Temporal Trends and Outcomes of Hospitalizations With Prinzmetal Angina: Perspectives From a National Database

CLINICAL RESEARCH STUDY

Temporal Trends and Outcomes of Hospitalizations With Prinzmetal Angina: Perspectives From a National Database Ayman Elbadawi, MD a, Islam Y. Elgendy, MD b, Syed Yaseen Naqvi, MD c, Ahmed H. Mohamed, MD d, Gbolahan O. Ogunbayo, MD e, Mohamed A. Omer, MD f, Amgad Mentias, MD g, Marwan Saad, MD, PHD h, J. Dawn Abbott, MD i, Hani Jneid, MD j, Deepak L. Bhatt, MD, MPHk a

Department of Cardiovascular Medicine, University of Texas Medical Branch, Galveston; bDivision of Cardiovascular Medicine, University of Florida, Gainesville; cDivision of Cardiovascular Medicine, University of Rochester, Rochester, N.Y.; dDepartment of Internal Medicine, Rochester General Hospital, Rochester, N.Y.; eDepartment of Cardiovascular Medicine, University of Kentucky, Lexington; f Saint Luke’s Mid America Heart Institute/University of Missouri−Kansas City; gDivision of Cardiovascular Medicine, University of Iowa, Iowa City; hDivision of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock; iDivision of Cardiovascular Medicine, Warren Alpert School of Medicine at Brown University, Providence, R.I.; jDivision of Cardiovascular Medicine, Baylor School of Medicine, Houston, Tex; kBrigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston, Mass.

ABSTRACT BACKGROUND: Contemporary data regarding the temporal changes in prevalence and outcomes of hospitalizations with Prinzmetal angina are limited. METHODS: We queried the National Inpatient Sample Database for the years 2002-2015 to identify hospitalizations with Prinzmetal angina. We described the temporal trends and outcomes in patients with Prinzmetal angina. RESULTS: A total of 97,280 hospitalizations with Prinzmetal angina were identified. There was a significant increase in the number of hospitalizations with Prinzmetal angina (3678 in 2002 vs 8633 in 2015, Ptrend < .001) as well as the proportion of hospitalizations with Prinzmetal angina among those with chest pain (Ptrend < .001). There was an increase in the rates of in-hospital mortality (0.24% in 2002 vs 0.85% in 2015, Ptrend = .02), which corresponded to a progressive increase in the burden of comorbidities among patients with Prinzmetal angina. Age >65 years, history of heart failure, chronic kidney disease, chronic liver disease, and acute myocardial infarction upon presentation were independent predictors of in-hospital mortality. Compared with patients with acute myocardial infarction without Prinzmetal angina, those with Prinzmetal angina presenting with acute myocardial infarction had a lower incidence of in-hospital mortality (odds ratio 0.24, 95% confidence interval 0.14-0.41). CONCLUSIONS: In this large national analysis, there has been an increase in the prevalence of hospitalizations with Prinzmetal angina. Older age, heart failure, chronic kidney disease, chronic liver disease, and acute myocardial infarction were predictors of higher mortality among patients with Prinzmetal angina. Patients with Prinzmetal angina who developed acute myocardial infarction had more favorable outcomes compared with myocardial infarction without Prinzmetal angina. Published by Elsevier Inc.  The American Journal of Medicine (2019) 132:1053-1061 KEYWORDS: Coronary vasospasm; Myocardial infarction; Percutaneous coronary intervention; Prinzmetal angina

Funding: See last page of article. Conflict of Interest: See last page of article. Authorship: See last page of article. Requests for reprints should be addressed to Dr. Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School, 75 Francis Street, Boston, MA 02115. E-mail address: [email protected]

0002-9343/Published by Elsevier Inc. https://doi.org/10.1016/j.amjmed.2019.04.005

INTRODUCTION Prinzmetal angina (ie, variant angina or vasospastic angina) represents a clinical entity characterized by rest angina as a result of a coronary vasospasm that responds to vasodilator therapy, nitrates in particular.1 Traditionally, this diagnosis

