ABSTRACT
Background
Today, cardiologists seek to minimize time from symptom onset to interventional treatment for the most favorable results.
Hypothesis
In the acute coronary syndrome (ACS) symptom complex, sweating can differentiate ST‐segment elevation myocardial infarction (STEMI) from non–ST‐segment elevation ACS (NSTE‐ACS) during early hours of infarction.
Methods
This single‐center, prospective, observational study compared symptoms of STEMI and NSTE‐ACS patients admitted from August 2012 to July 2014.
Results
Of 12 913 patients, 90.56% met ACS criteria. Among these, 22.51% had STEMI. Typical angina was the most common symptom (83.82%). On stepwise multiple regression, sweating (odds ratio: 97.06, 95% confidence interval [CI]: 82.16‐114.14, P < 0.0001) and typical angina (odds ratio: 2.72, 95% CI: 2.18‐3.38, P < 0.001) had significant association with STEMI. For diagnosis of STEMI, positive likelihood ratio (LR) and positive predictive value (PPV) were highest for typical angina with sweating (LR: 11.17, 95% CI: 10.31‐12.1; PPV: 76.09, 95% CI: 74.37‐77.75), followed by sweating with atypical angina (LR: 3.6, 95% CI: 3.07‐4.21; PPV: 50.61, 95% CI: 46.45‐54.76), typical angina (LR: 1.05, 95% CI: 1.03‐1.07; PPV: 22.97, 95% CI: 22.11‐23.84), and atypical angina (LR: 0.77, 95% CI: 0.69‐0.87; PPV: 18.09, 95% CI: 16.32‐19.97). C statistic values of 0.859 for typical angina with sweating and 0.519 for typical angina alone reflected high discriminatory value of sweating for STEMI prediction.
Conclusions
Presence of sweating with ACS symptoms predicts probability of STEMI, even before clinical confirmation. Sweating in association with typical or atypical angina is a much better predictor of STEMI than NSTE‐ACS.
Introduction
Failure to implement appropriate therapy in time is the major cause of increased cardiovascular morbidity and mortality in acute coronary syndrome (ACS) cases. Inability to deliver any form of reperfusion therapy in about 30% of patients and failure to minimize delays in reperfusion reflect missed opportunities for improvement in care of acute ST‐segment elevation myocardial infarction (STEMI).1 Only 25% of all patients presenting with suspected ACS in the emergency department (ED) have a confirmed diagnosis of ACS at discharge.2 Despite this, diagnosis of acute myocardial infarction (AMI) is missed in up to 11.1% of cases.3 Among AMI cases, 18% do not have chest pain2 at presentation; an initial 12‐lead electrocardiogram (ECG) has a sensitivity of only 20% to 60%; and a single set of biochemical markers also has poor sensitivity.4, 5, 6
In this era of intervention, cardiologists around the globe seek to minimize time from first medical contact to device/needle time for the most favorable results. The “time is muscle” concept for viable myocardium cannot be implemented unless patients present within a certain window of time. So identification of event by patients and primary‐care physicians is as important as is the golden hour of reperfusion. We undertook this study to discover any “red flags” in the ACS symptom complex that could identify STEMI with precision during the early hours of infarction. This red flag might increase community awareness and clinical acumen of health care professionals, thereby improving event‐to‐reperfusion time (ie, time from event onset to reperfusion).
Methods
Study Patients
This was a prospective, single‐center, observational study that included 12–913 patients admitted to the coronary care unit from August 1, 2012, to July 31, 2014, with presumed diagnosis of ACS after meticulous screening in the ED (Figure 1). We included patients age ≥30 years who presented to the ED with a chief symptom of chest, arm, jaw, or epigastric pain or discomfort, shortness of breath, dizziness, palpitations, syncope, or other symptoms suggestive of ACS. Cases with suspected pulmonary thromboembolism and known cases of coronary artery disease or heart failure were excluded from the study. Clinical data was recorded by multiple on‐duty cardiology fellows. History was self‐narrated and leading questions were asked according to a preset questionnaire. Other data of interest included sociodemographic information, ECG findings, serial creatine kinase MB (CK‐MB)/troponin T (TnT), and echocardiography. Discharge diagnosis was made by the senior ward physician and confirmed by a senior cardiologist.
Figure 1.
Flow of patients in SWIMI study. Abbreviations: NSTE‐ACS, non–ST‐segment elevation acute coronary syndrome; STEMI, ST‐segment elevation myocardial infarction; SWIMI, Sweating In Myocardial Infarction; USA, unstable angina.
