More than 900 000 Americans are expected to experience an episode of acute coronary syndrome (ACS) in 2016.1 Acute coronary syndrome includes the diagnosis of unstable angina, non-ST elevation myocardial infarction and ST elevation myocardial infarction (STEMI). Recognition of the symptoms of ACS is important because symptoms determine when, or if, patients seek care. Past studies have identified sex differences in symptoms of ACS; however, retrospective designs, abstraction of symptoms from medical records, and variations in assessment forms make it difficult to determine the clinical significance of sex differences or if sex-specific health messages are warranted.
Sex Differences in Symptoms
The most frequently reported symptoms of ACS are chest pain, dyspnea, unusual fatigue, and weakness.2–5 Although chest pain in particular continues to be labeled as the “typical” symptom and others, including unusual fatigue and weakness as “atypical,” there is compelling evidence that women experience these atypical symptoms more frequently than men do but report chest pain at similar rates to men during ACS.3,6 Some symptoms considered as atypical are also likely to be experienced by men.6,7 Several studies comparing women and men have identified a number of sex differences in symptoms of ACS.5,8,9 First, the symptoms themselves vary. In a review of sex differences in ACS symptoms, Canto et al10 noted a higher prevalence of back pain, neck pain, jaw pain, arm pain, shortness of breath, paroxysmal nocturnal dyspnea, nausea or vomiting, indigestion, loss of appetite, weakness or fatigue, cough, dizziness, syncope, and palpitations among women. Men report a higher occurrence of chest pain11–13 and diaphoresis14 in most studies. Furthermore, women are likely to experience a greater number of symptoms than men are.14,15 However, lack of prospective designs, systematic methods of data collection, standardized assessment forms, small sample sizes, and evaluation of the importance of the chief complaint10 limit the ability to draw definitive conclusions about these differences.
Other Factors Influencing Symptoms
Few have examined the sensitivity and specificity of the symptoms for a diagnosis of ACS. Milner et al16 found that only chest pain and diaphoresis were predictive of ACS for women. In a large study (n = 736), chest symptoms were common in patients with and without ACS, but several secondary symptoms were specific for a non-ACS diagnosis (shoulder, arm, and upper back pain; sweating, palpitations, and indigestion).6 Most studies examining the symptoms of ACS solely recruited patients with a confirmed diagnosis of ACS.3,17 Because symptoms may vary by diagnosis, determining the effects of diagnosis on sex differences in symptoms will provide more specific information to clinicians, thereby enhancing risk stratification for patients presenting with symptoms suggestive of ACS.
In general, women are older than men when diagnosed with coronary heart disease. Women were significantly older in the INTERHEART study, a case control study of myocardial infarction (MI) in 52 countries,18 and women participating in the National Registry for Myocardial Infarction 2 study were a mean of 7 years older than men (P < .001).19 According to 2016 statistics from the American Heart Association,1 women are a mean of 20 years older for clinical events such as MI and sudden death and 10 years older for total coronary heart disease. It is possible that differences in ACS symptoms can be partially explained by women’s older age at presentation.
Symptoms have also been reported to vary by race or ethnicity.1,20 African Americans and Latinos have more risk factors for cardiovascular disease than whites do. Although 10-year predicted risk of coronary heart disease has declined overall, 10-year predicted risk for African Americans continues to rise,21 and mortality rates for African Americans are significantly higher. The additional risk borne by African Americans, along with higher incidence of coronary heart disease, provides a rationale for evaluating the association of race with symptoms of ACS. African American and Hispanic women were less likely to report acute chest pain compared with white women at the time of MI in 1 study.22 Other investigators found that African American women and men had a higher symptom burden than whites do, reporting more symptom severity and more distress from symptoms.20
Concomitant comorbid conditions have also been implicated in the experience of symptoms during ACS. Diabetes is an established risk factor of ACS23–25 and may negate the protective effect of estrogen in premenopausal women.24,26 Patients with diabetic neuropathy are at higher risk for a silent MI23,27,28 are less likely to receive rapid, definitive treatment and are more likely to experience complications during and after hospitalization.27 Smoking, hypertension, hypercholesterolemia,25,29 obesity, and physical inactivity29 are major ACS risk factors. Women have higher rates of diabetes and hypertension at the time of ACS diagnosis compared with men but are less likely to have a history of smoking, MI, or previous revascularization.30
Finally, functional status or the ability to perform activities of daily living may be limited in patients with ischemic heart disease.31 Unusual fatigue, a frequent symptom of ACS, is more likely to be reported by women than men.32 Women with angina experience greater functional decline, which may influence symptom trajectory.33–35
The aim of this study is to determine the influence of sex on the occurrence and distress of 13 symptoms for patients presenting to the emergency department (ED) triggering a cardiac evaluation adjusting for diagnosis, age, race, comorbidities, and functional status.