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is established by coronary angiography showing focal or data with ICD-9 codes, whereas the last quarter used data diffuse spasm, occasionally only on provocation testing.1,2 with ICD-10 codes. We analyzed data by each quarter and Although reports have shown that there is a lower tendency found discontinuity across the two coding systems in the to perform provocative testing for coronary reactivity in frequency of study variables. In accordance with HCUP current practice,3 the diagnosis of Prinzmetal angina is recommendations, the trend analysis for 2015 was conoccasionally more challenging and might be overlooked.3 ducted using the ICD-9 codes and multiplied the denominaSome studies suggest a high prevator for reported prevalence by 0.75 lence of this condition among CLINICAL SIGNIFICANCE to compute the overall prevalence patients with chest pain, particufor that year.9 We also reported the  There was a significant increase in the trends in all-cause in-hospital morlarly among Asian ethnicities; however, few reports suggested a prevalence of Prinzmetal angina in the tality, the baseline characteristics, reduction in the prevalence in the and the utilization of percutaneous past decade. Western countries resulting from  Older age, history of heart failure, coronary intervention in hospitalizawidespread use of vasodilator medichronic kidney disease, chronic liver tions with Prinzmetal angina. cations such as nitrates and calcium disease, and acute myocardial infarc- Among hospitalizations with acute channel blockers.4,5 However, realtion were predictors of higher in-hos- myocardial infarction, we compared the clinical outcomes of patients world data regarding the prevalence pital mortality among patients with with Prinzmetal angina versus none. of Prinzmetal angina in the United Prinzmetal angina. The following in-hospital outcomes States are lacking. Moreover, dem Compared with patients with acute were evaluated: mortality, acute kidographics, outcomes, and prognosmyocardial infarction without Prinz- ney injury, requirement of hemoditic factors among patients with metal angina, those with Prinzmetal alysis, cardiogenic shock, cardiac Prinzmetal angina remain poorly angina had a lower incidence of in- arrest, the use of mechanical circulacharacterized. Hence, we conducted tory support devices, acute stroke, this study to explore temporal hospital mortality. ventricular arrhythmias, complete changes in the prevalence and outheart block, permanent pacemaker comes of hospitalizations with implantation, and percutaneous coronary intervention. The Prinzmetal angina using a large national database. baseline characteristics and clinical outcomes were identified using relevant ICD-9 codes, CCS, and Elixhauser METHODS comorbidities as reported by HCUP (Supplemental Table 1, available online). Data Source We conducted this analysis using the National Inpatient Sample (NIS) database, which is part of the Health Care Cost and Utilization Project (HCUP). The NIS is the largest publicly available all-payer inpatient care database in the United States, yielding national estimates from ~ 8 million hospital stays each year.6 Data from the NIS have been used for describing trend analyses in prior studies.7 The study was exempt from Institutional Review Board because data from the NIS are publicly available and do not contain any Health Insurance Portability and Accountability Act identifiers.

Study Population and Outcome Measures We queried the database years of 2002-2015 using International Classification of Diseases, Ninth Edition (ICD-9) diagnostic codes 413.1 to identify patients hospitalized with Prinzmetal angina. We also queried the database using ICD-9 Clinical Classification Software (CCS) code 100 to identify hospitalizations for a primary diagnosis of acute myocardial infarction. We excluded records with missing data on in-hospital mortality, baseline characteristics, and other study outcomes. Using the trend weights supplied by the NIS,8,9we described the temporal trends in admissions with Prinzmetal angina. For the year 2015, the first 3 quarters included

Statistical Analysis A multivariable regression model was conducted to identify predictors of in-hospital mortality among patients with Prinzmetal angina. The model included the following 21 clinical and hospital-related variables: age, sex, race, hypothyroidism, liver disease, connective tissue disease, pulmonary circulation disorders, hypertension, diabetes mellitus, history of heart failure, smoking history, chronic kidney disease, chronic lung disease, peripheral artery disease, carotid artery disease, obesity, anemia, valvular heart disease, drug abuse, alcohol abuse, and acute myocardial infarction upon presentation. We also conducted another multivariable regression model including the same clinical variables to compare in-hospital outcomes in patients with acute myocardial infarction with Prinzmetal angina versus not. Categorical variables were reported as numbers and percentages, continuous variables were reported as mean § standard deviation or median and interquartile range (depending if the variable was normally distributed). Categorical values were compared using chi-square test. Continuous variables were compared using Student t test or MannWhitney U test (depending if the variable was normally distributed or not). All outcomes were analyzed using the complex samples facility of SPSS to account for hospital strata,

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clustering, and weights.10 Associations were considered significant if the P value was <.05. We used the SPSS software (IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp Released 2016) and R software for all statistical analysis.11

