Results

Participants

A total of 8992 patients were enrolled at 11 sites (8 APACE, 3 High-STEACS). From April 2006 to August 2015, a total of 4122 eligible patients were recruited in APACE, and from June 2013 to February 2014, 4870 eligible patients were recruited in High-STEACS (online supplementary eFigure 1).

Relative incidence of unstable angina

In APACE, UA was the adjudicated final diagnosis in 8.9% (95% CI 8.0% to 9.7%, 366/4122), and in High-STEACS in 2.8% (95% CI 2.3 to 3.3, 137/4870) among patients presenting to the ED with suspected ACS. In APACE, NSTEMI was diagnosed in 15.1% (95% CI 14.0 to 16.2, 622/4122), NCCP in 52.3% (95% CI 50.7 to 53.8, 2154/4122), STEMI in 3.5% (95% CI 2.9 to 4.0, 143/4122), cardiac symptoms of origin other than CAD in 13.8% (95% CI 12.7 to 14.8, 568/4122) and symptoms of unknown origin in 6.5% (95% CI 5.8 to 7.3, 269/4122). In High-STEACS, NSTEMI was diagnosed in 13.2% (95% CI 12.4 to 14.3, 651/4870), STEMI in 2.7% (95% CI 2.2 to 3.1, 131/4870), NCoCP in 81.1% (95% CI 80.0 to 82.2, 3951/4870).

In the analysis using an aligned definition across studies, the relative incidence of UA was 6.1% (95% CI 5.7 to 6.6, 553/8992, Figure 1C+2C) when considering any maximum hs-cTn levels without evidence of acute necrosis, with 50 patients with NSTEMI being classified as UA in High-STEACS. When considering only maximum hs-cTn levels <99th percentile, the relative incidence of UA was 3.9% (95% CI 3.5 to 4.3, 352/8992), with 151 patients with UA being classified as NSTEMI in APACE.

Characteristics of UA

Patients with UA were more likely to have established cardiovascular risk factors, pre-existing CAD, previous MI and prior coronary revascularisation compared with patients with NSTEMI (table 1). The baseline characteristics of the patients with UA split according to the presence of hs-cTn >99th percentile are presented in online supplementary eTable 1. Angiographic data of patients with UA were comparable to the findings of patients with NSTEMI (online supplementary eTable 4).

Table 1

Baseline characteristics

Short-term and long-term outcomes

In APACE and High-STEACS, 30-day all-cause mortality was 0.5% and 0.7% in UA (table 2), which was lower as compared with NSTEMI (3.7%, p=0.002 and 7.4%, p=0.004) and not significantly different to NCCP/NCoCP (0.5%, p=0.734 and 2.3%, p=0.232).

Table 2

Incidence of prognostic end points all-cause death and future non-fatal myocardial infarction (AMI) stratified according to final diagnoses

The corresponding 1-year mortality was 3.1% and 4.5% in UA, lower than NSTEMI (9.1%, p<0.001, figure 1A and 19.2%, p<0.001, figure 1B), and not significantly different to NCCP/NCoCP (2.1%, p=0.228 and 6.7%, p=0.092).

Figure 1

One-year survival of patients stratified according to final adjudicated diagnoses. Panels A and B show the results from the APACE and High-STEACS cohorts individually. Panel C shows both cohorts combined. Panel D depicts the analysis using aligned definition of unstable angina splitting the patients with unstable angina in those without vs with any high-sensitivity cardiac troponin (hs-cTn) measurement >99th percentile. P values were calculated using the log-rank test. APACE, Advantageous Predictors of Acute Coronary Syndromes Evaluation; High-STEACS, High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

In contrast, the 30-day rate of future non-fatal MI was similar between patients with UA and NSTEMI: in APACE 4.6% of patients with UA, and 3.1% (p=0.277) of patients with NSTEMI had a future non-fatal MI, compared with one patient (0.0%, p<0.001) with NCCP. In High-STEACS, 2.2% of patients with UA and 3.1% (p=0.514) with NSTEMI had a future non-fatal MI, while the rate was lower at 0.1% (p<0.001) in those with NCoCP.

The corresponding 1-year rate of future non-fatal MI in APACE and High-STEACS was 11.2% and 4.4% in UA and comparable to NSTEMI (8.6%, p=0.135, figure 2A, and 10.3%, p=0.033, figure 2B*), and was higher than NCCP/NCoCP (0.6%, p<0.001 and 1.0%, p<0.001).

