Hospital Admissions for Chest Pain Associated with Cocaine Use in the United States

Accepted Manuscript Hospital Admissions for Chest Pain Associated with Cocaine use in the United States Vikas Singh, MD, Alex P. Rodriguez, MD, Badal Thakkar, MD MPH, Ghamshyambhai R. Savani, MD, Nileshkumar J. Patel, MD, Apurva O. Badheka, MD, Mauricio G. Cohen, MD, Carlos E. Alfonso, MD, Raul D. Mitrani, MD, Juan Viles-Gonzalez, MD, Jeffrey J. Goldberger, MD PII:

S0002-9343(16)31302-X

DOI:

10.1016/j.amjmed.2016.12.003

Reference:

AJM 13840

To appear in:

The American Journal of Medicine

Received Date: 31 October 2016 Revised Date:

7 December 2016

Accepted Date: 8 December 2016

Please cite this article as: Singh V, Rodriguez AP, Thakkar B, Savani GR, Patel NJ, Badheka AO, Cohen MG, Alfonso CE, Mitrani RD, Viles-Gonzalez J, Goldberger JJ, Hospital Admissions for Chest Pain Associated with Cocaine use in the United States, The American Journal of Medicine (2017), doi: 10.1016/j.amjmed.2016.12.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Running Head: Chest Pain Associated with Cocaine Use Hospital Admissions for Chest Pain Associated With Cocaine use in the United States

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Vikas Singh MD*1, Alex P. Rodriguez MD*2, Badal Thakkar MD MPH*3, Ghamshyambhai R. Savani MD4, Nileshkumar J. Patel MD2, Apurva O. Badheka MD5, Mauricio G. Cohen MD2, Carlos E. Alfonso MD2, Raul D. Mitrani MD2, Juan VilesGonzalez MD2, Jeffrey J. Goldberger MD2

* Vikas Singh, Alex P. Rodriguez, and Badal Thakkar contributed equally to this manuscript.

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1. Interventional Cardiology, Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 2. Cardiovascular Division, University of Miami Miller School of Medicine 3. Cardiovascular Division, Cleveland Clinic, Ohio 4. Prince George’s Hospital Centre, Cheverly, Maryland 5. Cardiovascular Division, The Everett Clinic, Everett, Washington. Word Count: 3287

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This statement is to certify that all authors have seen and approved the manuscript being submitted, have contributed significantly to the work, attest to the validity and legitimacy of the data and its interpretation, and agree to its submission. We attest that the article is the Authors' original work, has not received prior publication and is not under consideration for publication elsewhere. On behalf of all Co-Authors, the corresponding Author shall bear full responsibility for the submission. Any changes to the list of authors, including changes in order, additions or removals will require the submission of a new author agreement form approved and signed by all the original and added submitting authors. All authors are requested to disclose any actual or potential conflict of interest including any financial, personal or other relationships with other people or. The authors report no relationships that could be construed as a conflict of interest.

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Founding Source: None

Correspondance: Vikas Singh, M.D. Cardiology Division Massachusetts General Hospital, Harvard Medical School Boston, Massachusetts [email protected] Phone Number: 786-991-8555 Fax Number: 617 726-7855

ACCEPTED MANUSCRIPT 2 Chest Pain Associated with Cocaine use Abstract Background:

healthcare system are not well studied. Methods:

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The outcomes related to chest pain associated with cocaine use and its burden on

Data were collected from the Nationwide Inpatient Sample (2001 – 2012). Subjects were

myocardial infarction, stroke and cardiac arrest.

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Results:

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identified by using the ICD-9-CM codes. Primary outcome was a composite of mortality,

We identified 363,143 admissions for cocaine induced chest pain. Mean age was 44.9 (+ 21.1) years with male predominance. Left heart catheterizations were performed in 6.7%, whereas the frequency of acute MI and percutaneous coronary interventions were 0.69%

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and 0.22% respectively. The in-hospital mortality was 0.09% and the primary outcome occurred in 1.19% of patients. Statistically significant predictors of primary outcome included female sex (OR=1.16, CI 1.00-1.35, p=0.046), age > 50 years (OR=1.24, CI

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1.07-1.43, p=0.004), history of heart failure (OR=1.63, CI 1.37-1.93, p<0.001), supraventricular tachycardia (OR=2.94, CI 1.34-6.42, p=0.007), endocarditis (OR=3.5,

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CI 1.50-8.18, p=0.004), tobacco use (OR=1.3, CI 1.13-1.49, p<0.001, dyslipidemia (OR=1.5, CI 1.29-1.77, p<0.001), coronary artery disease (OR=2.37, CI 2.03-2.76, p<0.001), and renal failure (OR=1.27, CI 1.08-1.50, p=0.005). The total annual projected economic burden ranged from $155 to $226 million with a cumulative accruement of over $2 billion over a decade. Conclusion:

ACCEPTED MANUSCRIPT 3 Chest Pain Associated with Cocaine use Hospital admissions due to chest pain and concomitant cocaine use are associated with very low rates adverse outcomes. For the low risk cohort in whom acute coronary syndrome has been ruled out, hospitalization may not be beneficial and may result in

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unnecessary cardiac procedures.

Key Words:

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Cocaine use, chest pain, mortality, myocardial infarction, percutaneous coronary

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intervention

INTRODUCTION

Cocaine is a powerful sympathomimetic agent, which results in coronary and

peripheral arterial vasoconstriction, and its use is also linked with cardiac arrhythmias1. The deleterious cardiovascular and prothrombotic effects of cocaine use have been well established and may underlie a wide range of clinical cardiovascular presentations2. Its acute and more chronic presentations encompass a myriad of pathologies that range from

ACCEPTED MANUSCRIPT 4 Chest Pain Associated with Cocaine use acute coronary syndromes, heart failure, cardiomyopathies, arrhythmias, aortic dissection, among others3-5. Of these, chest pain continues to be the most common acute presentation of cocaine use and intoxication, which often leads to hospitalization and a

the hospital accounting for an annual cost over $83 million6.

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full cardiovascular evaluation. It is estimated that 57% of these patients are admitted to

Cocaine has indeed become a major economic burden and continues to burden the

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social and healthcare system7. However, its use reached unprecedented popularity in the 1980’s, and continued to increase to the point that in the 2000’s, it accounted for up to

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40% of emergency department visits for drug misuse or abuse4, 8. Data looking into the epidemiology of its cardiovascular and socioeconomic implications are scarce. The aims of this study are to analyze the trends of hospital admissions with chest pain associated with cocaine use as well as to study in-hospital outcomes and costs using the largest

METHODS

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publicly available inpatient database in the United States.

Data were collected from the Nationwide Inpatient Sample (NIS) between the

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years 2001 through 2012. The NIS database was developed for the Health Care Cost and Utilization Project (HCUP) and has been extensively used to identify, track, and analyze

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national trends in healthcare usage, patterns of major procedures, access, disparity of care, trends in hospitalizations, charges, quality and outcomes9-12. Subjects were identified by using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. Those below 18 years of age or with missing information about age, gender or disposition status were excluded from the study. The ICD-9-CM codes were

ACCEPTED MANUSCRIPT 5 Chest Pain Associated with Cocaine use also used to assess the comorbidities, complications, and the diagnostic or interventional procedures performed. The trends of patient and hospital level variables were studied to assess the

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baseline characteristics of the study population. Patient level characteristics such as age, sex, race, co-morbid conditions, median household income according to ZIP Code, primary payer, admission type (urgent/emergent vs. elective), day of admission

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(weekdays vs. weekend), and hospital level characteristics such as hospital location

(urban/rural), hospital bed size (small, medium, and large), region (Northeast, Midwest or

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North Central, South, and West), and teaching status were studied. We defined severity of comorbid conditions using the Deyo modification of the Charlson comorbidity index (CCI)13. This index contains 17 comorbid conditions with differential weights. A higher score corresponds to greater burden of comorbid diseases. Facilities were considered to

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be teaching hospitals if they had an American Medical Association approved residency program, were a member of the Council of Teaching Hospitals, or had a fulltime equivalent intern and resident to patient ratio of 0.25 or higher.