RESULTS Baseline Characteristics and Temporal Trends From 2002 to 2015, our analysis yielded 97,280 hospitalizations with the diagnosis of Prinzmetal angina. After excluding cases with missing data on mortality (n = 38) or baseline characteristics (n = 341), the final cohort included 96,901 hospitalizations, of which 10,077 (10.4%) developed acute myocardial infarction (Figure 1). Hospitalizations with Prinzmetal angina were more common in urban teaching and large-sized hospitals (Supplemental Table 2). In Table 1, we present the baseline characteristics of patients with Prinzmetal angina across the study years. In the earlier study years, patients with Prinzmetal angina were older compared with the more recent years. During the later years, patients with Prinzmetal angina had a higher burden of comorbidities and were more likely to present with acute myocardial infarction (Table 1). The absolute number of hospitalizations for Prinzmetal angina increased from 3678 cases in 2002 to 8633 cases in 2015 with a significant change in the trend (Ptrend <.001) (Central Figure). Similarly, among all hospitalizations with a primary diagnosis of chest pain, the percentage of patients with Prinzmetal angina increased from 0.4% in 2002 to 3.1%

Figure 1

Study flow diagram. MI = myocardial infarction.

1055 in 2015 with a significant increase in the trend (Ptrend <.001) (Figure 2). The in-hospital mortality rate among admissions with Prinzmetal angina overall was 0.7%, with a significant rise in the trend (0.24% in 2002 vs 0.85% in 2015) (ptrend = 0.02) (Central Figure). The utilization of percutaneous coronary intervention among patients with Prinzmetal angina overall was 4.9%, and there was no significant change in the trend (4.2% in 2002 vs 4.4% in 2015) (Ptrend = 0.40).

Predictors of Mortality Among Hospitalized Patients With Prinzmetal Angina On multivariate regression analysis, the following characteristics were independently associated with in-hospital mortality among patients who were hospitalized with a diagnosis of Prinzmetal angina: age > 65 years (odds ratio [OR] 2.01; 95% confidence interval [CI] 1.36-2.96, P <.001), history of heart failure (OR 2.62; 95% CI 1.345.10, P = .01), chronic kidney disease (OR 1.97; 95% CI 1.12-3.45, P = .02), chronic liver disease (OR 2.28; 95% CI 1.04-4.99, P = .04), and acute myocardial infarction (OR 2.12; 95% CI 1.35-3.34, P = .001) (Figure 3).

In-Hospital Outcomes of Acute Myocardial Infarction With and Without Prinzmetal Angina We identified 8,722,613 hospitalizations that had acute myocardial infarction listed as the primary diagnosis during the study period. After excluding cases with missing data on mortality (6801) and baseline characteristics (89,113),

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The American Journal of Medicine, Vol 132, No 9, September 2019 Baseline Characteristics for Patients with Prinzmetal Angina Across the Study Years

Characteristic

Overall Cohort (n = 96,901)

2002-2005 (n = 15,565 )

2006-2010 (n = 40,110)

2011-2015 (n= 41,227) N%

P Value

Age (mean § SD) Females White Black Hispanic Asian Pacific Islander Native American Other races Hypertension Diabetes Dyslipidemia Congestive heart failure Hypothyroidism Smokers Renal failure Chronic lung disease Pulmonary circulation disorder Peripheral vascular disease Carotid artery disease Obesity Anemia Valvular disease Alcohol abuse Drug abuse Prior myocardial infarction Liver disease AIDS syndrome Collagen vascular disease Lymphoma Metastatic cancer Solid tumor without metastasis Neurological disorders Acute myocardial infarction

56.0 (§14.2) 60,620 62.6% 56,913 58.7% 13,880 14.3% 5993 6.2% 1694 1.7% 468 0.6% 2130 2.2% 58,396 60.3% 17,643 18.2% 36,607 37.8% 3545 3.7% 11,472 11.8% 22,776 23.5% 4758 4.9% 20,067 20.7% 880 0.9% 4960 5.1% 875 0.9% 12,166 12,6% 9864 10.2% 2323 2.4% 5192 5.4% 10,521 10.9% 13455 13.9% 2173 2.2% 227 0.2% 3616 3.7% 415 0.4% 796 0.8% 1217 1.3% 5362 5.5% 10,077 10.5%