Figure 2

One-year survival free from future non-fatal myocardial infarction of patients stratified according to final adjudicated diagnoses. Panels A and B show the results from the APACE and High-STEACS cohorts individually. Panel C shows both cohorts combined. Panel D depicts the analysis using aligned definition of unstable angina splitting the patients in those without vs with any high-sensitivity cardiac troponin (hs-cTn) measurement >99th percentile. P values were calculated using the log-rank test. APACE, Advantageous Predictors of Acute Coronary Syndromes Evaluation;  High-STEACS, High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

Multivariable analysis of outcome

In our multivariable prognostic model, patients with UA had a mortality at 1 year similar to patients with NCCP (HR 1.3, 95% CI 0.7 to 2.6, p=0.40), while patients with NSTEMI carried a significantly increased risk (HR 2.5, 95% CI 1.3 to 4.7, p=0.007, table 3). In contrast, the risk of future non-fatal MI was similar to that of NSTEMI (HR 0.8, 95% CI 0.5 to 1.2, p=0.23), and significantly lower in patients with NCCP (HR 0.1, 95% CI 0.0 to 0.2, p<0.001, table 4). Results remained consistent when analysed with competing risk of death (NSTEMI HR 0.7, 95% CI 0.5 to 1.2, p=0.19; NCCP HR 0.1, 95% CI 0.04 to 0.2, p<0.001).

Table 3

Univariable and multivariable Cox proportional hazards analysis for mortality within 1 year in the APACE cohort

Table 4

Univariable and multivariable Cox proportional hazards analysis for future non-fatal myocardial infarction within 1 year in the APACE cohort

Aligned definitions of UA

In the total cohort, 1-year mortality was lower in patients with UA without versus with any hs-cTn concentration >99th percentile (2.6% vs 9.5%, p=0.001, figure 1D, online supplementary eTable 5). One-year rate of future non-fatal MI was also significantly lower in those without versus with any hs-cTn concentration >99th percentile (5.7% vs 14.6%, p=0.001, figure 2D).

Subgroup analysis

In the subgroup analysis, patients with UA had a lower rate of death than patients with NSTEMI in all groups, whereas risk of future non-fatal MI was similar when stratified by age, sex, prior ischaemic heart disease or ischaemia on the ECG (p>0.05 for all). The only subgroup in which there was heterogeneity was when stratification was performed according to whether there was any elevation in hs-cTn concentration (figure 3).

Figure 3

Subgroup analyses of risk for all-cause mortality (panel A) and future non-fatal myocardial infarction (panel B) in patients with unstable angina (UA) compared with patients with non-ST-segment elevation myocardial infarction (NSTEMI). IHD, ischaemic heart disease.

hs-cTn levels and short-term changes in UA

The majority of patients with UA (82%) did not exhibit a relevant change in hs-cTnT (≥2 ng/L within the first hour or ≥4 ng/L in the first 2 hours) on serial testing (figure 4A, B). Plasma concentrations of hs-cTnT in patients with UA were >99th percentile (≥14 ng/L) in 39% of all patients at the 0 hour, 1 hour or 2 hours measurements (figure 4C). Mortality seemed more closely associated with the absolute plasma concentration than with short-term changes (figure 4D).

Figure 4

Description of short-term changes within 1 hour and 2 hours as well as maximum absolute value in high-sensitive cardiac troponin T (hs-cTnT) in patients with unstable angina. Panels A and B show change from baseline to 1 hour and 2 hours, the black lines indicates the threshold chosen for significant dynamic (≥2 and ≥4 ng/L). Panel C shows the distribution of maximum absolute level measured at 0 hour, 1 hour or 2 hours, with the black line indicating the 99th percentile (≥14 ng/L). Panel D shows 1-year survival stratified according to whether the 99th percentile was reached and whether there was a significant change within 1 hour or 2 hours.

Discussion

Using two large prospective multicentre studies of patients with acute chest discomfort and central adjudication of the final diagnosis employing serial measurements of hs-cTn, we aimed to gain a better understanding of the incidence, patient characteristics, pathophysiology, management and outcome of UA. We report five major findings.

First, the incidence of UA among patients presenting to the ED with suspected ACS was <10% overall, and less than half that of MI. This finding extends and corroborates previous pilot studies with less stringent methodology.9 13–15 The more sensitive the cTn assay used for the adjudication of the final diagnosis, the less likely that a patient with true NSTEMI would be incorrectly classified as UA, and thereby the lower the incidence of UA.13 14 That this is not always seen in clinical practise20 might be due to two components of the diagnosis of UA, as illustrated by different incidences in the two cohorts: a) the different classification of patients with non-dynamic hs-cTn values >99th percentile, some of which were classified as UA in APACE, but not in High-STEACS, and b) the combination of more restrictive criteria where either functional or imaging evidence of obstructive CAD was necessary for adjudication of UA, and the less frequent use of these tests as in the High-STEACS population.

