A Specific Predictor of STSegment Elevation Myocardial Infarction Among the Symptoms of Acute Coronary Syndrome: Sweating In Myocardial Infarction (SWIMI) Study Group

A Specific Predictor of STSegment Elevation Myocardial Infarction Among the Symptoms of Acute Coronary Syndrome: Sweating In Myocardial Infarction (SWIMI) Study GroupA Specific Predictor of STSegment Elevation Myocardial Infarction Among the Symptoms of Acute Coronary Syndrome: Sweating In Myocardial Infarction (SWIMI) Study GroupA Specific Predictor of STSegment Elevation Myocardial Infarction Among the Symptoms of Acute Coronary Syndrome: Sweating In Myocardial Infarction (SWIMI) Study Group

Address for correspondence:

Bhanwar Lal Ranwa, MD Department of Cardiology Jawaharlal Nehru Medical College and Hospital

Ajmer, Rajasthan, India, Pin-305001 bhanwar.ranwa@gmail.com

Sweating: A Specific Predictor of ST-Segment

Elevation Myocardial Infarction Among the

Symptoms of Acute Coronary Syndrome:

Sweating In Myocardial Infarction (SWIMI)

Study Group

Rajendra K Gokhroo, MBBS, MD, FACC; Bhanwar L Ranwa, MBBS, MD; Kamal Kishor,

MBBS, MD; Kumari Priti, MBBS, MD; Avinash Ananthraj, MBBS, MD; Sajal Gupta, MD;

Devendra Bisht, MD

Department of Cardiology, Jawaharlal Nehru Medical College and Hospital, Ajmer, Rajasthan,

India

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

The authors have no funding, financial relationships, or conflicts

of interest to disclose

infarction (AMI) is missed in up to 11.1% of cases.3Among AMI cases, 18% do not have chest pain2at 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.4–6

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

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.8ST-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 (V1through

V4) diagnostic of posterior-wall STEMI, and multi-lead

ST-segment depression with coexistent ST-ST-segment elevation

in lead aVR were also included in the STEMI group.9–13

Symptoms were classified as typical angina and atypical

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.

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%

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)

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)

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)

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,16chest-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.15Nattel 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

Variable Total Patients, N = 10 867 STEMI Patients, n = 2410 NSTE-ACS Patients, n = 8457 P Value

Age, y

Symptoms

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 (%).

aSweating refers to profuse sweating in context of ACS.bChest pain other than typical angina.

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

non–ST-segment elevation acute coronary syndrome; OR, odds ratio; STEMI, ST-segment elevation myocardial infarction.

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.

aSweating refers to profuse sweating in context of ACS.

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

positive likelihood ratio; OR, odds ratio; PPV, positive predictive value.

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

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