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(Chest. 2004;126:461-469.)
© 2004 American College of Chest Physicians

Acute Coronary Syndromes Without Chest Pain, An Underdiagnosed and Undertreated High-Risk Group*

Insights From The Global Registry of Acute Coronary Events

David Brieger, MBBS, PhD; Kim A. Eagle, MD; Shaun G. Goodman, MD, MSc; P. Gabriel Steg, MD; Andrzej Budaj, MD, PhD; Kami White, MPH and Gilles Montalescot, MD, PhD; for the GRACE Investigators{dagger}

* From the University of Sydney (Dr. Brieger), Sydney, Australia; the University of Michigan Health System (Dr. Eagle), Ann Arbor, MI; the Canadian Heart Research Centre and Terrence Donnelly Heart Center (Dr. Goodman), Division of Cardiology, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada; Hôpital Bichat (Dr. Steg), Paris, France; Grochowski Hospital (Dr. Budaj), Warsaw, Poland; the University of Massachusetts Medical School (Dr. White), Worcester, MA; and Pitié-Salpêtrière Hospital (Dr. Montalescot), Paris, France. {dagger} A complete list of investigators and institutions can be found in the Appendix.

Correspondence to: David Brieger, MBBS, PhD, Department of Cardiology, Concord Repatriation General Hospital, Hospital Rd, Concord, Sydney, NSW, Australia 2139; e-mail: davidb{at}email.cs.nsw.gov.au


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Appendix
 References
 
Study objectives: The clinical manifestations of acute coronary syndromes (ACSs) vary, and patients present frequently with symptoms other than chest pain. In this analysis, a large contemporary database has been accessed to define the frequency, clinical characteristics, and outcomes of patients presenting without chest pain across different diagnostic categories of ACS.

Design and setting: The Global Registry of Acute Coronary Events is a multinational, prospective, observational study involving 14 countries.

Patients: Patients presenting to the hospital with a suspected ACS were stratified according to whether their predominant presenting symptoms included chest pain (ie, typical) or did not (ie, atypical). Demographics, medical history, hospital management, and outcomes were compared.

Measurements and results: Of the 20,881 patients in this analysis, 1,763 (8.4%) presented without chest pain, 23.8% of whom were not initially recognized as having an ACS. They were less likely to receive effective cardiac medications, and experienced greater hospital morbidity and mortality (13% vs 4.3%, respectively; p < 0.0001) than did patients with typical symptoms. After adjusting for potentially confounding variables, increased hospital mortality rates were noted in patients with dominant presenting symptoms of presyncope/syncope (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.4 to 2.9), nausea or vomiting (OR, 1.6; 95% CI, 1.1 to 2.4), and dyspnea (OR, 1.4; 95% CI, 1.1 to 1.9), and in those with painless presentations of unstable angina (OR, 2.2; 95% CI, 1.4 to 3.5) and ST-segment elevation myocardial infarction (OR, 1.7; 95% CI, 1.2 to 2.2).

Conclusion: Patients with ACSs who present without chest pain are frequently misdiagnosed and undertreated. With the exception of diaphoresis, each dominant presenting symptom independently identifies a population that is at increased risk of dying. These patients experience greater morbidity and a higher mortality across the spectrum of ACSs.

Key Words: acute coronary syndrome • atypical presentation • management • outcomes


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 Appendix
 References
 
Acute coronary syndromes (ACSs) offer a challenge from the standpoint of diagnosis, treatment, and prognosis, as the clinical manifestations vary considerably. The silent or atypical presentation of myocardial infarction is recognized as an important manifestation of coronary heart disease,123456 with most studies suggesting that it is associated with an unfavorable prognosis.78 These unfavorable outcomes may be partly attributable to a failure to use beneficial treatment strategies in these patients.56

Relative to myocardial infarction patients with atypical symptoms, very little information is available on atypical presentations in patients with less dramatic presentations of ACS such as unstable angina or non-ST-segment elevation myocardial infarction (NSTEMI).9 As these patients comprise 67% of all patients with ACSs,10 it would be valuable to document the frequency of atypical presentations among these patients and to determine whether their hospital-associated outcomes are similarly disappointing.