Second, patients with UA were more likely to have established cardiovascular risk factors, pre-existing CAD including previous MI, and prior coronary revascularisation compared with patients with NSTEMI.

Third, and possibly of most importance, all-cause mortality was very low in patients with UA, only about one-seventh and one-third that of NSTEMI at 30 days and 1 year, respectively and was similar to patients with NCCP. This finding was irrespective of the definition used, and even more pronounced for patients with UA without maximum hs-cTn levels >99th percentile. The lower mortality of UA may at least in part be related to the near universal use of aspirin and statins prior to presentation due to the very high rate of previously known CAD and possible modification of the ACS pathophysiology by these preventive therapies.

Fourth, in contrast, the rate of future non-fatal MI was high (11% at 1 year) and similar to that of patients with NSTEMI. The findings in the APACE and High-STEACS cohort were consistent when compared with patients without ACS, but differences were observed in the absolute rate of future non-fatal MI in those classified as UA between cohorts (11.2% and 5.1% respectively at 1 year). As this was likely due to the different approach concerning patients with elevation in hs-cTn concentration >99th percentile, we did an analysis aligning the UA definitions across studies. This showed that the rate of future non-fatal MI differed in patients with UA in whom maximum hs-cTn concentrations were <99th percentile compared with those with elevated hs-cTn. This highlights the important prognostic role of hs-cTn also in patients with UA, as well as the uncertainty in the current guidelines as to how to classify this group of patients and may imply the need for more aggressive management approaches in these individuals. Importantly, the rate of coronary angiography and angioplasty was high in patients with UA.

Fifth, the vast majority (82%) of patients with UA did not exhibit relevant 1 hour or 2 hours changes in hs-cTnT, making acute cardiomyocyte injury directly related to the ischaemic episode unlikely. Therefore, patients with UA seem to lack the pathognomonic feature of type I MI—cardiomyocyte injury related to thromboembolism from a culprit coronary plaque. This possibly indicates either a lack of distal embolisation or embolisation of platelet microparticles that are too small to cause cardiomyocyte injury. Future prospective studies using a systematic approach to imaging incorporating invasive optical imaging are required to better understand the coronary mechanisms of UA and to determine whether there is any evidence of intracoronary thrombus formation in patients with UA. This is further highlighted by the fact that in angiography the findings were similar in patients with UA and NSTEMI. It is possible that prior use of antiplatelet therapies in this group of patients, in whom the majority are known to have CAD, may modify the size of platelet microparticles released into the coronary circulation from culprit lesions, such that they are too small to cause cardiomyocyte injury. Both scenarios could explain the observations made in retrospective subgroup analyses of randomised controlled trials showing lack of benefit from intensified dual-antiplatelet therapy in patients with appropriately diagnosed UA and no cardiomyocyte injury as quantified by hs-cTn.4 5 13 14

Our findings extend and corroborate previous studies and are of major clinical importance.9 13–15 Overall, they provide strong support for the evolving concept that UA more closely reflects the pathophysiology and outcomes of stable CAD than MI, particularly in the absence of elevated hs-cTn concentrations. Considering the much higher prevalence of comorbidities including CAD (73% vs 23%) in patients with UA, it is notable that short-term mortality was similar to patients with non-cardiac causes of acute chest pain. Our findings seem well in line with current clinical practise guidelines recommending different monitoring requirements for patients with UA versus NSTEMI.1 Our findings should in no way be misinterpreted as indicating that UA is a benign disease as the higher rate of future non-fatal MI in patients with UA, at least twice the expected rate of 2% per year in patients with stable CAD,16 21 and prevalence of cardiovascular risk factors should prompt the clinician to optimise secondary prevention, including intensive patient education, motivation to achieve and maintain lifestyle changes, adherence to medical therapy including high-dose statins and need for close follow-up in this group.16 21