Analysis of Data
Diagnosis was confirmed on the basis of ECG, serial CK‐MB/TnT measurements, and echocardiography as per universal definition of myocardial infarction (MI). Unstable angina (UA) was defined as angina pectoris (or equivalent type of ischemic discomfort) with ≥1 out of 3 features: (1) occurring at rest (or minimal exertion) and usually lasting >20 minutes (if not interrupted by the administration of a nitrate or an analgesic); (2) being severe and usually described as frank pain; or (3) occurring with a crescendo pattern (ie, pain that awakens the patient from sleep or that is more severe, prolonged, or frequent than previously).7 Non–ST‐segment elevation myocardial infarction (NSTEMI) was as defined as ≥1 measurement of CK‐MB >10 µg/L or TnT >0.1 µg/L in the context of UA with absent ECG criteria for STEMI.8 ST‐segment elevation myocardial infarction was defined as a clinical syndrome with characteristic symptoms of myocardial ischemia in association with persistent ECG ST‐segment elevation and subsequent release of biomarkers of myocardial necrosis. Diagnostic ST‐segment in the absence of left ventricular (LV) hypertrophy or left bundle branch block was defined as new ST‐segment at the J point in ≥2 contiguous leads of ≥2 mm (0.2 mV) in men or ≥1.5 mm (0.15 mV) in women in leads V2 through V3 and/or of ≥1 mm (0.1 mV) in other contiguous chest leads or the limb leads. New or presumably new left bundle branch block at presentation, ST‐segment depression in ≥2 precordial leads (V1 through V4) diagnostic of posterior‐wall STEMI, and multi‐lead ST‐segment depression with coexistent ST‐segment elevation in lead aVR were also included in the STEMI group.9, 10, 11, 12, 13 Symptoms were classified as typical angina and atypical angina/angina equivalent. Typical angina was defined as substernal chest discomfort with a characteristic quality and duration that was provoked by exertion or emotional stress and relieved by rest or nitroglycerin.14 The rest of the symptoms suggestive of acute ischemia were grouped as atypical angina/angina equivalent. Sweating was used as synonymous to diaphoresis, defined as profuse drenching sweats inappropriate to the physical and environmental state.
Statistical Analysis
The statistical analyses were done using SPSS version 20 (IBM Corp., Armonk, NY). Odds ratios (OR) were calculated for the association between each potential risk factor and STEMI. We considered 95% confidence intervals (CIs) that excluded unity, or, equivalently, P < 0.05, as statistically significant. Univariate analysis was done to find statistically significant symptoms, which were then analyzed using multivariate logistic regression. In the multivariable analysis, the probability of STEMI was predicted using multiple logistic regression. All independent variables (symptoms) were entered in the regression models as categorical variables. Starting with the full multivariable model with all independent variables included, we excluded 1 insignificant independent variable at a time, starting with the variable with highest P value, until only significant and important predictors remained. Likelihood ratios (LR) and predictive values (PV) of different symptoms for STEMI were also calculated. The area under the receiver operating characteristic curve (ROC) was used as an overall measure of the discrimination abilities of different symptoms. The area under ROC, measured in percent, can be interpreted as the probability that a randomly chosen patient with a particular symptom has a higher probability of STEMI than a randomly chosen patient without that symptom.
Results
Among 12 913 patients, 11 695 (90.56%) were admitted with the diagnosis of ACS and 1218 (9.44%) patients had nonischemic chest pain. Of the ACS patients, 2474 had STEMI and 9221 had non–ST‐segment elevation acute coronary syndrome (NSTE‐ACS). For 223 patients with STEMI, their history could not be elicited as they presented to the ED in a moribund state (due to cardiogenic shock, stroke, ventricular fibrillation, or sudden cardiac death); therefore, they were excluded from the analysis. Six hundred five patients from the NSTE‐ACS group could not be further evaluated and were excluded. One hundred fifty‐nine patients admitted with NSTE‐ACS developed late ST‐segment elevation and were included in the STEMI group. Thus, the final cohort comprised 10 867 patients. Of these, 2410 (22.18%) patients had STEMI, 6751 (62.12%) had UA, and 1706 (15.7%) patients had NSTEMI. In our cohort, the majority of patients were in the age group of 51 to 70 years. Out of all patients, 6781 (62.49%) were male and 4086 (31.6%) were female. The NSTE‐ACS group had more females than did the STEMI group (42.08% vs 21.87%; P < 0.0001). The NSTE‐ACS patients had a higher prevalence of diabetes mellitus (32.43% vs 18.58%; P < 0.0001), hypertension (34.24% vs 27.30%; P < 0.0001), and dyslipidemia (38.61% vs 26.68%; P < 0.0001) than the STEMI group (Table 1). The site of infarction was anterior in 56.72%, inferior in 40.29%, posterolateral in 1.83%, lateral in 1.08%, and isolated right ventricular infarction in 0.08%.