The Global Registry of Acute Coronary Events (GRACE) is a large, prospective, multinational registry of patients who have been hospitalized with the spectrum of ACSs.1011 In this analysis, we identified a population of patients presenting without chest pain, and therefore with atypical symptoms of ACSs. The characteristics of these patients, treatment practices, and hospital outcomes are described, and are compared with those of patients presenting with chest pain in a contemporary, real-world setting.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 Appendix
 References
 
The full details of the GRACE rationale and methodology have been published.1011 GRACE is designed to reflect an unbiased population of patients with ACSs, irrespective of geographic region. Currently, 95 hospitals located in 14 countries (ie, Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Germany, Italy, New Zealand, Poland, Spain, the United Kingdom, and the United States) are participating in this observational study.

Patients enrolled in the registry had to be at least 18 years old, alive at the time of hospital presentation, admitted for ACS as a presumptive diagnosis (ie, have symptoms consistent with acute ischemia), and have at least one of the following symptoms: ECG changes consistent with ACS; serial increases in serum biochemical markers of cardiac necrosis; and/or documentation of coronary artery disease. The qualifying ACS was not to be precipitated or accompanied by significant comorbidity, trauma, or surgery.

Enrollment in GRACE commenced in April 1999. At hospital admission, patients were assigned a working diagnosis of myocardial infarction, unstable angina, rule-out myocardial infarction, chest pain, and other cardiac or noncardiac conditions. The dominant symptom that had precipitated the presentation was documented, together with other accompanying symptoms. A typical presentation was defined when the reported symptoms included chest pain. If the presentation was not accompanied by chest pain, the patient was regarded as presenting with atypical symptoms. Patients presenting who were in cardiac arrest were not included in this analysis because their poor outcomes have already been well-characterized.1213 Patients with a hospital discharge diagnosis of noncardiac chest pain or non-ACS presentation also were excluded. All cases were therefore assigned to one of the following categories: ST-segment elevation myocardial infarction (STEMI); NSTEMI; or unstable angina.

Patients received a diagnosis of STEMI when they had new or presumed new ST-segment elevation of ≥ 1 mm seen in any location, a new left bundle branch block on the index, or a qualifying ECG with at least one positive cardiac biochemical marker of necrosis (eg, troponin measurements, whether qualitative or quantitative). In cases of NSTEMI, at least one positive cardiac biochemical marker of necrosis without new ST-segment elevation seen on the index or qualifying ECG had to be present. Unstable angina was diagnosed when the levels of serum biochemical markers that were indicative of myocardial necrosis in the laboratory of each hospital were within the normal range. Patients originally admitted to the hospital because of unstable angina, but in whom myocardial infarction evolved during the hospital stay, were classified as having a myocardial infarction.

Data were collected at each site by a trained coordinator using a standardized case report form to collect information on demographic characteristics, medical history, presenting symptoms, time of presentation, duration of prehospital delay, biochemical and ECG findings, treatment practices, and a variety of hospital outcome data. Standardized definitions of all patient-related variables and clinical diagnoses were used.11

Statistical Analysis
Differences in patient demographics, clinical characteristics, and hospital management and outcomes between patients presenting with atypical and typical symptoms were assessed using the {chi}2 test or the Fisher exact test for categoric variables (expressed as frequencies and percentages), and the Wilcoxon rank sum test for continuous variables (expressed as medians and interquartile range). Multiple logistic regression was used to examine the association between atypical and typical presentations of acute coronary disease and the hospital case fatality rate, adjusting for factors associated with p < 0.25 on univariate analysis. These included the following: age; sex; diabetes; history of hyperlipidemia, hypertension, smoking, congestive heart failure, and percutaneous coronary intervention; type of ACS; systolic BP; diastolic BP; pulse; initial creatinine level; and Killip class. Hospital mortality among patients in these two groups according to type of ACS (ie, STEMI, NSTEMI, and unstable angina) was explored through the addition of interaction terms in our regression models. In addition, multivariate analysis was used to determine the significance of each of the four major characteristics of atypical presentation (ie, dyspnea, diaphoresis, nausea/vomiting, or syncope/presyncope) for hospital survival in relation to patients presenting with chest pain.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 Appendix
 References
 
Frequency of Atypical Symptoms
Over the period July 1999 to June 2002, 20,881 patients were admitted to the hospital with ACSs, of whom 1,763 (8.4%) presented with atypical symptoms. The dominant presenting symptoms in these patients were dyspnea in 869 (49.3%), diaphoresis in 462 (26.2%), nausea or vomiting in 426 (24.3%), and presyncope/syncope in 335 (19.1%) [Fig 1 ].