Some limitations merit consideration when interpreting the findings of this study. First, this was a secondary analysis from two large ongoing multicentre studies designed to improve the early diagnosis of MI. Second, patients with STEMI are under-represented in this study due to established patient pathways for STEMI diagnosed in the ambulance and/or transferring institution resulting in direct transfer to the catheter laboratory or coronary care unit and thereby bypassing the ED. This does not however affect the comparison between UA and NSTEMI. Third, studies on UA are challenging due to lack of a biomarker criterion. Even by experienced cardiologists applying current guideline recommendations,1–3 10 diagnostic uncertainty remained in some patients and it is possible that patients with non-cardiac chest pain, who were known to have CAD, were misclassified as UA. Particularly, the onset of chest pain is an unreliable measure of the onset of coronary instability. Accordingly, some of the patients with UA with slight non-dynamic cTn elevation in APACE may in fact be late presenters with small NSTEMI. There number however should be small, as known hs-cTn concentrations collected during previous assessments as well as prolonged serial sampling of hs-cTn was available in many patients. Fourth, the hs-cTnT assay is relatively insensitive at low concentrations and therefore some patients with UA with very low concentrations might have been adjudicated as NCCP. Fifth, clinical outcomes following a diagnosis of UA are likely influenced by the treatments initiated in the ED and the relatively high rate of future non-fatal MI could reflect less aggressive management. However, rates of coronary revascularisation within 30 days were broadly similar between UA and NSTEMI.

Conclusion

The incidence and the mortality of UA is substantially lower than that of NSTEMI, while the rate of future non-fatal MI is similar.

Key messages

What is already known on this subject? 

  • Unstable angina and non-ST-elevation myocardial infarction (NSTEMI) are often thought to have similar incidence, characteristics, pathophysiology and outcome, and are therefore treated similarly.

What might this study add?

  • Unstable angina differs substantially from NSTEMI.

  • Its incidence is substantially lower, its pathophysiology does not seem to include acute cardiomyocyte injury, and its event-related mortality is much lower.

  • Thirty-day mortality was only one-seventh that observed in patients with NSTEMI.

How might this impact on clinical practice?

  • Major differences in patients with unstable angina versus patients with NSTEMI suggest a need for different management strategies in unstable angina as compared with NSTEMI.

References

Footnotes

  • NLM and CM contributed equally.

  • CP, MG and PDA contributed equally.

  • Contributors The authors designed the study, gathered and analysed the data, vouch for the data and analysis, wrote the paper and decided to publish. CP, MG, PDA, NLM and CM had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors have read and approved the manuscript.

  • Funding Swiss National Science Foundation, Swiss Heart Foundation, Cardiovascular Research Foundation Basel, British Heart Foundation Project Grants, Butler Senior Clinical Research Fellowship, New Zealand Heart Foundation Overseas Research Fellowship, Chest Heart and Stroke Scotland.

  • Disclaimer The sponsors had no role in the design or conduct of the study, the gathering or analysing of the data, writing the manuscript or the decision to publish.

  • Competing interests Dr CP reports a personal grant from the PhD Educational Platform Health Sciences, outside this study. Dr MG report no conflicts of interest. Dr PDA reports grants from New Zealand Heart Foundation, during the conduct of the study, and grants from AstraZeneca, outside the submitted work. Dr AS reports other from Abbott Diagnostics, during the conduct of the study. Dr AA reports personal fees from Abbott Diagnostics, outside the submitted work. Dr MRG received speaker honoraria from Abbott, outside the submitted work. Dr RT reports grants from Swiss National Science Foundation (grant number P300PB-167803), personal fees from Roche Diagnostics, personal fees from Abbott, personal fees from Siemens, outside the submitted work. Dr TR has received research grants from the Goldschmidt-Jacobson Foundation, the Swiss National Science Foundation (PASMP3-136995), the Swiss Heart Foundation, the Professor Max Cloëtta Foundation, the University of Basel and the University Hospital Basel as well as speaker honoraria from Brahms and Roche, outside the submitted work. Dr NLM reports grants and personal fees from Abbott Diagnostics, Roche Diagnostics and Singulex outside the submitted work. Dr CM has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the Stiftung für kardiovaskuläre Forschung Basel; Abbott, Alere, AstraZeneca, Beckman Coulter, Biomerieux, Brahms, Roche, Siemens, Singulex, Sphingotec and the Department of Internal Medicine, University Hospital Basel, as well as speaker honoraria/consulting honoraria from Abbott, Alere, AstraZeneca, Biomerieux, Boehringer Ingelheim, BMS, Brahms, Cardiorentis, Novartis, Roche, Siemens and Singulex, during conduct of this study. All other authors report no conflicts of interest with this study.

  • Ethics approval This study was approved by the local ethics committees.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Not required.

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