Design, Sample, and Setting
This study was a large prospective, multicenter study examining the influence of sex on symptom characteristics during ACS. A novel approach, in which symptoms were recorded in the ED before the patient was treated, was used. We recruited individuals with symptoms triggering a cardiac evaluation, that is, those who went on to be ruled in and ruled out for ACS. Inclusion criteria were 21 years or older, fluent in English, evidence of ischemia on the electrocardiogram (ECG) or elevated initial troponin level, and arrival by private transportation or emergency medical services. Patients were excluded if they had an exacerbation of heart failure (B-type natriuretic peptide > 500 pg/mL), were transferred from a hemodialysis facility, were referred for evaluation of a dysrhythmia, had cognitive impairment (inability to provide informed consent), or no evidence of ischemia as evidenced on ECG or troponin levels. We used a targeted sampling plan in which patients who had ECG changes indicative of ischemia or elevated troponin levels were exclusively recruited. In so doing, we avoided enrolling thousands of patients who were ruled out for ACS and maximized the number of patients who ruled in. Enrollment occurred between January 2011 and December 2014 in 5 EDs in the Midwest, West, and Pacific Northwest regions of the United States. Sites included 4 urban academic medical centers and a rural regional referral center. Combined, the 5 sites treat more than 300 000 patients in the ED annually.
Acute Coronary Syndrome Symptom Checklist
Symptoms were measured with the validated 13-item ACS Symptom Checklist.5 The checklist, a reliable (Cronbach’s α = .81)36 and valid (content validity indexes of 0.88 and 0.94)5,37 instrument was tested in previous studies. Participants indicate whether the symptom is present or absent on presentation to triage. Symptoms not appearing on the checklist can be recorded in a blank space marked “other.” Each symptom is analyzed individually and there is no summary score. The patients were also asked to report their most distressing symptom, which was recorded as their chief complaint. Here we report the initial symptoms on presentation to the ED and before treatment.
Acute Coronary Syndrome Patient Information Questionnaire
This questionnaire includes patient-reported information on demographic and clinical variables, including symptom distress. The questionnaire was designed using the standardized reporting guidelines for studies evaluating ED patients with potential ACS.38 The criteria were established by the Multidisciplinary Standardized Reporting Criteria Task Force and are supported by the Society for Academic Medicine, the American College of Emergency Physicians, the American Heart Association, and the American College of Cardiology. The purpose of the questionnaire is to establish standardized reporting criteria that will facilitate research, study comparisons, and meta-analyses. Risk factors included on the instrument are high blood pressure, family history of heart disease or sudden cardiac death, diabetes, tobacco use, hypercholesterolemia, cocaine or amphetamine use, kidney disease, and obesity.
Charlson Comorbidity Index
Comorbid conditions were measured with the Charlson Comorbidity Index, a 19-item weighted index which has been used extensively to quantify risk associated with comorbid conditions.39,40 Higher scores represent a greater burden of disease. Correlations with mortality, disability, hospital readmission, and length of stay ranged from 0.35 to 0.93 (P < .001).41,42
Duke Activity Status Index
Functional status was measured with the 12-item Duke Activity Status Index.43 Scores range from 0 to 58.2, with higher scores representing better physical functioning. Items reflect metabolic energy expenditure and correlate highly with peak VO2 (r = 0.80, P < .0001)43 in patients with ACS.44
Institutional review board approval was obtained from all study sites and the sponsoring institution before study launch. Research staff were available to enroll patients between the hours of 7 AM and 11 PM. Patient responses to the ACS Symptom Checklist were recorded by research staff in the ED patient cubicle after the patient was evaluated in triage. The Symptom Checklist was completed in the catheterization laboratory for patients with STEMI who bypassed the ED. Symptoms were assessed within 15 minutes of ED presentation in most cases (range, 10–60 minutes). In a few cases, symptoms were not assessed for up to 1 hour when patients had to wait to be seen in triage. Patients triggering a cardiac workup were approached by the research staff for enrollment after they were deemed stable by the primary nurse or physician and had been transferred to a private examination room in either the ED or hospital. Patients were consented up to 24 hours after admission if their condition was unstable or their symptoms were not well controlled. The study purpose was explained, and once the patient provided written informed consent, additional clinical and individual characteristics were recorded. Most patients were consented within 1 hour of admission and data collection took approximately 45 minutes. Initial symptom data were destroyed if the patient declined to participate.