57.3 (§ 14.5) 10,761 69.2% 8462 54.4% 1311 8.4% 787 5.1% 160 1.0% 22 0.1% 211 1.4% 8181 52.6% 2336 15.0% 3502 22.5% 434 2.8% 1712 11.0% 2225 14.3% 216 1.4% 2925 18.8% 61 0.4% 639 4.1% 71 0.5% 1346 8.6% 1337 8.6% 371 2.4% 386 2.5% 463 3.0% 1892 12.2% 189 1.2% <11 524 3.4% 66 0.4% 56 0.4% 323 2.1% 562 3.6% 840 5.4%

55.5 (§14.2) 24,907 62.1% 22,509 56.1% 5215 13.0% 2197 5.5% 652 1.6% 210 0.5% 828 2.1% 23,592 58.8% 7057 17.6% 15,194 37.9% 1358 3.4% 4338 10.8% 9450 23.6% 1880 4.7% 8139 20.3% 369 0.9% 1910 4.8% 341 0.9% 4595 11.5% 3911 9.8% 860 2.1% 2073 5.2% 4251 10.6% 5268 13.1% 773 1.9% 77 0.2% 1374 3.4% 146 0.4% 276 0.7% 411 1.0% 1976 4.9% 3810 9.5%

55.8 (§ 14.1) 24,952 60.5% 25,942 62.9% 7354 17.8% 3009 7.3% 882 2.1% 236 0.6% 1091 2.6% 26,623 64.6% 8250 20.0% 17,911 43.4% 1753 4.3% 5422 13.2% 11101 26.9% 2662 6.5% 9003 21.8% 450 1.1% 2411 5.8% 463 1.1% 6225 15.1% 4616 11.2% 1092 2.6% 2733 6.6% 5807 14.1% 6295 15.3% 1211 2.9% 150 0.4% 1718 4.2% 203 0.5% 464 1.1% 483 1.2% 2824 6.8% 5541 13.4%

< .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 < .001 .002 < .001 < .001 < .001 < .001 < .001 < .001 .063 < .001 < .001 < .001 < .001

Figure 2 Trend in absolute number of hospitalizations and as ratio per admissions with chest pain.

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Figure 3 Predictors of in-hospital mortality among patients with Prinzmetal angina. MI= myocardial infarction.

Central Figure (A) Pathophysiological mechanisms implicated in Prinzmetal angina. (B) Temporal changes in the number of hospitalizations with Prinzmetal angina and in-hospital mortality for hospitalizations with Prinzmetal angina. (C) Independent predictors of in-hospital mortality for patients with Prinzmetal angina.

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The American Journal of Medicine, Vol 132, No 9, September 2019 In-Hospital Outcomes for Acute Myocardial Infarction with Prinzmetal Angina v None

Outcomes Mortality Cardiac arrest Cardiogenic shock Acute stroke Acute kidney injury Complete heart block Permanent pacemaker Ventricular arrhythmia Percutaneous coronary intervention

Prinzmetal Angina (n = 10,077) 114 367 190 39 353 45 15 553 1,479

1.1% 3.6% 1.9% 0.4% 3.5% 0.4% 0.1% 5.4% 14.5%

No Prinzmetal Angina (n = 8,616,508) 521,912 391,147 409,279 135,489 1,002,121 106,060 61,041 519,803 3,593,880

6.1% 4.5% 4.7% 1.6% 11.6% 1.2% 0.7% 6.0% 41.7%

Odds Ratio*

95% Confidence Interval

P Value

0.33 0.70 0.43 0.33 0.55 0.44 0.39 0.95 0.13

0.22-0.51 0.55-0.90 0.32-0.60 0.16-0.66 0.43-0.70 0.23-0.84 0.13-1.21 0.78-1.15 0.11-0.15

< .001 .004 < .001 .002 .001 .01 .10 .58 < .001

*Adjusted for age, sex, race, hypothyroidism, chronic liver disease, chronic pulmonary circulation disorders, hypertension, diabetes, history of heart failure, smoking history, chronic kidney disease, chronic lung disease, peripheral arterial disease, carotid artery disease, obesity, anemia, valvular heart disease, drug abuse, alcohol abuse, and connective tissue disease.