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  		Figure 1. Dominant presenting symptoms in patients without chest pain (total exceeds 100% as patients may have presented with more than one dominant symptom).

 
Patient Characteristics
Patients without chest pain were significantly older than those with typical symptoms. They were more likely to be women and to have a history of hypertension, diabetes, or heart failure, but they were less likely to have a history of smoking, hyperlipidemia, or percutaneous coronary intervention (Table 1 ). Patients with atypical symptoms took longer to present to the hospital than did those with typical symptoms (3.2 vs 2.9 h, respectively; p < 0.02) and were more likely to have signs of heart failure on presentation (Killip class II-IV, 41.8% vs 16.1%, respectively; p < 0.001). The nature of the presenting symptom (ie, typical vs atypical) did not influence the likelihood of there being ischemic changes on the presenting or index ECG.


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  		Table 1. Demographic and Medical History Characteristics of Patients According to Presenting Symptoms*

 
Frequently, atypical symptoms were not recognized as being caused by coronary ischemia. On presentation, 23.8% of patients were given incorrect diagnoses with other cardiac or noncardiac conditions, compared with 2.4% of those with typical presentations (Fig 2 ).



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  		Figure 2. Type of presentation by hospital admission diagnosis. Percentages represent patients in whom the diagnosis of an ACS was not recognized at presentation. MI = myocardial infarction; UA = unstable angina.

 
Treatment
After hospital presentation, there were differences in the medical and interventional treatments provided to patients. Patients with STEMI were less likely to receive either fibrinolysis or primary percutaneous coronary intervention if their symptoms were atypical. This group was also less likely to receive treatment with ß-blockers, a difference that was apparent within the first 24 h of presentation and persisted throughout their hospital stay. Similarly, the use of aspirin was lower in patients with atypical presentations, both within the first 24 h of presentation and throughout their hospital stay. The use of angiotensin-converting enzyme (ACE) inhibitors was comparable between the two groups during hospital admission, and, at the time of discharge from hospital, patients who had presented without chest pain were more likely to be receiving an ACE inhibitor. However, they were less likely to be receiving treatment with a ß-blocker, aspirin, or a statin at hospital discharge (Table 2 ).


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  		Table 2. Hospital Management: STEMI*

 
Patients with NSTEMI or unstable angina who presented with atypical symptoms were less likely to undergo coronary angiography and percutaneous coronary intervention during their hospital stay. They were also less likely to receive anticoagulant or antiplatelet treatment within 24 h of presentation. After this time, there was a decline in the use of these treatments in both groups. The prescription of ß-blockers was less frequent in patients with atypical presentations, both within the first 24 h and subsequently. Similar to STEMI patients, these patients were less likely to receive therapy with aspirin, a ß-blocker, or a statin at hospital discharge (Table 3 ).


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  		Table 3. Hospital Management: NSTEMI and Unstable Angina*

 
Hospital Outcomes
The hospital complications of heart failure, cardiogenic shock, arrhythmias, and renal failure were seen more commonly in patients with atypical presentations (Table 4 ). In addition, their hospital case fatality rates were increased, with 13.0% of atypical patients dying compared with 4.3% of typical patients (p < 0.001). This excess mortality rate remained after correction for other factors known to contribute to an unfavorable outcome (adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3 to 1.9).


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  		Table 4. Hospital Outcomes*

 
When hospital death rates were analyzed according to the type of ACS, almost 20% of patients with atypical symptoms of STEMI died in hospital (atypical symptoms, 18.7%; typical symptoms, 6.3%; p < 0.001). Those patients presenting with anterior STEMI had the highest mortality rate of any group (23.4% vs 7.4%, respectively; p < 0.001), but an atypical presentation also heralded a poor outcome for those with inferior or lateral STEMI (15.4% vs 5.4%, respectively; p < 0.001). Regardless of the type of ACS, atypical presentation was associated with an increased risk of hospital death compared with typical presentation (NSTEMI, 11.9% vs 4.2%, respectively; unstable angina, 8.0% vs 2.5%, respectively; p < 0.001 for both) [Fig 3 ]. This risk was attenuated after correction for other factors associated with a higher mortality rate but remained significant for patients with STEMI (adjusted OR, 1.7; 95% CI, 1.2 to 2.2) and unstable angina (adjusted OR, 2.2; 95% CI, 1.4 to 3.5).