Data were coded and entered into SPSS, version 22 (SPSS Inc, Chicago, Illinois). All statistical tests were 2 sided, and significance was set at P ≤ .05. Descriptive statistics were computed by using a χ2 test for categorical data and t tests for interval level data. Logistic regression analyses were used to determine whether the sex of the patient was predictive of symptoms after adjusting for age, functional status, burden of comorbidities, and African American race. Ordinary least squares regression was used to determine whether women and men differed in the number of symptoms reported (1–13) and the level of distress from symptoms (1–10) adjusting for the same potential covariates. Interaction terms were used to calculate the separate effects of sex on symptoms for patients with an ACS and non-ACS diagnosis.
Demographic and Clinical Characteristics
A total of 1064 patients, 474 (44.5%) with an ACS diagnosis and 590 (55.5%) with a non-ACS diagnosis, were enrolled. Overall, 1493 patients were eligible for the study and 1064 enrolled. Refusal rates ranged from 2.4% to 39.7% across sites, likely reflecting differences in the number of patients screened, the number of research assistants employed at the sites, and the individual’s health status. Most patients who declined to participate cited fatigue, anxiety, or lack of interest. The sample was predominantly male (664; 62.4%) and white (739; 69.5%) with a mean age of 60.2 years (range, 21–98). There were differences in final diagnosis, proportion of minority populations, and age across the 5 recruitment sites. Northwest site 1 had a significantly higher percentage of their patients ruled out for ACS compared with other sites (80.6% vs 9.8%–54.5%). There were also a significantly higher number of women at this site. This was the first site to begin enrollments and our sampling plan was altered after it became clear that we would grossly overenroll patients without ACS if we did not change our enrollment criteria to include only patients with some evidence of ischemia. Northwest site 2 enrolled primarily patients ruled in for ACS as they are a regional referral center. Participants at this site were also older. Finally, there were differences in the proportion of racial/ethnic groups enrolled by site, which was related to regional differences in population groups. These demographic variables were controlled for in statistical analyses. Demographic (Table 1) and clinical (Table 2) variables were compared between the sexes and between patients discharged with an ACS or non-ACS diagnosis. Women in the entire sample were more likely to be older (mean [SD], 61.3 [14.6] vs 59.5 [13.6] years; P = .037) and have Medicare (37.9% vs 30.5%; P = .004).
Women were more likely to have a non-ACS diagnosis (67.3% vs 48.3%; P < .001) and were less likely to have a STEMI when diagnosed with ACS (6.5% vs 13.9%; P < .001) compared with men. Body weight was measured in 6 categories from underweight to morbidly obese. Women were more likely to be in the underweight, normal weight, and morbidly obese (body mass index >40 kg/m2; P = .017) categories. Men were more likely to be in the overweight or obese category. Women were more likely to have never smoked (61.9% vs 50.2%) and were less likely to have used cocaine (2.5% vs 7.3%). Women had more physical limitations (Duke Activity Status Index: mean [SD], 29.7 [19.1] vs 37.2 [18.7]; P < .001) but did not have more comorbid conditions (Charlson Comorbidity Index: mean [SD], 1.8 [1.9] vs 1.9 [1.9]; P = .478). There were no differences in the presence of diabetes by sex or ACS diagnosis.