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The HCUP NIS reports data on total patient charges for each hospitalization, which represents the total amount that hospital billed for the services provided. Cost of

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each hospitalization was determined after merging data with cost-to-charge ratio (CCR) available from the HCUP. Total hospital charges were converted to data to cost estimates by using the merged data from CCRs and the total charges reported in the HCUP NIS. These costs are standardized and adjusted for each year. Inflation was accounted for by adjusting the cost of each year in reference to the 2012 US dollar value using Consumer Price Index data14. The total duration of hospital stay in days was estimated for all

ACCEPTED MANUSCRIPT 6 Chest Pain Associated with Cocaine use patients. NIS data include all the patients admitted under observation or inpatient status into participating hospitals. SAS 9.4 (SAS Institute Inc, Cary, North Carolina) was utilized for analyses. The

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categorical variables are expressed as percent of total population and the continuous

variables are expressed as median with interquartile range. To study the trend of major comorbidities, complications, outcomes, and the procedures performed, the Cochran-

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Armitage trend test was employed. P-value <0.05 was considered significant.

The multivariate hierarchical logistic regression model was used to identify

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significant predictors of a composite outcome of in-hospital mortality, cardiac arrest, myocardial infarction, and ischemic stroke (events that would require hospital admission for further management). We chose a composite outcome given low frequency of individual end points. In the two-level (patient-level factors nested within hospital-level

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factors) hierarchical model, the unique hospital identification number was incorporated as a random effect. The variables that were included in the model were age, gender, and the comorbidities presented in table 1. After identifying the significant predictors, the

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regression coefficients of those variables were used to give proportional weights to each significant risk-factor. Based on the weights, a risk-score for each predictor was

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calculated such that a total score of 100 was the maximum possible score for any patient. RESULTS

Between the years of 2001 and 2012, there were 363,143 hospital admissions

because of chest pain and concomitant cocaine abuse. Table 1 depicts the baseline characteristics of the studied population. Initially, there was an increase in the number of hospitalizations until the years 2006-2007, with a subsequent trend towards decline. The

ACCEPTED MANUSCRIPT 7 Chest Pain Associated with Cocaine use mean age of patients was 44.9 (+ 21.1) years and 52.3% of these individuals were between the ages of 35 and 49, with a 3:1 male to female ratio. More than half of these patients belonged to the lowest income quartile, and one third had no form of medical

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insurance. Most of the admissions were on an emergent-urgent basis and to large

teaching institutions. Most individuals had a Charlson comorbidity index 0 and almost half were smokers with chronic hypertension. About one quarter had a prior history of

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depression or psychosis. On average, throughout these years 16.8% had a previously

documented history of coronary artery disease and 10.3% had heart failure. There was a

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preferential geographical distribution to the Southern region of the United States. The overall rate of cardiovascular complications is shown in table 2. The most common medical complication was hypertensive emergency-urgency occurring in 32 to 51% of patients over the study period, with a trend toward an increased incidence over

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time (p<0.001). The frequency of coronary events was low with an average frequency for ST-elevation myocardial infarction (STEMI) of 0.15%, non-ST-elevation myocardial infarction (NSTEMI) of 0.42%, and coronary vasospasm of 0.22%. When compared to

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the acute coronary syndrome presentations, there was a substantially higher rate of left heart catheterization (6.7%) and very low rate of percutaneous coronary interventions

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(0.22%) (table 2). There was no statistically significant difference in acute coronary syndrome presentation trends (p = 0.279); nonetheless, there was a consistent increase in rate of cardiac catheterization over these years. Likewise, the rate of aortic pathologies was comparable to that of acute coronary syndrome with no trend. Supraventricular tachycardias were more common than ventricular ones whereas the in-hospitalization pacemaker and implantable cardioverter defibrillator (ICD)

ACCEPTED MANUSCRIPT 8 Chest Pain Associated with Cocaine use implantation rates were very low at 0.05 and 0.06% respectively. The rate of pericarditis and endocarditis was comparable throughout these years, and remained low despite higher frequencies of HIV and concomitant heroin use. Neurological complications were

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also reported with the most common being seizures and epilepsy, and less commonly acute strokes.

On average, throughout these years the median (IQ) duration of admission

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remained unchanged at 2 days (1-3). The median hospitalization cost ranged between

$4200 to just over $4900 with a steady uptrend on a yearly basis (p<0.001). Likewise,

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the total annual projected economic burden ranged from $155 to $226 million, with a cumulative decade accruement of over $2 billion.

The overall in-hospital mortality was low at 0.09%, without any particular trend over these years (p=0.10) and the primary outcome occurred in 1.19% of patients and

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increased from 0.58 to 2.04% over the study period (p trend<0.001). Table 3 represents the multivariate logistic regression analysis for predictors of primary composite outcome. Table 4 depicts the risk stratification algorithm and the weight assigned to each of these

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statistically significant predictors for the primary end-point. We created a scoring system which effectively stratified patients who were low risk (risk score≤15), intermediate risk

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(risk score= 16-30) and high risk (risk score ≥31). There was a 4.5-fold difference in primary outcome in patients in the low risk (0.8%) and high risk groups (3.6%). 75% of the study population had scores ≤15 and only 6% had scores ≥31. Figure 1 shows the population distribution according to the risk score and the pertinent percentage of primary outcome for that particular patient cohort. DISCUSSION

ACCEPTED MANUSCRIPT 9 Chest Pain Associated with Cocaine use This is the largest study to date, which provides insights into hospitalizations for chest pain associated with cocaine abuse in the US. In general, the number of hospital admissions remained stable over the last 12 years. We report that most of the patients

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were relatively young and healthy while the most common comorbid conditions were

tobacco use and hypertension. Hypertensive crises, heart failure and seizures were the most common concomitant presentations. We noted low rates of mortality and

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cardiovascular complications including significant tachyarrhythmias, cardiac arrest, and acute coronary syndromes. The rate of diagnostic angiography was several times higher

frequency of coronary interventions.

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than the incidence of acute coronary syndrome and this was evident in a relatively low

In our study, the average rate of acute myocardial infarction ranged from 0.4 to 1.32%. In an initial publication of the prospective COCaine Associated Chest Pain

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(COCHPA), the authors prospectively followed 246 consecutive patients who presented with cocaine-associated chest pain. They described a 6% incidence of acute coronary syndrome in patients that presented to the emergency department with chest pain after

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cocaine use15. In the latter publication, myocardial infarction was diagnosed in 14 patients using dynamic EKG changes indicative of ischemia and CK-MB isoenzyme

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elevations. The same authors, in a different retrospective analysis of cocaine users, reported a much lower myocardial infarction frequency of less than 0.16%16. A subsequent study, conducted in an urban university affiliated hospital revealed a 6% rate of acute coronary syndrome in 259 patients17. The more recent, larger, multicenter, Acute Cardiac Ischemia-Time Insensitive Predictive Instrument (ACI-TIPI) clinical trial enrolled much higher number of patients, and found a much lower rate of MIs, below 1%

ACCEPTED MANUSCRIPT 10 Chest Pain Associated with Cocaine use (n=10,689)18. Collin et al in a prospective study following over 3,800 patients demonstrated that in cocaine users younger than 40 years, the rate of acute coronary syndrome is low (0.5%), and so is the mortality (0.4%) after one year follow up

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There are multiple explanations for this array of findings, including the ones we described in our results. First, depending on the time of these publications, the cocaine use prevalence in metropolitan and rural areas varied, and so did the reporting and

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practitioner awareness. Furthermore, these selected urban populations were higher-thanaverage risk with greater comorbid condition burden including almost 50% history of

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recurrent chest pain. Feldman et al argue that for the ACI-TIPI study, they observed a marked diversity of acute coronary syndrome and cocaine use diagnoses among the involved institutions; thus, confirming that patient selection, diagnosis ascertainment, and misclassification biases may play a pivotal role in the observed myocardial infarction rate.

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Moreover, amongst these studies, there is marked difference in the definition of acute MI, cocaine use confirmatory testing, and patient evaluation guidelines, all of which contribute to the aforementioned inconsistency4. The current study evaluated

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hospitalizations all over US and is free from selection bias, which may have affected the single center or smaller studies.

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Despite the low rate of acute coronary syndrome, we show a relatively high

number of performed coronary angiographies. A total of 6.7% patients underwent coronary angiography whereas only 0.2% underwent a coronary intervention. One of the studies to report the largest angiographic records in this particular population found that 50% of the patients did not have any significant stenotic coronary lesions and 32% had single vessel disease19. In the latter study, a total of 90 patients underwent coronary

ACCEPTED MANUSCRIPT 11 Chest Pain Associated with Cocaine use angiography, one of the largest such reports. In another prospective study (n=344), the rate of cardiac catheterizations (6.95%) and subsequent percutaneous coronary intervention (0.66%) were very similar to the ones presented here20. Similarly, Walker

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et al, in a different analysis, noted that three quarters of the patients that underwent

angiography did not require any coronary intervnetion 21. Our study highlights this trend, and our range of both angiography and intervention oscillate between those previously

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published15, 16, 19, 21-24. Consequently, it could be argued that cocaine induced chest pain may not require routine catheterization, as this is a rather low risk population. Guidelines

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may need to be developed specifically for this population.