the final population included 8,626,699 hospitalizations with acute myocardial infarction. Among those, 10,077 (0.1%) had an associated diagnosis of Prinzmetal angina. On multivariable analysis, patients with acute myocardial infarction associated with Prinzmetal angina had a lower incidence of in-hospital mortality (1.1% vs 6.1%; OR 0.33; 95% CI 0.22-0.51, P <.001), cardiac arrest (3.6% vs 4.5%; OR 0.70; 95% CI 0.55-0.90, P = .004), cardiogenic shock (1.9% vs 4.7%; OR 0.43; 95% CI 0.32-0.60, P < .001), acute stroke (0.4% vs 1.6%; OR 0.33; 95% CI 0.16-0.66, P <.001), acute kidney injury (3.5% vs 11.6%; OR 0.55 95% CI 0.43-0.70, P = .001), complete heart block (0.4% v. 1.2%; OR 0.44; 95% CI 0.23-0.84, P = 0.01), and percutaneous coronary intervention (14.5% vs 41.7%; OR 0.13; 95% CI 0.11-0.15, P <.001) compared with acute myocardial infarction without Prinzmetal angina. There was no difference between the two groups in permanent pacemaker requirements (0.1% vs 0.7%; OR 0.39; 95% CI 0.13-1.21, P = .10), and ventricular arrhythmias (5.4% vs 6.0%; OR 0.95; 95% CI 0.78-1.15, P = 0.58) (Table 2).

DISCUSSION In this 14-year nationwide observational analysis, we explored the temporal trends and in-hospital outcomes of patients with Prinzmetal angina. The main study findings were: 1) The number of patients hospitalized with Prinzmetal angina has significantly increased from 3678 cases in 2002 to 8633 cases in 2015; additionally, the rate of in-hospital mortality has risen from 0.24% in 2002 to 0.85% in 2015; 2) Hospitalized patients with Prinzmetal angina were becoming younger, with an increasing burden of comorbidities; 3) Predictors of higher in-hospital mortality among patients with Prinzmetal angina included: age > 65 years, history of heart failure, chronic kidney disease, chronic liver disease, and the presentation with acute myocardial infarction; 4) Among all patients hospitalized with acute myocardial infarction, a diagnosis of Prinzmetal angina was associated with lower rates of mortality, cardiac arrest, cardiogenic shock, acute stroke, acute kidney injury,

complete heart block, and percutaneous coronary intervention compared with those who had no Prinzmetal angina.

Temporal Changes in the Prevalence of Prinzmetal Angina Few reports have described the prevalence of Prinzmetal angina in the contemporary era—but mostly from Asian countries. In a retrospective analysis including 2476 Korean patients with Prinzmetal angina, Kim et al showed that the prevalence of Prinzmetal angina has increased by 25% over a 7-year period with an associated increase in comorbidities, including dyslipidemia and diabetes.12 These findings were in contrast to studies from Western countries that suggest a reduced prevalence of Prinzmetal angina in the past two decades.1,13 In patients with acute coronary syndrome with normal coronaries, data from two European studies showed that 16% and 49% of patients had Prinzmetal angina compared with 79% of patients from another Asian study.4,5,14 Our study found a significant increase in admissions with the diagnosis of Prinzmetal angina, as an absolute number and also when indexed per admissions for chest pains. The rising prevalence of Prinzmetal angina in our study corresponded to an increase in the burden of comorbidities during the study period. The underlying pathophysiology for coronary vasospasm in Prinzmetal angina includes endothelial dysfunction, impaired coronary microcirculation, increased inflammation, and oxidative stress.1,15 Multiple reports have demonstrated a significant increase in traditional cardiovascular risk factors in the United States over past decade, including diabetes, hypertension, obesity, chronic kidney disease, and dyslipidemia.16,17 Studies have also linked many of those risk factors to enhancing the mechanisms for coronary vasospasm.18,19 The increase in those risk factors could have contributed to the increasing prevalence of Prinzmetal angina demonstrated in our study. Our analysis also showed a rise in the in-hospital mortality rates for patients with Prinzmetal angina across the study years. This seems to have resulted from a progressive increase in the comorbidities and in the proportion of

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patients who had acute myocardial infarction during this period. We found an overall 4.8% rate of utilization of percutaneous coronary intervention in patients with Prinzmetal angina with no significant change in the trends during study years. Because Prinzmetal angina responds well to vasodilator therapy, percutaneous coronary intervention is generally not recommended in patients with Prinzmetal angina, unless there is evidence of significant concomitant obstructive coronary artery disease (CAD) or in cases of vasospasm refractory to medical treatment. One study of 986 patients with Prinzmetal angina found that 7.2% had associated severe obstructive coronary artery disease,20 which might explain the proportion of patients who received percutaneous coronary intervention in our analysis.

coronary lesions.25 Similarly, chronic liver disease and older age are both associated with advanced endothelial and coronary microcirculatory dysfunction.18,27 Importantly, the presentation with acute myocardial infarction was a predictor of higher mortality among patients with Prinzmetal angina. Cho et al have reported similar findings with acute myocardial infarction being associated with higher mortality in patients with Prinzmetal angina.20 Those findings signal a more pronounced disease process among patients who develop acute myocardial infarction and a higher propensity for complications and mortality.