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  		Figure 3. In-hospital mortality rate in subgroups with ACSs according to presenting symptoms. Ant = anterior; Inf/lat = inferior or lateral.

 
The adverse outcomes among patients without chest pain could not be predicted by the dominant symptom that had accompanied their presentation. When patients were grouped according to these symptoms and compared with the population presenting with chest pain, a greater risk of dying was found for all patients except those presenting predominantly with diaphoresis (Fig 4 ).



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  		Figure 4. Adjusted OR (95% CI) plot for hospital mortality of typical vs atypical presentation according to principal presenting symptom (adjusted for age, sex, history of hyperlipidemia, history of smoking, history of diabetes, history congestive heart failure, history of percutaneous coronary intervention, BP, pulse, Killip class, initial creatinine level and standard diagnosis).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 Appendix
 References
 
Although presentations with ACSs share common underlying pathophysiologic mechanisms, they offer a challenge from the standpoint of diagnosis, treatment, and prognosis because the clinical manifestations of these conditions vary considerably. Most episodes of ACSs are characterized predominantly by chest pain. However, a proportion of patients may have atypical, minimal, or no symptoms.

In our population, patients with atypical symptoms were more likely to be older, female, hypertensive, and diabetic, and to have a history of heart failure. Previous studies1415161718192021 of patients with myocardial infarction have described similar characteristics among patients presenting without chest pain or with atypical symptoms. As the population continues to age, with women outliving men, it is likely that patients without chest pain will make up an increasing proportion of those presenting with an ACS.

The propensity for patients with diabetes to present with atypical or absent symptoms has been well-recognized2223 and is believed to be a manifestation of their tendency to autonomic neuropathy, with a consequent defective anginal warning system.24 It is notable, however, that in our cohort diabetes was noted in < 33% of the population with atypical symptoms, indicating that the problem extends to a much wider group of patients.

Approximately 25% of our patients were not recognized as having an ACS on presentation. This delay in the recognition of the diagnosis is particularly important for patients with STEMI, for whom early therapy is imperative.25 We previously reported26 that patients with STEMI are significantly less likely to receive reperfusion therapy. This current analysis indicates that, throughout the course of their hospital admission, these patients are less likely to receive treatment with ß-blockers, antiplatelet therapy, or statin therapy. Interestingly, they are more likely to be discharged from the hospital while receiving an ACE inhibitor than are patients with chest pain, suggesting that the greater prevalence of heart failure in this population is recognized, but the importance of secondary prevention against further coronary events is not.

In contrast to the significant body of literature describing atypical or unrecognized myocardial infarction, less attention has been paid to the frequency or significance of the atypical presentation of ACSs in patients either meeting the newer, more inclusive definitions of myocardial infarction (ie, elevated troponin levels) or not having myocardial necrosis (ie, unstable angina). In a retrospective medical chart review9 of 4,167 Medicare patients who had been hospitalized with unstable angina in 22 Alabama hospitals, atypical presentations were identified in > 50% of the population. However, unlike the diagnostic criteria adopted in GRACE, those for unstable angina in this study could be made in the absence of objective evidence of coronary disease. As symptoms are such an important component of the diagnosis, it is possible that many of these patients did not have an ACS. Consistent with this, the hospital mortality rate was very low in this elderly population (0.9%) and was not significantly different from that in patients who presented with chest pain (0.6%; p = 0.4).9

Of the patients with unstable angina and NSTEMI in our analysis, 5.7% and 12.3%, respectively, presented with atypical symptoms. Coronary angiography and subsequent treatment with revascularization, anticoagulant therapy, antiplatelet therapy, and ß-blocker therapy were used less frequently in patients with atypical symptoms than in those with chest pain. When discharged from hospital, these patients were less likely to be receiving aspirin, ß-blockers, or statins than were those presenting with chest pain. The reduced administration of these therapies early after hospital admission was presumably contributed to by the failure to recognize the diagnosis on presentation. However, it is clear from our data that these omissions in therapy were not adequately corrected during hospital admission and presumably contributed to the poorer outcomes of those patients.