Also consistent with prior studies, our data continue to validate the notion that inhospital mortality rate is low in this particular patient population. For most publications, the 1-month follow up mortality is close to negligible whereas at 1-year follow up it is

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generally less than 1%16, 18, 23, 25, 26. As previously stated, these results may actually be due to the population in question. Most patients were relatively young with two thirds being under 50 years of age, and over half had a zero score in the Charlson comorbidity

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index.

Cocaine predisposes to premature atherosclerosis, left ventricular hypertrophy,

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cardiomyopathy, all of which may increase cardiovascular complications and mortality27. Nonetheless, when compared to the non-cocaine users who present to the emergency department with chest pain, cocaine users are relatively younger and have less of the traditional cardiovascular comorbidities associated with coronary artery disease. It is therefore not surprising that the predictors of major adverse cardiovascular events differ between cocaine users and non-users. Cunningham et al looked at the short and long term

ACCEPTED MANUSCRIPT 12 Chest Pain Associated with Cocaine use medical outcomes and hospital recidivism after cocaine associated chest pain22. In the latter report, the authors showed that though a quarter of cocaine users with chest pain return to the hospital with similar presentations, most of them have a very low likelihood

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of having a poor cardiovascular outcome, including death. The highest risk patients included, as expected, those with prior heart failure, valvular disease, or prior

PERCUTANEOUS CORONARY INTERVENTION . Moreover, Weber et al in a

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different study argued that most of these patients could actually be safely discharged

from the emergency department. This conclusion was drawn after noting no patient died

continuous cocaine use20.

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30 days post-discharge, and only 4 suffered a non-fatal myocardial infarction after

Cocaine consumption is associated with other medical complications including but not limited to endocarditis, valvular disease, pericarditis, neurological, and

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concomitant use of other illicit substances. This underlines the complexity of drug abuse especially when associated with HIV. In our population we showed some relation between the latter and cocaine consumption, both of which are predisposing factors for

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early coronary artery disease development and higher mortality rates. All of these factors conjointly tend to underscore the magnitude and complexity of presentations because of

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cocaine-induced chest pain, as well as the energy and resources dedicated to identify higher risk patients that may indeed benefit from further testing and intervention. Nonetheless from the prior evidence cited, along with our own findings, it is presumably safe to assume that for low risk patients in whom acute coronary syndrome has been ruled out, exhaustive screening and diagnostic interventions may not be cost effective.

ACCEPTED MANUSCRIPT 13 Chest Pain Associated with Cocaine use Yet, the confounding element is the high degree of emergency department and hospital recidivism because of continuous cocaine use. A special area of concern is the increasing rates of medical expenses over the

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studied years. These values have been adjusted according to inflation as of 2012. We

show a 158% such increase in a decade. Analysis of NIS reveals that the current expense rate increase is higher than that observed for hospitalizations for adult congenital heart

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disease28, acute pulmonary embolism29, acute coronary syndrome 30, atrial fibrillation31, among others. Recently, multiple studies reported the accruing expenses of substance use

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disorders at $600 billion annually in medical services, crime, and productivity costs32. A prior study estimated the cost of cocaine associated chest pain admissions to be approximately $80 million per year6. This figure is close to the one observed initially in our study, however there was a steady but significant increase in the cost that ranged

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from 2 to 3 times that value even after accounting for inflation. Likewise, after careful inspection, one could speculate that the costs are only likely to increase with time. Thus, individualized patient re-stratification could potentially play a role in curtailing these

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expenses.

With respect to overall risk classification, to the best of our knowledge, there is

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thus far, not a conventional and dependable scoring system by which practitioners can stratify patients on a more individualized basis. This has been attempted in the past using the TIMI score, but has been found to have no clinically useful predictive value33, 34. Here, a risk-stratification algorithm is provided in the initial evaluation of cocaineinduced chest pain (Figure 1). From our analysis, it seems that three quarters of the population were very low risk (scored less than 15 points). In these patients, the overall

ACCEPTED MANUSCRIPT 14 Chest Pain Associated with Cocaine use rate of in-hospital mortality, MI, cardiac arrest, and stroke were overall low (0.8%). In patients with scores 15-30, who comprised 19% of the total study population, the incidence of negative outcome was 2.1%. However, with increasing cumulative risk

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scores, we noted an exponential increase in the occurrence of primary outcome. In

contrast to the prior reports that have only looked at very specific populations our study population is a representation of that in the US16, 18, 23, 25, 26. This proposed re-stratification

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system may be used to guide the management of patients and determine who may need admission or further evaluation by other diagnostic tests. Nevertheless, this should not,

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by any means, supersede clinical judgment, which along with individualized patient assessment should dictate medical care. In general, it could be safe to assume that scores less than 15 bode overall good prognosis whereas those above 45 do not. The large comprehensive data scope, the diversity of the studied population and

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hospitals, as well as the time frame are some of the many strengths of our study. First, our data, as previously stated, comprises the diverse national population of the US and the multiple hospitals that track, and report, their hospitalizations trends to the NIS.

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Furthermore, over a decade of data have been queried and analyzed; thus, making it a reliable sample of the observable trends nationwide. However, a few drawbacks deserve

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mentioning. First, just like prior studies and the American Heart Association (AHA) statement on cocaine-associated chest pain, we understand that currently practitioners mostly rely on self-reporting rather than on the more expensive, albeit reliable, laboratory diagnostic modalities34. This, in turn leads to underreporting, which predisposes to bias. However, we believe that in our study, given the number of patients analyzed, the data scope, and the protracted analysis, this is likely to have played a minor role. Secondly,

ACCEPTED MANUSCRIPT 15 Chest Pain Associated with Cocaine use the continuous cocaine use in a great percentage of the population, and the repeated hospital visits for this reason, may also influence subsequent diagnostic and therapeutic interventions. This point just emphasizes the fact that health care providers should be

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trained to provide a holistic education when it comes to this complex topic, rather than a focus one just by trying to rule-in or out a specific, notwithstanding infrequent, cardiac

complication. Lastly, the cross sectional nature of our data, hinders our ability to track

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individuals throughout time and possibly provide more insightful long term follow up information.

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In conclusion, hospital admissions due to chest pain and concomitant cocaine use correlate with very low rates of adverse outcomes as well as the need for interventions. It appears that identification and re-stratification of patients presenting to the emergency department can improve unnecessary hospital admissions and cardiac procedure rates.

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This is especially the case for low risk patients who do not seem to draw much benefit from further evaluation once an acute coronary syndrome is ruled out. Future publications and updated treatment guidelines could safely improve patient care while

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lowering cost.

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RI PT

31.

Healthcare Cost and Utilization Project (HCUP) databases. Journal of medical economics. 2014;17:191-197. Patel NJ, Deshmukh A, Pant S, et al. Contemporary trends of hospitalization for atrial fibrillation in the United States, 2000 through 2010: implications for healthcare planning. Circulation. 2014;129:2371-2379. McCollister K, Yang X, McKay JR. Cost-effectiveness analysis of a continuing care intervention for cocaine-dependent adults. Drug and alcohol dependence. 2016;158:38-44. Chase M, Brown AM, Robey JL, et al. Application of the TIMI risk score in ED patients with cocaine-associated chest pain. The American journal of emergency medicine. 2007;25:1015-1018. McCord J, Jneid H, Hollander JE, et al. Management of cocaine-associated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation. 2008;117:1897-1907.