Sex Differences in Symptoms by Acute Coronary Syndrome Diagnosis
Chest discomfort, chest pain, and chest pressure were the most commonly reported symptoms (65%–74%) for both women and men with ACS (Figure 1). For patients with ACS, women were more likely to experience nausea (odds ratio [OR], 1.56; confidence interval [CI], 1.00–2.42), shoulder pain (OR, 1.76; CI, 1.13– 2.73), and upper back pain (OR, 2.92; CI, 1.81–4.70) compared with men (Table 3). For women and men without ACS, the 3 chest symptoms and shortness of breath were the most frequently reported symptoms (57.9%–73.2%). After adjustment for pertinent covariates, women had a higher odds of experiencing chest pressure (OR, 1.51; CI, 1.05–2.17), nausea (OR, 1.72; CI, 1.21–2.46), upper back pain (OR, 1.75; CI, 1.21–2.53), and palpitations (OR, 1.54; CI, 1.05–2.25) compared with men (Table 3).
For patients with ACS, chest pain was the most frequently reported chief complaint for women and men (42.7% vs 54.3%) (Figure 1). After adjustment for relevant covariates, women had significantly lower odds than men did of reporting chest pain as their chief complaint (OR, 0.59; CI, 0.38–0.92). Chest pain was also the most common chief complaint for women and men (32.7% vs 34.5%) ruled out for ACS. The odds of reporting chest pressure as the chief complaint was much higher for women (19.4%) than for men (7.0%) without ACS (OR, 3.23; CI, 1.77–5.89).
In adjusted analyses, women with and without ACS reported more symptoms (mean [SD]: ACS, 6.1 [0.3] vs 5.5 [0.2], P = .026; non-ACS, 6.1 [0.2] vs 5.4 [0.2], P = .005). Women without ACS reported more symptom distress compared with men (mean [SD], 7.1 [0.2] vs 6.5 [0.1]; P = .004) (Figure 2).
A large, heterogeneous sample of patients with symptoms suggestive of ACS were enrolled in this study. Most symptom studies, to date, have included only patients with a diagnosis of ACS.11 Our study expanded on the limitations of a narrow, diagnosis-based population to represent the actual environment of the ED where patients arrive to triage without a diagnosis.45 Therefore, clinicians must make rapid decisions on the urgency with which diagnostic testing is performed and time to treatment.
Congruent with previous research,11,17,46 women in our study were more likely to be older, although the difference in age of 1.8 years may not be clinically meaningful. Women were more likely to have a non-ACS diagnosis (45.7% vs 27.6%; P < .001) and were less likely to have a STEMI when diagnosed with ACS (6.5% vs 13.9%; P < .001) compared with men. These have implications for treatment-seeking behaviors, triage, and diagnostic testing because women delay longer in seeking care for ACS,47 are less likely to receive an emergent triage designation,48 and are less likely to have occlusion in the epicardial coronary arteries.49
Analyses of sex differences in symptoms revealed that women were more likely than men to experience nausea, shoulder pain, and upper back pain. These results support findings from previous studies that demonstrated that women were more likely than men to report multiple symptoms in addition to chest pain.6,11,14 Women and men in this study reported comparable occurrence of chest symptoms, although women were more likely to report chest pressure rather than chest pain as their chief complaint. This may hinder rapid assessment or accurate triage if clinicians continue to assess for conditions other than ACS.50,51 Recent studies have demonstrated that accuracy of triage scores, and hence speed of treatment, varies by sex48,52 and race52–54 for symptoms of MI, with women more likely to be erroneously triaged to a less urgent category. Therefore, knowledge of sex differences in symptom descriptors has the potential to improve the accuracy of triage decisions.51
Our results do suggest that shoulder pain and upper back pain are symptoms that may be useful in making an ACS diagnosis for women. Recently, Canto et al10 concluded that identifying the chief complaint from associated ACS symptoms is important in forming a differential diagnosis and studies should attempt to discriminate primary versus secondary symptoms in ACS by sex. Our findings add to the body of symptom knowledge by analyzing data on chief complaint. Whereas the primary symptom of ACS is chest pain, pressure, or discomfort, the secondary symptoms of shoulder and upper back pain are important to both clinicians and the public, particularly women, in assessing the likelihood of an ACS diagnosis.