Predictors of Higher Mortality Among Patients With Prinzmetal Angina

This analysis showed that among patients with acute myocardial infarction, those with Prinzmetal angina had a more favorable prognosis (ie, less in-hospital mortality). In the CASPAR study, patients with acute coronary syndrome and proof of coronary vasospasm had significantly better longterm survival than patients with obstructive disease.21 Another retrospective study of 182 patients showed better survival rates among patients with acute myocardial infarction with normal coronaries, including patients with coronary vasospasm, compared with those who had obstructive coronary artery disease.4 These results support the hypothesis that myocardial infarction in the setting of coronary vasospasm portends a more benign course and possibly less myocardial damage than caused by obstructive disease28 that might explain the lower in-hospital complications in the Prinzmetal angina group who had acute myocardial infarction, including cardiogenic shock, acute kidney injury, arrhythmias, and lower mortality. Ischemic preconditioning from repetitive anginal attacks might have contributed as well to the more favorable outcomes among patients with Prinzmetal angina who developed acute myocardial infarction compared with those with no Prinzmetal angina.29,30

Older age, history of heart failure, chronic kidney disease, and chronic liver disease were independent predictors of in-hospital mortality in this study. These findings are in line with prior reports. The Coronary Artery Spasm in Patients with Acute Coronary Syndrome (CASPAR) study evaluated the 3-year prognosis of patients with acute coronary syndrome without culprit lesion and proof of coronary spasm.21 That analysis identified age and left ventricular ejection fraction as significant predictors of mortality and coronary events. In addition, Da costa et al showed that older age and left ventricular ejection fraction were independent predictors of long-term outcomes in patients with acute myocardial infarction and normal coronaries.4 A prognostic risk score was proposed by the Japanese Coronary Spasm Association to predict long-term cardiovascular events.22 Unlike our study, smoking history was identified in that score as a predictor for cardiovascular events, whereas age was not a predictor of cardiovascular events in patients with Prinzmetal angina.22 The difference in the ethnicities and follow-up periods between both studies might contribute to this discrepancy. Other reports associated hypertension with worse short- and long-term clinical outcomes in patients with Prinzmetal angina;23 however, in our study, hypertension did not correlate with in-hospital mortality. Coronary artery spasm in Prinzmetal angina has been linked to vascular endothelial dysfunction, as well as abnormalities in the coronary microcirculation resulting in decreased coronary flow reserve.1,15 Chronic kidney disease is strongly associated with endothelial dysfunction via decreasing bioavailability of nitric oxide.24 Coronary microcirculatory dysfunction frequently parallels the impaired renal microcirculation in patients with chronic kidney disease patients.24,25 Multiple studies have shown attenuation in coronary vasodilatory capacity in patients with chronic kidney disease, even in the absence of obstructive coronary disease.25,26 In a Japanese study, chronic kidney disease was associated with worse cardiovascular events in patients with Prinzmetal angina and no obstructive

Outcomes of Acute Myocardial Infarction With Prinzmetal Angina Versus Not

Future Perspective and Knowledge Gaps The rising rate of Prinzmetal angina in our study is an important finding. Clinicians should be more cognizant of the increasing prevalence of this condition, and appropriate diagnostic tests, including provocative testing for coronary reactivity, should be performed when clinically indicated. As mentioned previously, reports suggest that provocative testing for coronary reactivity is underused, despite demonstrating acceptable safety and diagnostic utility in multiple studies.2 Although the increasing prevalence of Prinzmetal angina could be attributed to the increase in traditional risk factors or comorbidities, other potentially contributing factors should be explored in future investigations. Also, further studies evaluating the ethnic variations, risk factors, and long-term prognosis of Prinzmetal angina are encouraged.