Table 1.
Baseline Characteristics and Symptom Profile of ACS Patients
| Variable | Total Patients, N = 10 867 | STEMI Patients, n = 2410 | NSTE‐ACS Patients, n = 8457 | P Value |
|---|---|---|---|---|
| Age, y | ||||
| ≤40 | 989 (9.10) | 221 (9.17) | 768 (9.08) | 0.925 |
| 41–50 | 1618 (14.89) | 546 (22.66) | 1072 (12.67) | <0.0001 |
| 51–60 | 3230 (29.72) | 722 (29.96) | 2508 (29.66) | 0.793 |
| 61–70 | 3116 (28.67) | 588 (24.70) | 2588 (30.60) | <0.0001 |
| 71–80 | 1654 (15.22) | 277 (11.49) | 1377 (16.28) | <0.0001 |
| >80 | 260 (2.40) | 56 (2.32) | 204 (2.41) | 0.860 |
| Male sex | 6781 (62.49) | 1883 (78.13) | 4898 (57.92) | <0.0001 |
| Smoker | 6310 (58.06) | 1408 (58.42) | 4902 (57.96) | 0.704 |
| DM | 3191 (29.36) | 448 (18.58) | 2743 (32.43) | <0.0001 |
| HTN | 3554 (32.70) | 658 (27.30) | 2896 (34.24) | <0.0001 |
| Obesity | 2868 (26.39) | 621 (25.76) | 2247 (26.57) | 0.446 |
| Dyslipidemia | 3908 (35.96) | 643 (26.68) | 3265 (38.61) | <0.0001 |
| CKD | 778 (7.16) | 121 (5.02) | 657 (7.77) | <0.0001 |
| Symptoms | ||||
| Typical angina | 9109 (83.82) | 2092 (86.80) | 7017 (82.97) | <0.0001 |
| Arm pain | 4965 (45.69) | 1179 (48.92) | 3786 (44.77) | 0.437 |
| Back pain | 4411 (40.59) | 1072 (44.48) | 3339 (39.48) | 0.709 |
| Epigastric pain | 3685 (33.91) | 874 (36.27) | 2811 (33.24) | 0.891 |
| Throat pain | 3258 (29.98) | 786 (32.61) | 2472 (29.23) | 0.656 |
| Sweatinga | 3074 (28.29) | 2192 (90.95) | 882(10.43) | <0.0001 |
| Palpitations | 2619 (24.10) | 564 (23.40) | 2055 (24.30) | 0.990 |
| Nausea | 2494 (22.95) | 531 (22.03) | 1963 (23.21) | 0.557 |
| Vomiting | 1837 (16.90) | 504 (20.91) | 1333 (15.76) | 0.083 |
| Dry mouth | 1355 (12.47) | 370 (15.35) | 985 (11.65) | 0.049 |
| Dyspnea | 1231 (11.33) | 315 (13.07) | 916 (10.83) | 0.578 |
| Other chest painb | 441 (4.06) | 53 (2.20) | 388 (4.59) | 0.099 |
| Vertigo | 141 (1.29) | 12 (0.50) | 129 (1.53) | 0.487 |
Abbreviations: ACS, acute coronary syndrome; CKD, chronic kidney disease; DM, diabetes mellitus; HTN, hypertension; NSTE‐ACS, non–ST‐segment elevation acute coronary syndrome; STEMI, ST‐segment elevation myocardial infarction.
Data are presented as n (%).
Sweating refers to profuse sweating in context of ACS.
Chest pain other than typical angina.