ACCEPTED MANUSCRIPT

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

Total

Total number of cases included in the study (n)

18,195

20,727

21,660

27,641

31,468

40,003

38,288

33,919

34,243

34,301

33,998

28,700

363,143

40.9 (0.15)

41.59 (0.14)

42.23 (0.13)

42.63 (0.12)

43.21 (0.11)

44.17 (0.10)

44.85 (0.11)

45.37 (0.11)

46.5 (0.11)

47.5 (0.11)

47.85 (0.11)

48.24 (0.13)

44.93 (0.04)

40.9 ± 19.96

41.59 ± 19.72

42.23 ± 19.74

42.63 ± 19.54

43.21 ± 20.36

44.17 ± 20.59

44.85 ± 20.61

45.37 ± 20.51

46.5 ± 20.58

47.5 ± 20.4

47.85 ± 20.86

48.24 ± 22.09

44.93 ± 21.1

<0.001

18-34

23.71

22.51

20.7

19.4

18.14

15.49

14.59

13.66

11.4

9.6

10.4

11.15

15.11

<0.001

35-49

60.46

59.02

58.65

58.45

57.43

56.07

53.83

52

49.35

47.17

43.13

39.08

52.27

<0.001

50-64

14.92

17.48

19.78

21.08

23.13

26.9

30.17

32.39

36.71

40.48

43.31

46.15

30.69

<0.001

≥65

0.91

0.99

0.87

1.07

1.3

1.54

Male

73.31

74.74

74.33

73.97

73.69

73.87

Female

26.69

25.26

25.67

26.03

26.31

Whites

21.18

21.89

22.59

23.19

Blacks

39.05

42.65

45.9

43.95

Hispanics

7.77

6.26

8.27

7.2

Others

0.19

0.22

0.32

0.42

Missing

31.8

28.98

22.93

0

69.58

68.53

64.77

1

21.6

22.46

25.16

≥2

8.82

9

Smoking

29.92

Dyslipidemia

7.23

Age, years - mean (std. error) Age, years - mean ± std. deviation

1.96

2.53

2.75

3.16

3.62

1.93

<0.001

71.85

71.52

72.14

71.78

70.58

71.55

72.63

<0.001

26.13

28.15

28.48

27.86

28.22

29.42

28.45

27.37

22.18

23.21

23.52

26.58

21.64

22.91

22.93

27.26

23.37

<0.001

35.88

41.61

42.53

41.51

50.91

58.67

56.43

56.76

46.64

<0.001

7.96

8.48

7.7

8.45

9.12

8.55

8.37

10.12

8.26

<0.001

0.5

0.72

0.83

0.47

0.55

0.62

0.76

0.71

0.57

<0.001

25.24

33.47

25.97

25.42

23

17.79

9.24

11.52

5.14

21.16

62.31

60.39

56.02

52.98

51.73

47.71

44.8

40.63

39.77

53.5

<0.001

25.9

27.27

26.47

26.54

27.19

27.99

28.87

27.47

26.49

<0.001

13.71

16.71

20.55

21.73

25.1

27.22

30.49

32.75

20.01

<0.001

39.36

42

46.44

53.38

54.24

55.62

60.44

61.69

63.55

49.96

<0.001

12.32

13.92

15.63

18.13

19.33

22.33

23.68

27.32

27.74

18.13

<0.001

12.61

13.11

15.58

17.06

17.36

19.8

20.83

23.32

22.56

16.76

<0.001

2.63

3.1

3.24

3.6

4.28

3.96

4.33

4.41

4.4

5.24

3.8

<0.001

7.9

7.82

7.23

8.23

9.89

9.3

10.5

11.74

12.43

12.26

9.47

<0.001

0

0.09

0.1

0.07

0.07

0.11

0.16

0.14

0.15

0.28

0.38

0.14

<0.001

4.01

5.2

5.97

6.61

7.05

8.15

9.71

11.08

12.05

14.5

15.17

9.04

<0.001

EP

26.6

10.07

11.08

35.9

37.22

9

9.76

9

9.73

12.11

Family history of coronary artery disease

1.82

2.96

Prior myocardial infarction

6.69

6.78

0 3.89

Carotid artery disease Heart failure

AC C

Comorbidities, (%)

Coronary artery disease

M AN U

TE D

Charlson comorbidity index (Deyo modification), (%)

Ptrend

1.41

Gender, (%)

Race, (%)

SC

Age, years (%)

RI PT

Baseline characteristics of the study population

ACCEPTED MANUSCRIPT

4.26

4.33

5.3

5.96

6.14

7.46

8.81

Hypertension Diabetes mellitus

.

31.9

.

10.54

Chronic pulmonary disease

.

Peripheral vascular disease Fluid-electrolyte abnormalities/renal failure

33.73

40.3

42.14

46.26

48.91

49.59

10.62

12.86

14.28

15.81

17.35

17.04

12.33

13.45

15.36

16.96

17.91

19.29

19.74

.

0.9

0.68

1.17

1.12

1.47

1.54

.

8.94

9.79

12.09

14.47

16

18.51

Neurological disorder or paralysis

.

3.62

5.32

5.34

5.43

5.06

6.12

Anemia/coagulopathy

.

5.29

6.12

7.12

8.23

7.59

9.6

Solid tumors/metastatic cancers/lymphoma

.

1.04

0.48

0.51

0.47

0.59

0.47

Depression/psychosis

.

19.08

18.96

21.98

25.16

24.22

0.08

0.12

0.06

0.09

0.14

0.12

Medicare

12.43

13

14.25

14.22

Medicaid

32.41

30.23

32.39

32.91

Private

21.15

20.74

18.56

18.05

No pay/self-pay/others

33.58

35.82

34.76

34.47

1. 0-25th percentile

19.09

12.86

47.76

2. 26-50th percentile

25.96

24.12

22.02

3. 51-75th percentile

25.81

28.12

17.58

4. 76-100th percentile

26.61

30.99

8.57

Small

10.43

6.01

Medium

26.31

30.07

Large

63.26

63.92

Urban non-teaching or rural

34.99

Urban teaching

Dementia Primary payer, (%)

10.82

6.79

<0.001

53.71

57

58.74

58.29

45.99

<0.001

19.78

19.81

21.34

22.44

16.12

<0.001

21.78

22.88

24.96

26.38

18.63

<0.001

1.94

2.03

2.74

2.64

2.96

1.71

<0.001

18.92

20.26

22.62

25.55

27.51

17.36

<0.001

6.12

6.66

7.79

7.64

8.45

5.92

<0.001

10.81

12.18

12.92

14.92

15.61

9.78

<0.001

0.61

0.81

1.04

1.26

1.13

0.72

<0.001

25.83

27.96

28.88

31.49

33.3

33.1

25.51

<0.001

0.09

0.15

0.22

0.25

0.18

0.26

0.15

<0.001

15.18

16.83

17.4

18.21

18.13

19.76

21.53

16.62

<0.001

35.25

32.55

30.18

34.37

37.39

37.37

43.2

41.03

35.16

<0.001

14.73

14.1

13.87

14.63

9.82

10.04

8.63

9.08

13.78

<0.001

34.99

38.05

38.7

33.37

34.4

33.82

28.16

28.12

34.14

<0.001

50.33

46.58

46.9

46.76

46.53

46.92

51.26

52.29

52.16

45.13

<0.001

22.82

22.25

21.65

20.83

22.12

19.77

20.32

18.94

19.67

21.41

<0.001

13.87

15.25

15.53

15.12

15

14.36

13.63

14.44

12.7

16.03

<0.001

9.41

9.58

9.3

10.66

10.33

8.12

6.88

7.98

9.29

11.17

<0.001

EP

Hospital bed size, (%)

10.52

14.7

TE D

Median household income category for patients' zip code, (%)

8.64

RI PT

4.52

SC

.