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Study Limitations To the best of our knowledge, this study represents the largest contemporary analysis exploring the trends and outcomes of Prinzmetal angina in the United States. Yet, our study has limitations. As an observational study, there is a risk of unmeasured confounding. We attempted to mitigate this risk by adjusting for multiple baseline patient and hospital-related characteristics. The NIS is an administrative database; hence, it is subjective to coding errors. The definition of Prinzmetal angina may not have been followed correctly in the database because many different doctors cared for these patients, and there was no way of ascertaining how accurate or not the diagnosis was. Despite this limitation, the results may be clinically useful, especially because the same improved mortality rates have been noted for patients with unstable angina leading up to acute myocardial infarction. Potentially, ischemic preconditioning is a factor here. The NIS lacks data on outcomes beyond hospitalization. The database does not provide certain clinical variables that would have been useful in our analysis, including medications, laboratory, and imaging data (such as left ventricular ejection fraction). Despite those limitations, our study provides potentially useful information regarding the prevalence, trends, and outcomes of hospitalizations with Prinzmetal angina.

CONCLUSION This large observational analysis from real-world contemporary national data showed a significant increase in the prevalence of Prinzmetal angina in the past decade. There was an increase in the in-hospital mortality rate that corresponded to a progressive increase in comorbidities and prevalence of acute myocardial infarction among patients with Prinzmetal angina. Older age, history of heart failure, chronic kidney disease, chronic liver disease, and acute myocardial infarction were predictors of higher in-hospital mortality among patients with Prinzmetal angina. Patients with Prinzmetal angina who developed acute myocardial infarction had more favorable outcomes than those with acute myocardial infarction without Prinzmetal angina.

References 1. Stern S, Bayes de Luna A. Coronary artery spasm: a 2009 update. Circulation 2009;119(18):2531-4. 2. Takagi Y, Yasuda S, Takahashi J, et al. Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association. Eur Heart J 2012;34(4):25867. 3. Zaya M, Mehta PK, Merz CNB. Provocative testing for coronary reactivity and spasm. J Am Coll Cardiol 2014;63(2):103-9. 4. Da Costa A, Isaaz K, Faure E, Mourot S, Cerisier A, Lamaud M. Clinical characteristics, aetiological factors and long-term prognosis of myocardial infarction with an absolutely normal coronary angiogram; a 3-year follow-up study of 91 patients. Eur Heart J 2001;22 (16):1459-65. 5. Ong P, Athanasiadis A, Hill S, Vogelsberg H, Voehringer M, Sechtem U. Coronary artery spasm as a frequent cause of acute coronary

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SUPPLEMENTARY DATA Supplementary data to this article can be found online at https://doi.org/10.1016/j.amjmed.2019.04.005.

Funding: None. Conflict of Interest: AE, IYE, SYN, AHM, GOO, MAO, AM, MS, and HJ report no conflicts. DLB discloses the following relationships: Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft;

1061 Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, PLx Pharma, Takeda. JDA discloses the following relationships: research funding without direct compensation from Sinomed, Abbott Vascular, Bristol Myers Squibb, Astra Zeneca, Biosensors Research USA. Authorship: All authors had access to the data and a role in writing the manuscript.

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The American Journal of Medicine, Vol 132, No 9, September 2019

Supplemental Table 1 International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9- CM) codes used to identify the baseline comorbidities, procedures, and in-hospital outcomes. Variable

Codes

Co-morbidities Smoking Carotid artery disease

V15.82, 30.51 433.10

Outcomes Acute myocardial infarction Undergoing percutaneous coronary intervention Cardiogenic shock Acute kidney injury Permanent pacemaker insertion Ventricular arrhythmias Complete heart block

CCS 100 00.66, 36.01, 36.02, 36.05, 36.06, and 36.07 785.51 584.5-9 37.8x

Supplemental Table 2 Hospital characteristics for hospitalizations with Prinzmetal angina. Characteristics Hospital bed size Small sized Medium sized Large sized Hospital region Northeast Midwest South West Location/teaching status Rural Urban non-teaching Urban teaching

Hospitalizations with Prinzmetal angina 9027 18718 53868

11% 22.8% 65.6%

14519 21619 30155 15833

17.7% 26.3% 36.7% 19.3%

9726 30538 41347

11.8% 37.2% 50.3%

427.1 426.0

Supplemental Figure 1 Trend in in-hospital mortality and utilization of percutaneous coronary intervention for admissions with Prinzmetal angina.