Given the greater baseline risk of the population presenting without chest pain, it is not surprising that they were more likely to experience complications during their hospital stay. Nonetheless, the excess mortality rate observed in this cohort was striking. As in patients with chest pain, there was a clear gradation of risk that was determined by the severity of the manifestation of the ACS, with almost 20% of STEMI patients presenting without chest pain dying in the hospital. However, the absence of chest pain predicted a greater likelihood of in-hospital death across the spectrum of ACSs, and, even after multivariate analysis, the excess mortality rate persisted among patients with unstable angina and STEMI. We had anticipated that a presenting characteristic, such as the nature of the dominant symptom, might have served as a distinctive predictor of mortality among patients presenting without chest pain. However, with the exception of diaphoresis, each of the dominant presenting symptoms independently identified a population that was at increased risk of dying. Therefore, from a prognostic point of view, the most important feature to identify was the absence of chest pain in these patients.

Strengths and Limitations
GRACE is the largest multinational registry study to include the complete spectrum of ACS patients. In addition, this registry employs standardized criteria for defining ACS and hospital outcomes, and the most rigorous quality control and audit measures of any current or previously published registry data sets.

A limitation that can apply to registries of this nature is that the information provided is often extracted from the medical record, requiring second-hand interpretation by the study coordinator or physician. However, the nature of a principal presenting symptom, which provided the basis of this analysis, is almost invariably well-documented in the medical record and was therefore unlikely to be subject to misinterpretation.


   Conclusions
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
Appendix
 References
 
This analysis has shown that patients with acute coronary ischemia in the absence of chest pain are older and sicker than those with chest pain. The diagnosis is often made belatedly, and initial and subsequent hospital management is suboptimal. With the exception of diaphoresis, each dominant presenting symptom independently identifies a population that is at increased risk of dying. These patients represent a high-risk group, independent of whether their presentation is accompanied by myocardial infarction. Emergency department and coronary care personnel need to have an increased awareness of this patient cohort, who should be provided with improved early diagnosis and better treatment options to reduce their significant morbidity and mortality.


   Appendix
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Appendix
References
 
GRACE Scientific Advisory Committee
GRACE Co-Chairs
Keith A. Fox, The Royal Infirmary of Edinburgh, Edinburgh, Scotland, UK; and Joel M. Gore, University of Massachusetts Medical School, Worcester, MA.

GRACE Publication Committee Co-Chairs
Kim A. Eagle, University Hospital, Ann Arbor, MI; and P. Gabriel Steg, Hôpital Bichat, Paris, France.

Committee Members
Giancarlo Agnelli, University of Perugia, Perugia, Italy; Frederick A. Anderson Jr, University of Massachusetts Medical School, Worcester, MA; Álvaro Avezum, CTI-A Hospital Albert Einstein, São Paulo, Brazil; David Brieger, Concord Hospital, Sydney, NSW, Australia; Andrzej Budaj, Grochowski Hospital, Warsaw, Poland; Marcus D. Flather, Royal Brompton & Harefield NHS Trust, London, UK; Robert J. Goldberg, University of Massachusetts Medical School, Worcester, MA; Shaun G. Goodman, St Michael’s Hospital, Toronto, ON, Canada; Christopher B. Granger, Duke University Medical Center, Durham, NC; Dietrich C. Gulba, Cardiology Krankenhaus Düren, Medizinische Klinik Düren, Düren, Germany; Enrique Gurfinkel, Buenos Aires University, Buenos Aires, Argentina; Brian M. Kennelly, Hoag Memorial Hospital Presbyterian, Newport Beach, CA; Werner Klein, Medizinische Universitätsklinik, Graz, Austria; José López-Sendón, Hospital Universitario Gregorio Marañon, Madrid, Spain; Gilles Montalescot, Pitié-Salpétrière Hospital, Paris, France; and Frans Van de Werf, University of Leuven, Leuven, Belgium.


   Acknowledgements
 
The authors of this report would like to express their gratitude to the physicians and nurses participating in GRACE. Further information about GRACE, along with a complete list of participants, is available at www.outcomes.org/grace.


   Footnotes
 
Abbreviations: ACE = angiotensin-converting enzyme; ACS = acute coronary syndrome; CI = confidence interval; GRACE = Global Registry of Acute Coronary Events; NSTEMI = non-ST-segment elevation myocardial infarction; OR = odds ratio; STEMI = ST-segment elevation myocardial infarction.

GRACE is supported by an unrestricted educational grant from Aventis Pharma, Bridgewater, NJ.

Received for publication November 3, 2003. Accepted for publication January 14, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Appendix
 References
 

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