M AN U

Obesity

8.22

9.33

13.34

9.47

8.55

7.74

7.75

6.57

11.48

9.14

<0.001

28.42

28.08

28.87

25.88

25.55

23.55

24.63

24.59

23.13

30.61

26.34

<0.001

61.7

63.7

61.8

60.67

64.91

67.88

66.08

66.55

68.46

57.91

64.07

<0.001

43.18

38.74

42

42

33.42

37.55

35.75

32.93

32.41

34.12

31.92

36.23

<0.001

65.01

56.82

61.23

58

58

66.46

62.38

64.22

65.52

66.48

64.03

68.08

63.32

Northeast

22.71

20.87

27.86

25.8

23.91

22.93

24.35

25.62

33.1

31.39

36.06

24.3

26.9

<0.001

Midwest

27.85

26.23

18.09

26.55

24.89

22.36

23.48

20.19

18.67

17.09

18.77

15.68

21.35

<0.001

Hospital teaching status, (%)

AC C

9.86

Hospital region, (%)

ACCEPTED MANUSCRIPT

South

33.38

36.57

32.33

39.22

41.45

40.34

37.43

40.25

32.89

35.98

30.38

28.82

36.04

<0.001

West

5.63

7.28

12.7

8.44

9.75

8.33

7.99

7.18

8.66

9.11

8.4

7.89

8.46

0.235

Emergency/urgent

90.8

96.2

96.19

95.65

96.68

97.13

97.11

97.47

97.28

95.93

97.26

96.64

96.45

<0.001

Elective

5.04

3.74

3.49

4.21

3.2

2.31

2.78

Weekday

69.4

70.16

70.74

70.37

70.52

71.16

71.61

Weekend

30.6

29.84

29.26

29.63

29.48

28.84

28.39

Discharge alive to home

80.59

79.39

79.64

79.53

78.47

78.69

Transfer to short-term hospital/other facilities/home health

12.08

Disposition, (%)

11.18

10.96

11.11

9.1

9.32

9.3

9.26

Died in hospital

0.08

0.11

0.1

0.1

Length of hospital stay, days - median (inter-quartile range)

2 (1 - 3)

2 (1 - 3)

2 (1 - 3)

2 (1 - 3)

Cost* of hospitalization, $ - median (inter-quartile range)

3,663 (2,425 5,551)

4,080 (2,711 6,525)

4,053 (2,735 6,563)

4,257 (2,858 6,595)

84,978,47 4

119,460,47 9

119,743,62 8

155,303,99 9

3.93

2.55

3.1

3.16

70.52

72.25

72.07

71.72

72.63

71.22

29.48

27.75

27.93

28.28

27.37

28.78

<0.001

79.4

80.33

79.72

79.37

77.87

79.17

0.01

11.94

10.71

10.17

11.1

12.1

12.6

11.25

<0.001

9.36

10.75

10.01

9.85

9.41

9.05

8.43

9.39

9.49

0.023

0.08

0.06

0.1

0.04

0.1

0.13

0.1

0.14

0.09

0.101

2 (1 - 3)

2 (1 - 3)

2 (1 - 3)

2 (1 - 3)

2 (1 - 3)

2 (1 - 4)

2 (1 - 4)

2 (1 - 4)

2 (1 - 3)

<0.001

4,223 (2,835 6,608)

4,398 (2,819 6,803)

4,646 (3,128 7,119)

4,599 (3,072 6,891)

4,485 (2,876 6,989)

4,718 (3,091 7,221)

4,904 (3,301 7,413)

4,904 (3,255 7,685)

4,468 (2,951 6,925)

<0.001

180,041,33 0

226,592,99 3

230,572,63 3

198,860,31 3

204,692,66 9

214,694,76 1

219,775,65 1

189,083,34 9

2,145,761,14 7

TE D

Total annual projected economic burden, $

10.5

2.67

77.95

M AN U

10.23

Discharge alive - others (AMA/destination unknown)

care

2.52

SC

Admission day, (%)

RI PT

Admission type, (%)

AC C

EP

Table 1.- Baseline yearly and cumulative populational characteristics. Cost has been appropriately adjusted for cost-to-charge rate of inflation as per year 2012.

ACCEPTED MANUSCRIPT

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

TOTAL

18,195

20,727

21,660

27,641

31,468

40,003

38,288

33,919

34,243

34,301

33,998

28,700

363,143

SEIZURES/EPILEPSY/CONVULSIONS, (%)

4.81

3.68

5.16

4.96

4.88

4.62

5.01

5.24

5.84

6.26

5.96

6.79

5.32

<0.001

ACUTE MYOCARDIAL INFARCTION, (%)

0.4

0.53

0.57

0.69

0.48

0.51

0.55

0.57

0.6

0.75

1.18

1.32

0.69

<0.001

STEMI

0.08

0.14

0.14

0.23

0.21

0.16

0.08

0.22

0.07

0.04

0.25

0.23

0.15

0.279

NSTEMI

0.22

0.21

0.26

0.25

0.24

0.2

0.38

0.28

0.42

0.62

0.8

0.98

0.42

<0.001

UNSPECIFIC MI

0.1

0.18

0.17

0.21

0.03

0.14

0.09

0.08

0.1

0.08

0.14

0.12

0.12

0.025

CARDIAC ARREST, (%)

0.03

0.04

0.07

0

0

0.04

0.03

0.03

0.04

0.06

0.07

0.12

0.04

<0.001

HEART FAILURE, (%)

5.06

5.15

6.58

7.42

7.99

8.84

10.24

11.17

11.9

12.88

15.04

15.92

10.3

<0.001

SUPRA-VENTRICULAR TACHYCARDIA, (%)

0.13

0.25

0.36

0.36

0.18

0.3

0.16

0.3

0.18

0.25

0.26

0.24

0.25

0.603

VENTRICULAR FIBRILLATION/FLUTTER, (%)

0.03

0.02

0.07

0.07

0.01

0.03

0.06

0.05

0.07

0.05

0.05

0.151

CARDIOPULMONARY RESUSCITATION, (%)

0.08

0.04

0.04

0

0.04

0

0.02

0.05

0.07

PRINZMETAL ANGINA/CORONARY VASOSPASM, (%) PERICARDITIS*, (%)

SC

M AN U

TOTAL NO. OF CASES INCLUDED IN THE STUDY (N)

RI PT

2001

0.05

0.04

PVALUE

0

0.02

0

0.01

0.01

0.03

0.04

0.08

0.1

0.04

<0.001

0.07

0.04

0.12

0.28

0.29

0.23

0.29

0.56

0.51

0.22

<0.001

0.09

0.06

0.1

0.1

0.08

0.1

0.1

0.07

0.07

0.08

0.041

0.02

0

0.06

0.04

0.03

0.03

0.01

0.03

0.03

0.03

0.719

0.15

0.17

0.21

0.28

0.51

0.29

0.79

0.64

0.78

0.38

<0.001

0.07

0.02

0.17

0.11

DISSECTION OF AORTA

0.03

0.07

0.05

0.08

0.06

0.09

0.08

0.19

0.05

0.3

0.15

0.17

0.12

<0.001

AORTIC ANEURYSM

0.17

0.1

0.07

0.07

0.13

0.12

0.2

0.33

0.24

0.5

0.5

0.63

0.27

<0.001

HIV, (%)

4.35

4.28

4.39

3.78

4.67

4.7

4.34

4.53

5.73

6.03

5.82

5.92

4.94

<0.001

ENDOCARDITIS, (%)

0.22

0.14

0.1

CONCONMITANT HEROIN USE, (%)

4.13

HYPERTENSIVE EMERGENY/URGENCY, (%)

31.57

CARDIAC STRESS TESTS, (%)

4.31

0.21

0.16

0.17

0.16

0.19

0.17

0.37

0.2

0.21

0.19

<0.001

3.34

3.32

3.92

3.74

3.64

3.81

4.39

4.85

5.09

5.63

5.44

4.33

<0.001

34.02

36.89

38.16

39.8

42.6

45.08

44.31

47.89

50.85

49.31

50.24

43.57

<0.001

EP

AORTIC PATHOLOGIES (ANEURYSM OR DISSECTION), (%)

TE D

0 0.19

ACUTE MYOCARDITIS**, (%)

3.11

3.73

3.18

3.59

4.91

2.58

3.26

3.16

2.88

2.67

3.41

<0.001

7.64

7.12

6.78

6.03

6.46

6.62

7.38

6.68

6.17

7.03

6.99

6.7

0.063

0.03

0.07

0.15

0.18

0.14

0.18

0.17

0.28

0.11

0.17

0.51

0.56

0.22

<0.001

0

0

0.06

0.12

0.08

0.1

0.11

0.13

0.05

0.07

0.16

0.19

0.1

<0.001 £

0.03

0.07

0.09

0.04

0.03

0.05

0.06

0.13

0.05

0.09

0.31

0.3

0.1

<0.001

INSERTION OF AICD***, (%)

0

0.02

0.04

0.02

0.02

0.04

0.08

0.08

0.03

0.1

0.09

0.17

0.06

<0.001

INSERTION OF PERMANENT PACEMAKER***, (%)

0

0.04

0.02

0.02

0.01

0.05

0.01

0.08

0.11

0.07

0.06

0.05

0.05

<0.001

PERCUTANEOUS CORONARY INTERVENTIONS, (%)

AC C

3.69

5.56

DIAGNOSTIC LEFT HEART CATHETERIZATION, (%)

INSERTION OF DRUG-ELUTING CORONARY STENT/S INSERTION OF BARE METAL CORONARY STENT/S

ACCEPTED MANUSCRIPT

0.08

0.11

0.1

0.1

0.08

0.06

0.1

0.04

0.1

0.13

0.1

0.14

0.09

0.101

ACUTE ISCHEMIC STROKE, (%)

0.11

0.35

0.3

0.31

0.4

0.3

0.39

0.38

0.46

0.47

0.5

0.52

0.39

<0.001

COMPOSITE OUTCOME OF IN-HOSPITAL MORTALITY + ACUTE MI + ACUTE ISCHEMICS STROKE, (%)

0.58

0.95

0.95

1.09

0.97

0.86

1.03

0.99

1.14

1.35

1.77

1.99

1.16

<0.001

RI PT

IN-HOSPITAL MORTALITY, (%)

SC

STEMI = ST-elevation myocardial infarction; NSTEM I= Non ST-elevation myocardial infarction; MI = myocardial infarction; AICD = automatic implantable cardioverter defibrillator. * Excluding constrictive/adhesive pericarditis. ** Excluding toxic/septic myocarditis. *** Excluding those with in-situ AICD/pacemaker at the time of admission.