In adjusted analyses, women with and without ACS reported more symptoms, although the differences are not likely to be clinically relevant. The information may be particularly valuable for both women and men who do not experience chest pain because the term chest pain sets off an alarm for clinicians, patients, and the public. Similarly, the presence of a greater number of comorbid conditions decreased the likelihood of reporting chest pain or chest discomfort individually or as the chief complaint and the likelihood of reporting any symptoms decreased with age. This implies that elders and those with more comorbidities may be particularly vulnerable to experiencing more nonspecific symptoms during ACS, which may lead to delayed treatment seeking,55 delayed diagnosis,11 and delayed treatment,56 as has been described previously.
The triage process requires that the clinician rapidly assess the acuity level of the patient as well as consider differential diagnoses. The patient’s presenting symptoms, chief complaint, and level of risk dictate triage designation and diagnostic strategies. Our data indicate that age and comorbidities be included in the assessment. Assessment of secondary symptoms, defined as other than chest symptoms, which have often been labeled as “atypical,” may aid triage clinicians in the ED in determining the likelihood of ACS and providing the most appropriate diagnostic work-up and treatment.
This well-powered study enrolled more than 1000 patients presenting to the ED with symptoms suggestive of ACS. Our heterogeneous sample of patients closely matched the ethnic and racial make-up of the United States, making these findings generalizable to the American population. We chose to include patients who went on to be both ruled in and ruled out for ACS as this represents the real-world environment of the ED and clinicians must evaluate and treat patients whose diagnosis is undifferentiated when they arrive at triage. We increased the internal validity of our findings by assessing symptoms on presentation to the ED, using a simple and validated 13-item symptom checklist, and adjusting for potential confounders of symptoms including age, race, comorbidities, and functional status.
We used a targeted sampling plan (abnormal ECG results and/or elevated troponins) to enroll a sufficient number of women and men ruled in for ACS. This was necessary because approximately 85% of patients presenting to the ED with potential ACS symptoms are eventually ruled out for ACS.57 As a result, not all patients ruled out for ACS were included and sampling bias may have been introduced. In addition, triage nurses and ED physicians make a professional judgment whether to pursue a cardiac evaluation based on clinical presentation and risk factor assessments. Therefore, patients with actual ACS may have been excluded from the study if they were not evaluated. We were also unable to enroll patients who arrived at the ED between 11 PM and 7 AM. It is unlikely, but possible, that these patients experienced a different clinical presentation. We acknowledge that some consider the use of self-report measures such as the ACS Symptom Checklist to be a limitation because symptoms cannot be objectively validated. However, we attempted to address this limitation by including only patients who presented to the ED for treatment and underwent emergent diagnostic testing as well as recording symptoms prospectively as they were occurring. Finally, individuals choosing to use the ED may represent another form of selection bias in that they made a conscious decision that their symptoms may have been serious and required urgent attention. Their symptom experience may vary from those who judge their symptoms to be nonacute or less distressing.
For more than a decade, investigators have sought to determine if there were sex differences in symptoms that should drive how we educate, treat, and facilitate the recovery of patients after ACS. Methodological limitations of previous studies confounded our ability to determine if statistically significant differences were clinically meaningful. The results of this study suggest that sex differences in symptoms are minimal for those presenting to the ED with and without ACS. We recommend that women’s awareness of their risk for heart disease be a priority for both primary care clinicians and those in specialty practices. Specifically, women should know that shoulder and upper back pain may be specific for a diagnosis of ACS in the presence of other symptoms.
What’s New and Important
- This study included a large, diverse sample, with and without ACS, and used a brief, validated symptom checklist to record symptoms on admission. Clinicians will find the data generalizable to other ED patients in large medical centers. The brief ACS Symptom Checklist is also suitable for use in the clinical setting.
- Sex differences in symptoms were minimal for those presenting to the ED with and without ACS. Therefore, clinicians should be vigilant for hallmark chest symptoms when triaging potential ACS patients.
- For women, shoulder and upper back pain may indicate a diagnosis of ACS in the presence of other symptoms. This provides valuable information for both patients and laypersons to respond to symptoms as well as an alert for clinicians to be vigilant for these symptoms, particularly in the absence of chest symptoms.
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