In the study cohort, typical angina (83.82%) was the most common presenting symptom in the ACS population, with greater prevalence in the STEMI group than in the NSTE‐ACS group (86.80% vs 82.97%, P < 0.0001; Table 1). Sweating was present in 90.95% of STEMI and 10.43% of NSTE‐ACS patients (P < 0.0001). On univariate analysis, all symptoms except nausea (P = 0.225) and palpitations (P = 0.364) were found to have significant association with STEMI. These significant independent variables were then analyzed using multivariate analysis. Using backward stepwise multiple logistic regression, 2 independent variables, typical angina (OR: 2.72, P < 0.0001) and sweating (OR: 97.06, P < 0.0001), were the only significant predictors of STEMI. Sweating (28.29%) in the context of ACS had the highest odds (OR: 97.06, P < 0.0001) of favoring STEMI. Arm pain (OR: 1.06, P = 0.437), back pain (OR: 1.03, P = 0.709), epigastric pain (OR: 1.01, P = 0.891), dyspnea (OR: 1.06, P = 0.57), nausea (OR: 1.05, P = 0.557), vomiting (OR: 1.17, P = 0.83), and vertigo (OR: 1.31, P = 0.487) favored STEMI over NSTE‐ACS, whereas palpitations (OR: 0.99, P = 0.99), mouth dryness (OR: 0.82, P = 0.049), chest pain other than typical angina (OR: 0.70, P = 0.099), and throat pain (OR: 0.97, P = 0.656) favored NSTE‐ACS over STEMI (Figure 2).
Figure 2.
Odds ratio plot of ACS symptoms on multivariate analysis. Abbreviations: ACS, acute coronary syndrome; CI, confidence interval; NSTE‐ACS, non–ST‐segment elevation acute coronary syndrome; OR, odds ratio; STEMI, ST‐segment elevation myocardial infarction.
The ROC curve was plotted to estimate the discriminatory performance of the logistic‐regression model. The C statistic value of typical angina with sweating for diagnosis of STEMI was 0.859, compared with 0.519 for typical angina alone.
To evaluate the impact of sweating for diagnosis of STEMI, all ACS symptoms were grouped into 2 categories, typical angina and atypical angina or angina equivalents. Atypical symptoms were more common in the NSTE‐ACS group (17.03% vs 13.2%; P < 0.0001). Despite being the most common clinical presentation (86.8%), typical angina had a low PPV (22.97), low LR (0.05), and low OR (1.35) for diagnosis of STEMI (Table 2).
Table 2.
Analysis of Symptoms for Prediction of STEMI
| Symptom | Total patients, N (%) | STEMI, n (%) | NSTE‐ACS, n (%) | PPV (95% CI) | LR+ (95% CI) | OR (95% CI) | P Value |
|---|---|---|---|---|---|---|---|
| Typical angina with sweatinga | 2497 (22.98) | 1900 (78.84) | 597 (7.06) | 76.09 (74.37‐77.75) | 11.17 (10.31‐12.1) | 111.11 (90.91‐125.00) | <0.0001 |
| Typical angina | 9109 (83.82) | 2092 (86.80) | 7017 (82.97) | 22.97 (22.11‐23.84) | 1.05 (1.03‐1.07) | 1.35 (1.18‐1.54) | <0.0001 |
| Atypical angina/angina equivalents with sweatinga | 577 (5.31) | 292 (12.12) | 285 (3.37) | 50.61 (46.45‐54.76) | 3.6 (3.07‐4.21) | 45.45 (30.30‐71.43) | <0.0001 |
| Atypical angina/angina equivalents | 1758 (16.18) | 318 (13.20) | 1440 (17.03) | 18.09 (16.32‐19.97) | 0.77 (0.69‐0.87) | 0.74 (0.65‐0.84) | <0.0001 |
Abbreviations: ACS, acute coronary syndrome; CI, confidence interval; LR+, positive likelihood ratio; NSTE‐ACS, non–ST‐segment elevation acute coronary syndrome; OR, odds ratio; PPV, positive predictive value; STEMI, ST‐segment elevation myocardial infarction.
Sweating refers to profuse sweating in context of ACS.
Presence of sweating in the context of typical angina increased PPV from 22.97 to 76.09, LR from 1.05 to 11.17, and OR from 1.35 to 111.11 for STEMI. Likewise, presence of sweating in the context of atypical angina improved PPV from 18.09 to 50.61, LR from 0.77 to 3.60, and OR from 0.74 to 45.45.
Among all ACS symptoms, typical angina with sweating had the highest PPV (76.09), positive LR (11.17), and OR (111.11) for diagnosis of STEMI. Presence of sweating markedly improved the statistical significance of anginal symptoms for diagnosis of STEMI (Table 2, Figure 3).
Figure 3.
Histogram showing PPV, OR, and LR values of typical and atypical angina symptoms with or without associated sweating. Abbreviations: LR, positive likelihood ratio; OR, odds ratio; PPV, positive predictive value.
On subgroup analysis, 159 STEMI patients initially did not meet the ECG criteria in the ED, and diagnostic ECG changes evolved after hospitalization. The majority of them, 142 (89.3%), had sweating at presentation. This implies the significance of symptoms for timely diagnosis and management of STEMI.