AC C

EP

TE D

M AN U

Table 2.- Conditions, complications, performed invasive procedures, and yearly trends.

ACCEPTED MANUSCRIPT

AGE ≥50 YEARS

Odds Ratio

LL of 95% CI of OR

UL of 95% CI of OR 1.43

P-value

1.24

1.07

1.00

1.35

0.046

1.37

1.93

<0.001

2.94

1.34

6.42

0.007

1.08

0.67

1.74

0.744

1.12

0.82

1.52

0.474

GENDER MALE 1.16

FEMALE COMORBIDITES

1.63

SC

HEART FAILURE PSVT EPILEPSY/CONVULSIONS

M AN U

HIV ENDOCARDITIS CONCOMITANT HEROIN USE SMOKING DYSLIPIDEMIA

OBESITY HYPERTENSIVE EMERGENCY DIABETES MELLITUS PERIPHERAL VASCULAR DISEASE

EP

FAMILY HISTORY OF CAD

TE D

CORONARY ARTERY DISEASE (CAD)

AC C

FLUID AND ELECTROLYTE ABNORMALITIES INCLUDING RENAL FAILURE NEUROLOGICAL DISORDER OR PARALYSIS ANEMIA OR COAGULOPATHY

RI PT

PREDICTORS

0.004

3.50

1.50

8.18

0.004

0.94

0.65

1.35

0.731

1.30

1.13

1.49

0.000

1.51

1.29

1.77

<0.001

2.37

2.03

2.76

<0.001

1.08

0.79

1.50

0.625

0.91

0.70

1.17

0.453

1.04

0.90

1.19

0.642

1.01

0.86

1.20

0.871

1.09

0.74

1.60

0.653

1.27

1.08

1.50

0.005

1.17

0.76

1.80

0.483

1.11

0.90

1.36

0.336

Table 3.- Multivariate logistic hierarchical regression model for the identification of significant predictors of composite outcomes (in-Hospital Mortality, Cardiac Arrest, VFib, Myocardial Infarction, Ischemic Stroke).

ACCEPTED MANUSCRIPT

5 5 5 5 10 10 15 20 25 100

M AN U

AGE ≥ 50 YEARS FEMALE SMOKING FLUID, ELECTROLYTE ABNORMALITIES, AND RENAL FAILURE HEART FAILURE DYSLIPIDEMIA CORONARY ARTERY DISEASE PSVT ENDOCARDITIS TOTAL SCORE

RI PT

SCORE

SC

RISK FACTOR FOR COMPOSITE OUTCOME

EP AC C

VFib, and Ishcemic Stroke.

TE D

Table 4.- Risk score prediction model for In-Hospital Mortality, Myocardial Infarction, Cardiac Arrest,

ACCEPTED MANUSCRIPT

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

Total

Total Number Of Cases Included In The Study (N)

18,195

20,727

21,660

27,641

31,468

40,003

38,288

33,919

34,243

34,301

33,998

28,700

363,143

40.9 (0.15)

41.59 (0.14)

42.23 (0.13)

42.63 (0.12)

43.21 (0.11)

44.17 (0.10)

44.85 (0.11)

45.37 (0.11)

46.5 (0.11)

47.5 (0.11)

47.85 (0.11)

48.24 (0.13)

44.93 (0.04)

40.9 ± 19.96

41.59 ± 19.72

42.23 ± 19.74

42.63 ± 19.54

43.21 ± 20.36

44.17 ± 20.59

44.85 ± 20.61

45.37 ± 20.51

46.5 ± 20.58

47.5 ± 20.4

47.85 ± 20.86

48.24 ± 22.09

44.93 ± 21.1

<0.001

18-34

23.71

22.51

20.7

19.4

18.14

15.49

14.59

13.66

11.4

9.6

10.4

11.15

15.11

<0.001

35-49

60.46

59.02

58.65

58.45

57.43

56.07

53.83

52

49.35

47.17

43.13

39.08

52.27

<0.001

50-64

14.92

17.48

19.78

21.08

23.13

26.9

30.17

32.39

36.71

40.48

43.31

46.15

30.69

<0.001

≥65

0.91

0.99

0.87

1.07

1.3

1.54

Male

73.31

74.74

74.33

73.97

73.69

73.87

Female

26.69

25.26

25.67

26.03

26.31

Whites

21.18

21.89

22.59

23.19

Blacks

39.05

42.65

45.9

43.95

Hispanics

7.77

6.26

8.27

7.2

Others

0.19

0.22

0.32

0.42

Missing

31.8

28.98

22.93

0

69.58

68.53

64.77

1

21.6

22.46

25.16

≥2

8.82

9

Smoking

29.92

Dyslipidemia

7.23

Age, Years - Mean (Std. Error) Age, Years - Mean ± Std. Deviation

1.96

2.53

2.75

3.16

3.62

1.93

<0.001

71.85

71.52

72.14

71.78

70.58

71.55

72.63

<0.001

26.13

28.15

28.48

27.86

28.22

29.42

28.45

27.37

22.18

23.21

23.52

26.58

21.64

22.91

22.93

27.26

23.37

<0.001

35.88

41.61

42.53

41.51

50.91

58.67

56.43

56.76

46.64

<0.001

7.96

8.48

7.7

8.45

9.12

8.55

8.37

10.12

8.26

<0.001

0.5

0.72

0.83

0.47

0.55

0.62

0.76

0.71

0.57

<0.001

25.24

33.47

25.97

25.42

23

17.79

9.24

11.52

5.14

21.16

62.31

60.39

56.02

52.98

51.73

47.71

44.8

40.63

39.77

53.5

<0.001

25.9

27.27

26.47

26.54

27.19

27.99

28.87

27.47

26.49

<0.001

13.71

16.71

20.55

21.73

25.1

27.22

30.49

32.75

20.01

<0.001

39.36

42

46.44

53.38

54.24

55.62

60.44

61.69

63.55

49.96

<0.001

12.32

13.92

15.63

18.13

19.33

22.33

23.68

27.32

27.74

18.13

<0.001

12.61

13.11

15.58

17.06

17.36

19.8

20.83

23.32

22.56

16.76

<0.001

2.63

3.1

3.24

3.6

4.28

3.96

4.33

4.41

4.4

5.24

3.8

<0.001

7.9

7.82

7.23

8.23

9.89

9.3

10.5

11.74

12.43

12.26

9.47

<0.001

0

0.09

0.1

0.07

0.07

0.11

0.16

0.14

0.15

0.28

0.38

0.14

<0.001

4.01

5.2

5.97

6.61

7.05

8.15

9.71

11.08

12.05

14.5

15.17

9.04

<0.001

EP

26.6

10.07

11.08

35.9

37.22

9

9.76

9

9.73

12.11

Family History Of Coronary Artery Disease

1.82

2.96

Prior Myocardial Infarction

6.69

6.78

0 3.89

Carotid Artery Disease Heart Failure

AC C

Comorbidities, (%)

Coronary Artery Disease

M AN U

TE D

Charlson Comorbidity Index (Deyo Modification), (%)

Ptrend

1.41

Gender, (%)

Race, (%)

SC

Age, years (%)

RI PT

Baseline Characteristics Of The Study Population

ACCEPTED MANUSCRIPT

4.26

4.33

5.3

5.96

6.14

7.46

8.81

Hypertension Diabetes Mellitus

.

31.9

.

10.54

Chronic Pulmonary Disease

.

Peripheral Vascular Disease Fluid-Electrolyte Abnormalities/Renal Failure

33.73

40.3

42.14

46.26

48.91

49.59

10.62

12.86

14.28

15.81

17.35

17.04

12.33

13.45

15.36

16.96

17.91

19.29

19.74

.

0.9

0.68

1.17

1.12

1.47

1.54

.

8.94

9.79

12.09

14.47

16

18.51

Neurological Disorder Or Paralysis

.

3.62

5.32

5.34

5.43

5.06

6.12

Anemia/Coagulopathy

.

5.29

6.12

7.12

8.23

7.59

9.6

Solid Tumors/Metastatic Cancers/Lymphoma

.

1.04

0.48

0.51

0.47

0.59

0.47

Depression/Psychosis

.

19.08

18.96

21.98

25.16

24.22

0.08

0.12

0.06

0.09

0.14

0.12

Medicare

12.43

13

14.25

14.22

Medicaid

32.41

30.23

32.39

32.91

Private

21.15

20.74

18.56

18.05

No Pay/Self-Pay/Others

33.58

35.82

34.76

34.47

1. 0-25th Percentile

19.09

12.86

47.76

2. 26-50th Percentile

25.96

24.12

22.02

3. 51-75th Percentile

25.81

28.12

17.58

4. 76-100th Percentile

26.61

30.99

8.57

Small

10.43

6.01

Medium

26.31

30.07

Large

63.26

63.92

Urban Non-Teaching Or Rural

34.99

Urban Teaching

Dementia Primary Payer, (%)

10.82

6.79

<0.001

53.71

57

58.74

58.29

45.99

<0.001

19.78

19.81

21.34

22.44

16.12

<0.001

21.78

22.88

24.96

26.38

18.63

<0.001

1.94

2.03

2.74

2.64

2.96

1.71

<0.001

18.92

20.26

22.62

25.55

27.51

17.36

<0.001

6.12

6.66

7.79

7.64

8.45

5.92

<0.001

10.81

12.18

12.92

14.92

15.61

9.78

<0.001

0.61

0.81

1.04

1.26

1.13

0.72

<0.001

25.83

27.96

28.88

31.49

33.3

33.1

25.51

<0.001

0.09

0.15

0.22

0.25

0.18

0.26

0.15

<0.001

15.18

16.83

17.4

18.21

18.13

19.76

21.53

16.62

<0.001

35.25

32.55

30.18

34.37

37.39

37.37

43.2

41.03

35.16

<0.001

14.73

14.1

13.87

14.63

9.82

10.04

8.63

9.08

13.78

<0.001

34.99

38.05

38.7

33.37

34.4

33.82

28.16

28.12

34.14

<0.001

50.33

46.58

46.9

46.76

46.53

46.92

51.26

52.29

52.16

45.13

<0.001

22.82

22.25

21.65

20.83

22.12

19.77

20.32

18.94

19.67

21.41

<0.001

13.87

15.25

15.53

15.12

15

14.36

13.63

14.44

12.7

16.03

<0.001

9.41

9.58

9.3

10.66

10.33

8.12

6.88

7.98

9.29

11.17

<0.001

EP

Hospital Bed Size, (%)

10.52

14.7

TE D

Median Household Income Category For Patients' Zip Code, (%)

8.64

RI PT

4.52

SC

.

M AN U

Obesity

8.22

9.33

13.34

9.47

8.55

7.74

7.75

6.57

11.48

9.14

<0.001

28.42

28.08

28.87

25.88

25.55

23.55

24.63

24.59

23.13

30.61

26.34

<0.001

61.7

63.7

61.8

60.67

64.91

67.88

66.08

66.55

68.46

57.91

64.07

<0.001

43.18

38.74

42

42

33.42

37.55

35.75

32.93

32.41

34.12

31.92

36.23

<0.001

65.01

56.82

61.23

58

58

66.46

62.38

64.22

65.52

66.48

64.03

68.08

63.32

Northeast

22.71

20.87

27.86

25.8

23.91

22.93

24.35

25.62

33.1

31.39

36.06

24.3

26.9

<0.001

Midwest

27.85

26.23

18.09

26.55

24.89

22.36

23.48

20.19

18.67

17.09

18.77

15.68

21.35

<0.001

Hospital Teaching Status, (%)

AC C

9.86

Hospital Region, (%)

ACCEPTED MANUSCRIPT

South

33.38

36.57

32.33

39.22

41.45

40.34

37.43

40.25

32.89

35.98

30.38

28.82

36.04

<0.001

West

5.63

7.28

12.7

8.44

9.75

8.33

7.99

7.18

8.66

9.11

8.4

7.89

8.46

0.235

Emergency/Urgent

90.8

96.2

96.19

95.65

96.68

97.13

97.11

97.47

97.28

95.93

97.26

96.64

96.45

<0.001

Elective

5.04

3.74

3.49

4.21

3.2

2.31

2.78

Weekday

69.4

70.16

70.74

70.37

70.52

71.16

71.61

Weekend

30.6

29.84

29.26

29.63

29.48

28.84

28.39

80.59

79.39

79.64

79.53

78.47

78.69

12.08

Disposition, (%)

11.18

10.96

11.11

9.1

9.32

9.3

9.26

Died In Hospital

0.08

0.11

0.1

0.1

Length Of Hospital Stay, Days - Median (Inter-Quartile Range)

2 (1 - 3)

2 (1 - 3)

2 (1 - 3)

2 (1 - 3)

Cost* Of Hospitalization, $ - Median (Inter-Quartile Range)

3,663 (2,425 5,551)

4,080 (2,711 6,525)

4,053 (2,735 6,563)

4,257 (2,858 6,595)

84,978,47 4

119,460,47 9

119,743,62 8

155,303,99 9

Total Annual Projected Economic Burden, $

10.5

3.93

2.55

3.1

3.16

70.52

72.25

72.07

71.72

72.63

71.22

29.48

27.75

27.93

28.28

27.37

28.78

<0.001

79.4

80.33

79.72

79.37

77.87

79.17

0.01

11.94

10.71

10.17

11.1

12.1

12.6

11.25

<0.001

9.36

10.75

10.01

9.85

9.41

9.05

8.43

9.39

9.49

0.023

0.08

0.06

0.1

0.04

0.1

0.13

0.1

0.14

0.09

0.101

2 (1 - 3)

2 (1 - 3)

2 (1 - 3)

2 (1 - 3)

2 (1 - 3)

2 (1 - 4)

2 (1 - 4)

2 (1 - 4)

2 (1 - 3)

<0.001

4,223 (2,835 6,608)

4,398 (2,819 6,803)

4,646 (3,128 7,119)

4,599 (3,072 6,891)

4,485 (2,876 6,989)

4,718 (3,091 7,221)

4,904 (3,301 7,413)

4,904 (3,255 7,685)

4,468 (2,951 6,925)

<0.001

180,041,33 0

226,592,99 3

230,572,63 3

198,860,31 3

204,692,66 9

214,694,76 1

219,775,65 1

189,083,34 9

2,145,761,14 7

TE D

10.23

Discharge Alive - Others (AMA/Destination Unknown)

Transfer To Short-Term Hospital/Other Facilities/Home Health Care

2.67

77.95

M AN U

Discharge Alive To Home

2.52

SC

Admission Day, (%)

RI PT

Admission Type, (%)

AC C

EP

Table 1.- Baseline yearly and cumulative populational characteristics. Cost has been appropriately adjusted for cost-to-charge rate of inflation as per year 2012.