Discussion
Diagnosis of STEMI with history has always been a clinical dilemma. Its diagnosis is delayed due to lack of specificity of any symptom, delayed patient presentation, and temporal delay in obtaining supporting evidence of biochemical parameters, ECG, and echocardiography. This study analyzed the symptoms of STEMI and NSTE‐ACS patients to see if any emerged as potential indicators for early diagnosis of STEMI.
Typical angina was most common presentation in both groups. In the STEMI group, 13.2% of patients, and 17.03% in the NSTE‐ACS group, had complaints other than typical angina, which is on par with observations by Pope and colleagues.2 Chest‐pain characteristics and duration are subjective and lack sound clinical evidence to pitch them for STEMI diagnosis. In a meta‐analysis by Chun and McGee15 and Panju et al,16 chest‐pain characteristics such as pressure and the like were not enough to be independently useful in establishing a MI diagnosis. Classic duration of pain lasting >30 minutes can be indicative of either an AMI or a nonischemic etiology, like gastroesophageal disease.17, 18 In a meta‐analysis of 64 studies, chest‐pain duration >30 minutes suggested low likelihood of MI (LR+: 0.1).15 Several studies have examined the ability of associated symptoms such as nausea, vomiting, and diaphoresis to predict AMI. Two meta‐analyses discovered that nausea and diaphoresis predict AMI.15 Nattel et al noted sweating in 53% of AMI cases. Diaphoresis was a more specific but less sensitive predictor of MI than prolonged chest pain.19 However, in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial, the association between diaphoresis and AMI disappeared on multivariable testing (OR: 1.1, P = 0.636).6 Underrepresentation of patients in older age groups and non–English‐speaking ethnic groups probably underestimated the association of sweating.
In our Sweating In Myocardial Infarction (SWIMI) study cohort, sweating and typical angina were the only significant symptoms for STEMI prediction. Sweating when added to angina, whether typical or atypical, improved the diagnostic accuracy of the symptom for STEMI in all statistical domains. Typical angina with sweating had the highest PPV and LR for STEMI.
Twenty percent of AMI and 37% of UA patients can present with an initially normal ECG.2 In our study, presence of sweating in 142 patients in the ED without diagnostic ECG changes, who later on developed STEMI, echoes the significance of this symptom. Paying due regard to this symptom in the ED may help to diagnose STEMI in the hyperacute phase.
A probable explanation of profuse sweating in STEMI is stimulation of the sympathetic nervous system as a protective phenomenon in response to pain. But this does not explain absence of profuse sweating in other diseases with severe pain, like trauma, burns, colic, pancreatitis, and others. A second explanation is transient hypotension due to acute myocardial stunning in STEMI activating the sympathetic nervous system, instantaneously resulting in profuse sweating. Lack of transmural infarction in NSTEMI, and absence of such severe acute insult, may explain the absence of sweating in this group. We propose that there might be some cross connection between the sympathetic nervous system innervating sweat glands and myocardial pain fibers, which have the same origin in the thoracolumbar region. So, parallel to the theory of referred pain, sweating could be a referred symptom, though this theory needs further validation.
In today's world, when time to treatment is a quality metric for acute STEMI care,20 we propose that this parameter should be expanded to event‐to‐reperfusion time. Because reperfusion salvages injured and not‐dead myocardium, patients presenting late will have dead reperfused myocardium. Improving time to treatment will have suboptimal results unless patients or primary‐care physicians suspect STEMI in time. Quality of care should now focus on event‐to‐reperfusion time, rather than time to treatment, to target unmet health goals. Sweating with typical STEMI symptoms can help emergency responders and ED staff have a high level of suspicion for STEMI, but treatment decisions should still be based on ECG criteria.
Study Limitations
Our study is a single‐center study, and to further validate our observations, a multicenter study is needed. Patient history was noted by multiple observers, so the chance of interobserver variation does exist. Variations in symptoms due to different educational qualifications and interpretation by patients may have affected study results.
Conclusion
In the SWIMI study, presence of sweating with ACS symptoms significantly increased probability of STEMI. Sweating in association with typical or atypical angina was the strongest predictor of STEMI. Moreover, event‐to‐treatment time, rather than time to treatment, should be the goal of STEMI medical care. If sweating becomes widely understood to be a red flag for STEMI, community awareness of this simple and inexpensive symptom tool can save many lives and health care dollars.
The authors have no funding, financial relationships, or conflicts of interest to disclose.
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