ACCEPTED MANUSCRIPT

Seizures/epilepsy/convulsions, (%)

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

TOTAL

18,195

20,727

21,660

27,641

31,468

40,003

38,288

33,919

34,243

34,301

33,998

28,700

363,143

4.81

3.68

5.16

4.96

4.88

4.62

5.01

5.24

5.84

6.26

5.96

6.79

5.32

<0.001

RI PT

Total no. of cases included in the study (n)

2001

PVALUE

0.53

0.57

0.69

0.48

0.51

0.55

0.57

0.6

0.75

1.18

1.32

0.69

<0.001

0.08

0.14

0.14

0.23

0.21

0.16

0.08

0.22

0.07

0.04

0.25

0.23

0.15

0.279

NSTEMI

0.22

0.21

0.26

0.25

0.24

0.2

0.38

0.28

0.42

0.62

0.8

0.98

0.42

<0.001

SC

0.4

STEMI

Acute myocardial infarction, (%)

0.18

0.17

0.21

0.03

0.14

0.09

0.08

0.1

0.08

0.14

0.12

0.12

0.025

0.03

0.04

0.07

0

0

0.04

0.03

0.03

0.04

0.06

0.07

0.12

0.04

<0.001

Heart failure, (%)

5.06

5.15

6.58

7.42

7.99

8.84

10.24

11.17

11.9

12.88

15.04

15.92

10.3

<0.001

Supra-ventricular tachycardia, (%)

0.13

0.25

0.36

0.36

0.18

0.3

0.16

0.3

0.18

0.25

0.26

0.24

0.25

0.603

Ventricular fibrillation/flutter, (%)

0.03

0.02

0.07

0.05

0.04

0.07

0.01

0.03

0.06

0.05

0.07

0.05

0.05

0.151

Cardiopulmonary resuscitation, (%)

0.08

0.04

0.04

0

0.02

0

0.01

0.01

0.03

0.04

0.08

0.1

0.04

<0.001

Prinzmetal angina/coronary vasospasm, (%) Pericarditis*, (%) Acute myocarditis**, (%)

0

0.04

0

0.07

0.04

0.12

0.28

0.29

0.23

0.29

0.56

0.51

0.22

<0.001

0.02

0.05

0.07

0.09

0.06

0.1

0.1

0.08

0.1

0.1

0.07

0.07

0.08

0.041

0

0.07

0.02

0.02

0

0.06

0.04

0.03

0.03

0.01

0.03

0.03

0.03

0.719

0.17

0.03

0.07

Aortic aneurysm

0.17

0.1

HIV, (%)

4.35

4.28

Endocarditis, (%)

0.22 4.13

Hypertensive emergency/urgency, (%)

31.57

0.14

0.15

0.17

0.21

0.28

0.51

0.29

0.79

0.64

0.78

0.38

<0.001

0.05

0.08

0.06

0.09

0.08

0.19

0.05

0.3

0.15

0.17

0.12

<0.001

0.07

0.07

0.13

0.12

0.2

0.33

0.24

0.5

0.5

0.63

0.27

<0.001

4.39

3.78

4.67

4.7

4.34

4.53

5.73

6.03

5.82

5.92

4.94

<0.001

0.21

0.16

0.17

0.16

0.19

0.17

0.37

0.2

0.21

0.19

<0.001

0.1

3.34

3.32

3.92

3.74

3.64

3.81

4.39

4.85

5.09

5.63

5.44

4.33

<0.001

34.02

36.89

38.16

39.8

42.6

45.08

44.31

47.89

50.85

49.31

50.24

43.57

<0.001

3.41

<0.001

AC C

Concomitant heroin use, (%)

0.11

EP

0.19

Dissection of aorta

Aortic pathologies (aneurysm or dissection), (%)

TE D

Unspecific MI

M AN U

0.1

Cardiac arrest, (%)

4.31

3.69

3.11

3.73

3.18

3.59

4.91

2.58

3.26

3.16

2.88

2.67

5.56

7.64

7.12

6.78

6.03

6.46

6.62

7.38

6.68

6.17

7.03

6.99

6.7

0.063

0.03

0.07

0.15

0.18

0.14

0.18

0.17

0.28

0.11

0.17

0.51

0.56

0.22

<0.001

0

0

0.06

0.12

0.08

0.1

0.11

0.13

0.05

0.07

0.16

0.19

0.1

<0.001 £

0.03

0.07

0.09

0.04

0.03

0.05

0.06

0.13

0.05

0.09

0.31

0.3

0.1

<0.001

Insertion of AICD***, (%)

0

0.02

0.04

0.02

0.02

0.04

0.08

0.08

0.03

0.1

0.09

0.17

0.06

<0.001

Insertion of permanent pacemaker***, (%)

0

0.04

0.02

0.02

0.01

0.05

0.01

0.08

0.11

0.07

0.06

0.05

0.05

<0.001

Cardiac stress tests, (%) Diagnostic left heart catheterization, (%) Percutaneous coronary interventions, (%) Insertion of drug-eluting coronary stent/s Insertion of bare metal coronary stent/s

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0.08

0.11

0.1

0.1

0.08

0.06

0.1

0.04

0.1

0.13

0.1

0.14

0.09

0.101

Acute ischemic stroke, (%)

0.11

0.35

0.3

0.31

0.4

0.3

0.39

0.38

0.46

0.47

0.5

0.52

0.39

<0.001

Composite outcome of in-hospital mortality + acute mi + acute ischemics stroke, (%)

0.58

0.95

0.95

1.09

0.97

0.86

1.03

0.99

1.14

1.35

1.77

1.99

1.16

<0.001

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In-hospital mortality, (%)

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STEMI = ST-elevation myocardial infarction; NSTEM I= Non ST-elevation myocardial infarction; MI = myocardial infarction; AICD = automatic implantable cardioverter defibrillator. * Excluding constrictive/adhesive pericarditis. ** Excluding toxic/septic myocarditis. *** Excluding those with in-situ AICD/pacemaker at the time of admission.

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Table 2.- Conditions, complications, performed invasive procedures, and yearly trends.

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LL of 95% CI of OR

UL of 95% CI of OR

P-value

1.24

1.07

1.43

0.004

1.00

1.35

0.046

1.37

1.93

<0.001

1.34

6.42

0.007

0.67

1.74

0.744

0.82

1.52

0.474

Gender Male 1.16

Female Comorbidities

1.63

PSVT

2.94

Epilepsy/Convulsions

1.08

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Heart Failure

1.12

3.50

1.50

8.18

0.004

0.94

0.65

1.35

0.731

1.30

1.13

1.49

0.000

1.51

1.29

1.77

<0.001

2.37

2.03

2.76

<0.001

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HIV

0.79

1.50

0.625

Endocarditis Concomitant Heroin Use Smoking Dyslipidemia Coronary Artery Disease (Cad) Obesity Hypertensive Emergency Diabetes Mellitus

1.08

EP

Family History Of Cad

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Age ≥50 Years

Odds Ratio

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Predictors

0.91

0.70

1.17

0.453

1.04

0.90

1.19

0.642

1.01

0.86

1.20

0.871

0.74

1.60

0.653

1.27

1.08

1.50

0.005

Neurological Disorder Or Paralysis

1.17

0.76

1.80

0.483

1.11

0.90

1.36

0.336

Anemia Or Coagulopathy

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1.09

Fluid And Electrolyte Abnormalities Including Renal Failure

Peripheral Vascular Disease

Table 3.- Multivariate logistic hierarchical regression model for the identification of significant predictors of composite outcomes (in-Hospital Mortality, Cardiac Arrest, VFib, Myocardial Infarction, Ischemic Stroke).

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5 5 5 5 10 10 15 20 25 100

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Age ≥ 50 Years Female Smoking Fluid, Electrolyte Abnormalities, And Renal Failure Heart Failure Dyslipidemia Coronary Artery Disease PSVT Endocarditis Total Score

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Score

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Risk Factor For Composite Outcome

Table 4.- Risk score prediction model for In-Hospital Mortality, Myocardial Infarction, Cardiac Arrest,

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VFib, and Ishcemic Stroke.

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Population and Risk Score for Negative Outcome Distribution 273,393 (75.3%)

12

250,000

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11.5%

150,000

10

8

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Population

200,000

6.4%

100,000 68,485 (18.9%)

50,000

2.1%

6

4

3.4%

2

Negative Outcome Distribution Percentage

14

300,000

0.8%

0 ≤15

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19,908 (5.5%)

>15 to 30

>30 to ≤45

1,315 (0.4%)

41 (0.01%)

>45 to ≤60

>60

0

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Risk Score Distribution

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Figure 1.- Population and Risk Score for composite Negative Outcome Distribution according to risk stratification model. The columns represent the population distribution with respect to the risk score points (X axis) whereas the dots and curve depict the frequency of overall composite outcomes (in-Hospital Mortality, Cardiac Arrest, VFib, Myocardial Infarction, Ischemic Stroke).

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Clinical significance:

•

The frequency of coronary events in patients with cocaine induced chest pain was very

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low with an average frequency for STEMI of 0.15%, NSTEMI of 0.42%, and coronary vasospasm of 0.22%. •

Identification and re-stratification of patients presenting to the emergency room can

We propose a scoring system which effectively stratifies patients into low, intermediate

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and high risk.

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•

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improve unnecessary hospital admissions and cardiac procedures.